ORCID Profile
0000-0002-2311-2174
Current Organisations
Florey Institute of Neuroscience and Mental Health
,
University of Melbourne
,
Austin Health
,
Royal Children's Hospital Melbourne
,
Royal Childrens Hospital
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Publisher: Wiley
Date: 22-09-2015
DOI: 10.1111/DMCN.12593
Abstract: Dravet syndrome, a severe infantile epilepsy syndrome, is typically resistant to anti-epileptic drugs (AED). Lamotrigine (LTG), an AED that is effective for both focal and generalized seizures, has been reported to aggravate seizures in Dravet syndrome. Therefore, LTG is usually avoided in Dravet syndrome. We describe two adults and a child with Dravet syndrome in whom LTG resulted in decreased seizure duration and frequency. This benefit was highlighted in each patient when LTG was withdrawn after 6 to 15 years, and resulted in an increased frequency of convulsive seizures together with longer seizure duration. A 25-year-old male required hospital admission for frequent seizures for the first time in 7 years, 6 weeks after ceasing LTG. Reintroduction of LTG improved seizure control, suggesting that in some patients with Dravet syndrome, LTG may be beneficial.
Publisher: Oxford University Press (OUP)
Date: 15-10-2005
DOI: 10.1093/HMG/DDI355
Abstract: Common idiopathic epilepsies are, clinically and genetically, a heterogeneous group of complex seizure disorders. Seizures arise from periodic neuronal hyperexcitability of unknown cause. The genetic component is mostly polygenic, where each susceptibility gene in any given in idual is likely to represent a small component of the total heritability. Two susceptibility genes have been so far identified, where genetic variation is associated with experimentally demonstrated changes in ion channel properties, consistent with seizure susceptibility. Rare variants and a polymorphic allele of the T-type calcium channel CACNA1H and a polymorphic allele and a rare variant of the GABA(A) receptor delta subunit gene have differential functional effects. We speculate that these and other as yet undiscovered susceptibility genes for complex epilepsy could act as 'modifier' loci, affecting penetrance and expressivity of the mutations of large effect in those 'monogenic' epilepsies with simple inheritance that segregate through large families. Discovery of epilepsy-associated ion channel defects in these rare families has opened the door to the discovery of the first two susceptibility genes in epilepsies with complex genetics. The susceptibility genes so far detected are not commonly involved in complex epilepsy suggesting the likelihood of considerable underlying polygenic heterogeneity.
Publisher: Oxford University Press (OUP)
Date: 11-05-2004
DOI: 10.1093/HMG/DDH146
Publisher: Wiley
Date: 12-2008
DOI: 10.1111/J.1528-1167.2008.01708.X
Abstract: The clinical features of absence seizures in idiopathic generalized epilepsy have been held to be syndrome-specific. This hypothesis is central to many aspects of epilepsy research yet has not been critically assessed. We examined whether specific factors such as epilepsy syndrome, age, and state determine the features of absence seizures. Children with newly presenting absence seizures were studied using video electroencephalography (EEG) recording. We analyzed whether a child's epilepsy syndrome, age, state of arousal, and provocation influenced specific clinical features of their absence seizures: duration, eyelid movements, eye opening, and level of awareness during the seizure. Seizures (509) were evaluated in 70 children with the following syndromes: Childhood absence epilepsy (CAE), 37 CAE plus photoparoxysmal response (PPR), 10 juvenile absence epilepsy (JAE), 8 juvenile myoclonic epilepsy (JME), 6 unclassified, 9. Seizure duration was associated with epilepsy syndrome as children with JME had shorter seizures than in other syndromes, independent of age. Age independently influences level of awareness and eye opening. Arousal or provocation affected all features except level of awareness. Specific factors unique to the child independently influenced all features the nature of these factors has not been identified. The view that the clinical features of absence seizures have syndrome-specific patterns is not supported by critical analysis. We show that confounding variables profoundly affect clinical features and that syndromes also show marked variation. Variation in clinical features of absence seizures results from a complex interaction of many factors that are likely to be genetically and environmentally determined.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-04-2023
DOI: 10.1212/WNL.0000000000207080
Abstract: The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the rates of convulsive status epilepticus (CSE), nonconvulsive status epilepticus (NCSE), and sudden unexplained death in epilepsy (SUDEP) in these diseases are not well understood. We aimed to describe the proportions of patients with frequently observed genetic DEEs who developed CSE, NCSE, mortality, and SUDEP. Understanding the risks of these serious presentations in each genetic DEE will enable earlier diagnosis and appropriate management. In this retrospective analysis of patients with a genetic DEE, we estimated the proportions with CSE, NCSE, and SUDEP and the overall and SUDEP-specific mortality rates for each genetic diagnosis. We included patients with a pathogenic variant in the genes SCN1A , SCN2A , SCN8A , SYNGAP1 , NEXMIF , CHD2 , PCDH19 , STXBP1 , GRIN2A , KCNT1 , and KCNQ2 and with Angelman syndrome (AS). The cohort comprised 510 in iduals with a genetic DEE, in whom we observed CSE in 47% and NCSE in 19%. The highest proportion of CSE occurred in patients with SCN1A -associated DEEs, including 181/203 (89% 95% CI 84–93) patients with Dravet syndrome and 8/15 (53% 95% CI 27–79) non-Dravet SCN1A -DEEs. CSE was also notable in patients with pathogenic variants in KCNT1 (6/10 60% 95% CI 26–88) and SCN2A (8/15 53% 95% CI 27–79). NCSE was common in patients with non-Dravet SCN1A -DEEs (8/15 53% 95% CI 27–79) and was notable in patients with CHD2 -DEEs (6/14 43% 95% CI 18–71) and AS (6/19 32% 95% CI 13–57). There were 42/510 (8%) deaths among the cohort, producing a mortality rate of 6.1 per 1,000 person-years (95% CI 4.4–8.3). Cases of SUDEP accounted for 19/42 (48%) deaths. Four genes were associated with SUDEP: SCN1A , SCN2A , SCN8A , and STXBP1. The estimated SUDEP rate was 2.8 per 1,000 person-years (95% CI 1.6–4.3). We showed that proportions of patients with CSE, NCSE, and SUDEP differ for commonly encountered genetic DEEs. The estimates for each genetic DEE studied will inform early diagnosis and management of status epilepticus and SUDEP and inform disease-specific counseling for patients and families in this high-risk group of conditions.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.NEURON.2017.12.005
Abstract: X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-10-2006
Publisher: Elsevier BV
Date: 08-2016
Publisher: Elsevier BV
Date: 11-2019
Publisher: Wiley
Date: 11-05-2018
DOI: 10.1111/EPI.14087
Publisher: Wiley
Date: 03-05-2022
DOI: 10.1111/EPI.17236
Abstract: In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike-wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.
Publisher: Wiley
Date: 12-2019
DOI: 10.1111/EPI.16386
Abstract: SCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with several epilepsy syndromes and a range of other diseases. SCN1A represents the archetypal channelopathy associated with a wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus (GEFS+), to developmental and epileptic encephalopathies (DEEs). SCN1A disorders also result in other diseases such as hemiplegic migraine and autism spectrum disorder (ASD). Dravet syndrome (DS) is the prototypic DEE with an early onset of febrile status epilepticus, hemiclonic or generalized tonic-clonic seizures, and later onset of additional seizure types. Electroencephalography (EEG) and magnetic resonance imaging (MRI) are normal at onset. Development is normal in the first year of life but plateaus rapidly, with most patients ultimately having intellectual disability. Epilepsy is drug-resistant and necessitates polytherapy. Most pathogenic variants occur de novo in the affected child, but they are inherited from mosaic affected or unaffected parents in rare cases. The molecular finding of haploinsufficiency is consistent with a loss-of-function defect in cells and animal models. Although seizures are the most commonly reported symptom in DS, many additional issues critically affect patients' cognitive and behavioral functioning. Hemiplegic migraine (HM) is a rare form of migraine with aura, characterized by the emergence of hemiparesis as part of the aura phase. All SCN1A mutations reported in sporadic/familial HM3 are missense mutations. Most of the experimental results show that they cause a gain of function of Na
Publisher: Wiley
Date: 03-2006
DOI: 10.1111/J.1528-1167.2006.00466.X
Abstract: Benign rolandic epilepsy (BRE) is considered a genetically determined idiopathic partial epilepsy. We analyzed a large s le of twins from four international twin registers to probe the genetics of BRE. We also aim to synthesize the apparently conflicting family and twin data into a model of BRE etiology. Large population-based twin registries of epilepsies from Odense (Denmark), Richmond, Virginia (United States), and Oslo (Norway) were reviewed for BRE cases and added to our Australian twin data. Diagnosis of classic BRE was based on electroclinical criteria with normal neurologic development. Cases with a compatible electroclinical picture but abnormal neurologic development were termed non-classic BRE. Eighteen twin pairs were identified (10 monozygous eight dizygous) of whom at least one twin was diagnosed with classic BRE among a total s le of 1,952 twin pairs validated for seizures, and all were discordant for BRE. The estimated monozygous pairwise concordance for BRE in this s le was 0.0 [95% confidence interval (CI), 0.0-0.3). Four twin pairs (one monozygous, three dizygous) had non-classic BRE, and all co-twins had seizures. The twin data showing an absence of any concordant twin pairs with classic BRE suggest that noninherited factors are of major importance in BRE. Modelling the data shows that the familial occurrence of centrotemporal spikes makes only a minor contribution to the familial aggregation of BRE. Genetic factors are probably more important in non-classic BRE. The etiology and mode(s) of inheritance of BRE are much more complicated than initially conceptualized.
Publisher: Wiley
Date: 02-2002
DOI: 10.1046/J.1528-1157.2002.19498.X
Abstract: We analyzed databases on chromosomal anomalies and epilepsy to identify chromosomal regions where abnormalities are associated with clinically recognizable epilepsy syndromes. The expectation was that these regions could then be offered as targets in the search for epilepsy genes. The cytogenetic program of the Oxford Medical Database, and the PubMed database were used to identify chromosomal aberrations associated with seizures and/or EEG abnormalities. The literature on selected small anomalies thus identified was reviewed from a clinical and electroencephalographic viewpoint, to classify the seizures and syndromes according to the current International League Against Epilepsy (ILAE) classification. There were 400 different chromosomal imbalances described with seizures or EEG abnormalities. Eight chromosomal disorders had a high association with epilepsy. These comprised: the Wolf-Hirschhorn (4p-) syndrome, Miller-Dieker syndrome (del 17p13.3), Angelman syndrome (del 15q11-q13), the inversion duplication 15 syndrome, terminal deletions of chromosome 1q and 1p, and ring chromosomes 14 and 20. Many other segments had a weaker association with seizures. The poor quality of description of the epileptology in many reports thwarted an attempt to make precise karyotype-phenotype correlations. We identified certain chromosomal regions where aberrations had an evident association with seizures, and these regions may be useful targets for gene hunters. New correlations with specific epilepsy syndromes were not revealed. Clinicians should continue to search for small chromosomal abnormalities associated with specific epilepsy syndromes that could provide important clues for finding epilepsy genes, and the epileptology should be rigorously characterized.
Publisher: Wiley
Date: 10-05-2019
DOI: 10.1111/EPI.15052
Publisher: Elsevier BV
Date: 08-2020
Publisher: Elsevier BV
Date: 1996
DOI: 10.1016/S0896-6273(00)80025-2
Abstract: Periventricular heterotopia (PH) involves dramatic malformations of the human cerebral cortex. Here we show that PH is closely linked to markers in distal Xq28 (maximal two-point lod score = 4.77 for F8C at theta = 0 maximal multipoint lod score = 5.37), so that affected females are obligatory mosaics for the mutation that PH is lethal to at least some affected males that PH malformations consist of well-differentiated cortical neurons filling the adult subependymal zone and that in iduals with PH are at high risk for epilepsy, though they have no other neurological or external stigmata. The PH gene may represent an important epilepsy susceptibility locus in addition to playing a key role in normal cortical development.
Publisher: Wiley
Date: 16-02-2018
DOI: 10.1111/DMCN.13687
Abstract: Ketogenic diet therapies have proven efficacy for refractory epilepsy. There are many reports of their use in the genetic developmental and epileptic encephalopathies however, little attention has been paid as to whether the diet is also effective in in iduals with an acquired structural aetiology. We observed remarkable efficacy of the diet in two patients with hypoxic-ischaemic encephalopathy. We then analysed our cases with refractory structural epilepsies of acquired origin to characterize their response to the ketogenic diet. The classical ketogenic diet was implemented with dietary ratios of 3:1 to 4.4:1. Seizure frequency at 1 month, 3 months, 6 months, 1 year, and 2 years was ascertained. A responder was defined as greater than 50% seizure reduction compared to baseline. Seven of the nine patients were responders at 3 months. Somewhat surprisingly we found that the ketogenic diet was effective in patients with a developmental and epileptic encephalopathy due to an acquired structural aetiology. This cohort may not be routinely considered for the ketogenic diet because of their structural and acquired, rather than genetic, basis. The ketogenic diet should be considered early in the management of patients with acquired structural encephalopathies as it can improve seizure control with the potential to improve developmental outcome. The ketogenic diet was effective in children with epilepsy associated with an acquired structural aetiology.
Publisher: BMJ
Date: 14-09-2007
Publisher: Elsevier BV
Date: 09-2002
Publisher: Wiley
Date: 24-08-2022
DOI: 10.1111/JPC.16181
Abstract: To report response to first treatment in infants with infantile spasms (IS), including incremental benefit of prednisolone 60 mg/day and vigabatrin following prednisolone 40 mg/day failure in infants commenced on the United Kingdom Infantile Spasms Study (UKISS) treatment sequence. In this retrospective analysis, we compared effectiveness of prednisolone, vigabatrin and nonstandard treatments as first treatment for IS. In infants who commenced the UKISS treatment sequence, we evaluated response to each step. Primary outcome was spasm cessation after 42 days. Secondary outcomes were severe side effects and spasm relapse after 42 days. Treatment response data were available for 151 infants. First treatment was prednisolone in 99 infants, vigabatrin in 18 and nonstandard treatment in 34. The rate of spasm cessation with first treatment was significantly higher with prednisolone (62/99, 63%) than vigabatrin (5/18, 28%, P = 0.01) or nonstandard treatment (2/34, 5.9%, P 0.01). Of 112 infants who commenced the UKISS treatment sequence, 71/112 (63%) responded to prednisolone 40 mg/day. Among non‐responders, 12/29 (41%) subsequently responded to prednisolone 60 mg/day, and 10/22 (45%) to vigabatrin. Severe side effects and spasm relapse were not significantly different between each treatment. We confirm higher rates of spasm cessation with initial treatment with prednisolone than vigabatrin and nonstandard therapy. Non‐use of prednisolone as first treatment in over one third of infants highlights a concerning treatment gap. The UKISS treatment sequence has high overall treatment response (total 93/112 83%), with similar benefit of subsequent prednisolone 60 mg/day and vigabatrin in prednisolone 40 mg/day non‐responders.
Publisher: Wiley
Date: 04-2022
DOI: 10.1111/EPI.17228
Abstract: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All s les were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger s le sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.EPLEPSYRES.2011.08.009
Abstract: We report a clinical and genetic follow-up study of a large consanguineous family from an endogamous Roma/Gypsy sub-isolate, where previous analyses have been inconclusive. Detailed clinical information was collected through extensive field work, repeat interviews and electrophysiological and neuroimaging investigations on 18 affected subjects. The phenotype is compatible with GEFS+, with some unusual features, e.g. GTCS persisting into late adult life and high frequency of focal epilepsy. Updated genealogical information, a dense SNP genome scan and linkage analysis identified a novel GEFS+ locus on 12p13.33, where 13 affected in iduals from two branches of the kindred shared an identical haplotype. This haplotype was not found in the 3rd branch or in the remaining 21 Roma epilepsy families in our collection. Genetic heterogeneity and evidence of bilineality were found despite the inbreeding and endogamous nature of the family and population of origin. These data add to the growing evidence of lack of founder effect and significant genetic heterogeneity in epilepsy in the Roma/Gypsy population. Sequencing of the coding regions of three genes linked to neurotransmitter transport and release, SLC6A12, SLC6A13 and ERC1, on 12p did not identify a causative mutation.
Publisher: Wiley
Date: 13-01-2012
DOI: 10.1111/J.1528-1167.2011.03379.X
Abstract: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.
Publisher: American Academy of Pediatrics (AAP)
Date: 09-2019
Abstract: Girls with pathogenic variants in FMR1, the gene responsible for Fragile X syndrome, have received relatively little attention in the literature. The reports of girls with trinucleotide expansions or deletions affecting FMR1 describe variable phenotypes having normal intelligence and no severe neurologic sequelae is not uncommon. We reviewed epilepsy genetics research databases for girls with FMR1 pathogenic variants and seizures to characterize the spectrum of epilepsy phenotypes. We identified 4 patients, 3 of whom had drug-resistant focal epilepsy. Two had severe developmental and epileptic encephalopathy with late-onset epileptic spasms. Our findings demonstrate that FMR1 loss-of-function variants can result in severe neurologic phenotypes in girls. Similar cases may be missed because clinicians may not always perform Fragile X testing in girls, particularly those with severe neurodevelopmental impairment or late-onset spasms.
Publisher: Frontiers Media SA
Date: 06-02-2020
Publisher: Springer Science and Business Media LLC
Date: 19-01-2202
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.BRAINDEV.2018.01.005
Abstract: Hemiconvulsion-hemiplegia-epilepsy (HHE) involves infantile-onset acute hemiconvulsive febrile status epilepticus with subsequent unilateral cerebral atrophy and hemiparesis. Chronic epilepsy later develops, typically involving refractory focal seizures however, the underlying pathophysiology of this epilepsy is not well understood. We present a boy who had a typical acute presentation of HHE at 23 months, but an unusual evolution to chronic epilepsy in which the initially unaffected hemisphere was significantly abnormal. His initial acute presentation was right-sided hemiconvulsive febrile status epilepticus, with subsequent left cerebral hemiatrophy and hemiparesis affecting the right face, arm and leg. Focal seizures began at 5 years and were refractory to medical treatment. At 9 years, video EEG monitoring showed a striking pattern of interictal slow spike-wave and paroxysmal fast activity, maximal over the right, initially unaffected, hemisphere. He had primarily focal tonic seizures involving left-sided stiffening, also appearing to originate from the right hemisphere. Following left functional hemispherotomy he became seizure-free and parents reported improved cognitive function, attention and quality of life. This boy had classic features of Lennox-Gastaut syndrome, but expressed almost exclusively over the right hemisphere, which was initially unaffected in his acute presentation of HHE. His evolution to "hemi-Lennox-Gastaut-like phenotype" illustrates the importance of monitoring chronic epilepsy in patients with HHE early surgical intervention might prevent pathologic recruitment of bilateral secondary networks leading to the refractory seizures and cognitive impairment associated with Lennox-Gastaut syndrome.
Publisher: Wiley
Date: 10-10-2023
DOI: 10.1111/AFE.12594
Publisher: Wiley
Date: 12-2008
DOI: 10.1111/J.1528-1167.2008.01652.X
Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a relatively benign epilepsy syndrome with few comorbidities. Here we describe two families with unusually severe ADNFLE, with associated psychiatric, behavioral, and cognitive features. Detailed clinical data on 17 affected in iduals were obtained, and genotyping of microsatellite markers, linkage analysis, and sequencing of candidate genes was performed. The severe ADNFLE phenotype in these families was often refractory to treatment, with status epilepticus occurring in 24% of subjects. Psychiatric or behavioral disorders occurred in 53%, with intellectual disability in 24%, and developmental regression in two in iduals. No mutations were identified in alpha4, alpha2, or beta2 nAChR subunits. In one family there was evidence of linkage to a region of 15q24 without nAChR subunit genes. In conclusion, severe ADNFLE has significant medical, psychiatric, and intellectual morbidity. The molecular basis of severe ADNFLE is unknown but may involve non-nAChR-related mechanisms.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-03-2013
Publisher: BMJ
Date: 23-10-2010
Abstract: The ring chromosome 20 syndrome (R20) is a rare genetic disorder associated with a refractory electroclinical epilepsy syndrome and variably expressed comorbidities of intellectual disability and dysmorphism. To understand the structure and composition of the ring chromosome 20 (r(20)) in this patient cohort, blood specimens from 28 affected in iduals were analysed by cytogenetic, fluorescence in situ hybridisation, and/or high resolution whole genome single nucleotide polymorphism array analysis. These studies revealed two distinct groups of patients. Group 1 (N=21) was mosaic for the r(20) and a normal cell line with no detectable deletions or duplications of chromosome 20 in either cell line. The mosaic nature of these rings suggests a postzygotic origin with formation of the ring by fusion of the telomeric regions with no apparent loss of subtelomeric or telomeric DNA. Group 2 (N=7) had non-mosaic ring chromosomes with a deletion at one or both ends of the chromosome, near the ring fusion point. The non-mosaic nature of these rings is consistent with a meiotic origin. The age of onset of seizures was significantly lower in the non-mosaic patients (group 2, median age of onset 2.1 years) than in the mosaic patients (group 1, median age of onset 6.0 years). Patients from group 2 had more extensive comorbidities. These studies demonstrate that r(20) is molecularly heterogeneous and formed by two distinct mechanisms, which, in turn, produce different phenotypic spectrums.
Publisher: Springer International Publishing
Date: 2020
Publisher: Wiley
Date: 08-2000
Publisher: Elsevier BV
Date: 09-2023
Publisher: Wiley
Date: 03-05-2022
DOI: 10.1111/EPI.17240
Abstract: The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017-2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients.
Publisher: Wiley
Date: 03-05-2022
DOI: 10.1111/EPI.17241
Abstract: The 2017 International League Against Epilepsy classification has defined a three-tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been ided into three categories: (1) self-limited focal epilepsies, comprising four syndromes: self-limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic-atonic seizures, Lennox-Gastaut syndrome, developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep, hemiconvulsion-hemiplegia-epilepsy syndrome, and febrile infection-related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations.
Publisher: Elsevier
Date: 2013
Publisher: Elsevier BV
Date: 2023
Publisher: Wiley
Date: 03-05-2022
DOI: 10.1111/EPI.17239
Abstract: The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene-related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an in idual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self-limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology-specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected in iduals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology-defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource-limited regions where laboratory confirmation, including EEG, MRI, and genetic testing, might not be available.
Publisher: Wiley
Date: 03-05-2022
DOI: 10.1111/EPI.17237
Abstract: Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as "a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious)." The diagnosis of a syndrome in an in idual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age-dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We ided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers.
Publisher: Wiley
Date: 04-2010
Publisher: Wiley
Date: 04-2007
DOI: 10.1111/J.1528-1167.2007.00977.X
Abstract: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls. The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced. We observed a significant effect in a small s le recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a s le recruited in Ireland and no association in larger s les of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region. The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6TB01233G
Abstract: A highly efficient nanozyme system, termed a hollow multipod Cu(OH) 2 superstructure (HMPS), has been developed via direct conversion from irregular nanoparticles.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.EJMG.2017.06.002
Abstract: Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected in iduals in the family. Identification of COL18A1 mutations in in iduals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.
Publisher: SPIE
Date: 19-11-2001
DOI: 10.1117/12.454607
Publisher: Elsevier BV
Date: 12-2010
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.PEDIATRNEUROL.2017.01.004
Abstract: Dravet syndrome is a developmental and epileptic encephalopathy that occurs as a result of SCN1A mutations in more than 80% of affected in iduals. The core clinical features of Dravet syndrome include febrile and afebrile seizures beginning before 12 months multiple seizure types, usually medically refractory, including hemiclonic, generalized tonic-clonic, focal impaired awareness, myoclonic, and absence seizures status epilepticus and normal early development with plateau or regression by age two years. Myoclonic absence seizures have not previously been described. This 20-year-old man had infantile-onset epilepsy with the classical clinical features of Dravet syndrome and a de novo A1326P SCN1A mutation. By five years of age, photosensitive myoclonic absence seizures had become his dominant seizure type, occurring up to 20 times per day. The seizures were refractory to multiple antiepileptic medications and a vagus nerve stimulator. Although photosensitivity is well recognized in Dravet syndrome, myoclonic absence seizures have not been previously reported. This rare seizure type may be underreported in Dravet syndrome, as the myoclonic features may be subtle and can be missed if thorough history taking and video recordings are not available.
Publisher: Wiley
Date: 03-2020
DOI: 10.1002/GEPI.22288
Publisher: Elsevier BV
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 28-04-2022
DOI: 10.1101/2022.04.26.22274147
Abstract: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. We screened 893 in iduals with developmental and epileptic encephalopathies (DEEs) for KCNH5 variants using targeted or exome sequencing. Additional in iduals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed seizure types and epilepsy syndromes were classified. We included three previously published in iduals including additional phenotypic details. We report a cohort of 17 patients, including nine with a recurrent de novo missense variant p.Arg327His, four with a recurrent missense variant p.Arg333His, and four additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using American College of Medical Genetics and Genomics (ACMG) criteria. All in iduals presented with epilepsy with a median seizure onset at six months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. In iduals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalised epilepsy and normal intellect, while the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two in iduals with variants in the pore-domain were more severely affected, with neonatal-onset DEE, profound disability, and childhood death. We report the first cohort of 17 in iduals with pathogenic or likely pathogenic missense variants in the voltage sensing and pore domains of Kv10.2, including 14 previously unreported in iduals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders (NDDs) and epilepsy.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Defense Technical Information Center
Date: 09-2013
DOI: 10.21236/ADA601230
Publisher: Elsevier BV
Date: 07-2007
Publisher: MDPI AG
Date: 27-10-2020
DOI: 10.3390/IJMS21217965
Abstract: Families comprising many in iduals with Autism Spectrum Disorders (ASD) may carry a dominant predisposing mutation. We implemented rigorous phenotyping of the “Broader Autism Phenotype” (BAP) in large multiplex ASD families using a novel endophenotype approach for the identification and characterisation of distinct BAP endophenotypes. We evaluated ASD/BAP features using standardised tests and a semi-structured interview to assess social, intellectual, executive and adaptive functioning in 110 in iduals, including two large multiplex families (Family A: 30 Family B: 35) and an independent s le of small families (n = 45). Our protocol identified four distinct psychological endophenotypes of the BAP that were evident across these independent s les, and showed high sensitivity (97%) and specificity (82%) for in iduals classified with the BAP. Patterns of inheritance of identified endophenotypes varied between the two large multiplex families, supporting their utility for identifying genes in ASD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-05-2004
DOI: 10.1212/01.WNL.0000125187.52952.E9
Abstract: Syndromes of bilateral symmetric polymicrogyria include an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP), in which the malformation is most severe rostrally. The authors describe a new syndrome they have termed "bilateral generalized polymicrogyria" (BGP), in which the malformation occurs in a generalized distribution but is often most severe in the perisylvian regions. Patients with bilateral polymicrogyria were identified from multiple medical centers worldwide. The diagnosis of BGP was based on findings from conventional spin echo MRI and, in one case, postmortem neuropathologic findings. Genetic analysis was performed for those patients from consanguineous pedigrees and those with multiple affected siblings to rule out linkage to the BFPP locus on chromosome 16q. Twelve patients were identified with BGP. Clinical features included cognitive and motor delay as well as seizures. Some specific features characteristic of other known bilateral polymicrogyria syndromes, such as pseudobulbar palsy and dysconjugate gaze, were not commonly seen in these patients. Radiologically, polymicrogyria appeared widespread but was often most severe in the perisylvian regions. Pathologic examination in one case revealed a diffusely thin and excessively folded cerebral cortex lacking normal six-layered architecture. Seven patients subjected to genetic analysis did not demonstrate linkage to the BFPP locus. BGP is a distinct syndrome of cortical malformation. Several features allow BGP to be distinguished from other disorders on the growing list of bilateral symmetric polymicrogyria syndromes.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2019
Publisher: Wiley
Date: 09-04-2021
DOI: 10.1002/EPI4.12484
Abstract: We aimed to describe the phenotypic spectrum of seizures in Sotos syndrome, a genetic condition involving overgrowth, macrocephaly, dysmorphic features, and learning disability, in which 60%‐90% have NSD1 pathogenic variants. Patients were recruited from clinics and referral from support groups. Those with seizures and a clinical diagnosis of Sotos syndrome were included. Phenotyping data were collected via structured clinical interview and chart review. Forty‐nine patients were included. Twenty had NSD1 testing results available of these, 15 (75%) had NSD1 pathogenic variants. Seizure onset age ranged from 3 months to 12 years. Staring spells (absence or focal impaired awareness seizure) were the most frequently reported semiology (33/49 67%), followed by febrile seizures (25/49 51%) and afebrile bilateral tonic‐clonic seizures (25/49 51%). Most patients (33/49 67%) had multiple seizure types. The majority (33/49 67%) had seizures controlled on a single antiseizure medication or no medication. Nine (18%) had drug‐resistant epilepsy. Epilepsy syndromes included febrile seizures plus, Lennox‐Gastaut syndrome, childhood absence epilepsy, and generalized tonic‐clonic seizures alone. The seizure phenotype in Sotos syndrome most commonly involves staring spells, afebrile tonic‐clonic seizures or febrile convulsions however, other seizure types may occur. Seizures are typically well‐controlled with medication, but drug‐resistant epilepsy occurs in a minority.
Publisher: Oxford University Press (OUP)
Date: 03-1997
Abstract: The clinical and genetic relationships of febrile seizures and the generalized epilepsies are poorly understood. We ascertained a family with genealogical information in 2000 in iduals where there was an unusual concentration of in iduals with febrile seizures and generalized epilepsy in one part of the pedigree. We first clarified complex consanguineous relationships in earlier generations and then systematically studied the epilepsy phenotypes in affected in iduals. In one branch (core family) 25 in iduals over four generations were affected. The commonest phenotype, denoted as 'febrile seizures plus' (FS+), comprised childhood onset (median 1 year) of multiple febrile seizures, but unlike the typical febrile convulsion syndrome, attacks with fever continued beyond 6 years, or afebrile seizures occurred. Seizures usually ceased by mid childhood (median 11 years). Other phenotypes included FS+ and absences, FS+ and myoclonic seizures, FS+ and atonic seizures, and the most severely affected in idual had myoclonic-astatic epilepsy (MAE). The pattern of inheritance was autosomal dominant. The large variation in generalized epilepsy phenotypes was not explained by acquired factors. Analysis of this large family and critical review of the literature led to the concept of a genetic epilepsy syndrome termed generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ has a spectrum of phenotypes including febrile seizures, FS+ and the less common MAE. Recognition of GEFS+ explains the epilepsy phenotypes of previously poorly understood benign childhood generalized epilepsies. In in idual patients the inherited nature of GEFS+ may be overlooked. Molecular genetic study of such large families should allow identification of genes relevant to febrile seizures and generalized epilepsies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-01-2016
Publisher: Elsevier BV
Date: 05-2019
Publisher: Public Library of Science (PLoS)
Date: 09-07-2014
Publisher: Oxford University Press (OUP)
Date: 07-2022
Abstract: Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients’ variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy. Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.
Publisher: Wiley
Date: 23-09-2020
DOI: 10.1111/JPC.15078
Publisher: Springer Science and Business Media LLC
Date: 03-1988
DOI: 10.1007/BF00182774
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2018
DOI: 10.1212/NXG.0000000000000297
Abstract: To examine the genotype to phenotype connection in glucose transporter type 1 (GLUT1) deficiency and whether a simple functional assay can predict disease outcome from genetic sequence alone. GLUT1 deficiency, due to mutations in SLC2A1 , causes a wide range of epilepsies. One possible mechanism for this is variable impact of mutations on GLUT1 function. To test this, we measured glucose transport by GLUT1 variants identified in population controls and patients with mild to severe epilepsies. Controls were reference sequence from the NCBI and 4 population missense variants chosen from public reference control databases. Nine variants associated with epilepsies or movement disorders, with normal intellect in all in iduals, formed the mild group. The severe group included 5 missense variants associated with classical GLUT1 encephalopathy. GLUT1 variants were expressed in Xenopus laevis oocytes, and glucose uptake was measured to determine kinetics (V max ) and affinity (K m ). Disease severity inversely correlated with rate of glucose transport between control (V max = 28 ± 5), mild (V max = 16 ± 3), and severe (V max = 3 ± 1) groups, respectively. Affinities of glucose binding in control (K m = 55 ± 18) and mild (K m = 43 ± 10) groups were not significantly different, whereas affinity was indeterminate in the severe group because of low transport rates. Simplified analysis of glucose transport at high concentration (100 mM) was equally effective at separating the groups. Disease severity can be partly explained by the extent of GLUT1 dysfunction. This simple Xenopus oocyte assay complements genetic and clinical assessments. In prenatal diagnosis, this simple oocyte glucose uptake assay could be useful because standard clinical assessments are not available.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2009
Abstract: Correction to McPoil TG, Cornwall MW, Medoff L, Vicenzion B, Fosberg K, Hilz D. Arch height change during sit-to-stand: an alternative for the navicular drop test. Journal of Foot and Ankle Research 2008 1:3.
Publisher: Radiological Society of North America (RSNA)
Date: 12-2016
DOI: 10.1148/RADIOL.2016150852
Abstract: Purpose To investigate whether it is possible in patients with periventricular nodular heterotopia (PVNH) to detect abnormal fiber projections that have only previously been reported in the histopathology literature. Materials and Methods Whole-brain diffusion-weighted (DW) imaging data from 14 patients with bilateral PVNH and 14 age- and sex-matched healthy control subjects were prospectively acquired by using 3.0-T magnetic resonance (MR) imaging between August 1, 2008, and December 5, 2012. All participants provided written informed consent. The DW imaging data were processed to generate whole-brain constrained spherical deconvolution (CSD)-based tractography data and super-resolution track-density imaging (TDI) maps. The tractography data were overlaid on coregistered three-dimensional T1-weighted images to visually assess regions of heterotopia. A panel of MR imaging researchers independently assessed each case and indicated numerically (no = 1, yes = 2) as to the presence of abnormal fiber tracks in nodular tissue. The Fleiss κ statistical measure was applied to assess the reader agreement. Results Abnormal fiber tracks emanating from one or more regions of heterotopia were reported by all four readers in all 14 patients with PVNH (Fleiss κ = 1). These abnormal structures were not visible on the tractography data from any of the control subjects and were not discernable on the conventional T1-weighted images of the patients with PVNH. Conclusion Whole-brain CSD-based fiber tractography and super-resolution TDI mapping reveals abnormal fiber projections in nodular tissue suggestive of abnormal organization of white matter (with abnormal fibers both within nodules and projecting to the surrounding white matter) in patients with bilateral PVNH.
Publisher: Wiley
Date: 03-08-2021
DOI: 10.1002/ANA.26174
Abstract: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterized postictal psychosis, which comprises about one quarter of epilepsy‐related psychoses, and has unknown causation. We conducted a case–control cohort study including patients diagnosed with postictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile, and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis 49 had postictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with postictal psychosis univariate associations with a p value 0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated. Cases were more likely to have seizure clustering (odds ratio [OR] = 7.59, p 0.001), seizures with a recollected aura (OR = 2.49, p = 0.013), and a family history of psychiatric disease (OR = 5.17, p = 0.022). Cases showed predominance of right temporal epileptiform discharges (OR = 4.87, p = 0.007). There was no difference in epilepsy duration, neuroimaging findings, or antiseizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of postictal psychosis cases (n = 58) were significantly higher than in 1,366 epilepsy controls ( R 2 = 3%, p = 6 × 10 −3 ), but not significantly different from 945 independent patients with schizophrenia ( R 2 = 0.1% , p = 0.775). Postictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (postictal psychosis) in a common disease. ANN NEUROL 2021 :464–476
Publisher: Wiley
Date: 11-2003
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.EJPN.2017.12.003
Abstract: Epilepsy with myoclonic absences is a rare generalized epilepsy syndrome with distinctive seizures. Two unrelated children had mild developmental impairment and onset of myoclonic-absences at 3 and 8 years. Seizures were characterized by bilateral 3 Hz myoclonic jerks superimposed on tonic abduction of the upper limbs. Events lasted 10-60 s, and complex gestural automatisms were often observed in one case, a boy undid his seatbelt and attempted to exit a moving vehicle. Post-ictally, both children immediately regained awareness without recollection of their actions. Ictal EEGs showed 3 Hz generalized spike-wave. Complex automatisms have not been described in myoclonic absence seizures. This generalized seizure type can be confused with focal seizures when these ictal behaviours occur.
Publisher: Wiley
Date: 21-11-2018
DOI: 10.1002/AJMG.A.38549
Abstract: Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β-galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-04-2005
Publisher: Elsevier BV
Date: 10-2014
Publisher: Wiley
Date: 12-2012
DOI: 10.1111/J.1528-1167.2012.03692.X
Abstract: Eyelid myoclonia with absences (EM) is an uncommon type of absence seizure associated with a variety of epilepsy syndromes. The syndrome of epilepsy with EM (EMA) has been proposed to denote the onset of frequent EM induced by eye closure and photic stimulation beginning in childhood. The clinical genetics of EMA has not been well characterized, although a family history of seizures is not infrequent. In iduals with EMA were ascertained by referral and through the investigators' clinical practices. All available family members were assessed for seizures using a validated seizure questionnaire. Electroclinical data were obtained on each proband and all affected family members pedigrees were constructed. Families were analyzed for phenotypic patterns. Eighteen in iduals with EMA were recruited. A history of seizures was found in 34 relatives in 15 (83%) of 18 families. In terms of epilepsy syndromes, 9 relatives from 7 of 15 families had febrile seizures. Two relatives had EMA. Classical genetic generalized epilepsy (GGE) syndromes were seen in five relatives: two generalized tonic-clonic seizures alone, two childhood absence epilepsy (CAE), and one juvenile myoclonic epilepsy (JME). Genetic epilepsy with febrile seizures plus (GEFS+) phenotypes occurred in 16 relatives. On review of the epilepsy syndromes within each family, seven families had a pattern consistent with GEFS+, whereas three families had classical GGE. The clinical genetics of EMA is suggestive of complex inheritance with shared genetic determinants overlapping with both classical GGE and GEFS+. The epilepsy syndromes in relatives of probands with EMA differ from those found in families of probands with CAE, supporting the concept that patients with EMA have a syndrome that is distinct from CAE. This presumably reflects different genetic components contributing to their genetic architecture.
Publisher: Wiley
Date: 11-07-2021
DOI: 10.1111/DMCN.14989
Abstract: To determine whether genes that cause developmental and epileptic encephalopathies (DEEs) are more commonly implicated in intellectual disability with epilepsy as a comorbid feature than in intellectual disability only. We performed targeted resequencing of 18 genes commonly implicated in DEEs in a cohort of 830 patients with intellectual disability (59% male) and 393 patients with DEEs (52% male). We observed a significant enrichment of pathogenic/likely pathogenic variants in patients with epilepsy and intellectual disability (16 out of 159 in seven genes) compared with intellectual disability only (2 out of 671) ( p .86×10 −10 , odds ratio 37.22, 95% confidence interval 8.60–337.0). We identified seven genes that are more likely to cause epilepsy and intellectual disability than intellectual disability only. Conversely, two genes, GRIN2B and SCN2A , can be implicated in intellectual disability without epilepsy in these instances intellectual disability is not a secondary consequence of ongoing seizures but rather a primary cause. A subset of genes are more commonly implicated in epilepsy than other neurodevelopmental disorders. GRIN2B and SCN2A are implicated in intellectual disability and epilepsy independently.
Publisher: Wiley
Date: 09-2009
DOI: 10.1002/ANA.21724
Abstract: Absence epilepsies of childhood are heterogeneous with most cases following complex inheritance. Those cases with onset before 4 years of age represent a poorly studied subset. We screened 34 patients with early-onset absence epilepsy for mutations in SLC2A1, the gene encoding the GLUT1 glucose transporter. Mutations leading to reduced protein function were found in 12% (4/34) of patients. Two mutations arose de novo, and two were familial. These findings suggest GLUT1 deficiency underlies a significant proportion of early-onset absence epilepsy, which has both genetic counseling and treatment implications because the ketogenic diet is effective in GLUT1 deficiency.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 1998
DOI: 10.1109/62.715537
Publisher: Wiley
Date: 02-2010
DOI: 10.1002/ANA.21968
Publisher: Wiley
Date: 20-10-2019
DOI: 10.1111/EPI.16372
Abstract: Pathogenic variants in GNB5 cause an autosomal recessive neurodevelopmental disorder with neonatal sinus bradycardia. Seizures or epilepsy occurred in 10 of 22 previously reported cases, including 6 children from one family. We delineate the epileptology of GNB5 encephalopathy. Our nine patients, including five new patients, were from seven families. Epileptic spasms were the most frequent seizure type, occurring in eight of nine patients, and began at a median age of 3 months (2 months to 3 years). Focal seizures preceded spasms in three children, with onset at 7 days, 11 days, and 4 months. One child presented with convulsive status epilepticus at 6 months. Three children had burst suppression on electroencephalography (EEG), three had hypsarrhythmia, and one evolved from burst suppression to hypsarrhythmia. Background slowing was present in all after age 3 years. Magnetic resonance imaging (MRI) showed cerebral atrophy in one child and cerebellar atrophy in another. All nine had abnormal development prior to seizure onset and ultimately had profound impairment without regression. Hypotonia was present in all, with contractures developing in two older patients. All in iduals had biallelic pathogenic variants in GNB5, predicted by in silico tools to result in protein truncation and loss-of-function. GNB5 developmental and epileptic encephalopathy is characterized by epileptic spasms, focal seizures, and profound impairment.
Publisher: Hindawi Limited
Date: 24-04-2019
DOI: 10.1002/HUMU.23731
Publisher: EMBO
Date: 25-03-2014
Publisher: American Society of Neuroradiology (ASNR)
Date: 13-10-2022
DOI: 10.3174/AJNR.A7663
Publisher: Springer Science and Business Media LLC
Date: 17-11-2015
DOI: 10.1038/NG.3144
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.SCR.2019.101516
Abstract: We have generated and characterized seven human induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells (PBMCs) from a single family, including unaffected and affected in iduals clinically diagnosed with Autism Spectrum Disorder (ASD). The reprogramming of the PBMCs was performed using non-integrative Sendai virus containing the reprogramming factors POU5F1 (OCT4), SOX2, KLF4 and MYC. All iPSC lines exhibited a normal karyotype and pluripotency was validated by immunofluorescence, flow cytometry and their ability to differentiate into the three embryonic germ layers. These iPSC lines are a valuable resource to study the molecular mechanisms underlying ASD.
Publisher: Elsevier BV
Date: 07-2022
Publisher: Wiley
Date: 22-09-2009
DOI: 10.1111/J.1528-1167.2009.02065.X
Abstract: Benign childhood epilepsy with centrotemporal spikes (BECTS) is the most common epilepsy syndrome of childhood and can be associated with language difficulties. The exact profile of these difficulties and their neurofunctional underpinnings, however, are not yet clear. To further understand the impact of the BECTS syndrome on language, we assessed language performance using standard neuropsychological measures, and patterns of language lateralization using functional magnetic resonance imaging (fMRI) in children with typical BECTS (n = 20) and healthy controls (n = 20). The fMRI analyses revealed that language-related activation was less lateralized to the left hemisphere in anterior brain regions in the patients relative to the control group. This finding was consistent with decreased performance in the BECTS group compared to the control group on the neuropsychological measure most dependent on the integrity of anterior aspects of the language axis, namely, sentence production. The converging lines of evidence from the neuropsychological and activation methodologies support the view that BECTS is associated with language difficulties that are regional, and anterior, in nature.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Elsevier BV
Date: 08-2003
Publisher: Oxford University Press (OUP)
Date: 21-08-2015
DOI: 10.1093/BRAIN/AWV243
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-11-2023
DOI: 10.1212/WNL.0000000000201438
Abstract: To determine the frequency and spectrum of complications of influenza infection in in iduals with SCN1A -positive Dravet syndrome ( SCN1A -DS). In iduals with SCN1A -DS were identified in neurologists' care at 2 hospitals in Melbourne, Australia, with additional searches of EEG databases, the Victorian PAEDS FluCan influenza database, and the University of Melbourne Epilepsy Genetics Research Program database. Medical records were searched and families questioned to identify in iduals who had an influenza infection reported infections were confirmed by pathology report. For these in iduals, we obtained baseline clinical characteristics and clinical details of the influenza infection. Twenty-one of 82 in iduals (26%) had 24 documented influenza infections (17 influenza A and 7 influenza B) at age 0.5–25 years (median 4 years). All presented to hospital, 18/24 (75%) for status epilepticus or seizure exacerbations. Recovery was prompt in 18/24 (75%) infections, delayed but complete in 1/24 (4%) and incomplete in 5/24 (21%). One child died from influenza pneumonia, and long-term neurologic sequelae were seen with 4 infections. These in iduals were poorly responsive after termination of status epilepticus. Brain imaging in 2 showed cerebral edema and 1 also having imaging features of laminar necrosis. All have ongoing neurologic deficits compared with their baseline, 1 having profound global impairment. Our data show that patients with SCN1A -DS are highly susceptible to neurologic complications during and severe sequelae after influenza infection, including moderate to severe persistent neurologic impairments and death. Safe administration of the seasonal influenza vaccine should be prioritized for this population.
Publisher: Elsevier BV
Date: 04-2022
Publisher: Elsevier BV
Date: 12-2019
Publisher: Elsevier BV
Date: 08-2018
Publisher: Wiley
Date: 04-2009
DOI: 10.1111/J.1528-1167.2009.02023.X
Abstract: SCN1A is the most clinically relevant epilepsy gene and is associated with generalized epilepsy and febrile seizure plus (GEFS+) and Dravet syndrome. We postulated that earlier onset of febrile seizures in the febrile seizure (FS) and febrile seizure plus (FS+) phenotypes may occur in the presence of a SCN1A mutation. This was because of the age-related onset of Dravet syndrome, which typically begins in the first year of life. We found that patients with FS and FS+ with SCN1A mutations had earlier median onset of febrile seizures compared to the population median. Patients with GABRG2 mutations had a similar early onset in contrast to patients with SCN1B mutations where onset was later. This study is the first to demonstrate that a specific genetic abnormality directly influences the FS and FS+ phenotype in terms of age of onset.
Publisher: Wiley
Date: 30-05-2019
DOI: 10.1002/AJMG.A.61216
Abstract: Pathogenic variants in the X-chromosome Aristaless-related homeobox (ARX) gene contribute to intellectual disability, epilepsy, and associated comorbidities in affected males. Here, we report a novel splice variant in ARX in a family with three affected in iduals. The proband had early onset developmental and epileptic encephalopathy, his brother and mother had severe and mild intellectual disability, respectively. Massively parallel sequencing identified a novel c.1449-1G>C in intron 4 of the ARX gene, predicted to abolish the splice acceptor site, retaining intron 4 and leading to a premature termination codon immediately after exon 4. As exon 5 is the last exon of the ARX gene, the premature termination codon at position p.L484* would be predicted to escape nonsense-mediated mRNA decay, potentially producing at least some C-terminally truncated protein. Analysis of cDNA from patient lymphoblastoid cells confirmed retention of intron 4 and loss of detectable expression of ARX mRNA across exon 4 to exon 5. We review published cases of variants that lead to altered or early termination of the ARX protein, but not complete loss of function, and are associated with phenotypes of intellectual disability and infantile onset developmental and epileptic encephalopathies, including Ohtahara and West syndromes. Taken together, this novel splice variant retaining intron 4 is likely to be the cause of the early onset developmental and epileptic encephalopathy in the proband.
Publisher: Oxford University Press (OUP)
Date: 18-04-2013
DOI: 10.1093/BRAIN/AWT073
Publisher: Elsevier BV
Date: 06-2017
Publisher: Springer Science and Business Media LLC
Date: 07-2016
DOI: 10.1007/S00439-016-1700-8
Abstract: Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder characterized by adult onset, involuntary muscle jerks, cortical myoclonus and occasional seizures. FAME is genetically heterogeneous with more than 70 families reported worldwide and five potential disease loci. The efforts to identify potential causal variants have been unsuccessful in all but three families. To date, linkage analysis has been the main approach to find and narrow FAME critical regions. We propose an alternative method, pedigree free identity-by-descent (IBD) mapping, that infers regions of the genome between in iduals that have been inherited from a common ancestor. IBD mapping provides an alternative to linkage analysis in the presence of allelic and locus heterogeneity by detecting clusters of in iduals who share a common allele. Succeeding IBD mapping, gene prioritization based on gene co-expression analysis can be used to identify the most promising candidate genes. We performed an IBD analysis using high-density single nucleotide polymorphism (SNP) array data followed by gene prioritization on a FAME cohort of ten European families and one Australian/New Zealander family eight of which had known disease loci. By identifying IBD regions common to multiple families, we were able to narrow the FAME2 locus to a 9.78 megabase interval within 2p11.2-q11.2. We provide additional evidence of a founder effect in four Italian families and allelic heterogeneity with at least four distinct founders responsible for FAME at the FAME2 locus. In addition, we suggest candidate disease genes using gene prioritization based on gene co-expression analysis.
Publisher: Elsevier BV
Date: 11-2018
Publisher: Wiley
Date: 09-11-2022
DOI: 10.1111/EPI.17431
Abstract: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS). Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n = 241) and -50.5% at Month 15 (n = 142, p .0001) 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was -45.9% (n = 192, p = .0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p .0001, n = 106) and 35.8% (p .0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%-44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%-41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 02-05-2008
Abstract: Certain mutations in specific parts of the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4, CHRNB2, and probably CHRNA2, can cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). All but one of the known causative mutations are located in the second transmembrane region (TM2), which serves as the major ion poreforming domain of the receptor. Functional characterization of these ADNFLE mutations has shown that although each mutant exhibits specific properties, they all confer a gain of function with increased sensitivity to acetylcholine. In this work, we characterize the second and third ADNFLE-associated mutations that are external to TM2 but affect different amino acid residues within the third transmembrane region (TM3). The two new CHRNB2 mutations were identified in three families of Turkish Cypriot, Scottish, and English origin. These TM3 mutations elicit the same gain of function pathomechanism as observed for the TM2 mutations with enhanced acetylcholine sensitivity, despite their unusual localization within the gene. Electrophysiological experiments, including single channel measurements, revealed that incorporation of these new mutant subunits does not affect the conductance of the ionic pore but increases the probability of opening. Determination of the sensitivity to nicotine for nAChRs carrying mutations in TM2 and TM3 showed clear differences in the direction and the extent to which the window current for nicotine sensitivity was shifted for in idual mutations, indicating differences in pharmacogenomic properties that are not readily correlated with increased ACh affinity.
Publisher: Wiley
Date: 07-2020
DOI: 10.1111/EPI.16582
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3EM00100H
Publisher: American Medical Association (AMA)
Date: 05-2020
Publisher: Wiley
Date: 31-10-2022
DOI: 10.1002/ACN3.51684
Abstract: Anti‐seizure medications that block sodium channels are generally considered contraindicated in Dravet syndrome. There is, however, considerable debate about the sodium‐channel blocker phenytoin, which is often used for status epilepticus, a frequent feature of Dravet syndrome. We describe four patients with Dravet syndrome in whom long‐term phenytoin therapy reduced seizure frequency and duration. In two patients, phenytoin produced prolonged periods without status epilepticus for the first time. Attempting to wean phenytoin in all patients after 1 to 20 years of use resulted in seizure exacerbation. Reintroducing phenytoin improved seizure control, suggesting phenytoin is beneficial in some patients with Dravet syndrome.
Publisher: Wiley
Date: 09-03-2023
DOI: 10.1111/EPI.17547
Abstract: “How many epilepsy genes are there?” is a frequently asked question. We sought to (1) provide a curated list of genes that cause monogenic epilepsies, and (2) compare and contrast epilepsy gene panels from multiple sources. We compared genes included on the epilepsy panels (as of July 29, 2022) of four clinical diagnostic providers: Invitae, GeneDx, Fulgent Genetics, and Blueprint Genetics and two research resources: PanelApp Australia and ClinGen. A master list of all unique genes was supplemented by additional genes identified via PubMed searches up until August 15, 2022, using the search terms “genetics” AND/OR “epilepsy” AND/OR “seizures”. Evidence supporting a monogenic role for all genes was manually reviewed those with limited or disputed evidence were excluded. All genes were annotated according to inheritance pattern and broad epilepsy phenotype. The comparison of genes included on epilepsy clinical panels revealed high heterogeneity in both number of genes (range: 144–511) and content. Just 111 genes (15.5%) were included on all four clinical panels. Subsequent manual curation of all “epilepsy genes” identified monogenic etiologies. Almost 90% of genes were associated with developmental and epileptic encephalopathies. By comparison only 5% of genes were associated with monogenic causes of “common epilepsies” (i.e., generalized and focal epilepsy syndromes). Autosomal recessive genes were most frequent (56% of genes) however, this varied according to the associated epilepsy phenotype(s). Genes associated with common epilepsy syndromes were more likely to be dominantly inherited and associated with multiple epilepsy types. Our curated list of monogenic epilepsy genes is publicly available: ahlolab/genes4epilepsy and will be regularly updated. This gene resource can be utilized to target genes beyond those included on clinical gene panels, for gene enrichment methods and candidate gene prioritization. We invite ongoing feedback and contributions from the scientific community via genes4-epilepsy@unimelb.edu.au .
Publisher: Wiley
Date: 14-04-2016
DOI: 10.1002/MGG3.217
Publisher: Hindawi Limited
Date: 04-10-2019
DOI: 10.1002/HUMU.23915
Abstract: Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel K
Publisher: Springer Science and Business Media LLC
Date: 18-05-2020
Publisher: Wiley
Date: 06-2011
DOI: 10.1111/J.1528-1167.2011.03101.X
Abstract: Concepts and terminology for classifying seizures and epilepsies have, until recently, rested on ideas developed nearly a century ago. In order for clinical epilepsy and practice to benefit fully from the major technological and scientific advances of the last several years, advances that are revolutionizing our understanding and treatment of the epilepsies, it is necessary to break with the older vocabulary and approaches to classifying epilepsies and seizures. The Commission on Classification and Terminology made specific recommendations to move this process along and ensure that classification will reflect the best knowledge, will not be arbitrary, and will ultimately serve the purpose of improving clinical practice as well as research on many levels. The recommendations include new terms and concepts for etiology and seizure types as well as abandoning the 1989 classification structure and replacing it instead with a flexible multidimensional approach in which the most relevant features for a specific purpose can be emphasized. This is not a finished product and will take yet more time to achieve. Waiting any longer, however, would be a disservice to patient care and will continue the longstanding frustrations with the earlier system which, at this point in time, can be viewed as both antiquated and arbitrary.
Publisher: Wiley
Date: 02-1999
DOI: 10.1002/1531-8249(199902)45:2<146::AID-ANA3>3.0.CO;2-N
Abstract: Mutations in the X-linked gene doublecortin, which encodes a protein with no dear structural homologues, are found in pedigrees in which affected females show "double cortex" syndrome (DC also known as subcortical band heterotopia or laminar heterotopia) and affected males show X-linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single-stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.JHAZMAT.2022.128482
Abstract: Petroleum hydrocarbon contamination is a global problem which can cause long-term environmental damage and impacts water security. Natural source zone depletion (NSZD) is the natural degradation of such contaminants. Chemotaxis is an aspect of NSZD which is not fully understood, but one that grants microorganisms the ability to alter their motion in response to a chemical concentration gradient potentially enhancing petroleum NSZD mass removal rates. This study investigates the distribution of potentially chemotactic and hydrocarbon degrading microbes (CD) across the water table of a legacy petroleum hydrocarbon site near Perth, Western Australia in areas impacted by crude oil, diesel and jet fuel. Core s les were recovered and analysed for hydrocarbon contamination using gas chromatography. Predictive metagenomic profiling was undertaken to infer functionality using a combination of 16 S rRNA sequencing and PICRUSt2 analysis. Naphthalene contamination was found to significantly increase the occurrence of potential CD microbes, including members of the Comamonadaceae and Geobacteraceae families, which may enhance NSZD. Further work to explore and define this link is important for reliable estimation of biodegradation of petroleum hydrocarbon fuels. Furthermore, the outcomes suggest that the chemotactic parameter within existing NSZD models should be reviewed to accommodate CD accumulation in areas of naphthalene contamination, thereby providing a more accurate quantification of risk from petroleum impacts in subsurface environments, and the scale of risk mitigation due to NSZD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-12-2022
DOI: 10.1212/WNL.0000000000201469
Abstract: Mosaic pathogenic variants restricted to the brain are increasingly recognized as a cause of focal epilepsies. We aimed to identify a mosaic pathogenic variant and its anatomical gradient in brain DNA derived from trace tissue on explanted stereoelectroencephalography (SEEG) electrodes. We studied a patient with nonlesional multifocal epilepsy undergoing presurgical evaluation with SEEG. After explantation, the electrodes were ided into 3 pools based on their brain location (right posterior quadrant, left posterior quadrant, hippoc us/temporal neocortex). Tissue from each pool was processed for trace DNA that was whole genome lified prior to high-depth exome sequencing. Droplet digital PCR was performed to quantify mosaicism. A brain-specific glial fibrillary acidic protein (GFAP) assay enabled cell-of-origin analysis. We demonstrated a mosaic gradient for a novel pathogenic KCNT1 loss-of-function variant (c.530G A, p.W177X) predicted to lead to nonsense-mediated decay. Strikingly, the mosaic gradient correlated strongly with the SEEG findings because the highest variant allele frequency was in the right posterior quadrant, reflecting the most epileptogenic region on EEG studies. An elevated GFAP level indicated enrichment of brain-derived cells in SEEG cell suspension. This study demonstrates a proof of concept that mosaic gradients of pathogenic variants can be established using trace tissue from explanted SEEG electrodes.
Publisher: American Medical Association (AMA)
Date: 05-2006
DOI: 10.1001/ARCHNEUR.63.5.705
Abstract: Abnormal paroxysmal events in sleep may be parasomnias or epileptic seizures. In nocturnal frontal lobe epilepsy (NFLE), the unusual seizure features often lead to diagnostic confusion with nonepileptic parasomnias video-electroencephalography monitoring is usually required to make the diagnosis. To examine the reliability of the clinical history in diagnosing NFLE, using the Frontal Lobe Epilepsy and Parasomnias (FLEP) scale. The FLEP scale, comprising specific questions reflecting the diagnostic features of NFLE and parasomnias, was developed by an expert panel following review of the literature. It was then validated in a s le of in iduals with firmly diagnosed nocturnal events. Patients were recruited after appropriate diagnostic workup in tertiary sleep and epilepsy referral centers in Melbourne, Australia. Sixty-two patients (45 males) [corrected] with paroxysmal nocturnal events. Intervention Two independent interviews were conducted in each case, with the patient and a witness, by researchers blinded to the diagnosis. The diagnosis obtained from scores on the FLEP scale was compared with the confirmed diagnosis in each patient. Nocturnal frontal lobe epilepsy was correctly diagnosed from the FLEP score in 31 of 31 patients, with a sensitivity of 1.0 (95% confidence interval [CI], 0.85-1.00), specificity of 0.90 (95% CI, 0.73-0.97), positive predictive value of 0.91 (95% CI, 0.75-0.97), and negative predictive value of 1.00 (95% CI, 0.85-1.00). A diagnosis of NFLE can be made reliably using the clinical features identified in the FLEP scale. This may reduce the requirement for tertiary referral and extensive inpatient monitoring.
Publisher: Wiley
Date: 23-04-2015
DOI: 10.1111/DMCN.12781
Abstract: We aimed to determine whether response to ketogenic dietary therapies (KDT) was due to undiagnosed glucose transporter type 1 deficiency syndrome (GLUT1-DS). Targeted resequencing of the SLC2A1 gene was completed in in iduals without previously known GLUT1-DS who received KDT for their epilepsy. Hospital records were used to obtain demographic and clinical data. Response to KDT at various follow-up points was defined as seizure reduction of at least 50%. Seizure freedom achieved at any follow-up point was also documented. Fisher's exact and gene-burden association tests were conducted using the PLINK/SEQ open-source genetics library. Of the 246 participants, one was shown to have a novel variant in SLC2A1 that was predicted to be deleterious. This in idual was seizure-free on KDT. Rates of seizure freedom in cases without GLUT1-DS were below 8% at each follow-up point. Two cases without SLC2A1 mutations were seizure-free at every follow-up point recorded. No significant results were obtained from Fisher's exact or gene-burden association tests. A favourable response to KDT is not solely explained by mutations in SLC2A1. Other genetic factors should be sought to identify those who are most likely to benefit from dietary treatment for epilepsy, particularly those who may achieve seizure freedom.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-10-2013
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2022
DOI: 10.1101/2022.05.15.22274630
Abstract: Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we ascertained 70 unrelated probands with a clinical diagnosis of CAS and performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1 , SETD1A and DDX3X , thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected in iduals are poised for precision medicine trials.
Publisher: Wiley
Date: 04-2010
DOI: 10.1002/ANA.21909
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-12-2018
DOI: 10.1212/WNL.0000000000006729
Abstract: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1 . We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%) high pain threshold (72%) eating problems, including oral aversion (68%) hypotonia (67%) sleeping problems (62%) autism spectrum disorder (54%) and ataxia or gait abnormalities (51%). SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.
Publisher: Wiley
Date: 21-08-2020
DOI: 10.1111/JCPP.13295
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.MCN.2007.03.003
Abstract: Seizure susceptibility is high in human infants compared to adults, presumably because of developmentally regulated changes in neural excitability. Benign familial neonatal-infantile seizures (BFNIS), characterized by both early onset and remission, are caused by mutations in the gene encoding a human sodium channel (NaV1.2). We analyzed neonatal and adult splice forms of NaV1.2 with a BFNIS mutation (L1563V) in human embryonic kidney cells. Computer modeling revealed that neonatal channels are less excitable than adult channels. Introduction of the mutation increased excitability in the neonatal channels to a level similar to adult channels. By contrast, the mutation did not affect the adult channel variant. This "adult-like" increased excitability is likely to be the mechanism underlying BFNIS in infants with this mutation. More generally, developmentally regulated NaV1.2 splicing may be one mechanism that counters the normally high excitability of neonatal neurons and helps to reduce seizure susceptibility in normal human infants.
Publisher: Wiley
Date: 12-03-2020
DOI: 10.1111/EPI.16475
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-09-2004
DOI: 10.1212/01.WNL.0000137051.33486.C7
Abstract: Alteration of ATP-binding cassette subfamily B member 1 transporter (ABCB1) can plausibly cause drug-resistant epilepsy as it influences brain penetration of drugs. The CC genotype at the ABCB1 C3435T polymorphism was reported to be associated with multidrug resistance. A replication study in 401 drug-resistant and 208 drug-responsive subjects with epilepsy showed no significant association between the CC genotype and drug-resistant epilepsy. The authors suggest the initial association may have arisen by chance.
Publisher: Wiley
Date: 20-03-2023
DOI: 10.1111/EPI.17562
Publisher: Wiley
Date: 24-03-2011
DOI: 10.1111/J.1469-8749.2011.03949.X
Abstract: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a treatable condition resulting from impaired glucose transport into the brain. The classical presentation is with infantile-onset epilepsy and severe developmental delay. Non-classical phenotypes with movement disorders and early-onset absence epilepsy are increasingly recognized and the clinical spectrum is expanding. The hallmark is hypoglycorrhachia (cerebrospinal fluid [CSF] glucose<2.2 mmol/l) in the presence of normoglycaemia with a CSF/blood glucose ratio of less than 0.4. GLUT1DS is due to a mutation in the solute carrier family 2, member 1 gene (SLC2A1). We present five in iduals (four males, one female), all of whom had a mild phenotype, highlighting the importance of considering this diagnosis in unexplained neurological disorders associated with mild learning difficulties, subtle motor delay, early-onset absence epilepsy, fluctuating gait disorders, and/or dystonia. The mean age at diagnosis was 8 years 8 months. This paper also shows phenotypical parallels between GLUT1DS and paroxysmal exertion-induced dyskinesia.
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1086/302649
Publisher: Oxford University Press (OUP)
Date: 24-03-2015
DOI: 10.1093/HMG/DDV101
Publisher: Wiley
Date: 24-09-2010
DOI: 10.1111/J.1528-1167.2010.02712.X
Abstract: Early onset absence epilepsy (EOAE) starting before the age of 4 years constitutes a rare subgroup of the idiopathic generalized epilepsies (IGEs). A strong genetic component in IGE has been suggested by twin and family studies. We describe a boy with absence seizures starting at the age of 9 months whose parents both had childhood absence epilepsy. A 192-kb duplication in 1q21.3 was identified in the proband and his father, encompassing the gene CHRNB2 coding for the β-2 subunit of the nicotinic acetylcholine receptor and the gene ADAR coding for adenosine deaminase, an enzyme responsible for RNA editing. Both are candidate genes for seizure disorders. The duplication was not identified in 191 independent IGE patients (93 EOAE 98 classical IGE) or in 1,157 population controls.
Publisher: Wiley
Date: 25-02-2018
DOI: 10.1111/JSR.12669
Abstract: The aim of this study was to evaluate the efficacy and tolerability of open-label lacosamide in patients with refractory sleep-related hypermotor epilepsy. The study was a case review of eight patients with refractory sleep-related hypermotor epilepsy treated with lacosamide. Seizure diaries compared the mean baseline seizure frequency with the most recent 3 months of follow-up. Five (62.5%) patients were responders, defined as ≥50% reduction in seizure frequency, over a mean duration of exposure of 21.5 months. The mean maintenance dose of lacosamide was 400 mg/day. No-one reported worsening of seizures. Lacosamide was well tolerated with initial fatigue being the main side-effect. Lacosamide is a potentially efficacious adjunctive therapy in patients with refractory sleep-related hypermotor epilepsy. A double-blind placebo-controlled study would determine its efficacy.
Publisher: Veterinary World
Date: 2018
Publisher: Elsevier BV
Date: 07-2022
Publisher: Springer Science and Business Media LLC
Date: 21-04-2021
DOI: 10.1186/S13023-021-01813-5
Abstract: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. In iduals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria. Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available.
Publisher: Wiley
Date: 30-09-2019
DOI: 10.1002/AUR.2209
Abstract: Little is known about executive functions (EFs) associated with advanced theory of mind (ToM) abilities. We aimed to determine if advanced ToM abilities were reduced in in iduals with subclinical traits of autism spectrum disorder (ASD), known as the "Broader Autism Phenotype" (BAP), and identify the EFs that predicted unimpaired performance on an advanced ToM task, the faux pas test. We assessed 29 participants (13 males) with the BAP who were relatives of children with ASD. Thirteen participants showed reduced ability to understand a faux pas. A discriminant function analysis correctly classified 79% of cases as impaired or unimpaired, with high sensitivity (80%) and specificity (77%), which was best predicted by language-mediated EFs, including verbal generativity, working memory, cognitive inhibition, and flexibility. Autism Res 2020, 13: 921-934. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Little is known about the complex cognitive processes that enable accurate interpretation of another person's thoughts and emotions, known as "theory of mind." In relatives of in iduals with autism, who had mild traits of autism themselves, approximately half had difficulty interpreting situations involving a social faux pas. Cognitive inhibition and flexibility, working memory, and verbal generativity were related to, and appeared to be protective for, unimpaired understanding of a faux pas.
Publisher: Elsevier BV
Date: 02-2000
DOI: 10.1086/302768
Publisher: Elsevier BV
Date: 1998
DOI: 10.1016/S0092-8674(00)80899-5
Abstract: X-linked lissencephaly and "double cortex" are allelic human disorders mapping to Xq22.3-Xq23 associated with arrest of migrating cerebral cortical neurons. We identified a novel 10 kb brain-specific cDNA interrupted by a balanced translocation in an XLIS patient that encodes a novel 40 kDa predicted protein named Doublecortin. Four double cortex/X-linked lissencephaly families and three sporadic double cortex patients show independent doublecortin mutations, at least one of them a de novo mutation. Doublecortin contains a consensus Abl phosphorylation site and other sites of potential phosphorylation. Although Doublecortin does not contain a kinase domain, it is homologous to the amino terminus of a predicted kinase protein, indicating a likely role in signal transduction. Doublecortin, along with the newly characterized mDab1, may define an Abl-dependent pathway regulating neuronal migration.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2018
DOI: 10.1007/S10803-018-3641-7
Abstract: The present study examined whether the ability to recognize vocal emotional expressions is negatively related to features of the Broader Autism Phenotype (BAP) in the general population. We assessed 61 typically developing adults on a BAP self-report measure (Broader Autism Phenotype Questionnaire) and a purpose-developed online emotion recognition task for efficient delivery of non-linguistic vocal stimuli corresponding to the six basic emotions. Contrary to expectations, we found that higher self-ratings of rigid BAP traits correlated with better recognition accuracy and higher intensity ratings for angry voices. We interpret this anger-specific association as an advantage for enhanced threat detection in the BAP and discuss this finding in the broader context of personality research and interpersonal theory.
Publisher: Georg Thieme Verlag KG
Date: 04-2001
DOI: 10.1055/S-2001-13882
Abstract: We report five cases of near-total absence of the cerebellum with accompanying pontine hypoplasia. The cerebellar remnant in each case comprised only antero-superior masses, the posterior fossa being otherwise fluid filled. Three of these patients, two teenagers and an infant, presented a fairly consistent clinical and neuroradiological phenotype, and a few similar cases are recorded in the literature. The cerebellar remnant was irregular and asymmetrical, and no ventral pontine prominence was discernible. In at least the older two, cerebellar motor functions were not greatly compromised, and intellectual handicap was of a mild degree. We propose that these cases represent a distinct entity of "near-total absence of the cerebellum with flat ventral pons, and relatively mild clinical affection". All cases have been sporadic, implying that the risk of recurrence within a family may be low. Quite different clinical pictures, of considerably greater severity, are demonstrated in the remaining two cases. One had pontocerebellar hypoplasia type 2, while the other had a complex cerebellar and cerebral malformation.
Publisher: Wiley
Date: 12-03-2015
DOI: 10.1002/ACN3.191
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-08-2017
DOI: 10.1212/WNL.0000000000004331
Abstract: To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation. We identified 9 children 3 to 12 years of age 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9 for the remaining case, the mother was negative and the father was unavailable. Here, we present a phenotype-genotype correlation for SCN1A . We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2022
DOI: 10.1212/WNL.0000000000200028
Abstract: Pathogenic variants in the neuronal sodium channel α1 subunit gene ( SCN1A ) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum, including severe childhood epilepsy Dravet syndrome, characterized by drug-resistant seizures, intellectual disability, and high mortality and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome vs GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of SCN1A -related epilepsies. We performed a retrospective multicenter cohort study comprising data from patients with SCN1A -positive Dravet syndrome and patients with GEFS+ consecutively referred for genetic testing (March 2001–June 2020) including age at seizure onset and a newly developed SCN1A genetic score. A training cohort was used to develop multiple prediction models that were validated using 2 independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome vs other GEFS+ phenotypes. A total of 1,018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1, and 60/72 (83%) in validation cohort 2. A high SCN1A genetic score (133.4 [SD 78.5] vs 52.0 [SD 57.5] p 0.001) and young age at onset (6.0 [SD 3.0] vs 14.8 [SD 11.8] months p 0.001) were each associated with Dravet syndrome vs GEFS+. A combined SCN1A genetic score and seizure onset model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC] 0.89 [95% CI 0.86–0.92]) and outperformed all other models (AUC 0.79–0.85 p 0.001). Model performance was replicated in both validation cohorts 1 (AUC 0.94 [95% CI 0.91–0.97]) and 2 (AUC 0.92 [95% CI 0.82–1.00]). The prediction model allows objective estimation at disease onset whether a child will develop Dravet syndrome vs GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (scn1a-prediction-model.broadinstitute.org/). This study provides Class II evidence that a combined SCN1A genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-07-2015
Publisher: Wiley
Date: 09-06-2021
DOI: 10.1111/DMCN.14955
Abstract: To delineate the speech and language phenotype of a cohort of in iduals with FOXP1 ‐related disorder. We administered a standardized test battery to examine speech and oral motor function, receptive and expressive language, non‐verbal cognition, and adaptive behaviour. Clinical history and cognitive assessments were analysed together with speech and language findings. Twenty‐nine patients (17 females, 12 males mean age 9y 6mo median age 8y [range 2y 7mo–33y] SD 6y 5mo) with pathogenic FOXP1 variants (14 truncating, three missense, three splice site, one in‐frame deletion, eight cytogenic deletions 28 out of 29 were de novo variants) were studied. All had atypical speech, with 21 being verbal and eight minimally verbal. All verbal patients had dysarthric and apraxic features, with phonological deficits in most (14 out of 16). Language scores were low overall. In the 21 in iduals who carried truncating or splice site variants and small deletions, expressive abilities were relatively preserved compared with comprehension. FOXP1 ‐related disorder is characterized by a complex speech and language phenotype with prominent dysarthria, broader motor planning and programming deficits, and linguistic‐based phonological errors. Diagnosis of the speech phenotype associated with FOXP1 ‐related dysfunction will inform early targeted therapy. In iduals with FOXP1 ‐related disorder have a complex speech and language phenotype. Dysarthria, which impairs intelligibility, is the dominant feature of the speech profile. No participants were receiving speech therapy for dysarthria, but were good candidates for therapy Features of speech apraxia occur alongside persistent phonological errors. Language abilities are low overall however, expressive language is a relative strength.
Publisher: Elsevier BV
Date: 08-2004
Publisher: BMJ
Date: 2003
DOI: 10.1136/JNNP.74.1.51
Abstract: Gamma oscillations (30-100 Hz gamma electroencephalographic (EEG) activity) correlate with high frequency synchronous rhythmic bursting in assemblies of cerebral neurons participating in aspects of consciousness. Previous studies in a kainic acid animal model of epilepsy revealed increased intensity of gamma rhythms in background EEG preceding epileptiform discharges, leading the authors to test for intensified gamma EEG in humans with epilepsy. 64 channel cortical EEG were recorded from 10 people with primary generalised epilepsy, 11 with partial epilepsy, and 20 controls during a quiescent mental state. Using standard methods of EEG analysis the strength of EEG rhythms (fast Fourier transformation) was quantified and the strengths of rhythms in the patient groups compared with with controls by unpaired t test at 1 Hz intervals from 1 Hz to 100 Hz. In patients with generalised epilepsy, there was a threefold to sevenfold increase in power of gamma EEG between 30 Hz and 100 Hz (p<0.01). Analysis of three unmedicated patients with primary generalised epilepsies revealed an additional 10-fold narrow band increase of power around 35 Hz-40 Hz (p<0.0001). There were no corresponding changes in patients with partial epilepsy. Increased gamma EEG is probably a marker of the underlying ion channel or neurotransmitter receptor dysfunction in primary generalised epilepsies and may also be a pathophysiological prerequisite for the development of seizures. The finding provides a new diagnostic approach and also links the pathophysiology of generalised epilepsies to emerging concepts of neuronal correlates of consciousness.
Publisher: AMPCo
Date: 24-05-2021
DOI: 10.5694/MJA2.51089
Publisher: Elsevier BV
Date: 04-2002
Publisher: Wiley
Date: 21-09-2020
DOI: 10.1111/EPI.16679
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.EPLEPSYRES.2015.02.011
Abstract: Recognition of the role of genetics in the epilepsies has increased dramatically, impacting on clinical practice across many epilepsy syndromes. There is limited research investigating the impact of gene identification on in iduals and families with epilepsy. While research has focused on the impact of delivering genetic information to families at the time of diagnosis in genetic diseases more broadly, little is known about how genetic results in epileptic diseases influences people's lives many years after it has been conveyed. This study used qualitative methods to explore the experience of receiving a genetic result in people with familial epilepsy. Interviews were conducted with in iduals with familial epilepsies in whom the underlying genetic mutation had been identified. Recorded interviews underwent thematic analysis. 20 in iduals from three families with different epilepsy syndromes and causative genes were interviewed. Multiple generations within families were studied. The mean time from receiving the genetic result prior to interview was 10.9 years (range 5-14 years). Three major themes were identified: 1) living with epilepsy: an in idual's experience of the severity of epilepsy in their family influenced their view. 2) Clinical utility of the test: participants expressed varying reactions to receiving a genetic result. While for some it provided helpful information and relief, others were not surprised by the finding given the familial context. Some valued the use of genetic information for reproductive decision-making, particularly in the setting of severely affected family members. While altruistic reasons for participating in genetic research were discussed, participants emphasised the benefit of participation to them and their families. 3) 'Talking about the family genes': in iduals reported poor communication between family members about their epilepsy and its genetic implications. The results provide important insights into the family experience of genetic epilepsies and communication within families. This information can be used to inform the development of guidelines for genetic result disclosure and genetic counselling for in iduals and families with epilepsies.
Publisher: Elsevier BV
Date: 05-2022
Publisher: Springer Science and Business Media LLC
Date: 22-02-2012
DOI: 10.1038/EJHG.2012.9
Publisher: Wiley
Date: 16-02-2005
DOI: 10.1002/AJMG.B.30156
Abstract: We report the case of a 10-year-old girl with the karyotype 46,XX,del(17)(p12p13.1) who presented a remarkable incongruence in higher cerebral functioning. Certain language skills were very superior, with reading and spelling at a 17-19 year-old level of proficiency. Nonverbal skills, however, were mostly below average, executive functioning and socialization were impaired, and a diagnosis of "nonverbal learning disability" is applied. We speculate that the genes deleted include one or some which code for certain specific categories of neural substrate that subserve aspects of visual processing and higher functioning, but that no "language loci" have been deleted. The particular neuropsychological profile that we describe may assist diagnosis of this chromosomal deletion.
Publisher: Wiley
Date: 03-2014
DOI: 10.1002/ANA.24080
Abstract: Mutations in KCNQ2 and KCNQ3, encoding the voltage-gated potassium channels KV 7.2 and KV 7.3, are known to cause benign familial neonatal seizures mainly by haploinsufficiency. Here, we set out to determine the disease mechanism of 7 de novo missense KCNQ2 mutations that were recently described in patients with a severe epileptic encephalopathy including pharmacoresistant seizures and pronounced intellectual disability. Mutations were inserted into the KCNQ2 cDNA. Potassium currents were recorded using 2-microelectrode voltage cl ing, and surface expression was analyzed by a biotinylation assay in cRNA-injected Xenopus laevis oocytes. We observed a clear loss of function for all mutations. Strikingly, 5 of 7 mutations exhibited a drastic dominant-negative effect on wild-type KV 7.2 or KV 7.3 subunits, either by globally reducing current litudes (3 pore mutations) or by a depolarizing shift of the activation curve (2 voltage sensor mutations) decreasing potassium currents at the subthreshold level at which these channels are known to critically influence neuronal firing. One mutation significantly reduced surface expression. Application of retigabine, a recently marketed KV 7 channel opener, partially reversed these effects for the majority of analyzed mutations. The development of severe epilepsy and cognitive decline in children carrying 5 of the 7 studied KCNQ2 mutations can be related to a dominant-negative reduction of the resulting potassium current at subthreshold membrane potentials. Other factors such as genetic modifiers have to be postulated for the remaining 2 mutations. Retigabine or similar drugs may be used as a personalized therapy for this severe disease.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2018
Publisher: American Chemical Society (ACS)
Date: 03-01-2019
DOI: 10.1021/JACS.8B12415
Publisher: Elsevier BV
Date: 05-2013
Publisher: Elsevier BV
Date: 03-2008
Publisher: Wiley
Date: 04-10-2022
DOI: 10.1111/EPI.17542
Abstract: WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy ( WWOX ‐DEE), also known as WOREE ( WWOX ‐related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX ‐DEE, and investigated genotype–phenotype correlations, particularly with regard to survival. We studied 13 patients from 12 families with WWOX ‐DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing in iduals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan–Meier method. All patients experienced multiple seizure types (median onset = 5 weeks, range = 1 day–10 months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic ( n = 5), myoclonic ( n = 2), epileptic spasms ( n = 2), focal ( n = 1), and migrating focal ( n = 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo‐occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippoc al, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk ( p ‐value = .0085, log‐rank test). Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.
Publisher: Elsevier BV
Date: 10-2004
Publisher: Elsevier BV
Date: 05-2015
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.ECL.2019.08.010
Abstract: Resistant hypertension is a common clinical entity, defined as suboptimal blood pressure response to multiple therapies after excluding medication nonadherence and secondary forms of hypertension. Patients with resistant hypertension generally share several comorbidities. Resistant hypertension is more common in in iduals of African descent. Blood pressure should be optimized using multiple strategies, including lifestyle changes and single-pill combination therapies, with the aim of reducing cardiovascular events while reducing side effects from using antihypertensive therapy. A renin/aldosterone-based diagnostic and treatment approach will help tailor therapy. The use of mineralocorticoid receptor antagonists or amiloride as appropriate is favored.
Publisher: Oxford University Press (OUP)
Date: 25-01-2014
DOI: 10.1093/HMG/DDU030
Publisher: Oxford University Press (OUP)
Date: 02-1995
Abstract: The disorder of autosomal dominant nocturnal frontal lobe epilepsy has recently been identified, and is now delineated in detail. A phenotypically homogeneous group of five families from Australia, Britain and Canada, containing 47 affected in iduals, was studied. The largest family contained 25 affected in iduals spanning six generations. This disorder is characterized by clusters of brief nocturnal motor seizures, with hyperkinetic or tonic manifestations. Subjects often experienced an aura, and remained aware throughout the attacks. Seizures occurred in clusters (mean eight attacks/night) typically as the in idual dozed, or shortly before awakening. The epilepsy usually began in childhood, and persisted through adult life, with considerable intra-family variation in severity. Seizures were often misdiagnosed as benign nocturnal parasomnias, psychiatric and medical disorders. Interictal EEG studies were unhelpful. Ictal video-EEG studies showed that the attacks were partial seizures with frontal lobe seizure semiology. Neuro-imaging was normal. Carbamazepine monotherapy was frequently effective. This disorder showed autosomal dominant inheritance. Recognition of this entity is clinically important for diagnosis, appropriate therapy and genetic counselling. Moreover, this disorder now offers an opportunity to identify a gene for partial epilepsy.
Publisher: Springer Science and Business Media LLC
Date: 04-01-2022
DOI: 10.1186/S13058-021-01484-X
Abstract: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-08-2010
Publisher: Elsevier BV
Date: 09-2007
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.EPLEPSYRES.2016.10.006
Abstract: We measured the mortality rate and the rate of Sudden Unexpected Death in Epilepsy (SUDEP) in Dravet Syndrome (DS). We studied a cohort of 100 consecutively recruited, unrelated patients with DS 87 had SCN1A mutations. Living cases had a median follow-up of 17 years. Seventeen patients died, at a median age of seven years (inter-quartile range 3-11 years) with causes of death: 10 SUDEP, four status epilepticus, two drowning and one asphyxia. The SUDEP classification included three Definite, one Definite Plus and six Probable. The Dravet-specific mortality rate/1000-person-years was 15.84 (98% CI 9.01-27.85). The Dravet-specific SUDEP rate was 9.32/1000-person-years (98% CI 4.46-19.45). The Dravet-specific SUDEP rate is the only documented syndrome-specific SUDEP rate. SUDEP in DS occurs mainly in childhood. It is also the highest SUDEP rate, considerably higher than the recent 5.1 SUDEP rate/1000-person-years for adults with refractory epilepsy.
Publisher: Oxford University Press (OUP)
Date: 29-06-2015
DOI: 10.1093/HMG/DDV245
Abstract: Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE also known as epilepsy and mental retardation limited to females, EFMR MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. We investigated transcriptomes of PCDH19-FE female and control primary skin fibroblasts, which are endowed to metabolize neurosteroid hormones. We identified a set of 94 significantly dysregulated genes in PCDH19-FE females. Intriguingly, 43 of the 94 genes (45.7%) showed gender-biased expression enrichment of such genes was highly significant (P = 2.51E-47, two-tailed Fisher exact test). We further investigated the AKR1C1-3 genes, which encode crucial steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Both mRNA and protein levels of AKR1C3 were significantly decreased in PCDH19-FE patients. In agreement with this, the blood levels of allopregnanolone were also (P < 0.01) reduced. In conclusion, we show that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE. Overall our findings provide evidence for a role of neurosteroids in epilepsy, ID and autism and create realistic opportunities for targeted therapeutic interventions.
Publisher: Elsevier BV
Date: 09-1994
Publisher: Elsevier BV
Date: 11-2022
Publisher: Wiley
Date: 21-02-2023
DOI: 10.1111/EPI.17536
Abstract: Familial adult myoclonic epilepsy (FAME) is an under‐recognized disorder characterized by cortical myoclonus, generalized tonic–clonic seizures, and additional clinical symptoms, which vary depending on the FAME subtype. FAME is caused by pentanucleotide repeat expansions of intronic TTTCA/TTTTA in different genes. FAME should be distinguished from a range of differential diagnoses. The differential diagnoses and frequent presentations leading to misdiagnosis of FAME were investigated from the available literature and reported based on an expert opinion survey. The phenotypic features of FAME, including generalized tonic–clonic and myoclonic seizures, are also seen in other epilepsy syndromes, such as juvenile myoclonic epilepsy, with a resultant risk of misdiagnosis and lack of identification of the underlying cause. Cortical myoclonus may mimic essential tremor or drug‐induced tremor. In younger in iduals, the differential diagnosis includes progressive myoclonus epilepsies (PMEs), such as Unverricht‐Lundborg disease, whereas, in adulthood, late‐onset variants of PMEs, such as sialidoses, myoclonus epilepsy, and ataxia due to potassium channel pathogenic variants should be considered. PMEs may also be suggested by cognitive impairment, cerebellar signs, or psychiatric disorders. Electroencephalography (EEG) may show similarities to other idiopathic generalized epilepsies or PMEs, with generalized spike–wave activity. Signs of cortical hyperexcitability may be seen, such as an increased litude of somatosensory evoked potentials or enhanced cortical reflex to sensory stimuli, together with the neurophysiological pattern of the movement disorder. Recognition of FAME will inform prognostic and genetic counseling and diagnosis of the insidious progression, which may occur in older in iduals who show mild cognitive deterioration. Distinguishing FAME from other disorders in in iduals or families with this constellation of symptoms is essential to allow the identification of underlying etiology.
Publisher: Wiley
Date: 05-01-2012
DOI: 10.1111/J.1528-1167.2011.03368.X
Abstract: To accurately determine the frequency and nature of the family history of seizures in patients with benign childhood epilepsy with centrotemporal spikes (BECTS). Participants with BECTS were recruited from the electroencephalography (EEG) laboratories of three pediatric centers and by referral. Pedigrees were constructed for up to three degrees of relatedness for each proband. All available affected and unaffected in iduals underwent phenotyping using a validated seizure questionnaire. The proportion of affected relatives according to degree of relatedness was calculated and phenotypic patterns were analyzed. Fifty-three probands with BECTS had a mean age of seizure onset at 7.8 years (range 2-12 years). Thirty-four (64%) of 53 patients were male. For 51 participants, pedigrees were available for three degrees of relatedness. Fifty-seven (2.7%) of 2,085 relatives had a history of seizures: Twenty-one (9.8%) of 214 first-degree, 15 (3%) of 494 second-degree, and 21 (1.5%) of 1,377 third-degree relatives. Febrile seizures were the most frequent phenotype, occurring in 26 of 57 affected relatives. There were 34 relatives with epilepsy: 6.5% (14 of 214) first-degree, 1.8% (9 of 494) second-degree, and 0.8% (11 of 1,377) third-degree relatives. Of 21 affected first-degree relatives: 8 of 21 had febrile seizures (FS), 4 had BECTS, 2 had epilepsy-aphasia spectrum disorder, one had temporal lobe epilepsy with hippoc al sclerosis, 2 had focal epilepsy of unknown cause, 2 had genetic generalized epilepsies, and 3 had miscellaneous. The frequency of epilepsies in relatives and the heterogeneous syndromes observed suggest that BECTS has a genetic component consistent with complex inheritance. Focal epilepsies are the most common seizure disorder observed in relatives, especially BECTS and epilepsy-aphasia spectrum disorder. Additional acquired or environmental factors are likely to be necessary for expression of the seizure disorder.
Publisher: Elsevier BV
Date: 05-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-01-2011
Publisher: Oxford University Press (OUP)
Date: 17-04-2014
DOI: 10.1093/BRAIN/AWU077
Abstract: Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1b) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-cl analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast with Scn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K+ channel opener that reduces input resistance, d ened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.
Publisher: Wiley
Date: 06-2009
DOI: 10.1111/J.1528-1167.2008.02001.X
Abstract: Factors influencing the electroencephalography (EEG) features of absence seizures in newly presenting children with idiopathic generalized epilepsy (IGE) have not been rigorously studied. We examined how specific factors such as state, provocation, age, and epilepsy syndrome affect the EEG features of absence seizures. Children with untreated absence seizures were studied using video-EEG recording. The influence of state of arousal, provocation (hyperventilation, photic stimulation), age, and epilepsy syndrome on specific EEG features was analyzed. Five hundred nine seizures were evaluated in 70 children with the following syndromes: childhood absence epilepsy (CAE) 37, CAE+ photoparoxysmal response (PPR) 10, juvenile absence epilepsy (JAE) 8, juvenile myoclonic epilepsy (JME) 6, and unclassified 9. Polyspikes occurred in all syndromes but were more common in JME. They were brought out by drowsiness and sleep in fragments of generalized spike and wave (GSW). Polyspikes were more likely to occur during photic stimulation, but were not influenced by age independently. GSW was more likely to be disorganized in JME than JAE, and in JAE than CAE. Increasing age and levels of arousal were more likely to result in organized GSW. Factors specific to each child independently influenced EEG features the nature of these factors has not been identified. The EEG features of absence seizures are influenced by a complex interaction of age, epilepsy syndrome, level of arousal, provoking factors, and other intrinsic factors. Epilepsy syndrome alone cannot predict specific features of GSW however, JME is more frequently associated with polyspikes and disorganization of the paroxysm.
Publisher: Georg Thieme Verlag KG
Date: 04-2010
Publisher: Wiley
Date: 10-2006
DOI: 10.1111/J.1528-1167.2006.00677.X
Abstract: Idiopathic generalized epilepsy (IGE) accounts for approximately 20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures. Genome-wide linkage scans were performed in 126 IGE-multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type-related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening. Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families. Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22-q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic-clonic seizures on awakening.
Publisher: Oxford University Press (OUP)
Date: 2003
DOI: 10.1093/BRAIN/AWG018
Abstract: Although several genes for idiopathic epilepsies from families with simple Mendelian inheritance have been found, genes for the common idiopathic generalized epilepsies, where inheritance is complex, presently are elusive. We studied a large family with epilepsy where the two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS), which offered a special opportunity to identify epilepsy genes. A total of 35 family members had seizures over four generations. The phenotypes comprised typical CAE (eight in iduals) FS alone (15), febrile seizures plus (FS(+)) (three) myoclonic astatic epilepsy (two) generalized epilepsy with tonic-clonic seizures alone (one) partial epilepsy (one) and unclassified epilepsy despite evaluation (two). In three remaining in iduals, no information was available. FS were inherited in an autosomal dominant fashion with 75% penetrance. The inheritance of CAE in this family was not simple Mendelian, but suggestive of complex inheritance with the involvement of at least two genes. A GABA(A) receptor gamma2 subunit gene mutation on chromosome 5 segregated with FS, FS(+) and CAE, and also occurred in in iduals with the other phenotypes. The clinical and molecular data suggest that the GABA(A) receptor subunit mutation alone can account for the FS phenotype. An interaction of this gene with another gene or genes is required for the CAE phenotype in this family. Linkage analysis for a putative second gene contributing to the CAE phenotype suggested possible loci on chromosomes 10, 13, 14 and 15. Examination of these loci in other absence pedigrees is warranted.
Publisher: Wiley
Date: 06-12-2021
DOI: 10.1111/EPI.16784
Abstract: Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.
Publisher: Wiley
Date: 07-01-2013
DOI: 10.1111/EPI.12065
Abstract: To characterize the frequency and nature of the family history of seizures in probands with epilepsy falling within the epilepsy-aphasia spectrum (EAS) in order to understand the genetic architecture of this group of disorders. Patients with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), Landau-Kleffner syndrome (LKS), atypical benign partial epilepsy (ABPE), and intermediate epilepsy-aphasia disorders (IEAD) were recruited. All affected and available unaffected relatives up to three degrees of relatedness underwent phenotyping using a validated seizure questionnaire. Pedigrees were constructed for all families. The proportion of affected relatives according to each degree of relatedness was calculated. The epilepsy phenotypes in close relatives were analyzed. The data were compared to the families of probands with benign childhood epilepsy with centrotemporal spikes (BECTS) using the same methodology. Thirty-one probands, including five ECSWS, three LKS, one ABPE, and 22 IEAD were recruited. The mean age of seizure onset was 3.9 (range 0.5-7) years. A male predominance was seen (68%, 21/31) . Sixteen (51.6%) of 31 had a positive family history of seizures. Among 1,254 relatives, 30 (2.4%) had a history of seizures: 13 (10.2%) of 128 first-degree relatives, 5 (1.7%) of 291 second-degree relatives, and 12 (1.4%) of 835 third-degree relatives. Thirteen had febrile seizures, including two who had both febrile seizures and epilepsy. Of the 19 relatives with epilepsy, 4 had BECTS, 4 epilepsies with focal seizures of unknown cause, 3 IEAD, and 7 unclassified. One had genetic generalized epilepsy. In the families of the BECTS probands, 9.8% of first-degree, 3% of second-degree, and 1.5% of third-degree relatives had seizures, which was not significantly different from the EAS cohort families. The frequencies of seizures in relatives of probands with EAS suggest that the underlying genetic influence of EAS is consistent with complex inheritance and similar to BECTS. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures. These findings suggest that a shared genetic predisposition to focal epilepsies underpins the epilepsy-aphasia spectrum.
Publisher: Wiley
Date: 05-08-2013
DOI: 10.1002/AJMG.A.36055
Abstract: Relatively little is known about the neurobiological basis of speech disorders although genetic determinants are increasingly recognized. The first gene for primary speech disorder was FOXP2, identified in a large, informative family with verbal and oral dyspraxia. Subsequently, many de novo and familial cases with a severe speech disorder associated with FOXP2 mutations have been reported. These mutations include sequencing alterations, translocations, uniparental disomy, and genomic copy number variants. We studied eight probands with speech disorder and their families. Family members were phenotyped using a comprehensive assessment of speech, oral motor function, language, literacy skills, and cognition. Coding regions of FOXP2 were screened to identify novel variants. Segregation of the variant was determined in the probands' families. Variants were identified in two probands. One child with severe motor speech disorder had a small de novo intragenic FOXP2 deletion. His phenotype included features of childhood apraxia of speech and dysarthria, oral motor dyspraxia, receptive and expressive language disorder, and literacy difficulties. The other variant was found in a family in two of three family members with stuttering, and also in the mother with oral motor impairment. This variant was considered a benign polymorphism as it was predicted to be non-pathogenic with in silico tools and found in database controls. This is the first report of a small intragenic deletion of FOXP2 that is likely to be the cause of severe motor speech disorder associated with language and literacy problems.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-04-2011
Publisher: MDPI AG
Date: 31-07-2023
Abstract: Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.
Publisher: BMJ
Date: 04-04-2017
Publisher: Wiley
Date: 07-11-2017
DOI: 10.1111/DMCN.13601
Abstract: Many children with severe developmental and epileptic encephalopathies experience significant sleep disturbance, causing major disruption to the family's quality of life. We aimed to determine the frequency and nature of sleep problems in in iduals with Dravet syndrome. The Sleep Disturbance Scale for Children and a seizure questionnaire were distributed to the parents/guardians of 96 patients with Dravet syndrome. Sixteen patients had two nights of home oximetry. Fifty-seven out of 96 questionnaires were completed. Forty-three out of 57 (75%) in iduals had sleep problems. Twenty-five out of 57 (44%) in iduals had an abnormal total sleep score, with difficulty initiating and maintaining sleep (22 out of 57, 39%), sleep-wake transition disorders (20 out of 57, 35%), and sleep breathing disorders (19 out of 57, 33%). Twenty-two out of 57 (39%) in iduals took medication to assist sleep, predominantly melatonin (n=14). Thirty out of 57 (53%) recently had nocturnal seizures. Overnight oximetry showed 14 out of 16 (88%) had a higher oxygen desaturation index (>3%), and six out of 16 (38%) had higher mean pulse rates than normative values. Home oximetry was normal or inconclusive in all patients. Seventy-five per cent of in iduals with Dravet syndrome had sleep problems, highlighting the importance of routinely assessing sleep and initiating appropriate behavioural and pharmacological interventions to improve the patient and family's quality of life. A high oxygen desaturation index and mean pulse rates on pulse oximetry may reflect unrecognized nocturnal seizures. More than 70% of patients with Dravet syndrome have sleep problems. Difficulty initiating and maintaining sleep was most common, particularly in those older than 20 years. Second most common were sleep-wake transition disorders, affecting more than 50% of those younger than 5 years. Sleep breathing disorders were a frequent problem across all age groups. Oximetry was not diagnostic of sleep-disordered breathing or obvious seizures.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1997
DOI: 10.1097/00019052-199704000-00007
Abstract: A minor genetic predisposition to partial epilepsy has been long recognized. Recently, a group of idiopathic partial epilepsies with autosomal dominant inheritance has been identified. The clinical features and molecular genetic findings in these epilepsies are outlined in the present review. The first genetic defect in an idiopathic epilepsy has been found in autosomal dominant nocturnal frontal lobe epilepsy, the archetype of this newly recognized group of inherited partial epilepsies.
Publisher: Lippincott Williams & Wilkins
Date: 25-04-2023
Publisher: Oxford University Press (OUP)
Date: 03-04-2023
Abstract: Dravet syndrome is an archetypal rare severe epilepsy, considered ‘monogenic’, typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its ersity, with an excess of rare variants in epilepsy-related genes as a set and ex les of blended phenotypes, including one in idual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. The polygenic risk score for intelligence was lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors.
Publisher: BMJ
Date: 15-11-2017
Abstract: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.
Publisher: Wiley
Date: 10-07-2012
DOI: 10.1111/J.1528-1167.2012.03585.X
Abstract: We aimed to refine the phenotypic spectrum and map the causative gene in two families with familial focal epilepsy with variable foci (FFEVF). A new five-generation Australian FFEVF family (A) underwent electroclinical phenotyping, and the original four-generation Australian FFEVF family (B) (Ann Neurol, 44, 1998, 890) was re-analyzed, including new affected in iduals. Mapping studies examined segregation at the chromosome 22q12 FFEVF region. In family B, the original whole genome microsatellite data was reviewed. Five subjects in family A and 10 in family B had FFEVF with predominantly awake attacks and active EEG studies with a different phenotypic picture from other families. In family B, reanalysis excluded the tentative 2q locus reported. Both families mapped to chromosome 22q12. Our results confirm chromosome 22q12 as the solitary locus for FFEVF. Both families show a subtly different phenotype to other published families extending the clinical spectrum of FFEVF.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2018
DOI: 10.1038/NRDP.2018.24
Abstract: Epilepsy affects all age groups and is one of the most common and most disabling neurological disorders. The accurate diagnosis of seizures is essential as some patients will be misdiagnosed with epilepsy, whereas others will receive an incorrect diagnosis. Indeed, errors in diagnosis are common, and many patients fail to receive the correct treatment, which often has severe consequences. Although many patients have seizure control using a single medication, others require multiple medications, resective surgery, neuromodulation devices or dietary therapies. In addition, one-third of patients will continue to have uncontrolled seizures. Epilepsy can substantially impair quality of life owing to seizures, comorbid mood and psychiatric disorders, cognitive deficits and adverse effects of medications. In addition, seizures can be fatal owing to direct effects on autonomic and arousal functions or owing to indirect effects such as drowning and other accidents. Deciphering the pathophysiology of epilepsy has advanced the understanding of the cellular and molecular events initiated by pathogenetic insults that transform normal circuits into epileptic circuits (epileptogenesis) and the mechanisms that generate seizures (ictogenesis). The discovery of >500 genes associated with epilepsy has led to new animal models, more precise diagnoses and, in some cases, targeted therapies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-05-2021
DOI: 10.1212/WNL.0000000000011855
Abstract: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients. We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing. Eight previously unreported missense variants were identified in SLC32A1 , coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected in iduals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype–phenotype spectrum associated with SLC32A1 variants.
Publisher: Oxford University Press (OUP)
Date: 05-2021
Abstract: Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single in iduals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations’ effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic in idual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, ‘profound’ phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two in iduals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, ‘profound’ and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-09-2023
Publisher: Society for Neuroscience
Date: 09-2000
Publisher: SAGE Publications
Date: 23-03-2012
Abstract: Benign neonatal sleep myoclonus is an uncommon, nonepileptic disorder characterized by myoclonic jerks appearing in the neonatal period that occur predominantly during sleep. Although self-limiting, the disorder is frequently confused with epileptic neonatal seizures. A few familial cases have been reported however the genetics has not been studied. We ascertained 3 families with 2 or more affected in iduals and analyzed the pedigrees. We used microsatellite markers to determine if the disorder was possibly linked to KCNQ2 or KCNQ3, the 2 genes that cause most cases of benign familial neonatal seizures, a disorder that it could be easily confused with. The 3 pedigrees, including one with 4 affected in iduals, were suggestive of autosomal dominant inheritance. The loci for KCNQ2 and KCNQ3 were excluded in the 2 larger families. We conclude that benign neonatal sleep myoclonus can show autosomal dominant inheritance and is not allelic with benign familial neonatal seizures.
Publisher: Wiley
Date: 07-07-2001
DOI: 10.1046/J.1528-1157.2001.042007837.X
Abstract: Severe myoclonic epilepsy of infancy (SMEI) is an intractable epilepsy of early childhood of unknown etiology. It is often associated with a family history of seizure disorders, but epilepsy phenotypes have not been well described. We sought to characterize the seizure phenotypes of relatives to better understand to the genetic basis of SMEI. Probands with SMEI were identified, and systematic family studies were performed. Epilepsy syndromes were characterized in affected family members. Twelve probands with SMEI were identified. Eleven of the 12 probands with SMEI had a family history of seizures, and the twelfth was the result of a consanguineous marriage. We found that 16.7% of full siblings and 8.3% of parents had definite seizures. A total of 39 affected family members was identified. The most common phenotype was febrile seizures in 14, febrile seizures plus in seven, partial epilepsy in two, and there were single in iduals with SMEI, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome, and 13 cases with unclassified or unconfirmed seizures. The family history of seizures in SMEI is in keeping with the spectrum of seizure phenotypes seen in generalized epilepsy with febrile seizures plus (GEFS+). Our findings suggest that SMEI is the most severe phenotype in the GEFS+ spectrum.
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.NEUROSCIENCE.2007.05.038
Abstract: Two novel mutations (R85C and R85H) on the extracellular immunoglobulin-like domain of the sodium channel beta1 subunit have been identified in in iduals from two families with generalized epilepsy with febrile seizures plus (GEFS+). The functional consequences of these two mutations were determined by co-expression of the human brain NaV1.2 alpha subunit with wild type or mutant beta1 subunits in human embryonic kidney (HEK)-293T cells. Patch cl studies confirmed the regulatory role of beta1 in that relative to NaV1.2 alone the NaV1.2+beta1 currents had right-shifted voltage dependence of activation, fast and slow inactivation and reduced use dependence. In addition, the NaV1.2+beta1 current entered fast inactivation slightly faster than NaV1.2 channels alone. The beta1(R85C) subunit appears to be a complete loss of function in that none of the modulating effects of the wild type beta1 were observed when it was co-expressed with NaV1.2. Interestingly, the beta1(R85H) subunit also failed to modulate fast kinetics, however, it shifted the voltage dependence of steady state slow inactivation in the same way as the wild type beta1 subunit. Immunohistochemical studies revealed cell surface expression of the wild type beta1 subunit and undetectable levels of cell surface expression for both mutants. The functional studies suggest association of the beta1(R85H) subunit with the alpha subunit where its influence is limited to modulating steady state slow inactivation. In summary, the mutant beta1 subunits essentially fail to modulate alpha subunits which could increase neuronal excitability and underlie GEFS+ pathogenesis.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1038/GIM.2017.100
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.EPLEPSYRES.2012.01.015
Abstract: Is the ketogenic diet (KD) more effective in certain epilepsy syndromes? The KD has been shown to be effective in treating multiple seizure types and epilepsy syndromes. We review the effectiveness of the KD in Dravet syndrome, epilepsy with myoclonic-atonic seizures, mitochondrial disease, tuberous sclerosis, late infantile and juvenile neuronal ceroid lipofuscinosis, and febrile infection-related epilepsy syndrome. In certain epilepsy syndromes, like epilepsy with myoclonic-atonic seizures, the diet should be considered early in the course of treatment.
Publisher: Wiley
Date: 02-2006
DOI: 10.1111/J.1528-1167.2006.00435.X
Abstract: Patients with childhood absence epilepsy (CAE) have normal clinical magnetic resonance imaging (MRI) studies. The presence of abnormalities in corticothalamic networks has been suggested to be the functional basis of absence seizure generation. We assessed whether structural grey and white matter volume changes of these areas occurred in patients with absence seizures by using optimized voxel-based morphometry (VBM). We recruited 13 patients with a clinical and EEG diagnosis of CAE (mean age at examination, 17 +/- 8 years) and compared them with a consecutive series of 109 controls (mean age, 29 +/- 9 years). The 3 tesla MRI examination included a 3D T(1)-weighted sequence, which was analyzed with an optimized VBM protocol using the SPM2 package. The threshold was set at p < 0.05, corrected for multiple comparisons. Compared with controls, CAE patients showed areas of grey matter decrease in both thalami and in the subcallosal gyrus. White matter decrease was found in the extranuclear subcortical area and in the white matter of the basal forebrain. Grey and white matter increase was restricted to small clusters of cortical and subcortical areas. Evidence exists of subcortical grey and white matter volume reduction in CAE patients. Bilateral thalamic atrophy may be either a result of damage from seizures (as in hippoc al sclerosis) or a reflection of a primary underlying pathology as the cause of absence seizures.
Publisher: Informa UK Limited
Date: 13-04-2017
DOI: 10.1080/14728222.2017.1316715
Abstract: Dishevelled, Egl-10 and Pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a protein subunit of the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 is a recently identified modulator of mechanistic target of rapamycin (mTOR) activity. mTOR is a key regulator of cell proliferation and metabolism disruption of the mTOR pathway is implicated in focal epilepsy, both acquired and genetic. Tuberous sclerosis is the prototypic mTOR genetic syndrome with epilepsy, however GATOR1 gene mutations have recently been shown to cause lesional and non-lesional focal epilepsy. Areas covered: This review summarizes the mTOR pathway, including regulators and downstream effectors, emphasizing recent developments in the understanding of the complex role of the GATOR1 complex. We review the epilepsy types associated with mTOR overactivity, including tuberous sclerosis, polyhydramnios megalencephaly symptomatic epilepsy, cortical dysplasia, non-lesional focal epilepsy and post-traumatic epilepsy. Currently available mTOR inhibitors are discussed, primarily rapamycin analogs and ATP competitive mTOR inhibitors. Expert opinion: DEPDC5 is an attractive therapeutic target in focal epilepsy, as effects of DEPDC5 agonists would likely be anti-epileptogenic and more selective than currently available mTOR inhibitors. Therapeutic effects might be synergistic with certain existing dietary therapies, including the ketogenic diet.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-05-2015
Publisher: Cold Spring Harbor Laboratory
Date: 19-03-2021
DOI: 10.1101/2021.03.19.436102
Abstract: To compare the frequency and impact on channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss-of-function KCNH2 variants as predictive biomarkers of SUDEP risk. We searched for KCNH2 variants with a minor allele frequency of 5%. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified. KCNH2 variants were found in 11.1% (10/90) of SUDEP in iduals compared to 6.0% (20/332) of epilepsy controls ( p = 0.11). Loss-of-function KCNH2 variants, defined as causing 20% reduction in maximal litude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about three-fold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2% 2/90) and epilepsy control (2.7% 9/332) cohorts ( p 0.99). Rare KCNH2 variants ( 1% allele frequency) associated with greater loss of function and an ∼11-fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis. These data show that loss-of-function KCNH2 variants are enriched in SUDEP patients and suggest that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss-of-function KCNH2 variants that could act as biomarkers of an in idual’s SUDEP risk.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-04-2020
DOI: 10.1212/WNL.0000000000009632
Abstract: To provide information on the effect of the coronavirus disease of 2019 (COVID-19) pandemic on people with epilepsy and provide consensus recommendations on how to provide the best possible care for people with epilepsy while avoiding visits to urgent care facilities and hospitalizations during the novel coronavirus pandemic. The authors developed consensus statements in 2 sections. The first was “How should we/clinicians modify our clinical care pathway for people with epilepsy during the COVID-19 pandemic?” The second was “What general advice should we give to people with epilepsy during this crisis? The authors in idually scored statements on a scale of −10 (strongly disagree) to +10 (strongly agree). Five of 11 recommendations for physicians and 3/5 recommendations for in iduals/families were rated by all the authors as 7 or above (strongly agree) on the first round of rating. Subsequently, a teleconference was held where statements for which there was a lack of strong consensus were revised. After revision, all consensus recommendations received a score of 7 or above. The recommendations focus on administration of as much care as possible at home to keep people with epilepsy out of health care facilities, where they are likely to encounter COVID-19 (including strategies for rescue therapy), as well as minimization of risk of seizure exacerbation through adherence, and through ensuring a regular supply of medication. We also provide helpful links to additional helpful information for people with epilepsy and health providers. These recommendations may help health care professionals provide optimal care to people with epilepsy during the coronavirus pandemic.
Publisher: Wiley
Date: 07-01-2013
DOI: 10.1111/EPI.12076
Abstract: The benign occipital epilepsies of childhood include Panayiotopoulos and Gastaut syndromes a third syndrome, idiopathic photosensitive occipital epilepsy may also begin in childhood or adolescence. We describe siblings with occipital epilepsy characterized by refractory, frequent, brief visual seizures and normal magnetic resonance imaging (MRI). Electroencephalography (EEG) with functional MRI (fMRI) supports localization of interictal epileptiform activity to the occipital lobes. Our hypothesis is that the siblings share a genetic focal epilepsy arising from a localized occipital network. Although they share many features of Gastaut syndrome, their refractory ongoing seizures in adolescence is unusual and likely due to underlying genetic determinants.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2000
DOI: 10.1097/00008480-200012000-00004
Abstract: Recent molecular insights into the human idiopathic epilepsies have suggested the central role of ligand-gated and voltage-gated ion channels in their etiology. So far, genes coding for sodium and potassium channel subunits as well as a nicotinic cholinergic receptor subunit have been identified for Mendelian idiopathic epilepsies. In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights in mechanisms underlying hyperexcitability. Similarly, spontaneous murine epilepsy models have been associated with calcium channel molecular defects. The major challenge before us in understanding the genetics of the epilepsies is to identify genes for common forms of epilepsy following complex inheritance. Once such genes are discovered, the gene-gene-environmental interactions producing specific epilepsy syndromes can be explored.
Publisher: Wiley
Date: 08-2018
Abstract: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome in which affected in iduals within a family typically have a variety of epilepsy phenotypes, varying from simple febrile seizures and febrile seizures plus with a good outcome to severe epileptic encephalopathies. Here, we review the spectrum of epilepsy phenotypes, the genetic architecture of GEFS+, and the implicated genes. Using an illustrative clinical case study, we describe important steps in managing patients with GEFS+: making the diagnosis of GEFS+, appropriate genetic testing, and counselling.
Publisher: Wiley
Date: 29-07-2019
DOI: 10.1111/EPI.16308
Publisher: Wiley
Date: 2012
DOI: 10.1002/ANA.22644
Abstract: KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists. We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail. We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80 10%) 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved. KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-02-2023
DOI: 10.1212/WNL.0000000000201492
Abstract: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. We screened 893 in iduals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional in iduals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed seizure types and epilepsy syndromes were classified. We included 3 previously published in iduals including additional phenotypic details. We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All in iduals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. In iduals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two in iduals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. We describe a cohort of 17 in iduals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported in iduals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.
Publisher: Research Square Platform LLC
Date: 22-09-2023
Publisher: Wiley
Date: 09-01-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-04-2004
DOI: 10.1212/01.WNL.0000118213.94650.81
Abstract: Background and Objectives: A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich , glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations. Methods: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1 . ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4 . Results: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 in iduals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T→G C42G) and 8 (c.1418C→T S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families. Conclusion: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.EPLEPSYRES.2018.01.014
Abstract: Bainbridge-Ropers syndrome is a genetic syndrome caused by heterozygous loss-of-function pathogenic variants in ASXL3, which encodes a protein involved in transcriptional regulation. Affected in iduals have multiple abnormalities including developmental impairment, hypotonia and characteristic facial features. Seizures are reported in approximately a third of cases however, the epileptology has not been thoroughly studied. We identified three patients with pathogenic ASXL3 variants and seizures at Austin Health and in the DECIPHER database. These three patients had novel de novo ASXL3 pathogenic variants, two with truncation variants and one with a splice site variant. All three had childhood-onset generalized epilepsy with generalized tonic-clonic seizures, with one also having atypical absence seizures. We also reviewed available clinical data on five published patients with Bainbridge-Ropers syndrome and seizures. Of the five previously published patients, three also had generalized tonic-clonic seizures, one of whom also had possible absence seizures a fourth patient had absence seizures and possible focal seizures. EEG typically showed features consistent with generalized epilepsy including generalized spike-wave, photoparoxysmal response, and occipital intermittent rhythmic epileptiform activity. Bainbridge-Ropers syndrome is associated with childhood-onset generalized epilepsy with generalized tonic-clonic seizures and/or atypical absence seizures.
Publisher: Cold Spring Harbor Laboratory
Date: 04-05-2023
DOI: 10.1101/2023.05.04.538282
Abstract: Pathogenic loss-of-function SCN1A variants cause a spectrum of seizure disorders. We previously identified variants in in iduals with SCN1A -related epilepsy that fall in or near a poison exon (PE) in SCN1A intron 20 (20N). We hypothesized these variants lead to increased PE inclusion, which introduces a premature stop codon, and, therefore, reduced abundance of the full-length SCN1A transcript and Na v 1.1 protein. We used a splicing reporter assay to interrogate PE inclusion in HEK293T cells. In addition, we used patient-specific induced pluripotent stem cells (iPSCs) differentiated into neurons to quantify 20N inclusion by long and short-read sequencing and Na v 1.1 abundance by western blot. We performed RNA-antisense purification with mass spectrometry to identify RNA-binding proteins (RBPs) that could account for the aberrant PE splicing. We demonstrate that variants in/near 20N lead to increased 20N inclusion by long-read sequencing or splicing reporter assay and decreased Na v 1.1 abundance. We also identified 28 RBPs that differentially interact with variant constructs compared to wild-type, including SRSF1 and HNRNPL. We propose a model whereby 20N variants disrupt RBP binding to splicing enhancers (SRSF1) and suppressors (HNRNPL), to favor PE inclusion. Overall, we demonstrate that SCN1A 20N variants cause haploinsufficiency and SCN1A -related epilepsies. This work provides insights into the complex control of RBP-mediated PE alternative splicing, with broader implications for PE discovery and identification of pathogenic PE variants in other genetic conditions.
Publisher: Oxford University Press (OUP)
Date: 19-08-2013
DOI: 10.1093/HMG/DDT403
Publisher: Elsevier BV
Date: 08-2019
Publisher: Wiley
Date: 07-2012
DOI: 10.1111/J.1528-1167.2012.03551.X
Abstract: Epilepsy classification is close to the heart of every clinician because it affects every consultation. Acceptance of change to fundamental concepts is difficult and implementation of new ideas requires considerable effort. It is therefore not surprising that the 2010 Organization of the epilepsies has evoked much passion and its fair share of criticism and controversy. Debate has been positive and has already led to modifications and gradual acceptance of the new framework. Although classification will never be perfect and continues to evolve with increasing knowledge, the time for updating our thinking to reflect current concepts and scientific understanding is well and truly here. Ongoing discussion will help to further mature the new organization.
Publisher: Springer Science and Business Media LLC
Date: 10-12-2018
DOI: 10.1038/S41467-018-07524-Z
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 in iduals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have erse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Springer Science and Business Media LLC
Date: 29-07-2012
DOI: 10.1038/NG.2358
Publisher: Wiley
Date: 06-2016
Abstract: KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient. Epilepsy is a key phenotypic feature in most in iduals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-04-2019
Publisher: Springer Science and Business Media LLC
Date: 17-10-2006
Abstract: Physical activity (PA) is inversely associated with obesity but the effect has been difficult to quantify using questionnaires. In particular, the shape of the association has not yet been well described. Pedometers provide an opportunity to better characterize the association. Residents of households over the age of 25 years in randomly selected census districts in Tasmania were eligible to participate in the AusDiab cross-sectional survey conducted in 1999-2000. 1848 completed the AusDiab survey and 1126 of these (609 women and 517 men) wore a pedometer for 2-weekdays. Questionnaire data on recent PA, TV time and other factors were obtained. The outcomes were waist circumference (in cm) and body mass index (BMI) (kg/m(2)). Increasing daily steps were associated with a decline in the obesity measures. The logarithmic nature of the associations was indicated by a sharper decline for those with lower daily steps. For ex le, an additional 2000 steps for those taking only 2000 steps per day was associated with a reduction of 2.8 (95% confidence interval (CI): 2.1,4.4) cm in waist circumference among men (for women 2.2 (95% CI: 0.6, 3.9 cm)) with a baseline of only 2000, steps compared to a 0.7 (95% CI 0.3, 1.1) cm reduction (for women 0.6 (95% CI: 0.2, 1.0)) for those already walking 10,000 steps daily. In the multivariable analysis, clearer associations were detected for PA and these obesity measures using daily step number rather than PA time by questionnaire. Pedometer measures of activity indicate that the inverse association between recent PA and obesity is logarithmic in form with the greatest impact for a given arithmetic step number increase seen at lower levels of baseline activity. The findings from this study need to be examined in prospective settings.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-03-2021
DOI: 10.1212/NXG.0000000000000579
Abstract: To describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia. We performed phenotyping on patients with MBD5 deletions, duplications, or point mutations and a history of seizures. Twenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days–13 years). The most common seizure type was generalized tonic-clonic focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance. MBD5 disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management.
Publisher: Wiley
Date: 23-02-2018
DOI: 10.1111/DMCN.13704
Abstract: To assess long-term safety and efficacy of stiripentol as an antiepileptic medication for people with Dravet syndrome. A prospective, observational open-label study (2003-2015) of the efficacy and long-term safety of stiripentol in patients with Dravet syndrome and ongoing seizures. Frequency of generalized tonic-clonic seizures, focal seizures, status epilepticus, and adverse events were recorded. Forty-one patients started stiripentol, with median age at enrolment 5 years 7 months (range 11mo-22y) and median duration of treatment 37 months (range 2-141mo). Twenty out of 41 patients had greater than or equal to 50% long-term reduction in frequency of generalized tonic-clonic seizures. Frequency of focal seizures was decreased by greater than or equal to 50% in 11 out of 23 patients over the long-term. Frequency of status epilepticus was decreased by 50% or more in 11 out of 26 patients. The most common adverse events were anorexia, weight loss, sedation, and behavioural changes. One patient had worsening of absence and myoclonic seizures. Another developed recurrent pancreatitis on concurrent valproate. Stiripentol improves long-term seizure frequency in approximately 50% of patients with Dravet syndrome, when used as part of unrestricted polytherapy. Long-term use appears safe. In more than 40% of patients, episodes of status epilepticus markedly decrease after stiripentol initiation. What this paper adds Frequency of status epilepticus is reduced in 40% of patients with Dravet syndrome after stiripentol initiation. Stiripentol is effective for generalized tonic-clonic and focal seizures. Stiripentol can be safely used with a range of antiepileptic drugs.
Publisher: Wiley
Date: 07-01-2021
DOI: 10.1111/EPI.16761
Abstract: Asparagine‐linked glycosylation 13 ( ALG13 ) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. We delineate the phenotypic spectrum of 38 in iduals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three in iduals carrying other likely pathogenic ALG13 variants. The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one‐half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one‐third of all cases paroxysms of fast activity with electrodecrement. ALG13 ‐related DEE was usually associated with severe to profound developmental delay ambulation was acquired by one‐third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. X‐linked ALG13 ‐related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1086/319516
Publisher: Springer Science and Business Media LLC
Date: 12-08-2014
DOI: 10.1038/NRNEUROL.2014.146
Abstract: Copy number variants (CNVs deletions or duplications of chromosomal regions) have emerged as an important cause of human disease. In a recent study, epilepsy could be attributed to a pathogenic CNV in 5% of patients, but understanding the implications of a CNV for an in idual patient can be challenging.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Georg Thieme Verlag KG
Date: 28-10-2021
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.EPLEPSYRES.2013.02.011
Abstract: Febrile seizures (FS) are the most common seizure syndrome. A strong genetic component has been well established through family and twin studies however, such studies have not examined the genetics of different FS types (simple, complex, febrile status epilepticus) and sub-syndromes (true FS, febrile seizures plus (FS+), 'FS with later epilepsy'). Here we used a community-based twin s le to analyze genetic factors within different FS subtypes and FS syndromes. Twin pairs were ascertained from the twin database of the Epilepsy Research Centre. A retrospective chart review was conducted and follow-up attempted for all subjects. Casewise concordance values were calculated for the different subgroups and intra-pair variation was analyzed. One hundred and seventy-nine twin pairs with FS were identified. Overall casewise concordance for FS in monozygotic (MZ) twins (0.62) was greater than in dizygotic (DZ) twins (0.16, p<0.0001). A greater concordance amongst MZ pairs than DZ twin pairs was also observed for all FS subtypes and FS sub-syndromes, particularly in twins with FS+. Within concordant MZ pairs, we did not observe the co-occurrence of FS and FS+. These results suggest a strong genetic contribution to different FS subtypes and sub-syndromes. They also support the existence of distinct genetic factors for different FS subtypes and sub-syndromes, especially FS+. This information is important for the strategic planning of next generation sequencing studies of febrile seizures.
Publisher: Springer Science and Business Media LLC
Date: 13-02-2017
DOI: 10.1038/NG.3792
Publisher: Wiley
Date: 05-04-2019
DOI: 10.1111/EPI.14698
Publisher: Cambridge University Press (CUP)
Date: 04-2010
Abstract: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including in iduals with a clinical diagnosis of RTT but who were negative for MECP2 mutations ( n = 102), males with X-linked mental retardation ( n = 9), patients with West syndrome ( n = 52), patients with autism ( n = 59), patients with epileptic encephalopathy ( n = 33), patients with Aicardi syndrome ( n = 7) and other patients with intellectual disability with or without seizures ( n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C T [p.S196L] c.58G C [p.G20R] c.2504delC [p.P835fs] deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.
Publisher: Wiley
Date: 2011
Publisher: Oxford University Press (OUP)
Date: 10-2012
DOI: 10.1093/BRAIN/AWS241
Publisher: Springer Science and Business Media LLC
Date: 08-1998
DOI: 10.1038/1252
Abstract: Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.
Publisher: BMJ
Date: 03-11-2008
Abstract: Microarray genome analysis is realising its promise for improving detection of genetic abnormalities in in iduals with mental retardation and congenital abnormality. Copy number variations (CNVs) are now readily detectable using a variety of platforms and a major challenge is the distinction of pathogenic from ubiquitous, benign polymorphic CNVs. The aim of this study was to investigate replacement of time consuming, locus specific testing for specific microdeletion and microduplication syndromes with microarray analysis, which theoretically should detect all known syndromes with CNV aetiologies as well as new ones. Genome wide copy number analysis was performed on 117 patients using Affymetrix 250K microarrays. 434 CNVs (195 losses and 239 gains) were found, including 18 pathogenic CNVs and 9 identified as "potentially pathogenic". Almost all pathogenic CNVs were larger than 500 kb, significantly larger than the median size of all CNVs detected. Segmental regions of loss of heterozygosity larger than 5 Mb were found in 5 patients. Genome microarray analysis has improved diagnostic success in this group of patients. Several ex les of recently discovered "new syndromes" were found suggesting they are more common than previously suspected and collectively are likely to be a major cause of mental retardation. The findings have several implications for clinical practice. The study revealed the potential to make genetic diagnoses that were not evident in the clinical presentation, with implications for pretest counselling and the consent process. The importance of contributing novel CNVs to high quality databases for genotype-phenotype analysis and review of guidelines for selection of in iduals for microarray analysis is emphasised.
Publisher: Cold Spring Harbor Laboratory
Date: 13-06-2019
DOI: 10.1101/659722
Abstract: Families comprising many in iduals with Autism Spectrum Disorder (ASD) may carry a dominant predisposing mutation. Our aim was to use rigorous phenotyping of the ‘Broader Autism Phenotype’ (BAP) in large multiplex ASD families to identify endophenotypes of the BAP for future genetic studies. We evaluated ASD/BAP features using standardised tests and a semi-structured interview to assess social, intellectual, executive and adaptive functioning in 109 in iduals, including two large multiplex families (Family A: 30 Family B: 34) and an independent s le of small families ( n =45). Our protocol identified four psychological endophenotypes of the BAP that were evident in both s les, and showed high sensitivity (97%) and specificity (82%) for in iduals classified with the BAP. The patterns of inheritance of these endophenotypes varied in the two large families, supporting their utility for identifying genes in autism.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 09-2014
Publisher: Springer Science and Business Media LLC
Date: 29-04-2015
DOI: 10.1007/S11910-015-0554-0
Abstract: The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20% of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes.
Publisher: Frontiers Media SA
Date: 08-09-2020
Publisher: Elsevier BV
Date: 12-2013
Publisher: Oxford University Press (OUP)
Date: 03-2003
DOI: 10.1093/BRAIN/AWG047
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2007
Publisher: Wiley
Date: 15-05-2015
DOI: 10.1111/EPI.13020
Abstract: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. Detailed clinical data were collected from 36 families comprising two or more in iduals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE) 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of in iduals with KCNQ2 mutations later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability a molecular lesion was identified in two the other family remains unsolved. Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.EPLEPSYRES.2010.12.009
Abstract: To analyze electroclinical features of absence seizures during sleep. 30 children with genetic generalized epilepsy had 52 paroxysms of GSW >2s during sleep. 18/52 (35%) demonstrated a clinical sign. Ictal GSW lasted an average of 6.5s. Motor manifestations are seen during GSW>2s in sleep. 72% likely represent true ictal motor features while the rest may be serendipitous sleep phenomenon.
Publisher: The Journal of Rheumatology
Date: 15-11-2011
Abstract: Unconfirmed reports describe association of ankylosing spondylitis (AS) with several candidate genes including ANKH . Cellular export of inorganic pyrophosphate is regulated by the ANK protein, and mutant mice (ank/ank), which have a premature stop codon in the 3’ end of the ank gene, develop severe ankylosis. We tested the association between single-nucleotide polymorphisms (SNP) in these genes and susceptibility to AS in a population of patients with AS. We investigated the role of these genes in terms of functional (BASFI) and metrological (BASMI) measures, and the association with radiological severity (mSASSS). Our study was conducted on 355 patients with AS and 95 ethnically matched healthy controls. AS was defined according to the modified New York criteria. Four SNP in ANKH (rs27356, rs26307, rs25957, and rs28006) were genotyped. Association analysis was performed using Cochrane-Armitage and linear regression tests for dichotomous and quantitative variables. Analyses of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASFI, and mSASSS were controlled for sex and disease duration. None of the 4 markers showed significant single-locus disease associations (p 0.05), suggesting that ANKH was not a major determinant of AS susceptibility in our population. No association was observed between these SNP and age at symptom onset, BASDAI, BASFI, BASMI, or mSASSS. These results confirm data in white Europeans that ANKH is probably not a major determinant of susceptibility to AS. ANKH polymorphisms do not markedly influence AS disease severity, as measured by BASMI and mSASSS.
Publisher: Wiley
Date: 04-2018
Abstract: The International League against Epilepsy (ILAE) published in the April 2017 edition of Epilepsia three companion articles on the classification of seizures and the epilepsies. These represent a long‐awaited update on the original 1981 and 1989 publications and provide a modern descriptive template. The new classification presents three levels of terminology, involving seizure types, epilepsy types, and syndromes. In this fourth paper, we present an interpretation of these new concepts for people with epilepsy and those who care for them, as well as for young medical doctors not specialized in epilepsy and nurses. Our goal in writing this paper is to ensure that everyone is speaking and understanding the same language, which is fundamental to the optimal management of people with epilepsy.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2015
DOI: 10.1038/MP.2015.5
Publisher: Springer Science and Business Media LLC
Date: 04-05-2020
DOI: 10.1038/S41398-020-0803-0
Abstract: Protocadherin-19 ( PCDH19 ) pathogenic variants cause an early-onset seizure disorder called girls clustering epilepsy (GCE). GCE is an X-chromosome disorder that affects heterozygous females and mosaic males, however hemizygous (“transmitting”) males are spared. We aimed to define the neuropsychiatric profile associated with PCDH19 pathogenic variants and determine if a clinical profile exists for transmitting males. We also examined genotype- and phenotype–phenotype associations. We developed an online PCDH19 survey comprising the following standardized assessments: The Behavior Rating Inventory of Executive Function the Social Responsiveness Scale, 2nd edition the Strengths and Difficulties Questionnaire and the Dimensional Obsessive-Compulsive Scale. Genetic, seizure, and developmental information were also collected. The survey was completed by patients or by caregivers on behalf of patients. Of the 112 in iduals represented (15 males), there were 70 unique variants. Thirty-five variants were novel and included a newly identified recurrent variant Ile781Asnfs*3. There were no significant differences in phenotypic outcomes between published and unpublished cases. Seizures occurred in clusters in 94% of in iduals, with seizures resolving in 28% at an average age of 17.5 years. Developmental delay prior to seizure onset occurred in 18% of our cohort. Executive dysfunction and autism spectrum disorder (ASD) occurred in approximately 60% of in iduals. The ASD profile included features of attention-deficit hyperactivity disorder. In addition, 21% of in iduals met criteria for obsessive-compulsive disorder that appeared to be distinct from ASD. There were no phenotypic differences between heterozygous females and mosaic males. We describe a mosaic male and two hemizygous males with atypical clinical profiles. Earlier seizure onset age and increased number of seizures within a cluster were associated with more severe ASD symptoms ( p = 0.001), with seizure onset also predictive of executive dysfunction ( p = 4.69 × 10 −4 ) and prosocial behavior ( p = 0.040). No clinical profile was observed for transmitting males. This is the first patient-derived standardized assessment of the neuropsychiatric profile of GCE. These phenotypic insights will inform diagnosis, management, and prognostic and genetic counseling.
Publisher: Wiley
Date: 17-10-2013
DOI: 10.1002/ANA.23998
Publisher: Wiley
Date: 27-04-2023
DOI: 10.1111/EPI.17616
Abstract: This study was undertaken to analyze phenotypic features of a cohort of patients with protracted CLN3 disease to improve recognition of the disorder. We analyzed phenotypic data of 10 patients from six families with protracted CLN3 disease. Haplotype analysis was performed in three reportedly unrelated families. Visual impairment was the initial symptom, with onset at 5–9 years, similar to classic CLN3 disease. Mean time from onset of visual impairment to seizures was 12 years (range = 6–41 years). Various seizure types were reported, most commonly generalized tonic–clonic seizures focal seizures were present in four patients. Progressive myoclonus epilepsy was not seen. Interictal electroencephalogram revealed mild background slowing and 2.5–3.5‐Hz spontaneous generalized spike–wave discharges. Additional interictal focal epileptiform discharges were noted in some patients. Age at death for the three deceased patients was 31, 31, and 52 years. Molecular testing revealed five in iduals were homozygous for c.461‐280_677 + 382del966, the "common 1‐kb" CLN3 deletion. The remaining in iduals were compound heterozygous for various combinations of recurrent pathogenic CLN3 variants. Haplotype analysis demonstrated evidence of a common founder for the common 1‐kb deletion. Dating analysis suggested the deletion arose approximately 1500 years ago and thus did not represent cryptic familial relationship in this Australian cohort. We highlight the protracted phenotype of a disease generally associated with death in adolescence, which is a combined focal and generalized epilepsy syndrome with progressive neurological deterioration. The disorder should be suspected in an adolescent or adult patient presenting with generalized or focal seizures preceded by progressive visual loss. The common 1‐kb deletion has been typically associated with classic CLN3 disease, and the protracted phenotype has not previously been reported with this genotype. This suggests that modifying genetic factors may be important in determining this somewhat milder phenotype and identification of these factors should be the subject of future research.
Publisher: Wiley
Date: 17-08-2023
DOI: 10.1111/EPI.17737
Abstract: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. This multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2–18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6‐week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo. A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo ( p .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group ( p .0001). The median longest seizure‐free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group ( p .0001). The most common adverse events ( % in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.
Publisher: Wiley
Date: 18-11-2021
DOI: 10.1111/EPI.16766
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.EJPN.2012.04.007
Abstract: Dravet syndrome is a severe infantile-onset epilepsy syndrome with a distinctive but complex electroclinical presentation. A healthy, developmentally normal infant presents at around 6 months of age with convulsive status epilepticus, which may be hemiclonic or generalized seizures may be triggered by fever, illness or vaccination. The infant typically has further episodes of status epilepticus every month or two, often triggered by fever. Other seizure types including focal dyscognitive seizures, absence and myoclonic seizures develop between 1 and 4 years. Atonic drop attacks and episodes of non-convulsive status may occur. Early development is normal but slows in the second year. Developmental regression may occur, particularly with status epilepticus. EEG studies are initially normal, but after 2 years they show generalized spike-wave and polyspike-wave activity with multifocal discharges. Photosensitivity may be seen. Imaging is normal or shows non-specific findings such as atrophy. Dravet syndrome is associated with mutations of the gene encoding the alpha-1 subunit of the sodium channel, SCN1A, in >70% of patients. These include sequencing mutations and copy number variant anomalies 90% of mutations arise de novo. PCDH19 mutational analysis is a second-tier test for girls with a Dravet-like picture who do not have SCN1A mutations. Outcome is poor, with intellectual disability in most patients and ongoing seizures. Intellectual impairment varies from severe in 50% patients, to moderate and mild intellectual disability each accounting for 25% cases. Rare patients have normal intellect. The long-term course involves ongoing, brief nocturnal convulsions and a characteristic deterioration in gait.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-08-2015
Publisher: Wiley
Date: 05-08-2020
DOI: 10.1002/JIMD.12290
Abstract: Asparagine‐linked glycosylation 13 homolog ( ALG13 ) encodes a nonredundant, highly conserved, X‐linked uridine diphosphate (UDP)‐ N ‐acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N‐linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13‐CDG. Twenty‐four previously reported ALG13‐CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13‐CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13‐deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported in iduals with de novo variants in ALG13 . This more than doubles the number of known cases. A key finding is that a vast majority of the in iduals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these in iduals.
Publisher: Wiley
Date: 15-04-2013
DOI: 10.1111/EPI.12168
Abstract: This report is a practical reference guide for genetic testing of SCN1A, the gene encoding the α1 subunit of neuronal voltage-gated sodium channels (protein name: Nav 1.1). Mutations in this gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilepsy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. Recommendations for testing: (1) Testing is particularly useful for people with suspected DS and sometimes in other early onset infantile epileptic encephalopathies such as MPSI because genetic confirmation of the clinical diagnosis may allow optimization of antiepileptic therapy with the potential to improve seizure control and developmental outcome. In addition, a molecular diagnosis may prevent the need for unnecessary investigations, as well as inform genetic counseling. (2) SCN1A testing should be considered in people with possible DS where the typical initial presentation is of a developmentally normal infant presenting with recurrent, febrile or afebrile prolonged, hemiclonic seizures or generalized status epilepticus. After age 2, the clinical diagnosis of DS becomes more obvious, with the classical evolution of other seizure types and developmental slowing. (3) In contrast to DS, the clinical utility of SCN1A testing for GEFS+ remains questionable. (4) The test is not recommended for children with phenotypes that are not clearly associated with SCN1A mutations such as those characterized by abnormal development or neurologic deficits apparent at birth or structural abnormalities of the brain. Interpreting test results: (1) Mutational testing of SCN1A involves both conventional DNA sequencing of the coding regions and analyses to detect genomic rearrangements within the relevant chromosomal region: 2q24. Interpretation of the test results must always be done in the context of the electroclinical syndrome and often requires the assistance of a medical geneticist, since many genomic variations are possible and it is essential to differentiate benign polymorphisms from pathogenic mutations. (2) Missense variants may have no apparent effect on the phenotype (benign polymorphisms) or may represent mutations underlying DS, MPSI, GEFS+, and related syndromes and can provide a challenge in interpretation. (3) Conventional methods do not detect variations in introns or promoter or regulatory regions therefore, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype. (4) It is important to note that a negative test does not rule out the clinical diagnosis of DS or other conditions because genes other than SCN1A may be involved. Obtaining written informed consent and genetic counseling should be considered prior to molecular testing, depending on the clinical situation and local regulations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1998
DOI: 10.1097/00019052-199804000-00009
Abstract: The relationship between febrile seizures and epilepsy has long been debated. We argue that there is some specificity to the types of epilepsy that follow febrile seizures, rather than febrile seizures being a nonspecific marker of a lowered seizure threshold. The relationship between febrile seizures and later epilepsy is frequently genetic. Recent clinical and molecular genetic studies suggest that there are a number of syndrome-specific genes for febrile seizures.
Publisher: Springer Science and Business Media LLC
Date: 23-10-2017
DOI: 10.1038/NG.3785
Publisher: Oxford University Press (OUP)
Date: 19-04-2010
DOI: 10.1093/BRAIN/AWQ078
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-06-2019
DOI: 10.1212/NXG.0000000000000340
Abstract: To map functional MRI (fMRI) connectivity within and between the somatosensory cortex, putamen, and ventral thalamus in in iduals from a family with a GABAergic deficit segregating with febrile seizures and genetic generalized epilepsy. We studied 5 adults from a family with early-onset absence epilepsy and/or febrile seizures and a GABA A receptor subunit gamma2 pathogenic variant ( GABRG2[R43Q] ) vs 5 age-matched controls. We infer differences between participants with the GABRG2 pathogenic variant and controls in resting-state fMRI connectivity within and between the somatosensory cortex, putamen, and ventral thalamus. We observed increased fMRI connectivity within the somatosensory cortex and between the putamen and ventral thalamus in all in iduals with the GABRG2 pathogenic variant compared with controls. Post hoc analysis showed less pronounced changes in fMRI connectivity within and between the primary visual cortex and precuneus. Although our s le size was small, this preliminary study suggests that in iduals with a GABRG2 pathogenic variant, raising risk of febrile seizures and generalized epilepsy, display underlying increased functional connectivity both within the somatosensory cortex and in striatothalamic networks. This human network model aligns with rodent research and should be further validated in larger cohorts, including other in iduals with generalized epilepsy with and without known GABA pathogenic variants.
Publisher: Oxford University Press (OUP)
Date: 22-06-2020
Abstract: Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All s les were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.
Publisher: Oxford University Press (OUP)
Date: 12-01-2022
Abstract: Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P & 5 × 10−10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10−4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population s le. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
Publisher: SAGE Publications
Date: 11-10-2019
Abstract: [Box: see text]
Publisher: Research Square Platform LLC
Date: 14-09-2022
DOI: 10.21203/RS.3.RS-2041176/V1
Abstract: We aimed to determine whether SNP-microarray genomic testing of saliva had a greater diagnostic yield than blood for pathogenic copy number variants (CNVs). We selected patients who underwent CMA testing of both blood and saliva from 23,289 blood and 21,857 saliva s les. Our cohort comprised 370 in iduals who had testing of both, 224 with syndromic intellectual disability (ID) and 146 with isolated ID. Mosaic pathogenic CNVs or aneuploidy were detected in saliva but not in blood in 20/370 (4.4%). All 20 in iduals had syndromic ID, accounting for 9.1% of the syndromic ID sub-cohort. Pathogenic CNVs were large in size (median of 46 Mb), and terminal in nature, with median mosaicism of 27.5% (not exceeding 40%). By contrast, non-mosaic pathogenic CNVs were 100% concordant between blood and saliva, considerably smaller in size (median of 0.65 Mb), and predominantly interstitial in location. Given that salivary microarray testing has increased diagnostic utility over blood in in iduals with syndromic ID, we recommend it as a first-tier testing in this group.
Publisher: Wiley
Date: 18-08-2021
DOI: 10.1002/ANA.26191
Publisher: Springer Science and Business Media LLC
Date: 11-2018
Publisher: Wiley
Date: 21-07-2016
DOI: 10.1002/EPI4.5
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-06-2017
DOI: 10.1212/WNL.0000000000004152
Abstract: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 ( DNM1 ), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. The phenotypic spectrum of DNM1 -related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-08-2012
Publisher: Elsevier BV
Date: 12-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-09-2011
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.CELREP.2018.11.029
Abstract: The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an ex le of a primate-specific genomic element supporting brain development.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-08-2005
DOI: 10.1212/01.WNL.0000172920.34994.63
Abstract: Objective: To examine the genetic relationships among epilepsies with different seizure types—myoclonic, absence, and generalized tonic-clonic—within the idiopathic generalized epilepsies (IGEs). Background: Careful phenotype definition in the epilepsies may allow ision into groups that share susceptibility genes. Examination of seizure type, a phenotypic characteristic less complex than IGE syndrome, may help to define more homogeneous subgroups. Methods: Using the approach that found evidence of distinct genetic effects on myoclonic vs absence seizures in families from the Epilepsy Family Study of Columbia University, the authors examined an independent s le of families from Australia and Israel. They also examined the familial clustering of generalized tonic-clonic seizures (GTCs) within the IGEs in two combined data sets. Families were defined as concordant if all affected members had the same type of seizure or IGE syndrome, as appropriate for the analysis performed. Results: The proportion of families concordant for myoclonic vs absence seizures was greater than expected by chance in the Australian families. In addition, GTCs clustered in families with IGEs to a degree greater than expected by chance. Conclusions: These results provide additional evidence for distinct genetic effects on myoclonic vs absence seizures in an independent set of families and suggest that there is a genetic influence on the occurrence of generalized tonic-clonic seizures within the idiopathic generalized epilepsies.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Massachusetts Medical Society
Date: 25-05-2017
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1038/S41523-019-0127-5
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1 , BRCA2 , PALB2 , ATM , and CHEK2 are associated with breast cancer risk. FANCM , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2 . These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM −/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79 P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM :p.Arg658* and found that also FANCM :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96 P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM -associated tumors.
Publisher: Wiley
Date: 03-2019
DOI: 10.1111/EPI.14678
Abstract: To investigate the occurrence of psychosis and serious behavioral problems in females with protocadherin 19 gene (PCDH19) pathogenic variants. We evaluated whether psychosis and serious behavioral problems had occurred in 60 females (age 2-75 years) with PCDH19 pathogenic variants belonging to 35 families. Patients were identified from epilepsy genetics databases in Australia, New Zealand, the United States, and Canada. Neurologic and psychiatric disorders were diagnosed using standard methods. Eight of 60 females (13%) from 7 families developed a psychotic disorder: schizophrenia (6), schizoaffective disorder (1), or an unspecified psychotic disorder (1). Median age at onset of psychotic symptoms was 21 years (range 11-28 years). In our cohort of 39 females aged 11 years or older, 8 (21%) developed a psychotic disorder. Seven had ongoing seizures at onset of psychosis, with 2 continuing to have seizures when psychosis recurred. Psychotic disorders occurred in the setting of mild (4), moderate (2), or severe (1) intellectual disability, or normal intellect (1). Preexisting behavioral problems occurred in 4 patients, and autism spectrum disorder in 3. Two additional females (3%) had psychotic features with other conditions: an adolescent had recurrent episodes of postictal psychosis, and a 75-year-old woman had major depression with psychotic features. A further 3 adolescents (5%) with moderate to severe intellectual disability had onset of severe behavioral disturbance, or significant worsening. We identify that psychotic disorders, including schizophrenia, are a later-onset manifestation of PCDH19 Girls Clustering Epilepsy. Affected girls and women should be carefully monitored for later-onset psychiatric disorders.
Publisher: Wiley
Date: 06-06-2018
DOI: 10.1111/EPI.14438
Abstract: Sudden unexpected death in epilepsy (SUDEP) is a tragic and devastating event for which the underlying pathophysiology remains poorly understood this study investigated whether abnormalities in heart rate variability (HRV) are linked to SUDEP in patients with epilepsy due to mutations in sodium channel (SCN) genes. We retrospectively evaluated HRV in epilepsy patients using electroencephalographic studies to study the potential contribution of autonomic dysregulation to SUDEP risk. We extracted HRV data, in wakefulness and sleep, from 80 patients with drug-resistant epilepsy, including 40 patients with mutations in SCN genes and 40 control patients with non-SCN drug-resistant epilepsy. From the SCN group, 10 patients had died of SUDEP. We compared HRV between SUDEP and non-SUDEP groups, specifically studying awake HRV and sleep:awake HRV ratios. The SUDEP patients had the most severe autonomic dysregulation, showing lower awake HRV and either extremely high or extremely low ratios of sleep-to-awake HRV in a subgroup analysis. A secondary analysis comparing the SCN and non-SCN groups indicated that autonomic dysfunction was slightly worse in the SCN epilepsy group. These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of HRV to SUDEP merits further study HRV may eventually have potential as a biomarker of SUDEP risk, which would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.
Publisher: Wiley
Date: 04-2021
DOI: 10.1111/EPI.16854
Abstract: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy. We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene‐level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion‐deletion (indel) variants, and copy number variants present in leukocyte‐derived DNA. Across the cohort of 86 in iduals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2 , including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome‐wide threshold of significance in the gene‐level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2 , we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62 , all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy‐associated and neurodevelopmental disease‐associated genes ( SCN2A in two in iduals, GRIA3 , CACNA1C ) and a 597‐kb deletion at 15q25, a neurodevelopmental disease susceptibility locus. This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio‐based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A , GRIA3 , CACNA1C , and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2012
DOI: 10.1038/NG.2440
Abstract: We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies.
Publisher: Wiley
Date: 23-10-2020
DOI: 10.1111/EPI.16732
Publisher: Elsevier BV
Date: 11-2019
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.EPLEPSYRES.2017.07.014
Abstract: The ketogenic diet (KD) is a medically supervised, high fat, low carbohydrate and restricted protein diet which has been used successfully in patients with refractory epilepsy. Only one published report has explored its effect on the skeleton. We postulated that the KD impairs skeletal health parameters in patients on the KD. Patients commenced on the KD were enrolled in a prospective, longitudinal study, with monitoring of Dual-energy X-ray absorptiometry (DXA) derived bone parameters including bone mineral content and density (BMD). Areal BMD was converted to bone mineral apparent density (BMAD) where possible. Biochemical parameters, including Vitamin D, and bone turnover markers, including osteocalcin, were assessed. Patients were stratified for level of mobility using the gross motor functional classification system (GMFCS). 29 patients were on the KD for a minimum of 6 months (range 0.5-6.5 years, mean 2.1 years). There was a trend towards a reduction in lumbar spine (LS) BMD Z score of 0.1562 (p=0.071) per year and 20 patients (68%) had a lower BMD Z score at the end of treatment. While less mobile patients had lower baseline Z scores, the rate of bone loss on the diet was greater in the more mobile patients (0.28 SD loss per year, p=0.026). Height adjustment of DXA data was possible for 13 patients, with a mean reduction in BMAD Z score of 0.19 SD. Only two patients sustained fractures. Mean urinary calcium-creatinine ratios were elevated (0.77), but only 1 patient developed renal calculi. Children on the KD exhibited differences in skeletal development that may be related to the diet. The changes were independent of height but appear to be exaggerated in patients who are ambulant. Clinicians should be aware of potential skeletal side effects and monitor bone health during KD treatment. Longer term follow up is required to determine adult eak bone mass and fracture risk throughout life.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-03-2023
DOI: 10.1212/WNL.0000000000206758
Abstract: We aimed to determine the population-based cumulative incidence and prevalence of developmental and epileptic encephalopathies (DEEs) and intellectual disability and epilepsy (ID+E) in children. We analyzed the cumulative incidence of specific epilepsy syndromes. Children younger than 16 years with a DEE or ID+E were ascertained using EEG records from 2000 to 2016 in the Wellington region of New Zealand. Epilepsy syndromes were diagnosed on medical record and EEG review. Point prevalence and cumulative incidence for children with epilepsy and developmental impairment, DEE and ID+E were calculated. Cumulative incidence for each epilepsy syndrome was calculated. The cohort comprised 235 children (58% male) with developmental impairment and epilepsy, including 152 (65%) with DEE and 83 (35%) with ID+E. The median age of seizure onset was 15.4 months (range day 1–15 years). The median follow-up from seizure onset was 7.9 years (range 0–18.2 years). Point prevalence for the broad group of children with epilepsy and developmental impairment was 175/100,000 children (95% CI 149–203 DEE 112 and ID+E 63/100,000 children). Cumulative incidence for DEE was 169/100,000 children (95% CI 144–199) and that for ID+E was 125/100,000 children (95% CI 95.4–165). Cumulative incidence per 100,000 children was as follows: infantile epileptic spasms syndrome 58.2 (95% CI 45.0–75.3), epilepsy with myoclonic-atonic seizures 16.4 (95% CI 9.69–27.7), Lennox-Gastaut syndrome 13.2 (95% CI 4.1–41.9), and Dravet syndrome 5.1 (95% CI 2.1–12.2). Fifty/152 (33%) of children with DEE and 70/83 (84%) with ID+E could not be diagnosed with a known epilepsy syndrome. Epilepsy and developmental impairment before the age of 16 years occurs in 1 in 340 children, with 1 in 590 having a DEE and 1 in 800 having ID+E. These in iduals require significant health and community resources therefore, these data will inform complex health service and education planning. Epidemiologic studies have focused on early childhood–onset DEEs. These do not fully reflect the burden of these disorders because 27% of DEEs and 70% of ID+E begin later, with seizure onset after the age of 3 years. Understanding the cumulative incidence of specific syndromes together with the broad group of DEEs is essential for the planning of therapeutic trials. Given trials focus on specific syndromes, there is a risk that effective therapies will not be developed for one-third of children with DEE.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2022
DOI: 10.1038/S42003-022-03454-1
Abstract: In SCN2A- related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 in iduals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential cl (DAPC) and voltage cl . Results show that 36/38 variants are associated with only one phenotypic group (30 early-infantile, 5 later-onset, 1 ID/ASD). Unexpectedly, we revealed major differences in outcome severity between in iduals with the same variant for 40% of early-infantile variants studied. DAPC was superior to voltage cl in predicting the impact of mutations on neuronal excitability and confirmed GoF produces early-infantile phenotypes and LoF later-onset phenotypes. For one early-infantile variant, the co-expression of the α 1 and β 2 subunits of the Na v 1.2 channel was needed to unveil functional impact, confirming the prediction of 3D molecular modeling. Neither DAPC nor voltage cl reliably predicted phenotypic severity of early-infantile variants. Genotype, phenotypic group and DAPC are accurate predictors of the biophysical impact of SCN2A variants, but other approaches are needed to predict severity.
Publisher: Oxford University Press (OUP)
Date: 06-09-2013
DOI: 10.1093/BRAIN/AWT233
Publisher: Springer Science and Business Media LLC
Date: 11-06-2018
Publisher: Hindawi Limited
Date: 21-10-2022
DOI: 10.1002/HUMU.24289
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.EJMG.2022.104551
Abstract: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. This study aimed to identify the genetic causes for a group of in iduals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. Twenty-six in iduals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2023
Publisher: Wiley
Date: 04-09-2015
DOI: 10.1111/EPI.13121
Publisher: Wiley
Date: 07-10-2013
DOI: 10.1111/EPI.12395
Abstract: Lennox-Gastaut syndrome (LGS) is a devastating childhood-onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography (EEG) features of LGS of unknown or genetic cause (LGS(u)). The Epilepsy Phenome/Genome Project (EPGP) aims to characterize LGS(u) by phenotypic analysis of patients with LGS(u) and their parents. One hundred thirty-five patients with LGS with no known etiology and their parents were enrolled from 19 EPGP centers in the United States and Australia. Clinical data from medical records, standardized questionnaires, imaging, and EEG were collected with use of online informatics systems developed for EPGP. LGS(u) in the EPGP cohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p < 0.0002), and was associated with normal development prior to seizure onset in 59.2% of patients. Despite the diagnosis, almost half of the adult patients with LGS(u) completed secondary school. Parents were cognitively normal. All subjects had EEG recordings with generalized epileptiform abnormalities with a spike wave frequency range of 1-5 Hz (median 2 Hz), whereas 8.1% of subjects had EEG studies with a normal posterior dominant rhythm. Almost 12% of patients evolved from West syndrome. LGS(u) has distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description of LGS(u) coupled with future genetic studies will advance our understanding of this epilepsy syndrome.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2017
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/917565
Abstract: Sixty cases of febrile seizures from a Chinese cohort had previously been reported with a strong association between variants in the seizure-related ( SEZ ) 6 gene and febrile seizures. They found a striking lack of genetic variation in their controls. We found genetic variation in SEZ6 at similar levels at the same DNA sequence positions in our 94 febrile seizure cases as in our 96 unaffected controls. Two of our febrile seizure cases carried rare variants predicted to have damaging consequences. Combined with some of the variants from the Chinese cohort, these data are compatible with a role for SEZ6 as a susceptibility gene for febrile seizures. However, the polygenic determinants underlying most cases of febrile seizures with complex inheritance remain to be determined.
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2021
DOI: 10.1101/2021.03.09.434675
Abstract: The MAST family of microtubule-associated serine-threonine kinases (STK) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been associated with neurological disease, with de novo variants in in iduals with a neurodevelopmental disorder, including a mega corpus callosum. Using exome sequencing we identify MAST3 missense variants in in iduals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. We identify de novo missense variants in the STK domain in 11 in iduals, including two recurrent variants p.G510S (n=5) and p.G515S (n=3). All 11 in iduals had Developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at 2 years of age. All patients developed multiple seizures types, while 9/11 had seizures triggered by fever and 9/11 had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wildtype. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Oxford University Press (OUP)
Date: 20-09-2013
DOI: 10.1093/BRAIN/AWT249
Abstract: Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Wiley
Date: 05-09-2018
DOI: 10.1111/BCP.13711
Publisher: Informa UK Limited
Date: 22-09-2021
DOI: 10.1080/14737175.2021.1981288
Abstract: Mosaic variants arising in brain tissue are increasingly being recognized as a hidden cause of focal epilepsy. This knowledge gain has been driven by new, highly sensitive genetic technologies and genome-wide analysis of brain tissue from surgical resection or autopsy in a small proportion of patients with focal epilepsy. Recently reported novel strategies to detect mosaic variants limited to brain have exploited trace brain DNA obtained from cerebrospinal fluid liquid biopsies or stereo-electroencephalography electrodes. The authors review the data on these innovative approaches published in PubMed before 12 June 2021, discuss the challenges associated with their application, and describe how they are likely to improve detection of mosaic variants to provide new molecular diagnoses and therapeutic targets for focal epilepsy, with potential utility in other nonmalignant neurological disorders. These cutting-edge approaches may reveal the hidden genetic etiology of focal epilepsies and provide guidance for precision medicine.
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000500554
Abstract: b i Objective: /i /b The clinical course of childhood apraxia of speech (CAS) is poorly understood. Of the few longitudinal studies in the field, only one has examined adolescent outcomes in speech, language, and literacy. This study is the first to report long-term speech, language, and academic outcomes in an adolescent, Liam, with CAS. b i Methods: /i /b Speech, language, literacy, and academic outcome data were collected, including 3 research-based assessments. Overall, data were available at 17 time points from 3 to 15 years. b i Results: /i /b Liam had moderate-to-severe expressive language impairment and poor reading, writing, and spelling up to 10 years. His numeracy was at or above the national average from 8 to 14 years. He made gains in preadolescence, with average expressive language at 11 years and above average reading and writing at 14 years. Nonword reading, reading comprehension, and spelling remained areas of weakness. Receptive language impairment was evident at 13 years, which was an unexpected finding. b i Conclusion: /i /b Findings from single cases can be hypothesis generating but require verification in larger cohorts. This case shows that at least some children with CAS may gain ground in adolescence, relative to same age peers, in expressive language and academic areas such as reading and writing.
Publisher: Wiley
Date: 10-1991
DOI: 10.1111/J.1469-8749.1991.TB14803.X
Abstract: A case of second-trimester congenital varicella infection, in association with isolated microcephaly and severe brain damage, is reported, and cases of classical congenital varicella syndrome are compared on a clinical and immunological basis. This case, together with others cited in the literature, suggests that congenital varicella infection may lead to microcephaly and neurological abnormalities, without the presence of skin lesions. Although first-trimester infection has been considered the most likely to produce congenital abnormalities, the second trimester may be more commonly implicated indeed there may not be a critical period if varicella causes secondary disruption of differentiated tissues.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2023
DOI: 10.1038/S41380-022-01764-8
Abstract: Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1 , SETD1A and DDX3X , thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected in iduals are poised for precision medicine trials.
Publisher: Informa UK Limited
Date: 19-01-2021
Publisher: Oxford University Press (OUP)
Date: 08-2001
Abstract: Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.YEBEH.2010.01.168
Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the alpha4 nicotinic acetylcholine receptor (nAChR). The nAChR modulates aspects of memory and attention. We examined the neuropsychological phenotype of ADNFLE, with a particular emphasis on understanding the impact on frontal lobe functions. We used standard clinical tests as well as focused measures of frontal lobe function in a well-defined group of patients with ADNFLE. Their performance was compared with that of a group of age-, sex-, and education-matched control participants. Patients with ADNFLE showed impairments on tasks requiring cognitive flexibility against a background of well-preserved intellectual abilities. In accord with existing research, verbal memory impairments were identified in the patient group the level of impairment on these tasks correlated with disease-related factors. In our study of ADNFLE associated with one mutation, cognitive flexibility appears to be the core cognitive deficit.
Publisher: Wiley
Date: 19-01-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-01-2022
DOI: 10.1212/NXG.0000000000000652
Abstract: The 2-hit model of genetic disease is well established in cancer, yet has only recently been reported to cause brain malformations associated with epilepsy. Pathogenic germline and somatic variants in genes in the mechanistic target of rapamycin (mTOR) pathway have been implicated in several malformations of cortical development. We investigated the 2-hit model by performing genetic analysis and searching for germline and somatic variants in genes in the mTOR and related pathways. We searched for germline and somatic pathogenic variants in 2 brothers with drug-resistant focal epilepsy and surgically resected focal cortical dysplasia (FCD) type IIA. Exome sequencing was performed on blood- and brain-derived DNA to identify pathogenic variants, which were validated by droplet digital PCR. In vitro functional assays of a somatic variant were performed. Exome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG p.Ser17Alafs*70) in NPRL3 in both brothers. NPRL3 is a known FCD gene that encodes a negative regulator of the mTOR pathway. Somatic variant calling in brain-derived DNA from both brothers revealed a low allele fraction somatic variant (c.338C T p.Ala113Val) in the WNT2 gene in 1 brother, confirmed by droplet digital PCR. In vitro functional studies suggested a loss of WNT2 function as a consequence of this variant. A second somatic variant has not yet been found in the other brother. We identify a pathogenic germline mTOR pathway variant ( NPRL3 ) and a somatic variant ( WNT2 ) in the intersecting WNT signaling pathway, potentially implicating the WNT2 gene in FCD and supporting a dual-pathway 2-hit model. If confirmed in other cases, this would extend the 2-hit model to pathogenic variants in different genes in critical, intersecting pathways in a malformation of cortical development. Detection of low allele fraction somatic second hits is challenging but promises to unravel the molecular architecture of FCDs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-09-2010
Publisher: Springer Science and Business Media LLC
Date: 11-2018
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.WATRES.2019.115314
Abstract: During the First Gulf War (1991) a large number of oil wells were destroyed and oil fires subsequently extinguished with seawater. As a result Kuwait's sparse fresh groundwater resources were severely contaminated with crude oil. Since then limited research has focused on the microbial community ecology of the groundwater and their impact on the associated contamination. Here, the microbial community ecology (bacterial, archaeal and eukaryotic) and how it relates to the characteristics of the hydrocarbon contaminants were examined for the first time since the 1991 event. This study was conducted using 15 wells along the main groundwater flow direction and detected several potential hydrocarbon degrading microorganisms such as Hyphomicrobiaceae, Porphyromonadaceae and Eurotiomycetes. The beta ersity of the microbial communities correlated significantly with total petroleum hydrocarbon (TPH) concentrations and salinity. The TPH consisted mainly of polar compounds present as an unresolved complex mixture (UCM) of a highly recalcitrant nature. Based on the proportions of TPH to dissolved organic carbon (DOC), the results indicate that some minor biodegradation has occurred within highly contaminated aquifer zones. However, overall the results from this study suggest that the observed variations in TPH concentrations among the s led wells are mainly induced by mixing/dilution with pristine groundwater rather than by biodegradation of the contaminants. The findings make an important contribution to better understand the fate of the groundwater pollution in Kuwait, with important implications for the design of future remediation efforts.
Publisher: American Medical Association (AMA)
Date: 06-2009
DOI: 10.1001/ARCHNEUROL.2009.108
Abstract: Automatisms are well recognized to occur in complex partial seizures however, their occurrence in generalized epilepsies is not always appreciated. There has been considerable debate regarding the nature, triggers, and timing of automatisms in absence seizures. To examine the frequency and nature of automatisms in new-onset absence seizures and assess the influence of the state of arousal, provocation, age, and epilepsy syndrome on the presence and type of automatisms. Analysis of absence seizures through video electroencephalogram (EEG) recordings. British Columbia's Children's Hospital, Vancouver, British Columbia, Canada. Seventy consecutive children with new-onset untreated absence seizures in idiopathic generalized epilepsy recruited between January 1, 1992, and June 30, 1997. Each seizure was analyzed for the presence and characteristics of automatisms. The influence of the following variables on the presence of automatisms was statistically analyzed: state of arousal (awake, drowsy, asleep), provocation (hyperventilation, photic stimulation), age, and epilepsy syndrome. Automatisms occurred in 163 of 405 seizures (40%) in 53 of 70 children (76%). Automatisms were more likely in longer seizures and hyperventilation. Only 23% of spontaneous awake seizures had automatisms. Automatisms were similar for an in idual child however, automatisms were not present in all their seizures. Age, epilepsy syndrome, or state of alertness had no effect on the presence of automatisms. Automatisms are frequently seen during childhood absence seizures. The high frequency of automatisms during EEG recordings is predominantly due to the effect of hyperventilation. Their preponderance during longer seizures may relate to opportunity for automatisms to occur. The characteristic pattern of automatisms suggests a reactive phenomenon to internal and external stimuli.
Publisher: Public Library of Science (PLoS)
Date: 05-05-2016
Publisher: Wiley
Date: 09-2013
DOI: 10.1002/ANA.23934
Publisher: Elsevier BV
Date: 12-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-12-2020
DOI: 10.1212/NXI.0000000000000924
Abstract: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody–associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort. Using a live cell–based assay, we diagnosed 271 adults with MOGAD (2013–2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement. We identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls ( p = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model. Myeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.
Publisher: Oxford University Press (OUP)
Date: 13-06-2014
DOI: 10.1093/HMG/DDU300
Publisher: Oxford University Press (OUP)
Date: 2023
DOI: 10.1093/BRAINCOMMS/FCAD156
Abstract: Pathogenic variants in HCN1 are an established cause of developmental and epileptic encephalopathy (DEE). To date, the stratification of patients with HCN1-DEE based on the biophysical consequence on channel function of a given variant has not been possible. Here, we analysed data from eleven patients carrying seven different de novo HCN1 pathogenic variants located in the transmembrane domains of the protein. All patients were diagnosed with severe disease including epilepsy and intellectual disability. The functional properties of the seven HCN1 pathogenic variants were assessed using two-electrode voltage-cl recordings in Xenopus oocytes. All seven variants showed a significantly larger instantaneous current consistent with cation leak. The impact of each variant on other biophysical properties was variable, including changes in the half activation voltage and activation and deactivation kinetics. These data suggest that cation leak is an important pathogenic mechanism in HCN1-DEE. Furthermore, published mouse model and clinical case reports suggest that seizures are exacerbated by sodium channel blockers in patients with HCN1 variants that cause cation leak. Stratification of patients based on their ‘cation leak’ biophysical phenotype may therefore provide key information to guide clinical management of in iduals with HCN1-DEE.
Publisher: Oxford University Press (OUP)
Date: 04-2003
DOI: 10.1093/BRAIN/AWG080
Abstract: Occipital epilepsies often elude diagnosis as they frequently masquerade as other seizure syndromes. Visual hallucinations are the key clinical symptoms indicating an occipital focus, but may be difficult to elicit on history, especially from children, and are not always present. When visual symptoms are not prominent, the seizure semiology and scalp EEG may lead the clinician away from considering an occipital focus, as they often reflect seizure propagation rather than seizure origin. Clinical and neuroimaging advances have led to the recognition of many new occipital epilepsy syndromes, which generally present in childhood or adolescence. Major groups include malformations of cortical development [focal cortical dysplasia, periventricular heterotopia (PVH), subcortical band heterotopia (SBH), polymicrogyria], vascular (including epilepsy with bilateral occipital calcifications often associated with coeliac disease), metabolic and the emerging idiopathic occipital epilepsies. The idiopathic occipital epilepsies now comprise three identifiable electroclinical syndromes of childhood and adolescence, the biological inter-relationships and overlap with idiopathic generalized epilepsies of which are discussed here. We emphasize the clues to recognition of specific occipital epilepsies, some of which now have specific treatments. Where medical therapy is ineffective, occipital corticectomy should be considered. Emerging evidence suggests that some syndromes have a good surgical outcome, and the consequences to visual function may be less severe than anticipated.
Publisher: Wiley
Date: 18-05-2021
DOI: 10.1002/ACN3.51381
Abstract: To compare the frequency and impact on the channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss‐of‐function KCNH2 variants as predictive biomarkers of SUDEP risk. We searched for KCNH2 variants with a minor allele frequency of %. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified. KCNH2 variants were found in 11.1% (10/90) of SUDEP in iduals compared to 6.0% (20/332) of epilepsy controls ( p = 0.11). Loss‐of‐function KCNH2 variants, defined as causing % reduction in maximal litude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about threefold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2% 2/90) and epilepsy control (2.7% 9/332) cohorts ( p 0.99). Rare KCNH2 variants ( % allele frequency) associated with greater loss of function and an ~11‐fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis. These data show that loss‐of‐function KCNH2 variants are enriched in SUDEP patients when compared to an epilepsy population older than 50 years, suggesting that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss‐of‐function KCNH2 variants that could act as biomarkers of an in idual’s SUDEP risk.
Publisher: Wiley
Date: 11-2012
DOI: 10.1002/ANA.23702
Abstract: We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs). The IGEs are common, heritable epilepsies that usually follow complex inheritance currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood-brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced. Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE. SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders.
Publisher: Wiley
Date: 25-01-2019
DOI: 10.1111/EPI.14653
Publisher: Oxford University Press (OUP)
Date: 16-06-2014
DOI: 10.1093/HMG/DDU306
Abstract: Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected in iduals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-08-2020
DOI: 10.1126/SCITRANSLMED.AAY6848
Abstract: A machine learning method can predict loss- versus gain-of-function effects of human genetic variants in disease-associated ion channels.
Publisher: Wiley
Date: 09-2001
DOI: 10.1046/J.1528-1157.2001.0420S5016.X
Abstract: Recent molecular insights into the human idiopathic epilepsies have suggested the central role of ligand-gated and voltage-gated ion channels in their etiology. So far, genes coding for sodium and potassium channel subunits as well as a nicotinic cholinergic receptor subunit have been identified for mendelian idiopathic epilepsies. In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights into mechanisms underlying hyperexcitability. Similarly, spontaneous murine epilepsy models have been associated with calcium channel molecular defects. The major challenge before us in understanding the genetics of the epilepsies is to identify genes for common forms of epilepsy following complex inheritance. Once such genes are discovered, the gene-gene-environmental interactions producing specific epilepsy syndromes can be explored.
Publisher: Wiley
Date: 09-09-2020
DOI: 10.1111/BPA.12891
Abstract: Sudden unexpected death in epilepsy (SUDEP) is mechanistically complex and one probable cause is seizure‐related respiratory dysfunction. Medullary respiratory regulatory nuclei include the pre‐Bötzinger complex (pre‐BötC) in the ventrolateral medulla (VLM), the medullary raphé nuclei (MR) and nucleus of solitary tract in the dorsomedial medulla (DMM). The region of the VLM also contains intermingled tyrosine hydroxylase (TH) catecholaminergic neurones which directly project to the pre‐BötC and regulate breathing under hypoxic conditions and our aim was to evaluate these neurones in SUDEP cases. In post‐mortem cases from three groups [SUDEP (18), epilepsy controls (8) and non‐epilepsy controls (16)] serial sections of medulla (obex + 2 to + 13 mm) were immunolabeled for TH. Three regions of interest (ROI) were outlined (VLM, DMM and MR) and TH‐immunoreactive (TH‐IR) neurones were evaluated using automated detection for overall labeling index (neurones and processes) and neuronal densities and compared between groups and relative to obex level. C‐fos immunoreactivity was also semi‐quantitatively evaluated in these regions. We found no significant difference in the density of TH‐IR neurones or labeling index between the groups in all regions. Significantly more TH‐IR neurones were present in the DMM region than VLM in non‐epilepsy cases only ( P 0.01). Regional variations in TH‐IR neurones with obex level were seen in all groups except SUDEP. We also identified occasional TH neurones in the MR region in all groups. There was significantly less c‐fos labeling in the VLM and MR in SUDEP than non‐epilepsy controls but no difference with epilepsy controls. In conclusion, in this series we found no evidence for alteration of total medullary TH‐IR neuronal numbers in SUDEP but noted some differences in their relative distribution in the medulla and c‐fos neurones compared to control groups which may be relevant to the mechanism of death.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-09-2020
DOI: 10.1212/WNL.0000000000010708
Abstract: To determine whether familial aggregation of status epilepticus (SE) occurs in a large cohort of familial common epilepsies. We used the Epilepsy Phenome/Genome Project dataset, which consisted of 2,197 participants in 1,043 family units with ≥2 members having a common generalized or nonacquired focal epilepsy (NAFE). We identified participants with a history of traditionally defined SE (TSE) (seizures ≥30 minutes) and operationally defined SE (OSE) (seizures ≥10 minutes) by chart review. We assessed familial aggregation of TSE and OSE using χ 2 analysis and generalized estimating equations (GEE). One hundred fifty-five (7%) participants in 1,043 families had ≥1 episodes of TSE. Two hundred fifty (11%) had ≥1 episodes of OSE. In a χ 2 analysis, the number of family units with ≥2 members having TSE (odds ratio [OR] 4.79, 95% confidence interval [CI] 2.56–8.97) or OSE (OR 4.23, 95% CI 2.67–6.70) was greater than expected by chance. In GEE models adjusted for sex, broad epilepsy class (GE or NAFE), age at onset, and duration of epilepsy, TSE in a proband predicted TSE in a first-degree relative (OR 2.79, 95% CI 1.24–6.22), and OSE in a proband predicted OSE in a first-degree relative (OR 2.91, 95% CI 1.65–5.15). The results remained significant in models addressing epilepsy severity by incorporating the number of antiseizure medications used or epilepsy surgery. TSE and OSE showed robust familial aggregation in a cohort of familial epilepsy independently of epilepsy severity or class, suggesting that genetic factors contribute to SE independently of the genetic cause of these epilepsies. NCT00552045.
Publisher: Wiley
Date: 19-02-2009
DOI: 10.1111/J.1469-8749.2008.03163.X
Abstract: Earlier research has suggested a link between epileptiform activity in the electroencephalogram (EEG) and developmental speech-language disorder (DSLD). This study investigated the strength of this association by comparing the frequency of EEG abnormalities in 45 language-normal children (29 males, 16 females mean age 6y 11mo, SD 1y 10mo, range 4y-9y 10mo) and 54 community-ascertained children (35 males, 19 females mean age 5y 7mo, SD 1y 6mo, range 4y-9y 11mo) with a diagnosis of severe DSLD, defined as a score at least 2 SD below the mean on at least one speech-language measure, and a performance IQ of at least 80 points. All participants underwent sleep EEGs after sedation. Children with DSLD also had detailed speech-language, hearing, and psychological assessments. Results failed to support the previously identified strong association between abnormal EEG and DSLD. There was a weak, non-significant relationship between DSLD and epileptiform EEG. Epileptiform EEG was significantly associated with low performance IQ (p=0.04). This study draws into question previously reported associations between epileptiform activity and DSLD probably because it examined a purer cohort of children with more severe language difficulties who did not have seizures.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.WATRES.2011.12.032
Abstract: Laboratory and field experiments were undertaken to assess the fate of N-nitrosodimethylamine (NDMA) in aerobic recycled water that was recharged into a deep anaerobic pyritic aquifer, as part of a managed aquifer recharge (MAR) strategy. Laboratory studies demonstrated a high mobility of NDMA in the Leederville aquifer system with a retardation coefficient of 1.1. Anaerobic degradation column and (14)C-NDMA microcosm studies showed that anaerobic conditions of the aquifer provided a suitable environment for the biodegradation of NDMA with first-order kinetics. At microgram per litre concentrations, inhibition of biodegradation was observed with degradation half-lives (260±20 days) up to an order of magnitude greater than at nanogram per litre concentrations (25-150 days), which are more typical of environmental concentrations. No threshold effects were observed at the lower ng L(-1) concentrations with NDMA concentrations reduced from 560 ng L(-1) to <6 ng L(-1) over a 42 day 14C-NDMA aerobic microcosm experiment. Aerobic (14)C-NDMA microcosm studies were also undertaken to assess potential aerobic degradation, likely to occur close to the recharge bore. These microcosm experiments showed a faster degradation rate than anaerobic microcosms, with a degradation half-life of 8±2 days, after a lag period of approximately 10 days. Results from a MAR field trial recharging the Leederville aquifer with aerobic recycled water showed that NDMA concentrations reduced from 2.5±1.0 ng L(-1) to 1.3±0.4 ng L(-1) between the recharge bore and a monitoring location 20 m down gradient (an estimated aquifer residence time of 10 days), consistent with data from the aerobic microcosm experiment. Further down gradient, in the anaerobic zone of the aquifer, NDMA degradation could not be assessed, as NDMA concentrations were too close to their analytical detection limit (<1 ng L(-1)).
Publisher: Cambridge University Press (CUP)
Date: 06-2019
DOI: 10.1017/CJN.2019.150
Abstract: Background: Sotos syndrome is a genetic condition caused by NSD1 alterations, characterized by overgrowth, macrocephaly, dysmorphic features, and learning disability. Approximately half of children with Sotos syndrome develop seizures. We investigated the spectrum of seizure phenotypes in these patients. Methods: Patients were recruited from clinics and referral from support groups. Those withclinical or genetic diagnosis of Sotos syndrome and seizures were included. Phenotyping data was collected via structured clinical interview and medical chart review. Results: 25 patients with typical Sotos syndrome features were included. Of 14 tested patients, 64% (n=9) had NSD1 alterations. Most had developmental impairment (80%, n=20) and neuropsychiatric comorbidities (68%, n=17). Seizure onset was variable (2 months to 12 years). Febrile and absence seizures were the most frequent types (64%, n=16). Afebrile generalized tonicclonic (40%, n=10) and atonic (24%, n=6) seizures followed. Most patients (60%, n=15) had multiple seizure types. The majority (72%, n=18) was controlled on a single antiepileptic, or none 4% (n=1) remained refractory to antiepileptics. Conclusions: The seizure phenotype in Sotos syndrome most commonly involves febrile convulsions or absence seizures. Afebrile tonic-clonic or atonic seizures may also occur. Seizures are typically well-controlled with antiepileptics. The rate of developmental impairment and neuropsychiatric comorbidities is high.
Publisher: Wiley
Date: 25-10-2012
DOI: 10.1111/EPI.12007
Abstract: Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike-waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in-frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE.
Publisher: Wiley
Date: 19-10-2020
DOI: 10.1111/EPI.16722
Publisher: Elsevier BV
Date: 12-2015
Publisher: Wiley
Date: 14-02-2013
DOI: 10.1111/EPI.12124
Abstract: Mutations in STXBP1 have been identified in a subset of patients with early onset epileptic encephalopathy (EE), but the full phenotypic spectrum remains to be delineated. Therefore, we screened a cohort of 160 patients with an unexplained EE, including patients with early myoclonic encephalopathy (EME), Ohtahara syndrome, West syndrome, nonsyndromic EE with onset in the first year, and Lennox-Gastaut syndrome (LGS). We found six de novo mutations in six patients presenting as Ohtahara syndrome (2/6, 33%), West syndrome (1/65, 2%), and nonsyndromic early onset EE (3/64, 5%). No mutations were found in LGS or EME. Only two of four mutation carriers with neonatal seizures had Ohtahara syndrome. Epileptic spasms were present in five of six patients. One patient with normal magnetic resonance imaging (MRI) but focal seizures underwent epilepsy surgery and seizure frequency dropped drastically. Neuropathology showed a focal cortical dysplasia type 1a. There is a need for additional neuropathologic studies to explore whether STXBP1 mutations can lead to structural brain abnormalities.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2019
DOI: 10.1038/S41598-019-48804-Y
Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC , has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1 , BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 20-12-2018
Publisher: Springer Science and Business Media LLC
Date: 09-2016
Publisher: American Medical Association (AMA)
Date: 2009
DOI: 10.1001/ARCHNEUROL.2008.559
Abstract: Voltage-gated sodium channels are critical for membrane excitability. Mutations in the genes coding for these proteins cause diseases related to altered excitability of cardiac or skeletal muscle and neurons. Mutations in the central nervous system-specific voltage-gated sodium channel alpha1 subunit gene (SCN1A) lead not only to seizure syndromes but also to familial hemiplegic migraine. The epilepsies range from benign febrile seizures to the catastrophic epileptic encephalopathy of Dravet syndrome (severe myoclonic epilepsy of infancy). Recently developed animal models of SCN1A mutants recapitulate the human disease. These models exemplify the potential inherent in translational research to debunk preconceived ideas regarding pathogenesis by showing the cellular substrate of Dravet syndrome to be interneurons rather than excitatory cells. This illustrates the key role that basic science plays in the development of targeted novel therapies and, ultimately, in the prevention of devastating genetic disorders.
Publisher: Cambridge University Press
Date: 14-04-2011
Publisher: Wiley
Date: 1999
DOI: 10.1002/1531-8249(199901)45:1<75::AID-ART13>3.0.CO;2-W
Abstract: We examined the phenotypic variation and clinical genetics in nine families with generalized epilepsy with febrile seizures plus (GEFS+). This genetic epilepsy syndrome with heterogeneous phenotypes was hitherto described in only one family. We obtained genealogical information on 799 in iduals and conducted detailed evaluation of 272 in iduals. Ninety-one in iduals had a history of seizures and 63 had epilepsy consistent with the GEFS+ syndrome. Epilepsy phenotypes were febrile seizures (FS) in 31, febrile seizures plus (FS+) in 15, FS+ with other seizure types (atonic, myoclonic, absence, or complex partial) in 8, and myoclonic-astatic epilepsy in 9 in iduals. Inheritance was autosomal dominant with approximately 60% penetrance. This study confirms and expands the spectrum of GEFS+ and provides new insights into the phenotypic relationships and genetics of FS and the generalized epilepsies of childhood. Moreover, the ability to identify large families with this newly recognized common, childhood-onset, generalized genetic epilepsy syndrome suggests that it should be a prime target for attempts to identify genes relevant to FS and generalized epilepsy.
Publisher: Wiley
Date: 06-2000
DOI: 10.1002/1531-8249(200006)47:6<840::AID-ANA28>3.0.CO;2-V
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-08-2014
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.WATRES.2011.02.018
Abstract: The fate of N-nitrosomorpholine (NMOR) was evaluated at microgram and nanogram per litre concentrations. Experiments were undertaken to simulate the passage of groundwater contaminants through a deep anaerobic pyritic aquifer system, as part of a managed aquifer recharge (MAR) strategy. Sorption studies demonstrated the high mobility of NMOR in the Leederville aquifer system, with retardation coefficients between 1.2 and 1.6. Degradation studies from a 351 day column experiment and a 506 day stop-flow column experiment showed an anaerobic biologically induced reductive degradation process which followed first order kinetics. A biological lag-time of less than 3 months and a transient accumulation of morpholine (MOR) were also noted during the degradation. Comparable half-life degradation rates of 40-45 days were observed over three orders of magnitude in concentration (200 ng L(-1) to 650 μg L(-1)). An inhibitory effect on microorganism responsible to the biodegradation of NMOR at 650 μg L(-1) or a threshold effect at 200 ng L(-1) was not observed during these experiments.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Elsevier BV
Date: 10-2023
Publisher: Elsevier BV
Date: 02-2022
Publisher: Springer Science and Business Media LLC
Date: 16-03-2202
Publisher: Springer Science and Business Media LLC
Date: 20-07-2023
DOI: 10.1038/S41467-023-39539-6
Abstract: Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 in iduals with seizure disorders, 16,109 in iduals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 in iduals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of in iduals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between in idual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.
Publisher: The Japan Epilepsy Society
Date: 30-06-2019
DOI: 10.3805/JJES.37.24
Publisher: Wiley
Date: 08-03-2017
DOI: 10.1111/EPI.13670
Abstract: The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) "partial" becomes "focal" (2) awareness is used as a classifier of focal seizures (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset (6) focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.
Publisher: Wiley
Date: 08-03-2017
DOI: 10.1111/EPI.13671
Abstract: This companion paper to the introduction of the International League Against Epilepsy (ILAE) 2017 classification of seizure types provides guidance on how to employ the classification. Illustration of the classification is enacted by tables, a glossary of relevant terms, mapping of old to new terms, suggested abbreviations, and ex les. Basic and extended versions of the classification are available, depending on the desired degree of detail. Key signs and symptoms of seizures (semiology) are used as a basis for categories of seizures that are focal or generalized from onset or with unknown onset. Any focal seizure can further be optionally characterized by whether awareness is retained or impaired. Impaired awareness during any segment of the seizure renders it a focal impaired awareness seizure. Focal seizures are further optionally characterized by motor onset signs and symptoms: atonic, automatisms, clonic, epileptic spasms, or hyperkinetic, myoclonic, or tonic activity. Nonmotor-onset seizures can manifest as autonomic, behavior arrest, cognitive, emotional, or sensory dysfunction. The earliest prominent manifestation defines the seizure type, which might then progress to other signs and symptoms. Focal seizures can become bilateral tonic-clonic. Generalized seizures engage bilateral networks from onset. Generalized motor seizure characteristics comprise atonic, clonic, epileptic spasms, myoclonic, myoclonic-atonic, myoclonic-tonic-clonic, tonic, or tonic-clonic. Nonmotor (absence) seizures are typical or atypical, or seizures that present prominent myoclonic activity or eyelid myoclonia. Seizures of unknown onset may have features that can still be classified as motor, nonmotor, tonic-clonic, epileptic spasms, or behavior arrest. This "users' manual" for the ILAE 2017 seizure classification will assist the adoption of the new system.
Publisher: Springer Science and Business Media LLC
Date: 15-10-2019
DOI: 10.1038/S41467-019-12435-8
Abstract: Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2 —whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
Publisher: Wiley
Date: 19-11-2019
DOI: 10.1002/ANA.25619
Publisher: Hindawi Limited
Date: 06-04-2020
DOI: 10.1002/HUMU.24015
Publisher: Elsevier BV
Date: 09-2015
Publisher: Wiley
Date: 18-01-2017
DOI: 10.1111/EPI.13666
Abstract: Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications.
Publisher: BMJ
Date: 05-07-2022
DOI: 10.1136/JMEDGENET-2021-108177
Abstract: To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in in iduals with bi-allelic variants in Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG. Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.
Publisher: Wiley
Date: 16-07-2018
DOI: 10.1111/EPI.14516
Publisher: Wiley
Date: 18-11-2019
DOI: 10.1002/ANA.25625
Publisher: Wiley
Date: 21-01-2021
DOI: 10.1111/EPI.16810
Abstract: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. A population‐based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. Seventy‐three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS‐like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS‐like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe–profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe–profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS‐like," or "unifocal epilepsy" had severe–profound delay, and only two of 64 (3%) were deceased. Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
Publisher: Elsevier BV
Date: 2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-03-2016
Publisher: Wiley
Date: 12-1998
Abstract: Familial partial epilepsy with variable foci (FPEVF) joins the recently recognized group of inherited partial epilepsies. We describe an Australian family with 10 in iduals with partial seizures over four generations. Detailed electroclinical studies were performed on all affected and 17 clinically unaffected family members. The striking finding was that the clinical features of the seizures and interictal electroencephalographic foci differed among family members and included frontal, temporal, occipital, and centroparietal seizures. Mean age of seizure onset was 13 years (range, 0.75-43 years). Two in iduals without seizures had epileptiform abnormalities on electroencephalographic studies. Penetrance of seizures was 62%. A genome-wide search failed to demonstrate definitive linkage, but a suggestion of linkage was found on chromosome 2q with a LOD score of 2.74 at recombination fraction of zero with the marker D2S133. FPEVF differs from the other inherited partial epilepsies where partial seizures in different family members are clinically similar. The inherited nature of this new syndrome may be overlooked because of relatively low penetrance and because of the variability in age at onset and electroclinical features between affected family members.
Publisher: Wiley
Date: 08-06-2016
DOI: 10.1111/EPI.13422
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-04-2021
DOI: 10.1212/WNL.0000000000011698
Abstract: To determine whether specific speech, language, and oromotor profiles are associated with different patterns of polymicrogyria, we assessed 52 patients with polymicrogyria using a battery of standardized tests and correlated findings with topography and severity of polymicrogyria. Patients were identified via clinical research databases and invited to participate, irrespective of cognitive and verbal language abilities. We conducted standardized assessments of speech, oromotor structure and function, language, and nonverbal IQ. Data were analyzed according to normative assessment data and descriptive statistics. We conducted a correlation analysis between topographic pattern and speech and language findings. Fifty-two patients (33 male, 63%) were studied at an average age of 12.7 years (range 2.5–36 years). All patients had dysarthria, which ranged from mild impairment to anarthria. Developmental speech errors (articulation and phonology), oral motor structure and function deficits, and language disorder were frequent. A total of 23/29 (79%) had cognitive abilities in the low average to extremely low range. In the perisylvian polymicrogyria group (36/52), speech, everyday language, and oral motor impairments were more severe, compared to generalized (1 patient), frontal (3), polymicrogyria with periventricular nodular heterotopia (3), parasagittal parieto-occipital (1), mesial occipital (1), and other (7) patterns. Dysarthria is a core feature of polymicrogyria, often accompanied by receptive and expressive language impairments. These features are associated with all polymicrogyria distribution patterns and more severe in in iduals with bilateral polymicrogyria, particularly in the perisylvian region.
Publisher: Elsevier BV
Date: 11-2001
DOI: 10.1016/S0387-7604(01)00272-8
Abstract: The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no etiology is found on imaging and metabolic studies, and genetic factors are important. Myoclonic-astatic epilepsy (MAE) and severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome, are epileptic encephalopathies where multiple seizure types begin in the first few years of life associated with developmental slowing. Clinical and molecular genetic studies of the families of probands with MAE and SMEI suggest a genetic basis. MAE was originally identified as part of the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus (GEFS(+)). Recent clinical genetic studies suggest that SMEI forms the most severe end of the spectrum of the GEFS(+). GEFS(+) has now been associated with molecular defects in three sodium channel subunit genes and a GABA subunit gene. Molecular defects of these genes have been identified in patients with MAE and SMEI. Interestingly, the molecular defects in MAE have been found in the setting of large GEFS(+) pedigrees, whereas, more severe truncation mutations arising de novo have been identified in patients with SMEI. It is likely that future molecular studies will shed light on the interaction of a number of genes, possibly related to the same or different ion channels, which result in a severe phenotype such as MAE and SMEI.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-11-2021
DOI: 10.1212/WNL.0000000000012784
Abstract: To determine the period prevalence and incidence of treated epilepsy in a New Zealand pediatric cohort with a focus on ethnicity and socioeconomic status. This was a retrospective cohort study. The New Zealand Pharmaceutical Collection database was searched for in iduals ≤18 years of age dispensed an antiseizure medication (ASM) in 2015 from areas capturing 48% of the New Zealand pediatric population. Medical records of identified cases were reviewed to ascertain the indication for the ASM prescription. Population data were derived from the New Zealand 2013 Census. A total of 3,557 ASMs were prescribed during 2015 in 2,594 children, of whom 1,717 (66%) children had epilepsy. An indication for prescription was ascertained for 3,332/3,557 (94%) ASMs. The period prevalence of treated epilepsy was 3.4 per 1,000 children. Children in the most deprived areas had 1.9 times the rate of treated epilepsy (95% confidence interval [CI] 1.6–2.2) as those from the least deprived areas. Prevalence was similar for most ethnic groups (European/other: 3.7, 95% CI 3.4–3.9 Pacific Peoples: 3.6, 95% CI 3.2–4.1 Māori: 3.4, 95% CI 3.1–3.8) apart from Asians, who had a lower prevalence of 2.3 per 1,000 (95% CI 2.0–2.6). However, when adjusted for socioeconomic deprivation, the prevalence of epilepsy was highest in European and similar in Māori, Pacific, and Asian children. This is the largest pediatric epidemiology epilepsy study where diagnosis of epilepsy was confirmed by case review. This is the first study to provide epidemiologic information for pediatric epilepsy in Māori and Pacific children.
Publisher: Oxford University Press (OUP)
Date: 23-02-2019
DOI: 10.1093/BRAIN/AWZ018
Abstract: Speech disorders are highly prevalent in the preschool years, but frequently resolve. The neurobiological basis of the most persistent and severe form, apraxia of speech, remains elusive. Current neuroanatomical models of speech processing in adults propose two parallel streams. The dorsal stream is involved in sound to motor speech transformations, while the ventral stream supports sound/letter to meaning. Data-driven theories on the role of these streams during atypical speech and language development are lacking. Here we provide comprehensive behavioural and neuroimaging data on a large novel family where one parent and 11 children presented with features of childhood apraxia of speech (the same speech disorder associated with FOXP2 variants). The genetic cause of the disorder in this family remains to be identified. Importantly, in this family the speech disorder is not systematically associated with language or literacy impairment. Brain MRI scanning in seven children revealed large grey matter reductions over the left temporoparietal region, but not in the basal ganglia, relative to typically-developing matched peers. In addition, we detected white matter reductions in the arcuate fasciculus (dorsal language stream) bilaterally, but not in the inferior fronto-occipital fasciculus (ventral language stream) nor in primary motor pathways. Our findings identify disruption of the dorsal language stream as a novel neural phenotype of developmental speech disorders, distinct from that reported in speech disorders associated with FOXP2 variants. Overall, our data confirm the early role of this stream in auditory-to-articulation transformations. 10.1093/brain/awz018_video1 awz018media1 6018582401001.
Publisher: Wiley
Date: 06-02-2012
DOI: 10.1111/J.1528-1167.2011.03394.X
Abstract: We report the efficacy of the ketogenic diet in refractory epilepsies focusing on outcomes with regard to epilepsy syndromes and etiology in children and adults with refractory epilepsy. Sixty-four consecutive children and four adults were prospectively enrolled from 2002 to 2009 seven were excluded from analysis. The classical ketogenic diet was initiated on an inpatient basis with dietary ratios ranging from 2:1 to 4:1 fat to carbohydrate and protein. Patients were classified according to syndrome and etiology using the 1989 and more recent 2010 International League Against Epilepsy (ILAE) classification systems. Responders were defined as >50% reduction in seizure frequency compared to baseline. Syndromes included symptomatic generalized (52), genetic (idiopathic) generalized (7), and focal epilepsies (2) and etiologies included structural (24), genetic (18), and unknown (19). Twenty-nine (48%) of 61 patients were responders at 3 months. Two children became seizure-free: one with focal epilepsy of unknown etiology and another with refractory childhood absence epilepsy. Responsive syndromes included migrating partial epilepsy of infancy, childhood absence epilepsy, focal epilepsy, epilepsy with myoclonic-atonic seizures, and Dravet syndrome. Children with lissencephaly and hypoxic ischemic encephalopathy had surprisingly good responses. The ketogenic diet is an effective treatment for children and adults with refractory epilepsy. The response is predicted by type of epilepsy syndrome. Accurate characterization of the electroclinical syndrome is an important factor in decisions about timing of initiation of the ketogenic diet.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2013
DOI: 10.1038/NG.2646
Publisher: Cold Spring Harbor Laboratory
Date: 14-10-2021
DOI: 10.1101/MCS.A006133
Abstract: Nevus sebaceous syndrome (NSS) is a rare, multisystem neurocutaneous disorder, characterized by a congenital nevus, and may include brain malformations such as hemimegalencephaly or focal cortical dysplasia, ocular, and skeletal features. It has been associated with several eponyms including Schimmelpenning and Jadassohn. The isolated skin lesion, nevus sebaceous, is associated with postzygotic variants in HRAS or KRAS in all in iduals studied. The RAS proteins encode a family of GTPases that form part of the RAS/MAPK signaling pathway, which is critical for cell cycle regulation and differentiation during development. We studied an in idual with nevus sebaceous syndrome with an extensive nevus sebaceous, epilepsy, intellectual disability, and hippoc al sclerosis without pathological evidence of a brain malformation. We used high-depth gene panel sequencing and droplet digital polymerase chain reaction (PCR) to detect and quantify RAS/MAPK gene variants in nevus sebaceous and temporal lobe tissue collected during plastic and epilepsy surgery, respectively. A mosaic KRAS c.34G T p.(Gly12Cys) variant, also known as G12C, was detected in nevus sebaceous tissue at 25% variant allele fraction (VAF), at the residue most commonly substituted in KRAS . Targeted droplet digital PCR validated the variant and quantified the mosaicism in other tissues. The variant was detected at 33% in temporal lobe tissue but was absent from blood and healthy skin. We provide molecular confirmation of the clinical diagnosis of NSS. Our data extends the histopathological spectrum of KRAS G12C mosaicism beyond nevus sebaceous to involve brain tissue and, more specifically, hippoc al sclerosis.
Publisher: American Medical Association (AMA)
Date: 06-2022
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.BRAINDEV.2009.01.001
Abstract: Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+) can both arise due to mutations of SCN1A, the gene encoding the alpha 1 pore-forming subunit of the sodium channel. GEFS+ refers to a familial epilepsy syndrome where at least two family members have phenotypes that fit within the GEFS+ spectrum. The GEFS+ spectrum comprises a range of mild to severe phenotypes varying from classical febrile seizures to Dravet syndrome. Dravet syndrome is a severe infantile onset epilepsy syndrome with multiple seizure types, developmental slowing and poor outcome. More than 70% of patients with Dravet syndrome have mutations of SCN1A these include both truncation and missense mutations. In contrast, only 10% of GEFS+ families have SCN1A mutations and these comprise missense mutations. GEFS+ has also been associated with mutations of genes encoding the sodium channel beta 1 subunit, SCN1B, and the GABA(A) receptor gamma 2 subunit, GABRG2. The phenotypic heterogeneity that is characteristic of GEFS+ families is likely to be due to modifier genes. Interpretation of the significance of a SCN1A missense mutation requires a thorough understanding of the phenotypes in the GEFS+ spectrum whereas a de novo truncation mutation is likely to be associated with a severe phenotype. Early recognition of Dravet syndrome is important as aggressive control of seizures may improve developmental outcome.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2023
DOI: 10.1038/S41431-022-01166-Y
Abstract: Several neurological disorders, such as myotonic dystrophy are caused by expansions of short tandem repeats (STRs) which can be difficult to detect by molecular tools. Methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. We recruited a multi-generational family (family A) ascertained for genetic studies of autism spectrum disorder. WGS was performed on seven children from four nuclear families from family A and analyzed for REs of STRs known to cause neurological disorders. We detected an expansion of a heterozygous intronic CCTG STR in CNBP in two siblings. This STR causes myotonic dystrophy type 2 (DM2). The expansion did not segregate with the ASD phenotype. Repeat-primed PCR showed that the DM2 CCTG motif was expanded above the pathogenic threshold in both children and their mother. On subsequent examination, the mother had mild features of DM2. We show that screening of STRs in WGS datasets has diagnostic utility, both in the clinical and research domain, with potential management and genetic counseling implications.
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2AY00221C
Abstract: The legacy use of aqueous film-forming foam (AFFF) has led to the generation of large volumes of per- and poly-fluoroalkyl substances (PFAS)-contaminated asphalt materials, especially at airports and fire training areas.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2014
Publisher: Elsevier BV
Date: 05-2007
Publisher: Wiley
Date: 06-11-2019
DOI: 10.1111/DMCN.14087
Abstract: There are hundreds of compounds found in the marijuana plant, each contributing differently to the antiepileptic and psychiatric effects. Cannabidiol (CBD) has the most evidence of antiepileptic efficacy and does not have the psychoactive effects of ∆
Publisher: Elsevier BV
Date: 12-2019
Publisher: Georg Thieme Verlag KG
Date: 2006
Publisher: Springer Science and Business Media LLC
Date: 12-06-2023
DOI: 10.1186/S13023-023-02745-Y
Abstract: We refine the clinical spectrum of FOXG1 syndrome and expand genotype–phenotype correlations through evaluation of 122 in iduals enrolled in an international patient registry. The FOXG1 syndrome online patient registry allows for remote collection of caregiver-reported outcomes. Inclusion required documentation of a (likely) pathogenic variant in FOXG1 . Caregivers were administered a questionnaire to evaluate clinical severity of core features of FOXG1 syndrome. Genotype–phenotype correlations were determined using nonparametric analyses. We studied 122 registry participants with FOXG1 syndrome, aged 12 months to 24 years. Caregivers described delayed or absent developmental milestone attainment, seizures (61%), and movement disorders (58%). Participants harbouring a missense variant had a milder phenotype. Compared to in iduals with gene deletions (0%) or nonsense variants (20%), missense variants were associated with more frequent attainment of sitting (73%). Further, in iduals with missense variants (41%) achieved independent walking more frequently than those with gene deletions (0%) or frameshift variants (6%). Presence of epilepsy also varied by genotype and was significantly more common in those with gene deletions (81%) compared to missense variants (47%). In iduals with gene deletions were more likely to have higher seizure burden than other genotypes with 53% reporting daily seizures, even at best control. We also observed that truncations preserving the forkhead DNA binding domain were associated with better developmental outcomes. We refine the phenotypic spectrum of neurodevelopmental features associated with FOXG1 syndrome. We strengthen genotype-driven outcomes, where missense variants are associated with a milder clinical course.
Publisher: Springer Science and Business Media LLC
Date: 26-01-2021
DOI: 10.1038/S41416-020-01185-W
Abstract: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. For pregnanediol-3-glucuronide, there were no genome-wide significant associations for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10 –18 ) in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10 –8 ). The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
Publisher: Elsevier BV
Date: 11-1995
DOI: 10.1016/0920-1211(95)00049-6
Abstract: Familial frontal epilepsy has been recently described in six pedigrees. All families reported show autosomal dominant inheritance with incomplete penetrance. Affected in iduals develop predominantly nocturnal seizures with frontal lobe semiology. In 1959, a genetic mouse model for partial epilepsy, the El mouse, was reported. In the El mouse, a major seizure susceptibility gene, El-1, segregates in an autosomal dominant fashion and has been localized to a region distal to the centromere of mouse ch 9. Comparative genetic maps between man and mouse have been used to predict the location of several human disease genes. The El-1 locus in the mouse is homologous to human chromosomes 3p23-p21.2, 3p11.2-q11.2, 3q21-q25.3, 6p12-q12 and 15q24. Polymorphic microsatellite markers covering these candidate regions were used for genotyping in iduals in the three larger families ascertained, one of which is French-Canadian and two are Australian. Significant negative two-point and multipoint lod scores were obtained separately for each family, thus excluding linkage with the candidate regions on chromosomes 3, 6 and 15.
Publisher: Public Library of Science (PLoS)
Date: 12-03-2015
Publisher: Wiley
Date: 31-01-2017
DOI: 10.1111/EPI.13676
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.EPLEPSYRES.2015.04.014
Abstract: To describe clinical and EEG phenotypes of a family with an unusual familial epilepsy syndrome characterized by myoclonus and dystonia. Family members underwent electroclinical phenotyping including review of EEGs and MRI. DNA from family members was genotyped using Illumina OmniExpress genotyping arrays. Parametric and nonparametric linkage analyses were performed using MERLIN. The disorder followed autosomal dominant (AD) inheritance and affected seven in iduals over two generations. Seizures began at a mean of 14.5 years. Six in iduals had spontaneous myoclonic seizures, of which five also had photic-induced myoclonus and four had photic-induced occipital seizures. Six in iduals had convulsive seizures generalized in two and focal in four. Photosensitivity was prominent with generalized spike wave and polyspike wave in four in iduals of which two also had occipital spikes. MRI scans were normal in the four in iduals tested. Extensive metabolic investigation was normal. Juvenile myoclonic epilepsy (JME) occurred in two and JME overlapping with idiopathic photosensitive epilepsy (IPOE) in four in iduals. All three affected males had a more severe disorder than the four affected females. Two males had a progressive neurological disorder with progressive myoclonus epilepsy and deterioration in their early 30s. They developed episodes of paroxysmal cervical dystonia with cognitive decline during periods of poor seizure control. One plateaued after years of poor seizure control but remained intractable with periods of deterioration. The other deteriorated with episodes of status dystonicus and status epilepticus, ataxia and a progressive ophthalmoplegia before succumbing at 38 years. Parametric linkage analysis identified three peaks achieving a maximum LOD score of 1.21. Nonparametric analysis identified eight peaks achieving LOD scores above 0.80. These were not statistically significant. This is a novel autosomal dominant familial epilepsy syndrome. "Myoclonic occipital photosensitive epilepsy with dystonia" (MOPED) involves a spectrum of phenotypes from JME, sometimes with an IPOE overlap, to progressive myoclonus epilepsy with paroxysmal dystonia.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 11-2020
Publisher: American Academy of Pediatrics (AAP)
Date: 04-2017
Abstract: Dravet syndrome (DS) is a well-recognized developmental and epileptic encephalopathy associated with SCN1A mutations and 15% mortality by 20 years. Although over half of cases succumb to sudden unexpected death in epilepsy, the cause of death in the remainder is poorly defined. We describe the clinical, radiologic, and pathologic characteristics of a cohort of children with DS and SCN1A mutations who developed fatal cerebral edema causing mass effect after fever-associated status epilepticus. Cases were identified from a review of children with DS enrolled in the Epilepsy Genetics Research Program at The University of Melbourne, Austin Health, who died after fever-associated status epilepticus. Five children were identified, all of whom presented with fever-associated convulsive status epilepticus, developed severe brain swelling, and died. All had de novo SCN1A mutations. Fever of 40°C or greater was measured in all cases. Signs of brainstem dysfunction, indicating cerebral herniation, were first noted 3 to 5 days after initial presentation in 4 patients, though were apparent as early as 24 hours in 1 case. When MRI was performed early in a patient’s course, focal regions of cortical diffusion restriction were noted. Later MRI studies demonstrated diffuse cytotoxic edema, with severe cerebral herniation. Postmortem studies revealed diffuse brain edema and widespread neuronal damage. Laminar necrosis was seen in 1 case. Cerebral edema leading to fatal brain herniation is an important, previously unreported sequela of status epilepticus in children with DS. This potentially remediable complication may be a significant contributor to the early mortality of DS.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41467-019-12763-9
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same in idual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
Publisher: The Japan Epilepsy Society
Date: 30-06-2019
DOI: 10.3805/JJES.37.6
Publisher: Springer Science and Business Media LLC
Date: 11-2018
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
DOI: 10.1038/NG.3826
Publisher: Cold Spring Harbor Laboratory
Date: 13-10-2023
Publisher: Springer Science and Business Media LLC
Date: 05-1995
DOI: 10.1038/NG0595-117
Abstract: The epilepsies comprise a group of syndromes that are ided into generalized and partial (focal) types. Familial occurrence has long been recognized but progress in mapping epilepsy genes has been slow except for rare cases where the inheritance is easily determined from classical genetic studies. Linkage is established for three generalized syndromes: the EBN1 and EBN2 genes for benign familial neonatal convulsions (BFNC) map to chromosomes 20q and 8q (refs 2-5), the EPM1 gene for Unverricht-Lundborg disease maps to 21q (ref. 6) and the gene for the northern epilepsy syndrome maps to 8p (ref. 7). A claim for linkage of the EJM1 gene for the common generalized syndrome of juvenile myoclonic epilepsy to 6p is currently in dispute. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was recently described in five families. We now report the chromosomal assignment, to 20q13.2, for the gene for ADNFLE in one large Australian kindred with 27 affected in iduals spanning six generations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-02-2015
Publisher: Springer Science and Business Media LLC
Date: 19-10-2011
DOI: 10.1007/S10067-011-1854-7
Abstract: The availability of population-specific normative data regarding disease severity measures is essential for patient assessment. The goals of the current study were to characterize the pattern of ankylosing spondylitis (AS) in Portuguese patients and to develop reference centile charts for BASDAI, BASFI, BASMI and mSASSS, the most widely used assessment tools in AS. AS cases were recruited from hospital outpatient clinics, with AS defined according to the modified New York criteria. Demographic and clinical data were recorded. All radiographs were evaluated by two independent experienced readers. Centile charts for BASDAI, BASFI, BASMI and mSASSS were constructed for both genders, using generalized linear models and regression models with duration of disease as independent variable. A total of 369 patients (62.3% male, mean ± (SD) age 45.4 ± 13.2 years, mean ± (SD) disease duration 11.4 ± 10.5 years, 70.7% B27-positive) were included. Family history of AS in a first-degree relative was reported in 17.6% of the cases. Regarding clinical disease pattern, at the time of assessment 42.3% had axial disease, 2.4% peripheral disease, 40.9% mixed disease and 7.1% isolated enthesopatic disease. Anterior uveitis (33.6%) was the most common extra-articular manifestation. The centile charts suggest that females reported greater disease activity and more functional impairment than males but had lower BASMI and mSASSS scores. Data collected through this study provided a demographic and clinical profile of patients with AS in Portugal. The development of centile charts constitutes a useful tool to assess the change of disease pattern over time and in response to therapeutic interventions.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Wiley
Date: 14-08-2007
DOI: 10.1002/ANA.21169
Abstract: The relationship between genetic variation in the T-type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which CACNA1H variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures. Exons 3 to 35 of CACNA1H were screened for variants in 240 epilepsy patients (167 unrelated) and 95 control subjects by single-stranded conformation analysis followed by direct sequencing. Cascade testing of families was done by sequencing or single-stranded conformation analysis. Selected variants were introduced into the CACNA1H protein by site-directed mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired. More than 100 variants were detected, including 19 novel variants leading to amino acid changes in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy. Electrophysiological analysis of 11 variants showed that 9 altered channel properties, generally in ways that would be predicted to increase calcium current. Variants in CACNA1H that alter channel properties are present in patients with various generalized epilepsy syndromes. We propose that these variants contribute to an in idual's susceptibility to epilepsy but are not sufficient to cause epilepsy on their own. The genetic architecture is dominated by rare functional variants therefore, CACNA1H would not be easily identified as a susceptibility gene by a genome-wide case-control study seeking a statistical association.
Publisher: Wiley
Date: 23-05-2007
DOI: 10.1111/J.1528-1167.2007.01138.X
Abstract: Photosensitive epilepsy is less frequent among males than females. Red is the most epileptogenic color. The X-linked red pigment gene contains the polymorphism Ser180Ala the Ser180 allele increases red sensitivity. We hypothesized that the paucity of males with photosensitive epilepsy is explained by the distribution of this sex-linked allele, and predicted photosensitive males would have a low frequency of this allele. We genotyped 35 males with photosensitive epilepsy and 84 male controls. Allele frequencies did not differ between these groups. The hypothesis was not supported, so alternate reasons for the sex bias in photosensitive epilepsy must be sought.
Publisher: Wiley
Date: 26-06-2019
DOI: 10.1002/ANA.25522
Abstract: Recent reports have described single in iduals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-cl recording. Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-cl recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019 :181-192.
Publisher: Georg Thieme Verlag KG
Date: 02-1992
Abstract: Autosomal recessive microcephaly has long been recognized in association with normal early motor development and mild to severe mental retardation. We report three sibling pairs with microcephaly and severe neurological impairment. These cases and other sibling pairs reported in the literature illustrate that microcephaly with spasticity and severe mental retardation may also have autosomal recessive inheritance. Furthermore this severely affected group of patients forms a significant proportion of cases of genetic microcephaly. We looked for specific morphological features to identify these forms of genetic microcephaly for genetic counselling, but failed to find characteristic abnormalities among our group of patients.
Publisher: Wiley
Date: 13-01-2017
DOI: 10.1111/EPI.13649
Abstract: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by heterogeneous phenotypes ranging from mild disorders such as febrile seizures to epileptic encephalopathies (EEs) such as Dravet syndrome (DS). Although DS often occurs with de novo SCN1A pathogenic variants, milder GEFS+ spectrum phenotypes are associated with inherited pathogenic variants. We identified seven cases with non-EE GEFS+ phenotypes and de novo SCN1A pathogenic variants, including a monozygotic twin pair. Febrile seizures plus (FS+) occurred in six patients, five of whom had additional seizure types. The remaining case had childhood-onset temporal lobe epilepsy without known febrile seizures. Although early development was normal in all in iduals, three later had learning difficulties, and the twin girls had language impairment and working memory deficits. All cases had SCN1A missense pathogenic variants that were not found in either parent. One pathogenic variant had been reported previously in a case of DS, and the remainder were novel. Our finding of de novo pathogenic variants in mild phenotypes within the GEFS+ spectrum shows that mild GEFS+ is not always inherited. SCN1A screening should be considered in patients with GEFS+ phenotypes because identification of pathogenic variants will influence antiepileptic therapy, and prognostic and genetic counseling.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-10-2012
Publisher: American Medical Association (AMA)
Date: 06-2023
DOI: 10.1001/JAMANEUROL.2023.0473
Abstract: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. To test the association between pathogenic somatic variants in the hippoc us and MTLE. This case-control genetic association study analyzed the DNA derived from hippoc al tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy–associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Drug-resistant MTLE. Presence and abundance of pathogenic somatic variants in the hippoc us vs the unaffected temporal neocortex. Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippoc us relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9] P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11 , SOS1 , KRAS , BRAF , and NF1 , all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippoc al tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Hippoc al somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.
Publisher: Hindawi Limited
Date: 12-2005
DOI: 10.1111/J.1600-0404.2005.00509.X
Abstract: Recent exciting developments in epilepsy genetics have led to significant insights into the mechanisms underlying seizure disorders. Success in epilepsy genetics research to date has resulted from identification of genes responsible for rare monogenic disorders, the majority encoding either voltage- or ligand-gated ion channels. For some conditions, such as benign familial neonatal seizures, an understanding of the underlying genetics is helpful in predicting prognosis. However, for other disorders, such as autosomal dominant nocturnal frontal lobe epilepsy, phenotypic severity is determined by factors other than the major dominant nicotinic subunit mutation found in some families. Further complexity arises when single-gene mutations give rise to heterogeneous phenotypes, as typically occur with generalized epilepsy with febrile seizures plus. Another area of increasing genetic endeavour, pharmacogenetics will allow tailoring of antiepileptic medication for each patient. Pharmacogenetics explores genetic polymorphisms in genes coding for drug-metabolizing enzymes, receptors and transporters. Polymorphisms have been identified that result in marked ethnic and interin idual differences in response to treatment. With further understanding of the impact of these differences, pharmacogenetic screening is likely to guide the management of epilepsy in the future.
Publisher: Oxford University Press (OUP)
Date: 28-03-2018
DOI: 10.1093/BRAIN/AWY078
Publisher: Springer Science and Business Media LLC
Date: 11-08-2013
DOI: 10.1038/NG.2727
Publisher: Wiley
Date: 04-03-2019
DOI: 10.1111/DMCN.14186
Abstract: To assess the relevance and generalizability across countries of concepts of the impact of Dravet syndrome beyond seizures, as recognized by families. Caregivers of children with Dravet syndrome in four countries (Australia [n=8] USA, UK, and Italy [all n=4]) participated in 1-hour qualitative telephone interviews, identifying key Dravet syndrome concepts. Interviews were recorded, transcribed, and, where necessary, translated into English for thematic analysis. Conceptual saturation was assessed and findings compared to the previously developed French conceptual disease model. The most common seizure types reported by caregivers were tonic-clonic, absence, or focal-impaired awareness (localized artial). Fever and physical activity were the most commonly reported triggers. Patient-relevant impacts included impairment in cognition, motor skills, communication, social skills, and behavioural functioning. Caregivers consistently reported negative social, physical, and family impacts. Concepts identified in the interviews showed similarity with the French conceptual model. Minor differences between countries are likely to reflect variations in health care systems. Findings in Italy, Australia, UK, and USA confirm that the key impacts of Dravet syndrome on children and caregivers identified in France are generalizable across countries. Key symptom and impact concepts relevant to children and parents should be targeted as critical outcomes in new therapy evaluations. Relevance of the impact of Dravet syndrome on children and caregivers was confirmed across countries. Patient and caregiver-relevant Dravet syndrome impacts contribute to poorer health-related quality of life. Indirect seizure impacts were reported to be as important as direct impacts. Country-specific differences in concepts probably reflect differences in health care systems.
Publisher: Oxford University Press (OUP)
Date: 23-02-2006
DOI: 10.1093/HMG/DDL035
Abstract: The rolandic and sylvian fissures ide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.
Publisher: SAGE Publications
Date: 07-2011
DOI: 10.5698/1535-7511-11.4.107
Abstract: With the burgeoning array of molecular tests available in the epilepsies, the clinician needs to know which tests to order for each patient. Epileptic encephalopathies are the most important clinical group for genetic testing with an increasing number of distinctive epilepsy syndromes being recognized. Identification of the causative mutation affects treatment as well as prognostic and genetic counseling.
Publisher: Springer Science and Business Media LLC
Date: 04-2007
DOI: 10.1016/J.NURT.2007.01.009
Abstract: Approximately 70% of all patients with epilepsy lack an obvious extraneous cause and are presumed to have a predominantly genetic basis. Both familial and de novo mutations in neuronal voltage-gated and ligand-gated ion channel subunit genes have been identified in autosomal dominant epilepsies. However, patients with dominant familial mutations are rare and the majority of idiopathic epilepsy is likely to be the result of polygenic susceptibility alleles (complex epilepsy). Data on the identity of the genes involved in complex epilepsy is currently sparse but again points to neuronal ion channels. The number of genes and gene families associated with epilepsy is rapidly increasing and this increase is likely to escalate over the coming years with advances in mutation detection technologies. The genetic heterogeneity underlying idiopathic epilepsy presents challenges for the rational selection of therapies targeting particular ion channels. Too little is currently known about the genetic architecture of the epilepsies, and genetic testing for the known epilepsy genes remains costly. Pharmacogenetic studies have yet to explain why 30% of patients do not respond to the usual antiepileptic drugs. Despite this, the recognition that the idiopathic epilepsies are a group of channelopathies has, to a limited extent, explained the therapeutic action of the common antiepileptic drugs and has assisted clinical diagnosis of some epilepsy syndromes.
Publisher: Wiley
Date: 24-08-2004
Publisher: Georg Thieme Verlag KG
Date: 05-1991
Abstract: The clinical features and investigation results of 7 patients with Pelizaeus-Merzbacher disease (PMD) are described one patient had a brain biopsy and two patients had an autopsy. This paper tries to differentiate the clinical features of the connatal and classical types of PMD. Transient stridor and nystagmus were early signs in both types of PMD. Our findings support the view that the more severe connatal form shows rapid neurological deterioration from an early age leading to death usually in the first decade. In younger patients in whom the evolution is still unclear, severe feeding problems and extrapyramidal features may suggest the connatal form. By contrast, in the classical form of PMD, cerebellar signs and cognitive deterioration are more prominent with a more slowly progressive course. Nuclear magnetic resonance imaging and brainstem auditory evoked potentials were very helpful in supporting the diagnosis of PMD either in a known affected family or in sporadic cases, but were not useful in distinguishing between the two types of PMD. Genetic counseling in this condition is difficult, particularly in the connatal form in which inheritance may be either X-linked or autosomal recessive.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2013
DOI: 10.1038/NRNEUROL.2012.272
Abstract: Research on epilepsies in 2012 has substantially advanced our knowledge of these often devastating conditions. From important discoveries that revealed causative factors and the molecular basis of disease, to major implications for surgical decision-making, these studies set the scene for future advances in the field.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1999
DOI: 10.1097/00019052-199904000-00008
Abstract: Epilepsies, like other common diseases, have complex inheritance, and molecular genetic studies in such conditions are difficult. There has been recent success in identifying the molecular basis of certain epilepsies, particularly in those syndromes with autosomal dominant inheritance. All four genes discovered to date for idiopathic epilepsies code for ion channel subunits, either ligand-gated or voltage-gated. The idiopathic epilepsies thus appear, at least in part, to be a family of channelopathies.
Publisher: The Japan Epilepsy Society
Date: 30-06-2019
DOI: 10.3805/JJES.37.15
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-09-2003
DOI: 10.1212/01.WNL.0000086379.71183.78
Abstract: Mutations in SCN1A, the gene encoding the alpha1 subunit of the sodium channel, have been found in severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). Mutations in SMEI include missense, nonsense, and frameshift mutations more commonly arising de novo in affected patients. This finding is difficult to reconcile with the family history of GEFS+ in a significant proportion of patients with SMEI. Infantile spasms (IS), or West syndrome, is a severe epileptic encephalopathy that is usually symptomatic. In some cases, no etiology is found and there is a family history of epilepsy. The authors screened SCN1A in 24 patients with SMEI and 23 with IS. Mutations were found in 8 of 24 (33%) SMEI patients, a frequency much lower than initial reports from Europe and Japan. One mutation near the carboxy terminus was identified in an IS patient. A family history of seizures was found in 17 of 24 patients with SMEI. The rate of SCN1A mutations in this cohort of SMEI patients suggests that other factors may be important in SMEI. Less severe mutations associated with GEFS+ could interact with other loci to cause SMEI in cases with a family history of GEFS+. This study extends the phenotypic heterogeneity of mutations in SCN1A to include IS.
Publisher: Wiley
Date: 18-05-2021
DOI: 10.1111/EPI.16922
Abstract: Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations. Confounding factors, including the heterogeneous etiology of epilepsies and medication effects, h er studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome‐wide association study (GWAS) on epilepsy ( n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG ( n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset ( n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses. Our analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations. Our results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-02-2020
Publisher: Oxford University Press (OUP)
Date: 09-09-2010
DOI: 10.1093/BRAIN/AWQ238
Abstract: The epileptic encephalopathies of infancy and childhood are a collection of epilepsy disorders characterized by refractory, severe seizures and poor neurological outcome, in which the mechanism of disease is poorly understood. We report the clinical presentation and evolution of epileptic encephalopathy in a patient, associated with a loss-of-function mutation in the phospholipase C-β 1 gene. We ascertained a consanguineous family containing a male infant who presented with early-onset epileptic encephalopathy for detailed clinical phenotyping and molecular genetic investigation. In addition, a cohort of 12 consanguineous families of children with infantile spasms were analysed for linkage to the phospholipase C-β 1 gene locus. The male infant presented with tonic seizures in early infancy and subsequently developed infantile spasms. Over time, he developed drug-resistant epilepsy associated with severe neurological regression and failure to thrive. Molecular genetic investigation revealed a homozygous loss-of-function 0.5-Mb deletion, encompassing the promoter element and exons 1, 2 and 3 of phospholipase C-β 1 in the index case. Linkage to the phospholipase C-β 1 locus was excluded in the 12 other consanguineous families, consistent with genetic heterogeneity in this disorder. Although phospholipase C-β 1 deficiency has not previously been reported in humans, the Plcb1 homozygote knockout mouse displays early-onset severe tonic seizures and growth retardation, thus recapitulating the human phenotype. Phospholipase C-β 1 has important functions in both hippoc al muscarinic acetylcholine receptor signalling and in cortical development. Thus, the discovery of a phospholipase C-β 1 mutation allows us to propose a novel potential underlying mechanism in early-onset epileptic encephalopathy.
Publisher: Public Library of Science (PLoS)
Date: 29-11-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2006
Publisher: Wiley
Date: 12-12-2020
DOI: 10.1002/ANA.25650
Abstract: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81). Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020 :281-288.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2014
DOI: 10.1038/NRNEUROL.2014.146
Abstract: Copy number variants (CNVs deletions or duplications of chromosomal regions) have emerged as an important cause of human disease. In a recent study, epilepsy could be attributed to a pathogenic CNV in 5% of patients, but understanding the implications of a CNV for an in idual patient can be challenging.
Publisher: Springer Science and Business Media LLC
Date: 13-10-2016
DOI: 10.1038/SREP35192
Abstract: FOXP2 is the major gene associated with severe, persistent, developmental speech and language disorders. While studies in the original family in which a FOXP2 mutation was found showed volume reduction and reduced activation in core language and speech networks, there have been no imaging studies of different FOXP2 mutations. We conducted a multimodal MRI study in an eight-year-old boy (A-II) with a de novo FOXP2 intragenic deletion. A-II showed marked bilateral volume reductions in the hippoc us, thalamus, globus pallidus, and caudate nucleus compared with 26 control males (effect sizes from −1 to −3). He showed no detectable functional MRI activity when repeating nonsense words. The hippoc us is implicated for the first time in FOXP2 diseases. We conclude that FOXP2 anomaly is either directly or indirectly associated with atypical development of widespread subcortical networks early in life.
Publisher: Wiley
Date: 17-05-2013
DOI: 10.1002/AJMG.A.35946
Publisher: Springer Science and Business Media LLC
Date: 05-2001
DOI: 10.1038/88259
Publisher: Wiley
Date: 03-12-2022
DOI: 10.1111/JPC.15847
Publisher: Hindawi Limited
Date: 06-09-2022
DOI: 10.1002/HUMU.24454
Abstract: Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. Most patients have germline mutations in TSC1 or TSC2 but, 10%-15% patients do not have TSC1/TSC2 mutations detected on routine clinical genetic testing. We investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. Thirty-one sporadic TSC patients negative on routine testing and eight families with suspected parental mosaicism were sequenced using deep panel sequencing followed by droplet digital polymerase chain reaction. Pathogenic variants were found in 22/31 (71%) unsolved sporadic patients, 16 were mosaic (median variant allele fraction [VAF] 6.8% in blood) and 6 had missed germline mutations. Parental mosaicism was detected in 5/8 families (median VAF 1% in blood). Clinical testing laboratories typically only report pathogenic variants with allele fractions above 10%. Our findings highlight the critical need to change laboratory practice by implementing higher sensitivity assays to improve diagnostic yield, inform patient management and guide reproductive counseling.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.EJMG.2019.103799
Abstract: Mutations in ATP6V1B2, which encodes the B2 subunit of the vacuolar H + ATPase have previously been associated with Zimmermann-Laband syndrome 2 (ZLS2) and deafness-onychodystrophy (DDOD) syndrome. Recently epilepsy has also been described as a potentially associated phenotype. Here we further uncover the role of ATP61VB2 in epilepsy and report autosomal dominant inheritance of a novel missense variant in ATP6V1B2 in a large Polish family with relatively mild gingival and nail problems, no phalangeal hypoplasia and with generalized epilepsy. In light of our findings and review of the literature, we propose that the ATP6V1B2 gene should be considered in families with autosomal dominant epilepsy both with or without intellectual disability, and that presence of subtle gingival and nail problems may be another characteristic calling card of affected in iduals with ATP6V1B2 mutations.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2010
Publisher: Oxford University Press (OUP)
Date: 11-2002
DOI: 10.1093/BRAIN/AWF248
Abstract: Subcortical band heterotopia (SBH) or double cortex syndrome is a neuronal migration disorder, which occurs very rarely in males: to date, at least 110 females but only 11 in males have been reported. The syndrome is usually associated with mutations in the doublecortin (DCX) (Xq22.3-q23) gene, and much less frequently in the LIS1 (17p13.3) gene. To determine whether the phenotypic spectrum, the genetic basis and genotype-phenotype correlations of SBH in males are similar to those in females, we compared the clinical, imaging and molecular features in 30 personally evaluated males and 60 previously reported females with SBH. Based on the MRI findings, we defined the following band subtypes: partial, involving one or two cerebral lobes intermediate, involving two lobes and a portion of a third diffuse, with substantial involvement of three or more lobes and pachygyria-SBH, in which posterior SBH merges with anterior pachygyria. Karyo typing and mutation analysis of DCX and/or LIS1 were performed in 23 and 24 patients, respectively. The range of clinical phenotypes in males with SBH greatly overlapped that in females. MRI studies revealed that some anatomical subtypes of SBH, such as partial and intermediate posterior, pachygyria-SBH and diffuse bands with posterior predominance, were more frequently or exclusively present in males. Conversely, classical diffuse SBH and diffuse bands with anterior predominance were more frequent in females. Males had either mild or the most severe band subtypes, and these correlated with the over-representation of normal/borderline intelligence and severe mental retardation, respectively. Conversely, females who had predominantly diffuse bands exhibited mostly mild or moderate mental retardation. Seven patients (29%) had missense mutations in DCX in four, these were germline mutations, whereas in three there was evidence for somatic mosaicism. A germline missense mutation of LIS1 and a partial trisomy of chromosome 9p were identified in one patient (4%) each. One male each had a possible pathogenic intronic base change in both DCX and LIS1 genes. Our study shows that SBH in males is a clinically heterogeneous syndrome, mostly occurring sporadically. The clinical spectrum is similar to that of females with SBH. However, the greater cognitive and neuroradiological heterogeneity and the small number of mutations identified to date in the coding sequences of the DCX and LIS1 genes in males differ from the findings in females. This suggests other genetic mechanisms such as mutations in the non-coding regions of the DCX or LIS1 genes, gonadal or somatic mosaicism, and finally mutations of other genes.
Publisher: Springer Berlin Heidelberg
Date: 2009
Publisher: Wiley
Date: 06-2010
Abstract: SCN1A mutations account for a large proportion of Dravet syndrome patients, and are reported in other cases of epilepsy, such as some families with genetic epilepsy with febrile seizures plus (GEFS+). While most Dravet syndrome cases are caused by de novo mutations, 5% inherit a mutation from a mildly affected or symptom-free parent. Parental mosaicism has been identified, with documented cases involving truncating mutations or gene rearrangements. We describe a Roma/Gypsy family, where a missense mutation in SCN1A, p.D194N, is transmitted from a mosaic GEFS+ father to a child with Dravet syndrome. Mosaicism may be more common than assumed and should be considered regardless of the nature of the mutation.
Publisher: Elsevier BV
Date: 07-2022
Publisher: Research Square Platform LLC
Date: 28-10-2020
DOI: 10.21203/RS.3.RS-96773/V1
Abstract: Background : CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2), or Late-Infantile Neuronal Ceroid Lipofuscinosis (LINCL), is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. Methods : An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. In iduals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria. Results: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). Conclusion: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease. This addresses the clinical need to complement other information available.
Publisher: Elsevier
Date: 2008
Publisher: Springer Science and Business Media LLC
Date: 26-10-2000
Abstract: The filamin-1 (FLN-1) gene is responsible for periventricular nodular heterotopia (PNH), which is an X-linked dominant neuronal migration disorder. To review the clinical and imaging findings in a series of patients with documented filamin-1 mutations. A retrospective review of the medical records and MR studies of a series of patients with PNH and confirmed FLN-1 mutations was done. There were 16 female patients (age range: .67-71 years mean = 28.6) with filamin-1 gene mutations. In six of the patients the same mutation was inherited in four generations in one pedigree. In a second pedigree, a distinct mutation was found in two patients in two generations. In a third pedigree, a third mutation was found in four patients in two generations. The remaining four patients had sporadic de novo mutations that were not present in the parents. Ten patients had seizures, and all patients had normal intelligence. In all 16 patients MR demonstrated bilateral near-continuous PNH. There were no consistent radiographic or clinical differences between patients carrying different mutations. Patients with confirmed FLN-1 gene mutations are usually female and have a distinctive MR pattern of PNH. Other female patients with this same MR pattern probably harbor FLN-1 mutations and risk transmission to their progeny. This information is important for genetic counseling.
Publisher: Elsevier BV
Date: 02-2007
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.GIM.2022.08.020
Abstract: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.
Publisher: Wiley
Date: 06-02-2014
DOI: 10.1111/EPI.12533
Abstract: Focal cortical dysplasia is a common cortical malformation and an important cause of epilepsy. There is evidence for shared molecular mechanisms underlying cortical dysplasia, ganglioglioma, hemimegalencephaly, and dysembryoplastic neuroepithelial tumor. However, there are no familial reports of typical cortical dysplasia or co-occurrence of cortical dysplasia and related lesions within the same pedigree. We report the clinical, imaging, and histologic features of six pedigrees with familial cortical dysplasia and related lesions. Twelve patients from six pedigrees were ascertained from pediatric and adult epilepsy centers, eleven of whom underwent epilepsy surgery. Pedigree data, clinical information, neuroimaging findings, and histopathologic features are presented. The families comprise brothers with focal cortical dysplasia, a male and his sister with focal cortical dysplasia, a female with focal cortical dysplasia and her brother with hemimegalencephaly, a female with focal cortical dysplasia and her female first cousin with ganglioglioma, a female with focal cortical dysplasia and her male cousin with dysembryoplastic neuroepithelial tumor, and a female and her nephew with focal cortical dysplasia. This series shows that focal cortical dysplasia can be familial and provides clinical evidence suggesting that cortical dysplasia, hemimegalencephaly, ganglioglioma, and dysembryoplastic neuroepithelial tumors may share common genetic determinants.
Publisher: American Academy of Sleep Medicine (AASM)
Date: 15-10-2018
DOI: 10.5664/JCSM.7376
Publisher: Wiley
Date: 10-1995
Abstract: We describe a family of 9 affected in iduals in three generations with nocturnal oro-facio-brachial partial seizures, secondarily generalized partial seizures, and centro-temporal epileptiform discharges, associated with oral and speech dyspraxia and cognitive impairment. The speech disorder was prominent, but differed from that of Landau-Kleffner syndrome and of epilepsy with continuous spike and wave during slow-wave sleep. The electroclinical features of this new syndrome of autosomal dominant rolandic epilepsy resemble those of benign rolandic epilepsy, a common inherited epilepsy of childhood. This family shows clinical anticipation of the seizure disorder, the oral and speech dyspraxia, and cognitive dysfunction, suggesting that the genetic mechanism could be expansion of an unstable triplet repeat. Molecular studies on this syndrome, where the inheritance pattern is clear, could also be relevant to identifying a gene for benign rolandic epilepsy where anticipation does not occur and the mode of inheritance is uncertain.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-06-2016
Publisher: Wiley
Date: 25-04-2017
DOI: 10.1111/EPI.13746
Abstract: This study was designed to describe the spectrum of epilepsy phenotypes in Koolen-de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1. We were invited to attend a large gathering of in iduals with KdVS and their families. While there, we recruited in iduals with KdVS and seizures, and performed thorough phenotyping. Additional subjects were included who approached us after the family support group brought attention to our research via social media. Inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least one seizure. Thirty-one in iduals were studied, aged 2-35 years. Median age at seizure onset was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset. Focal impaired awareness seizures were the most frequent seizure type occurring in 20 of 31, usually with prominent autonomic features. Twenty-one patients had prolonged seizures and, at times, refractory status epilepticus. Electroencephalography (EEG) showed focal/multifocal epileptiform discharges in 20 of 26. MRI studies of 13 patients were reviewed, and all had structural anomalies. Corpus callosum dysgenesis, abnormal hippoc i, and dilated ventricles were the most common, although periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also observed. One patient underwent epilepsy surgery for a lesion that proved to be an angiocentric glioma. The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features. Multifocal epileptiform discharges are the typical EEG pattern. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Epilepsy surgery should be undertaken with care given the widespread neuroanatomic abnormalities however, tumors are a rare, yet important, occurrence.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-04-2020
DOI: 10.1212/WNL.0000000000009441
Abstract: Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10 CDK13 , EBF3 , GNAO1 , GNB1 , DDX3X , MEIS2 , POGZ , SETBP1 , UPF2 , ZNF142 ) or copy number (n = 1 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.
Publisher: Wiley
Date: 22-12-2011
DOI: 10.1111/J.1528-1167.2011.03350.X
Abstract: Febrile infection-related epilepsy syndrome (FIRES) is an increasingly recognized epileptic syndrome that presents with multifocal refractory status epilepticus in previously normal children and evolves into a chronic, refractory, focal epilepsy with associated cognitive and behavioral difficulties. Herein we describe the features of the chronic epilepsy and critically review evidence for the etiology of this syndrome. Seven patients with FIRES were studied. The duration of follow-up in six survivors was 5-17 years. Clinical, electroencephalography (EEG), neuroimaging, and other investigative findings during the acute and chronic phases were reviewed. These previously normal children presented with a febrile illness and status epilepticus that was refractory to antiepileptic medications in all children, to immunotherapies (including immunoglobulin, corticosteroids, plasma exchange, and rituximab) in four, and to acute vagus nerve stimulation in one. Markers of cerebral inflammation were few and response to antiepileptic and immunomodulatory therapies was poor. Evolution to chronic epilepsy occurred without a silent period. Seizure characteristics in the chronic phase were strikingly stereotyped and similar to the acute phase, with head and eye version, unilateral facial jerking, asymmetric tonic posturing, and unilateral limb jerking in all patients. Electrographic ictal onset was lateralized in all recorded seizures, unilateral in one patient, and independent bilateral in three. Seizures were refractory to multiple antiepileptic medications in all patients and partly responsive to chronic vagus nerve stimulation in two patients. Moderate to severe intellectual impairment was noted in four patients, and borderline intellectual abilities were noted in two. Magnetic resonance imaging (MRI) in the chronic phase was normal in three patients and showed mild diffuse cortical atrophy and/or mild hippoc al atrophy or sclerosis in three. The similar perirolandic and perisylvian features of acute and chronic seizures, the lack of a silent period, the absence of evidence of cerebral inflammation, and the poor response to immunotherapies suggest FIRES is best conceptualized as a chronic epilepsy with explosive onset, not a remote-symptomatic epilepsy with an acute inflammatory antecedent.
Publisher: Elsevier BV
Date: 12-2015
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.EJPN.2019.12.020
Abstract: PCDH19 Girls clustering epilepsy (GCE) has a phenotypic spectrum that includes developmental and epileptic encephalopathy. PCDH19-GCE presents with clusters of seizures in the first years of life. Although patients typically outgrow their seizures, many are left with intellectual disability. Here we retrospectively assess the effect of levetiracetam in two independent cohorts of females with PCDH19-GCE. Cohort A was identified by searching our epilepsy genetics research database for girls with PCDH19-GCE who had trialled levetiracetam. Cohort B consisted of girls aged 2 years or older, including women, participating in an international online questionnaire. Information regarding seizure frequency and levetiracetam use was obtained by in-person patient interview and review of clinical records for cohort A, and by patient report for cohort B. Cohort A consisted of 17 females, aged 3-37 years, who had a trial of levetiracetam at an average age of 10.7 years. 13/17 females became seizure free for >12 months while 10/17 remained seizure free for >24 months. Cohort B comprised 62 females, aged 1.5-41 years. 26/62 became seizure free for >12 months, and 19/62 for >24 months on levetiracetam therapy. Levetiracetam was effective in two cohorts of females with PCDH19-GCE where 42% and 76% of females became seizure free for >12 months, respectively. Levetiracetam is an effective therapy for females with PCDH19-GCE and should be considered early in the management of the highly refractory clusters of seizures that characterise this genetic disease.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.EPLEPSYRES.2019.106161
Abstract: Over the past decade there has been a substantial increase in genetic studies of brain malformations, fueled by the availability of improved technologies to study surgical tissue to address the hypothesis that focal lesions arise from focal, post-zygotic genetic disruptions. Traditional genetic studies of patients with malformations utilized leukocyte-derived DNA to search for germline variants, which are inherited or arise de novo in parental gametes. Recent studies have demonstrated somatic variants that arise post-zygotically also underlie brain malformations, and that somatic mutation explains a larger proportion of focal malformations than previously thought. We now know from studies of non-diseased in iduals that somatic variation occurs routinely during cell ision, including during early brain development when the rapid proliferation of neuronal precursor cells provides the ideal environment for somatic mutation to occur and somatic variants to accumulate. When confined to brain, pathogenic variants contribute to the "hidden genetics" of neurological diseases. With burgeoning novel high-throughput genetic technologies, somatic genetic variations are increasingly being recognized. Here we discuss accumulating evidence for the presence of somatic variants in normal brain tissue, review our current understanding of somatic variants in brain malformations associated with lesional epilepsy, and provide strategies to identify the potential contribution of somatic mutation to non-lesional epilepsies. We also discuss technologies that may improve detection of somatic variants in the future in these and other neurological conditions.
Publisher: Cold Spring Harbor Laboratory
Date: 20-03-2023
DOI: 10.1101/2023.03.16.23287290
Abstract: Diffusion MRI has provided insight into the widespread structural connectivity changes that characterise the epilepsies. Although syndrome-specific white matter abnormalities have been demonstrated, studies have predominantly relied on statistical comparisons between patient and control groups. For diffusion MRI techniques to be of clinical value, they should be able to detect white matter microstructural changes in in idual patients. In this study, we apply an in idualised approach to a novel technique known as fixel-based analysis, to examine fibre-tract-specific abnormalities in in iduals with epilepsy. We explore the potential clinical value of this in idualised fixel-based approach in epilepsy patients with differing syndromic diagnoses. Diffusion MRI data from 90 neurologically healthy control participants and 10 patients with epilepsy (temporal lobe epilepsy, Progressive Myoclonus Epilepsy, Dravet Syndrome, malformations of cortical development) were included in this study. Measures of fibre density and cross-section were extracted for all participants across brain white matter fixels, and mean values computed within select tracts-of-interest. Scanner harmonised and normalised data were then used to compute Z-scores for in idual patients with epilepsy. Microstructural white matter abnormalities were observed in distinct patterns in in idual patients with epilepsy, both at the tract and fixel level. For patients with specific epilepsy syndromes, the detected white matter abnormalities were largely in line with expected syndrome-specific clinical phenotypes. In patients with lesional epilepsies (e.g., hippoc al sclerosis, periventricular nodular heterotopia, bottom-of-sulcus dysplasia), microstructural abnormalities were concordant with lesion location. This study demonstrates the clinical potential of translating advanced diffusion MRI methodology to in idual patient-level use in epilepsy. This technique could be useful both in aiding diagnosis of specific epilepsy syndromes, and in localising structural abnormalities, and is readily amenable to other neurological disorders. We have included code and data for this study, so that in idualised white matter changes can be explored robustly in larger cohorts in future work.
Publisher: Wiley
Date: 26-08-2016
DOI: 10.1111/EPI.13505
Abstract: There is considerable difficulty in diagnosing hippoc al malrotation (HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE). We studied the MRI of 155 adult patients with MRI-negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI-negative TLE. We found that the features that are most correlated with the expert diagnosis of HIMAL are hippoc al shape change with hippoc al diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus (DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of unilateral or bilateral HIMAL was made in 25 of 103 controls (24.3% of people, 14.6% of hippoc i-14 left, six right, 10 bilateral) that did not differ from 155 lesion-negative TLE patients where 25 had HIMAL (16.1% of patients, 11.6% of hippoc i-12 left, two right, 11 bilateral). Of the 12 with left HIMAL only, 9 had seizures arising from the left temporal lobe, whereas 3 had right-sided seizures. Of the two with right HIMAL only, both had seizures arising from the left temporal lobe. HIMAL is an anatomic variant commonly found in controls. HIMAL is also an incidental nonpathologic finding in adult MRI-negative TLE and should not influence surgical decision making.
Publisher: American Medical Association (AMA)
Date: 05-2020
Publisher: Wiley
Date: 27-04-2005
DOI: 10.1111/J.1528-1167.2005.49004.X
Abstract: gamma-Aminobutyric acid (GABA)-receptor genes are prime candidates for a role in seizure susceptibility. An association between the c.1465G-->A variant in the GABA(B) receptor 1 gene (GABBR1) and susceptibility to temporal lobe epilepsy (TLE) has been reported in an Italian cohort. We sought to replicate this association in an independent Australian cohort. The 234 patients with TLE and 164 healthy controls were genotyped for the c.1465G-->A variant, by using inclusion criteria identical to those of the first study. The c.1465G-->A variant was found in one TLE patient and one control subject. Genotype and allele frequencies did not differ between groups. We did not replicate the reported associations between the c.1465G-->A variant and susceptibility to TLE. We suggest that the initial positive association may be due to undetected population stratification the importance of genomic control is emphasized. Population-specific effects also may play a role, and we highlight the need to demonstrate an in vitro functional effect to give biologic meaning to any proposed association.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Wiley
Date: 09-2012
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.EJMG.2009.09.004
Abstract: Microdeletions at 14q12 that include FOXG1, or loss of function mutations in FOXG1, are associated with the congenital variant of Rett syndrome. By SNP microarray analysis we identified a corresponding microduplication at 14q12 in a nine year old girl with symptomatic generalised epilepsy, severe intellectual impairment, and minor dysmorphisms, but without microcephaly. The 14q12 microduplication comprised 4.45 Mb of DNA and included FOXG1. This is the first report of duplication involving FOXG1 and suggests a dosage sensitive role for FOXG1 in brain development.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.EJPN.2019.12.023
Abstract: The recent introduction of the term 'developmental and epileptic encephalopathy' by the International League Against Epilepsy has added another conceptual layer to understanding the most severe group of epilepsies. An epileptic encephalopathy is defined by the presence of frequent epileptiform activity that impacts adversely on development, typically causing slowing or regression of developmental skills, and usually associated with frequent seizures. Many of the epileptic encephalopathies are now known to have an identifiable molecular genetic basis. The term 'developmental' was introduced as there are multiple facets leading to developmental impairment in affected in iduals. The underlying genetic cause often results in developmental delay in its own right, with the epileptic encephalopathy further adversely affecting development. Treatment of the epileptic encephalopathy may improve developmental progress, so early recognition and active management are essential to improve developmental outcomes. Equally, understanding that the genetic aetiology independently leads to developmental impairment means that precision therapies need to be holistic in addressing the devastating consequences of this group of diseases.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-08-2002
DOI: 10.1212/WNL.59.3.348
Abstract: To describe a new syndrome of X-linked myoclonic epilepsy with generalized spasticity and intellectual disability (XMESID) and identify the gene defect underlying this disorder. The authors studied a family in which six boys over two generations had intractable seizures using a validated seizure questionnaire, clinical examination, and EEG studies. Previous records and investigations were obtained. Information on seizure disorders was obtained on 271 members of the extended family. Molecular genetic analysis included linkage studies and mutational analysis using a positional candidate gene approach. All six affected boys had myoclonic seizures and TCS two had infantile spasms, but only one had hypsarrhythmia. EEG studies show diffuse background slowing with slow generalized spike wave activity. All affected boys had moderate to profound intellectual disability. Hyperreflexia was observed in obligate carrier women. A late-onset progressive spastic ataxia in the matriarch raises the possibility of late clinical manifestations in obligate carriers. The disorder was mapped to Xp11.2-22.2 with a maximum lod score of 1.8. As recently reported, a missense mutation (1058C>T/P353L) was identified within the homeodomain of the novel human Aristaless related homeobox gene (ARX). XMESID is a rare X-linked recessive myoclonic epilepsy with spasticity and intellectual disability in boys. Hyperreflexia is found in carrier women. XMESID is associated with a missense mutation in ARX. This disorder is allelic with X-linked infantile spasms (ISSX MIM 308350) where polyalanine tract expansions are the commonly observed molecular defect. Mutations of ARX are associated with a wide range of phenotypes functional studies in the future may lend insights to the neurobiology of myoclonic seizures and infantile spasms.
Publisher: SAGE Publications
Date: 07-2018
Publisher: Wiley
Date: 04-2014
DOI: 10.1111/EPI.12550
Abstract: Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for in iduals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1997
DOI: 10.1212/WNL.49.4.969
Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a newly recognized autosomal dominant partial epilepsy. We studied seizure localization and intrafamilial variation using video-EEG monitoring (VEM) and functional neuroimaging in two pairs of subjects from unrelated families. The clinical features of seizures were similar from seizure to seizure in each in idual, but varied between in iduals. As is often found in frontal lobe epilepsies, ictal EEG localization was imprecise in three of four cases. One patient showed a consistent left fronto-polar onset that was corroborated by congruent focal hypometabolism on interictal PET and focal hyperperfusion on ictal single photon emission computed tomography (SPECT). A second case studied with ictal SPECT showed a right parasagittal, midfrontal focus. We conclude that this autosomal dominant epilepsy syndrome, which in one of the two families was due to a known neuronal nicotinic acetylcholine receptor mutation, causes frontal lobe foci that are unilateral and in variable locations in different in iduals.
Publisher: Springer Science and Business Media LLC
Date: 10-2020
DOI: 10.1038/S41467-020-18723-Y
Abstract: Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance ( p 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5% e.g., GABRG2 and UIMC1 ) of which, 61 reach FWER significance ( p 3.64E−07 e.g., CASZ1 ). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes ( CTCF , HNRNPU , KCNQ3 , ZBTB18 , TCF12 , SPEN , and LEO1 ) based on this large-scale targeted sequencing effort.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.NEUROIMAGE.2010.01.109
Abstract: Simultaneous EEG and functional MRI (EEG-fMRI) studies of focal epileptiform spikes commonly use the canonical haemodynamic response function (HRF) to model the blood-oxygenation-level-dependent (BOLD) response to these events. Support for the use of the canonical HRF has come from large studies that contain mixed cohorts of epilepsy syndromes and discharge types, and has demonstrated plausible epileptic localisation results in the majority of patients. Other studies, however, have reported that some patients show a BOLD response that differs markedly from a canonical HRF. Our aim in this study was to see if the BOLD response is well modelled by a canonical HRF in a homogeneous cohort of patients with benign epilepsy with centrotemporal spikes (BECTS), an idiopathic partial epilepsy with stereotypical centrotemporal spikes on the EEG. We studied eight well-characterised and typical BECTS patients and found that the shape of the average BOLD response was different to the canonical HRF. Furthermore, a localisation analysis using the group-average response provided increased sensitivity and specificity compared to the canonical HRF. Our findings suggest that the canonical HRF may not provide the best model for the BOLD response in some epilepsy syndromes or spike-types. In studies of homogeneous patient groups, therefore, localisation results may be improved by using a group-specific BOLD response.
Publisher: Hindawi Limited
Date: 13-11-2017
DOI: 10.1002/HUMU.23357
Abstract: Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage cl recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism.
Publisher: Frontiers Media SA
Date: 10-03-2022
DOI: 10.3389/FNEUR.2022.834252
Abstract: Variants in HCN1 are associated with a range of epilepsy syndromes including developmental and epileptic encephalopathies. Here we describe a child harboring a novel de novo HCN1 variant, E246A, in a child with epilepsy and mild developmental delay. By parental report, the child had difficulty in discriminating between colors implicating a visual deficit. This interesting observation may relate to the high expression of HCN1 channels in rod and cone photoreceptors where they play an integral role in shaping the light response. Functional analysis of the HCN1 E246A variant revealed a right shift in the voltage dependence of activation and slowing of the rates of activation and deactivation. The changes in the biophysical properties are consistent with a gain-of-function supporting the role of HCN1 E246A in disease causation. This case suggests that visual function, including color discrimination, should be carefully monitored in patients with diseases due to HCN1 pathogenic variants.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Oxford University Press (OUP)
Date: 16-02-2010
DOI: 10.1093/BRAIN/AWQ016
Publisher: Elsevier
Date: 2009
Publisher: Wiley
Date: 29-05-2012
Publisher: Oxford University Press (OUP)
Date: 03-2022
Publisher: Oxford University Press (OUP)
Date: 13-06-2022
Abstract: Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected in iduals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-cl electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8 confidence interval = 5.4–69.3 P = 1.3 × 10−7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current litude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current litude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.
Publisher: Wiley
Date: 22-03-2004
DOI: 10.1002/ANA.20028
Publisher: BMJ
Date: 07-2019
DOI: 10.1136/JNNP-2019-ANZAN.9
Abstract: Mutations in SCN1A encoding the Na v 1.1 subunit of the neuronal sodium channel underlie the devastating epilepsy of Dravet’s syndrome. 1 The mechanism by which Na v 1.1 dysfunction causes seizures is not clear. In vitro and in silico channel evaluation can support mutation pathogenicity but cannot define the in vivo impact of channel dysfunction. Axonal excitability studies can show the pattern of single-channel dysfunction in disorders where the channel is peripherally expressed. 2 This study was undertaken to determine whether axonal excitability studies could detect changes in Dravet’s patients related to the condition or due to medication effect. Patients with Dravet’s syndrome were recruited from clinics in Sydney and Melbourne and axonal excitability studies were performed. Excitability results were analysed in 3 age groups and compared to age-matched normal controls. Twenty six patients (ages 2–46) were studied. Findings were most pronounced in patients aged 20–46 (n=7) with 6.9% greater increase in threshold during hyperpolarization(p=0.1), 7.6% greater threshold decrease on depolarization(p=0.005) and, in the recovery cycle, 19.7% reduction in superexcitability(p=0.002) and 26% reduction in subexcitability(p=0.03). Axonal excitability studies resembled previously published changes seen in patients with sodium channel blockade caused by acute tetrodotoxin poisoning. 3 Changes in excitability of axonal membrane in Dravet’s syndrome are consistent with a decrease in sodium channel function. As the affected channel in Dravet’s syndrome is not peripherally expressed, the effect seen is likely due to the heavy anticonvulsant regime required to control epilepsy, combined with a progressive loss of sodium channel function that occurs with age. Meisler MH, O’Brien JE, Sharkey LM. Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. J Physiol 2010 :1841–1848. Tomlinson SE, Howells J, Burke D. In vivo assessment of neurological channelopathies: Application of peripheral nerve excitability studies. Neuropharmacology . 2018 Apr :98–107. Kiernan MC, Isbister GK, Lin CS, Burke D, Bostock H. Acute tetrodotoxin-induced neurotoxicity after ingestion of puffer fish. Ann Neurol 2005 :339–48.
Publisher: Springer Science and Business Media LLC
Date: 21-07-2022
DOI: 10.1038/S41467-022-31752-Z
Abstract: HNRNPU encodes the heterogeneous nuclear ribonucleoprotein U, which participates in RNA splicing and chromatin organization. Microdeletions in the 1q44 locus encompassing HNRNPU and other genes and point mutations in HNRNPU cause brain disorders, including early-onset seizures and severe intellectual disability. We aimed to understand HNRNPU’s roles in the developing brain. Our work revealed that HNRNPU loss of function leads to rapid cell death of both postmitotic neurons and neural progenitors, with an apparent higher sensitivity of the latter. Further, expression and alternative splicing of multiple genes involved in cell survival, cell motility, and synapse formation are affected following Hnrnpu’s conditional truncation. Finally, we identified pharmaceutical and genetic agents that can partially reverse the loss of cortical structures in Hnrnpu mutated embryonic brains, ameliorate radial neuronal migration defects and rescue cultured neural progenitors’ cell death.
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.NEUBIOREV.2016.12.036
Abstract: Richard, A.E., I.E. Scheffer and S.J. Wilson. Features of the broader autism phenotype in people with epilepsy support shared mechanisms between epilepsy and autism spectrum disorder. NEUROSCI BIOBEHAV REV 21(1) XXX-XXX, 2016. To inform on mechanisms underlying the comorbidity of epilepsy and autism spectrum disorder (ASD), we conducted meta-analyses to test whether impaired facial emotion recognition (FER) and theory of mind (ToM), key phenotypic traits of ASD, are more common in people with epilepsy (PWE) than controls. We contrasted these findings with those of relatives of in iduals with ASD (ASD-relatives) compared to controls. Furthermore, we examined the relationship of demographic (age, IQ, sex) and epilepsy-related factors (epilepsy onset age, duration, seizure laterality and origin) to FER and ToM. Thirty-one eligible studies of PWE (including 1449 in iduals: 77% with temporal lobe epilepsy), and 22 of ASD-relatives (N=1295) were identified by a systematic database search. Analyses revealed reduced FER and ToM in PWE compared to controls (p<0.001), but only reduced ToM in ASD-relatives (p<0.001). ToM was poorer in PWE than ASD-relatives. Only weak associations were found between FER and ToM and epilepsy-related factors. These findings suggest shared mechanisms between epilepsy and ASD, independent of intellectual disability.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2015
Publisher: Proceedings of the National Academy of Sciences
Date: 29-05-2018
Abstract: SCN2A , encoding the voltage-gated sodium channel Na v 1.2, has emerged as a major gene implicated in neonatal-, infantile-, and even childhood-onset epilepsies. Many of these epilepsies are also associated with cognitive and behavioral impairments that range in type and severity. The biophysical, neurophysiological, and clinical impacts of SCN2A mutations are poorly understood. Here, we use clinical evaluation and biophysical analyses to explore the mechanisms underpinning distinctive phenotypes produced by SCN2A variants associated with mild familial or severe de novo forms of epilepsy. We show that dynamic cl analysis provides clear benefits over conventional voltage cl for a rapid and definitive prediction of neuron-scale phenotypic consequences, and is well positioned to impact diagnosis and drug discovery in genetic epilepsy.
Publisher: Wiley
Date: 24-04-2020
DOI: 10.1111/JPC.14890
Publisher: Wiley
Date: 08-2005
DOI: 10.1111/J.1528-1167.2005.52904.X
Abstract: Malformations of cortical development (MCDs) are usually highly epileptogenic, and their hyperexcitability could facilitate the occurrence of reflex seizures. We sought to characterize reflex seizures in patients with MCDs and refractory epilepsy. Clinical, electrographic, and neuroimaging data were reviewed in eight patients with MCDs who had reflex seizures reproduced during presurgical evaluation. All eight patients had both reflex and spontaneous seizures. In six, however, drop attacks or axial myoclonic seizures occurred only upon specific sensory stimulation. Reflex seizures were induced by more than one type of stimulus in most patients, but anatomofunctional correlations could usually be invoked. Six patients had significant intellectual impairment. Surgical resection controlled seizures in two patients. Reflex seizures in patients with MCDs may be medically refractory and may often manifest as drop attacks or axial myoclonus. Surgical resection of focal lesions can bring reflex seizures under control. Putative mechanisms related to the relatively low frequency of reflex seizures in MCDs are discussed.
Publisher: American Medical Association (AMA)
Date: 11-2010
DOI: 10.1001/ARCHNEUROL.2010.155
Abstract: To establish whether early electroencephalography (EEG) or later sleep-deprived EEG (SD-EEG) has a higher yield of epileptiform and background abnormalities in children with new-onset seizures, and to use EEG results to assist in diagnosis of electroclinical epilepsy syndromes at presentation. Prospective analysis blinded to EEG protocol and epilepsy diagnosis. Regional service capturing a pediatric population of 121,000. Consecutive untreated children aged 2 to 16 years presenting to emergency departments with new-onset seizures (excluding myoclonic and absence seizures). Each child had 2 EEG protocols: an early EEG study (within 24 hours following a seizure) and an SD-EEG study (48 hours to 4 weeks following a seizure). Epilepsy diagnosis was made independently by 2 pediatric epileptologists. Rate of epileptiform abnormalities and slowing in the 2 EEG studies. The secondary outcome measure was diagnosis of epilepsy syndrome where possible. Of 92 children studied, 50 (54%) had a single seizure 42 (46%) had 2 or more seizures at presentation. Seizures were focal in 61 children (66%) and generalized in 19 (21%). Epileptiform discharges occurred in 56 SD-EEGs (61%) and 52 early EEGs (57%) (P = .27). Background slowing occurred in 26 SD-EEGs (28%) and 42 early EEGs (46%) (P < .001). Parents preferred early EEG (65 parents [71%]) to later SD-EEG (14 parents [15%]) because of availability of earlier results and epilepsy diagnosis. Forty-two of 92 children (46%) were diagnosed with a specific electroclinical syndrome. Early EEG and SD-EEG studies have a similar yield of epileptiform abnormalities. Background abnormalities are more frequent in early EEGs. The EEG results at presentation in new-onset seizures support epilepsy diagnosis, with electroclinical syndromes diagnosed in almost 50% of children.
Publisher: Wiley
Date: 25-01-2019
DOI: 10.1111/DMCN.14153
Abstract: We aimed to systematically review the speech production, language, and oral function phenotype of bilateral perisylvian polymicrogyria (BPP), and examine the correlation between the topography of polymicrogyria and the severity of speech, language, and oral functional impairment. A systematic search of MEDLINE, Embase, and PubMed databases was completed on 26th October 2017 using Medical Subject Heading terms synonymous with BPP and speech, language, or oral motor impairment. In total, 2411 papers were identified and 48 met inclusion criteria. Expressive and receptive language impairment and oral structural and functional deficits are frequent in BPP. Expressive deficits are frequently more severe than receptive. Only one study used formal assessments to demonstrate the presence of speech disorder, namely dysarthria. Seven studies reported an association between diffuse BPP and more severe language impairment. Findings confirmed that language deficits are common in BPP, though assessment of the specific speech phenotype is limited. The paucity of high quality studies detailing the specific communication phenotype of BPP highlights the need for further investigation. Improving understanding of this phenotype will inform the development of targeted therapies and lead to better long-term outcomes. Speech, language, and oral functional impairments are common in in iduals with bilateral perisylvian polymicrogyria. Posterior polymicrogyria is associated with a less severe language impairment than anterior polymicrogyria. Deeper investigation of speech is needed to understand implicated networks in this malformation.
Publisher: Springer Science and Business Media LLC
Date: 26-09-2015
Publisher: Elsevier BV
Date: 03-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-08-2018
DOI: 10.1212/WNL.0000000000006199
Abstract: To delineate the electroclinical features of SCN8A infantile developmental and epileptic encephalopathy (EIEE13, OMIM #614558). Twenty-two patients, aged 19 months to 22 years, underwent electroclinical assessment. Sixteen of 22 patients had mildly delayed development since birth. Drug-resistant epilepsy started at a median age of 4 months, followed by developmental slowing, pyramidal/extrapyramidal signs (22/22), movement disorders (12/22), cortical blindness (17/22), sialorrhea, and severe gastrointestinal symptoms (15/22), worsening during early childhood and plateauing at age 5 to 9 years. Death occurred in 4 children, following extreme neurologic deterioration, at 22 months to 5.5 years. Nonconvulsive status epilepticus recurred in 14 of 22 patients. The most effective antiepileptic drugs were oxcarbazepine, carbamazepine, phenytoin, and benzodiazepines. EEG showed background deterioration, epileptiform abnormalities with a temporo-occipital predominance, and posterior delta/beta activity correlating with visual impairment. Video-EEG documented focal seizures (FS) (22/22), spasm-like episodes (8/22), cortical myoclonus (8/22), and myoclonic absences (1/22). FS typically clustered and were prolonged ( minutes) with (1) cyanosis, hypomotor, and vegetative semiology, sometimes unnoticed, followed by (2) tonic-vibratory and (3) (hemi)-clonic manifestations ± evolution to a bilateral tonic-clonic seizure. FS had posterior-temporal/occipital onset, slowly spreading and sometimes migrating between hemispheres. Brain MRI showed progressive parenchymal atrophy and restriction of the optic radiations. SCN8A developmental and epileptic encephalopathy has strikingly consistent electroclinical features, suggesting a global progressive brain dysfunction primarily affecting the temporo-occipital regions. Both uncontrolled epilepsy and developmental compromise contribute to the profound impairment (increasing risk of death) during early childhood, but stabilization occurs in late childhood.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.SEIZURE.2015.03.020
Abstract: To determine clinical phenotypes, evolution and genetic background of a large family with a combination of two unusual forms of reflex epilepsies. Phenotyping was performed in eighteen family members (10 F, 8 M) including standardized EEG recordings with intermittent photic stimulation (IPS). Genetic analyses (linkage scans, Whole Exome Sequencing (WES) and Functional studies) were performed using photoparoxysmal EEG responses (PPRs) as affection status. The proband suffered from speaking induced jaw-jerks and increasing limb jerks evoked by flickering sunlight since about 50 years of age. Three of her family members had the same phenotype. Generalized PPRs were found in seven members (six above 50 years of age) with myoclonus during the PPR. Evolution was typical: Sensitivity to lights with migraine-like complaints around adolescence, followed by jerks evoked by lights and spontaneously with dropping of objects, and strong increase of light sensitivity and onset of talking induced jaw jerks around 50 years. Linkage analysis showed suggestive evidence for linkage to four genomic regions. All photosensitive family members shared a heterozygous R129C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. Mutation screening of 134 unrelated PPR patients and 95 healthy controls, did not replicate these findings. This family presents a combination of two rare reflex epilepsies. Genetic analysis favors four genomic regions and points to a shared SCNM1 mutation that was not replicated in a general cohort of photosensitive subjects. Further genetic studies in families with similar combination of features are warranted.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-01-2012
Publisher: Wiley
Date: 21-03-2004
DOI: 10.1002/ANA.20029
Abstract: We recently reported mutations in the sodium channel gene SCN2A in two families with benign familial neonatal-infantile seizures (BFNISs). Here, we aimed to refine the molecular-clinical correlation of SCN2A mutations in early childhood epilepsies. SCN2A was analyzed in 2 families with probable BFNIS, 9 with possible BFNIS, 10 with benign familial infantile seizures, and in 93 additional families with various early childhood epilepsies. Mutations effecting changes in conserved amino acids were found in two of two probable BFNIS families, in four of nine possible BFNIS families, and in none of the others. Our eight families had six different SCN2A mutations one mutation (R1319Q) occurred in three families. BFNIS is an autosomal dominant disorder presenting between day 2 and 7 months (mean, 11.2 +/- 9.2 weeks) with afebrile secondarily generalized partial seizures neonatal seizures were not seen in all families. The frequency of seizures varied some in iduals had only a few attacks without treatment and others had clusters of many per day. Febrile seizures were rare. All cases remitted by 12 months. Ictal recordings in four subjects showed onset in the posterior quadrants. SCN2A mutations appear specific for BFNIS the disorder can now be strongly suspected clinically and the families can be given an excellent prognosis.
Publisher: Hindawi Limited
Date: 15-06-2021
DOI: 10.1002/HUMU.24237
Abstract: PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause infantile-onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA-sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor, and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification.
Publisher: American Medical Association (AMA)
Date: 03-09-2021
Publisher: Society for Neuroscience
Date: 22-02-2023
DOI: 10.1523/JNEUROSCI.1615-22.2022
Abstract: Pathogenic variants in HCN1 are associated with a range of epilepsy syndromes including a developmental and epileptic encephalopathy. The recurrent de novo HCN1 pathogenic variant (M305L) results in a cation leak, allowing the flux of excitatory ions at potentials where the wild-type channels are closed. The Hcn1 M294L mouse recapitulates patient seizure and behavioral phenotypes. As HCN1 channels are highly expressed in rod and cone photoreceptor inner segments, where they shape the light response, mutated channels are likely to impact visual function. Electroretinogram (ERG) recordings from male and female mice Hcn1 M294L mice revealed a significant decrease in the photoreceptor sensitivity to light, as well as attenuated bipolar cell (P2) and retinal ganglion cell responses. Hcn1 M294L mice also showed attenuated ERG responses to flickering lights. ERG abnormalities are consistent with the response recorded from a single female human subject. There was no impact of the variant on the structure or expression of the Hcn1 protein in the retina. In silico modeling of photoreceptors revealed that the mutated HCN1 channel dramatically reduced light-induced hyperpolarization, resulting in more Ca 2+ flux during the response when compared with the wild-type situation. We propose that the light-induced change in glutamate release from photoreceptors during a stimulus will be diminished, significantly blunting the dynamic range of this response. Our data highlight the importance of HCN1 channels to retinal function and suggest that patients with HCN1 pathogenic variants are likely to have a dramatically reduced sensitivity to light and a limited ability to process temporal information. SIGNIFICANCE STATEMENT Pathogenic variants in HCN1 are emerging as an important cause of catastrophic epilepsy. HCN1 channels are ubiquitously expressed throughout the body, including the retina. Electroretinogram recordings from a mouse model of HCN1 genetic epilepsy showed a marked decrease in the photoreceptor sensitivity to light and a reduced ability to respond to high rates of light flicker. No morphologic deficits were noted. Simulation data suggest that the mutated HCN1 channel blunts light-induced hyperpolarization and consequently limits the dynamic range of this response. Our results provide insights into the role HCN1 channels play in retinal function as well as highlighting the need to consider retinal dysfunction in disease caused by HCN1 variants. The characteristic changes in the electroretinogram open the possibility of using this tool as a biomarker for this HCN1 epilepsy variant and to facilitate development of treatments.
Publisher: Wiley
Date: 24-02-2005
DOI: 10.1002/ANA.20398
Publisher: Wiley
Date: 15-04-2020
DOI: 10.1002/ANA.25724
Publisher: Wiley
Date: 28-06-2004
DOI: 10.1002/ANA.20153
Abstract: Benign rolandic epilepsy (BRE) is considered to be a genetically determined idiopathic partial epilepsy. We studied twins with BRE and compared the concordance with a twin s le of idiopathic generalized epilepsy (IGE). All eight BRE pairs (six monozygous [MZ], two dizygous [DZ]) were discordant. MZ pairwise concordance was 0 (95% confidence interval [CI], 0-0.4) for BRE compared with 0.7 (95% CI, 0.5-0.9) for 26 IGE MZ pairs. Our data suggest that conventional genetic influences in BRE are considerably less than for IGE, and other mechanisms need to be explored.
Publisher: Springer Science and Business Media LLC
Date: 04-2011
DOI: 10.1186/AR3309
Abstract: A number of genetic-association studies have identified genes contributing to ankylosing spondylitis (AS) susceptibility but such approaches provide little information as to the gene activity changes occurring during the disease process. Transcriptional profiling generates a 'snapshot' of the s led cells' activity and thus can provide insights into the molecular processes driving the disease process. We undertook a whole-genome microarray approach to identify candidate genes associated with AS and validated these gene-expression changes in a larger s le cohort. A total of 18 active AS patients, classified according to the New York criteria, and 18 gender- and age-matched controls were profiled using Illumina HT-12 whole-genome expression BeadChips which carry cDNAs for 48,000 genes and transcripts. Class comparison analysis identified a number of differentially expressed candidate genes. These candidate genes were then validated in a larger cohort using qPCR-based TaqMan low density arrays (TLDAs). A total of 239 probes corresponding to 221 genes were identified as being significantly different between patients and controls with a P -value .0005 (80% confidence level of false discovery rate). Forty-seven genes were then selected for validation studies, using the TLDAs. Thirteen of these genes were validated in the second patient cohort with 12 downregulated 1.3- to 2-fold and only 1 upregulated (1.6-fold). Among a number of identified genes with well-documented inflammatory roles we also validated genes that might be of great interest to the understanding of AS progression such as SPOCK2 (osteonectin) and EP300 , which modulate cartilage and bone metabolism. We have validated a gene expression signature for AS from whole blood and identified strong candidate genes that may play roles in both the inflammatory and joint destruction aspects of the disease.
Publisher: SAGE Publications
Date: 07-2013
Abstract: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype–genotype study designed to gather and analyze detailed phenotypic information and DNA s les on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.
Publisher: Wiley
Date: 24-02-2005
DOI: 10.1002/ANA.20399
Publisher: Elsevier BV
Date: 04-2019
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.SCITOTENV.2019.135401
Abstract: Composting is an important technology to treat biowastes and recycle nutrients, but incurs nitrogen (N) losses that lower the value of the final products and cause pollution. Technologies aimed at reducing N losses during composting have inconsistent outcomes. To deepen insight into mitigation options, we conducted a global meta-analysis based on 932 observations from 121 peer-reviewed published studies. Overall, N losses averaged 31.4% total N (TN), 17.2% NH
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0896-6273(00)80651-0
Abstract: Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 10-2015
Publisher: Elsevier BV
Date: 10-2021
Publisher: Elsevier BV
Date: 10-2007
Publisher: Oxford University Press (OUP)
Date: 16-06-2004
DOI: 10.1093/BRAIN/AWH211
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9NR02636C
Abstract: Novel materials from self-assembled nanocrystals hold great promise for applications ranging from inorganic catalysis to bio-imaging.
Publisher: SAGE Publications
Date: 27-09-2021
Publisher: Wiley
Date: 20-12-2018
DOI: 10.1111/EPI.13980
Abstract: To investigate the significance of variation in ADGRV1 (also known as GPR98, MASS1, and VLGR1), MEF2C, and other genes at the 5q14.3 chromosomal locus in myoclonic epilepsy. We studied the epilepsy phenotypes of 4 in iduals with 5q14.3 deletion and found that all had myoclonic seizures. We then screened 6 contiguous genes at 5q14.3, MEF2C, CETN3, MBLAC2, POLR3G, LYSMD3, and ADGRV1, in a 95-patient cohort with epilepsy and myoclonic seizures. Of these genes, point mutations in MEF2C cause a phenotype involving seizures and intellectual disability. A role for ADGRV1 in epilepsy has been proposed previously, based on a recessive mutation in the Frings mouse model of audiogenic seizures, as well as a shared homologous region with another epilepsy gene, LGI1. Six patients from the myoclonic epilepsy cohort had likely pathogenic ultra-rare ADGRV1 variants, and statistical analysis showed that ultra-rare variants were significantly overrepresented when compared to healthy population data from the Genome Aggregation Database. Of the remaining genes, no definite pathogenic variants were identified. Our data suggest that the ADGRV1 variation contributes to epilepsy with myoclonic seizures, although the inheritance pattern may be complex in many cases. In patients with 5q14.3 deletion and epilepsy, ADGRV1 haploinsufficiency likely contributes to seizure development. The latter is a shift from current thinking, as MEF2C haploinsufficiency has been considered the main cause of epilepsy in 5q14.3 deletion syndrome. In cases of 5q14.3 deletion and epilepsy, seizures likely occur due to haploinsufficiency of one or both of ADGRV1 and MEF2C.
Publisher: Wiley
Date: 26-03-2007
DOI: 10.1111/J.1528-1167.2007.01049.X
Abstract: Mutations of the sodium channel subunit gene SCN2A have been described in families with benign familial neonatal-infantile seizure (BFNIS). We describe two large families with BFNIS and novel SCN2A mutations. The families had 12 and 9 affected in iduals, respectively, with phenotypes consistent with BFNIS. Two mutations were discovered in SCN2A (E430Q I1596S). Both families had in iduals with neonatal onset but the typical age of onset was in the early infantile period (mean 3.0 months). One mutation positive in idual, with an otherwise typical clinical pattern, had seizures beginning at 13 months. Two in iduals with SCN2A mutations were identified with seizures in later life. In each family a single in idual with infantile seizures was mutation negative and thus represented phenocopies. This study extends the age range of presentation of BFNIS, confirms that neonatal and early infantile onsets are characteristic, and emphasizes the role of molecular diagnosis to confirm the etiology.
Publisher: Springer Science and Business Media LLC
Date: 05-2001
DOI: 10.1038/NG0501-49
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-08-2019
DOI: 10.1212/WNL.0000000000008126
Abstract: To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures. In this double-blind trial (SP0969 NCT01921205 ), patients (age ≥4– years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide lacebo. After a 6-week titration, patients who reached the target dose range for their weight ( kg: 8–12 mg/kg/d oral solution ≥30– kg: 6–8 mg/kg/d oral solution ≥50 kg: 300–400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance. Three hundred forty-three patients were randomized 306 (lacosamide 152 of 171 [88.9%] placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1% placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% ( p = 0.0003). During maintenance, median percent reduction in focal seizure frequency per 28 days was 51.7% for lacosamide and 21.7% for placebo. Fifty percent responder rates (≥50% reduction) were 52.9% and 33.3% (odds ratio 2.17, p = 0.0006). During treatment, treatment-emergent AEs were reported by 67.8% lacosamide-treated patients (placebo 58.1%), most commonly (≥10%) somnolence (14.0%, placebo 5.2%) and dizziness (10.5%, placebo 3.5%). Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4– years) with focal seizures. NCT01921205. This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.
Publisher: Wiley
Date: 23-03-2017
DOI: 10.1002/ACN3.401
Publisher: IOP Publishing
Date: 13-09-2002
Publisher: Elsevier BV
Date: 02-2021
Publisher: Wiley
Date: 05-2011
DOI: 10.1111/J.1528-1167.2011.03031.X
Abstract: In a substantial number of patients with epilepsy, the etiology of the seizure disorder remains unknown. In recent years, the detection of autoantibodies has contributed to the etiologic understanding of a substantial number of so far unexplained epilepsies. The associated syndromes are mainly related to the temporal lobes (with presentation as limbic encephalitis or chronic mediotemporal lobe epilepsy) or to extended brain areas (presenting as diffuse encephalopathies with seizures). However, the full spectrum of autoantibody-associated epilepsies is about to be determined. A promising ex le for this incipient expansion of the clinical spectrum is the description of a novel seizure type found in patients with antibodies to the voltage-gated potassium channel (VGKC) complex. At present, the antibodies most relevant in epileptology are those directed to molecules on the surface of neurons, namely to components of the VGKC complex and to the N-methyl-d-aspartate-receptor other antigenic targets located on the surface of neurons are the γ-aminobutyric acid (GABA)(B) -receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor. There are several reasons to believe that these antibodies are directly pathogenic to the brain. Other autoantibodies target intracellular antigens like those directed to the enzyme glutamic acid decarboxylase (GAD) and the onconeural antibodies. Most researchers think that these antibodies are markers of the immunopathological process rather than being pathogenically active by themselves. Especially the epilepsies associated with antibodies to surface antigens seem to respond to immunotherapies. This offers novel promising therapeutic avenues for the epileptologist. The precise pathogenic effects of autoantibodies still need to be elucidated.
Publisher: American Physical Society (APS)
Date: 28-11-2017
Publisher: Wiley
Date: 18-11-2015
DOI: 10.1002/ANA.24520
Publisher: Wiley
Date: 05-2004
Publisher: BMJ
Date: 10-2003
Publisher: American Society of Neuroradiology (ASNR)
Date: 24-01-2013
DOI: 10.3174/AJNR.A3427
Publisher: Georg Thieme Verlag KG
Date: 10-03-2014
Abstract: Epilepsy genetics has undergone a revolution in the past 19 years since the discovery of the first gene for epilepsy. The story of our increasing knowledge and how it impacts on patient care is presented with reference to recent discoveries. Understanding the significance of a genetic variant is challenging both in terms of molecular pathogenicity and in how this finding fits into the rubric of causation. In some cases, it may only be a contributing susceptibility factor whereas in others, it explains the patient's disease. A brief overview of the clinicomolecular approaches is discussed in the context of the discovery of epilepsy genes. These include family studies and, more recently, next generation sequencing using multigene panels and whole exome sequencing. Recent studies illustrating the way in which epilepsy genetics is changing clinical practice are described. A particular focus is DEPDC5, the first gene for nonlesional focal epilepsy likely to be relevant to sporadic patients with focal epilepsies and those from small families, in contrast to rare large families with autosomal dominant focal epilepsies. As DEPDC5 is a negative regulator of the mammalian target of rapamycin (mTOR) pathway, it is likely that some patients with DEPDC5 mutations may have malformations of cortical development akin to the two-hit hypothesis suggested in tuberous sclerosis. The greatest impact of epilepsy genetics at a clinical level is for patients with epileptic encephalopathies as many have de novo mutations-a rapidly expanding list of causative genes is being found. Epilepsy genetics is changing clinical practice enabling diagnosis in many patients, informing our understanding of comorbidities, prognosis, and genetic counseling. Importantly, a genetic finding may impact on treatment choices. At a biological level, new insights promise to lead to the development of novel therapies and bring together the seemingly disparate genetics of nonlesional epilepsies and epilepsies associated with cortical malformations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-09-2020
DOI: 10.1212/WNL.0000000000010794
Abstract: To define the risks and consequences of cardiac abnormalities in ATP1A3 -related syndromes. Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl +/− ) to determine the sequence of events in seizure-related cardiac death. Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay during induced seizures, heart block or complete sinus arrest led to death. We found increased prevalence of ECG dynamic abnormalities in all ATP1A3 -related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3 -related disease. ATP1A3 -related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
Publisher: MDPI AG
Date: 25-03-2021
DOI: 10.3390/W13070898
Abstract: Petroleum contaminants are exposed to weathering when released into environment, resulting in the alteration of their chemical composition. Here, we investigated microbial communities through the soil profile at an industrial site, which was exposed to various petroleum products for over 50 years. The petroleum is present as light non-aqueous phase liquid (LNAPL) and is undergoing natural source zone depletion (NSZD). Microbial community composition was compared to the contaminant type, concentration, and its depth of obtained soil cores. A large population of Archaea, particularly Methanomicrobia and Methanobacteria and indication of complex syntrophic relationships of methanogens, methanotrophs and bacteria were found in the contaminated cores. Different families were enriched across the LNAPL types. Results indicate methanogenic or anoxic conditions in the deeper and highly contaminated sections of the soil cores investigated. The contaminant was highly weathered, likely resulting in the formation of recalcitrant polar compounds. This research provides insight into the microorganisms fundamentally associated with LNAPL, throughout a soil depth profile above and below the water table, undergoing NSZD processes at a legacy petroleum site. It advances the potential for integration of microbial community effects on bioremediation and in response to physicochemical partitioning of LNAPL components from different petroleum types.
Publisher: Oxford University Press (OUP)
Date: 17-03-2015
DOI: 10.1093/BRAIN/AWV052
Publisher: Wiley
Date: 13-06-2013
DOI: 10.1111/DMCN.12197
Abstract: STXBP1 encephalopathy is associated with a range of movement disorders. We observed head stereotypies in three patients. These comprised a slow (<1Hz), high- litude, horizontal, 'figure-of-eight' pattern, beginning at age 4-6 years and resulting in neck muscle hypertrophy, in two males a faster (2-3Hz), side-to-side, 'no' movement, starting at the age of 9 years 6 months was observed in one female. Upper limb and truncal stereotypies and vocalization occurred intermittently with the head movements. The stereotypies increased with excitement but settled with concentration and sleep. Head and upper limb stereotypies are valuable clinical clues to the diagnosis of STXBP1 encephalopathy in patients with profound impairments.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2003
Publisher: Wiley
Date: 21-11-2020
DOI: 10.1111/NAN.12653
Publisher: Hindawi Limited
Date: 06-2005
DOI: 10.1002/HUMU.20178
Abstract: SCN1A is part of the SCN1A-SCN2A-SCN3A gene cluster on chromosome 2q24 that encodes for alpha pore forming subunits of sodium channels. The 26 exons of SCN1A are spread over 100 kb of genomic DNA. Genetic defects in the coding sequence lead to generalized epilepsy with febrile seizures plus (GEFS+) and a range of childhood epileptic encephalopathies of varied severity (e.g., SMEI). All published mutations are collated. More than 100 novel mutations are spread throughout the gene with the more debilitating usually de novo. Some clustering of mutations is observed in the C-terminus and the loops between segments 5 and 6 of the first three domains of the protein. Functional studies so far show no consistent relationship between changes to channel properties and clinical phenotype. Of all the known epilepsy genes SCN1A is currently the most clinically relevant, with the largest number of epilepsy related mutations so far characterized.
Publisher: Wiley
Date: 04-2011
DOI: 10.1111/J.1528-1167.2011.02997.X
Abstract: Dravet syndrome (DS), otherwise known as severe myoclonic epilepsy of infancy (SMEI), is an epileptic encephalopathy presenting in the first year of life. DS has a genetic etiology: between 70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset. The remaining SCN1A mutations comprise splice-site and missense mutations, most of which fall into the pore-forming region of the sodium channel. Mutations are randomly distributed across the SCN1A protein. Most mutations are de novo, but familial SCN1A mutations also occur. Somatic mosaic mutations have also been reported in some patients and might explain the phenotypical variability seen in some familial cases. SCN1A exons deletions or chromosomal rearrangements involving SCN1A and contiguous genes are also detectable in about 2-3% of patients. A small percentage of female patients with a DS-like phenotype might carry PCDH19 mutations. Rare mutations have been identified in the GABARG2 and SCN1B genes. The etiology of about 20% of DS patients remains unknown, and additional genes are likely to be implicated.
Publisher: Wiley
Date: 08-2017
DOI: 10.1111/EPI.13821
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.EPLEPSYRES.2018.04.008
Abstract: SCN8A-related epilepsies are often severe developmental and epileptic encephalopathies. Seizures can be treatment resistant, and patients suffer from severe intellectual disability. Reports have suggested that SCN8A-related epilepsies have a high mortality with SUDEP as the major underlying cause. SUDEP is a catastrophic event, and the risk of occurrence should be correctly and carefully discussed with patients and families. We tested the hypothesis of SUDEP as the main cause of death in SCN8A-related epilepsies by reviewing all the currently reported patients with SCN8A. In addition, we collected unpublished patients through an international network. In total, we reviewed the data of 190 patients. In our cohort, 10 patients were deceased, and the overall mortality was 5.3%. Within the ten deceased patients, age at death ranged from 16 months to 17 years the majority (7/10) of them died in early childhood. Three patients died of probable or definite SUDEP. Thus, our data do not indicate an increased risk when compared to other DEEs. Indeed, death in SCN8A-related epilepsies seems to occur most often in children experiencing a relentless worsening of their epilepsy and neurological condition, rendering them susceptible to pulmonary infections and respiratory distress that ultimately can be fatal.
Publisher: Elsevier BV
Date: 02-2021
DOI: 10.1016/J.EPLEPSYRES.2020.106537
Abstract: We investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive. We recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA. Sixty-two patients were included 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43 0.43-27.65 p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82 1.68-8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy. We conclude that if CACNA1H rare variants predict lack of response to ETX, a larger s le is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.
Publisher: Wiley
Date: 12-2005
Publisher: Massachusetts Medical Society
Date: 18-04-2019
DOI: 10.1056/NEJMC1805100
Publisher: BMJ
Date: 03-2004
Publisher: Wiley
Date: 08-03-2017
DOI: 10.1111/EPI.13709
Publisher: Wiley
Date: 30-04-2018
DOI: 10.1002/ANA.25222
Abstract: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). The de novo p.Glu590Lys variant was identified by whole‐exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5–21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike‐wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox‐Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile‐onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018 :926–934
Publisher: Elsevier BV
Date: 12-2015
Publisher: Springer Science and Business Media LLC
Date: 10-1995
DOI: 10.1038/NG1095-201
Abstract: Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.
Publisher: Cold Spring Harbor Laboratory
Date: 29-03-2023
DOI: 10.1101/2023.03.27.23287689
Abstract: PPFIA3 encodes the Protein-Tyrosine Phosphatase, Receptor-Type, F Polypeptide-Interacting Protein Alpha-3 (PPFIA3), which is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family involved in synaptic vesicle transport and presynaptic active zone assembly. The protein structure and function are well conserved in both invertebrates and vertebrates, but human diseases related to PPFIA3 dysfunction are not yet known. Here, we report 14 in iduals with rare mono-allelic PPFIA3 variants presenting with features including developmental delay, intellectual disability, hypotonia, autism, and epilepsy. To determine the pathogenicity of PPFIA3 variants in vivo , we generated transgenic fruit flies expressing either human PPFIA3 wildtype (WT) or variant protein using GAL4-UAS targeted gene expression systems. Ubiquitous expression with Actin-GAL4 showed that the PPFIA3 variants had variable penetrance of pupal lethality, eclosion defects, and anatomical leg defects. Neuronal expression with elav-GAL4 showed that the PPFIA3 variants had seizure-like behaviors, motor defects, and bouton loss at the 3 rd instar larval neuromuscular junction (NMJ). Altogether, in the fly overexpression assays, we found that the PPFIA3 variants in the N-terminal coiled coil domain exhibited stronger phenotypes compared to those in the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of fly Liprin- α leads to embryonic lethality. This lethality is partially rescued by the expression of human PPFIA3 WT, suggesting human PPFIA3 protein function is partially conserved in the fly. However, the PPFIA3 variants failed to rescue lethality. Altogether, the human and fruit fly data reveal that the rare PPFIA3 variants are dominant negative loss-of-function alleles that perturb multiple developmental processes and synapse formation.
Publisher: American Chemical Society (ACS)
Date: 14-09-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-07-2022
DOI: 10.1212/WNL.0000000000200715
Abstract: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18–58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All in iduals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living. STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-06-2013
Publisher: Wiley
Date: 21-03-2022
DOI: 10.1111/DMCN.15211
Abstract: To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. Participants aged 7 years and older with a history of developmental stuttering were recruited. Self‐reported phenotypic data were collected online including stuttering symptomatology, co‐occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months range = 18–93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years range = 7–17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies. Half of the study cohort had a family history of stuttering. While 75.9% of participants had sought stuttering therapy, only 15.5% identified as having recovered. There was a significant negative correlation between age and stuttering frequency and severity in adults.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.EPLEPSYRES.2012.04.007
Abstract: Levetiracetam, a broad spectrum antiepileptic drug, binds to membrane protein SV2A. The protein coding region of SV2A was sequenced in 158 patients with focal or generalized epilepsies ided into three groups based on their response to levetiracetam: responders (>75% decrease), exacerbators (50% increase) and non-responders. Nonsynonymous coding variation within SV2A was extremely rare, suggesting that rare variation is not likely to account for the in idual differences in response to levetiracetam.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.EPLEPSYRES.2010.01.013
Abstract: Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.
Publisher: Springer Science and Business Media LLC
Date: 21-04-2023
DOI: 10.1007/S11936-023-00983-8
Abstract: This review examines the significance of seizures in young athletes and the complex inter-relationship between seizures, epilepsy, and sudden cardiac death. A history of seizures may reflect a diagnosis of epilepsy, which should be medically optimized for athletic participation. Epilepsy is associated with sudden unexplained cardiac death (sudden unexplained death in epilepsy, SUDEP), with multiple genetic links identified to define some patients as experiencing a “cardiocerebral channelopathy.” It is also important to consider that a history of seizures may reflect a misdiagnosis of cardiac syncope, requiring careful cardiac evaluation and risk stratification. A history of seizures in a young athlete is important to characterize fully and investigate as required. The association of seizures with young sudden cardiac death is still under investigation.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Springer Science and Business Media LLC
Date: 11-06-2018
Publisher: Elsevier BV
Date: 08-2016
Publisher: Oxford University Press (OUP)
Date: 04-1997
DOI: 10.1093/HMG/6.4.555
Abstract: While disorders of neuronal migration are associated with as much as 25% of recurrent childhood seizures, few of the genes required to establish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migration disorders producing epilepsy and variable cognitive impairment, can be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five families and physical mapping of a balanced X translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the breakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysis. Markers used for somatic cell hybrid and fluorescence in situ hybridization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutation of a single gene, XLIS, that the milder SBH phenotype in females results from random X-inactivation (Lyonization), and that cloning of genes from the breakpoint region on X will yield XLIS.
Publisher: AMPCo
Date: 03-2018
DOI: 10.5694/MJA17.00951
Abstract: The International League Against Epilepsy has recently published a new classification of epileptic seizures and epilepsies to reflect the major scientific advances in our understanding of the epilepsies since the last formal classification 28 years ago. The classification emphasises the importance of aetiology, which allows the optimisation of management. Antiepileptic drugs (AEDs) are the main approach to epilepsy treatment and achieve seizure freedom in about two-thirds of patients. More than 15 second generation AEDs have been introduced since the 1990s, expanding opportunities to tailor treatment for each patient. However, they have not substantially altered the overall seizure-free outcomes. Epilepsy surgery is the most effective treatment for drug-resistant focal epilepsy and should be considered as soon as appropriate trials of two AEDs have failed. The success of epilepsy surgery is influenced by different factors, including epilepsy syndrome, presence and type of epileptogenic lesion, and duration of post-operative follow-up. For patients who are not eligible for epilepsy surgery or for whom surgery has failed, trials of alternative AEDs or other non-pharmacological therapies, such as the ketogenic diet and neurostimulation, may improve seizure control. Ongoing research into novel antiepileptic agents, improved techniques to optimise epilepsy surgery, and other non-pharmacological therapies fuel hope to reduce the proportion of in iduals with uncontrolled seizures. With the plethora of gene discoveries in the epilepsies, "precision therapies" specifically targeting the molecular underpinnings are beginning to emerge and hold great promise for future therapeutic approaches.
Publisher: Wiley
Date: 16-04-2015
DOI: 10.1111/EPI.12984
Abstract: To describe the antiepileptic drug (AED) treatment of patients with early infantile epileptic encephalopathy due to KCNQ2 mutations during the neonatal phase and the first year of life. We identified 15 patients and reviewed the electroclinical, neuroimaging, and AED treatment data. Seizure onset was between 1 and 4 days of age with daily tonic asymmetric, focal and clonic seizures in nine patients and status epilepticus in the remaining six. Electroencephalography (EEG) showed multifocal epileptiform abnormalities in nine patients and a burst-suppression pattern in six. All patients were trialed with adequate daily doses of several AEDs before they reached seizure freedom. Six patients (40%) achieved seizure control within 2 weeks of carbamazepine (CBZ) administration and five (33%) were seizure-free with phenytoin (PHT). The last four patients (27%) were successfully treated with topiramate (TPM) (two patients), levetiracetam (LEV) (one), and a combination of LEV with TPM (one). Most patients reached seizure freedom within the first year of life and remained seizure-free thereafter. Twelve patients had moderate-to-severe developmental delay at follow-up. However, the two patients whose seizures ceased within a few days of onset showed only mild cognitive impairment. Our findings suggest that drugs acting on sodium channels including CBZ and PHT should be considered as first-line treatment in patients with KCNQ2 encephalopathy. Voltage-gated sodium and potassium channels co-localize at the neuronal membrane. Therefore, the efficacy of drugs acting as sodium-channel blockers could be linked to their modulating effect on both channels. The type of KCNQ2 mutation might influence AED response as well as developmental outcome. Early recognition of KCNQ2 encephalopathy followed by the most appropriate and effective treatment may be important for reducing the neurodevelopmental impairment associated with this disorder.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-07-2004
DOI: 10.1212/01.WNL.0000131909.74506.5F
Abstract: Persistent, frequent, nonepileptic paroxysmal eyelid movements were observed in 19 children and adults with well-controlled generalized epilepsy. Patients were identified from five epilepsy centers. Seventeen patients were female and two male. All had generalized photosensitive epilepsy requiring antiepileptic drugs (AEDs). In two children, paroxysmal eyelid movements began 2 to 4 years before their epilepsy was noted in the remainder, it was noted when epilepsy was first diagnosed. Age at last follow-up was 8 to 38 years (average 21 years) with average follow-up of 9 years. All patients showed photosensitive generalized spike-wave discharges on EEG. Paroxysmal eyelid movements were a source of diagnostic confusion, but direct examination and video during EEG recording distinguished the attacks from absence seizures. In all cases, the epilepsy is completely or nearly completely controlled with AEDs, but the paroxysmal eyelid movements have not resolved with age. In 12 cases, there was a family history of the eyelid disorder without epilepsy. Videos of patients and an affected parent are available on the Neurology Web site. There is an association between paroxysmal eyelid movements and photosensitive generalized epilepsy, creating diagnostic confusion.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-05-2002
Abstract: Generalized epilepsy with febrile seizures plus (GEFS(+)) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS(+) and FS patients were screened for mutations in the sodium channel beta-subunits SCN1B and SCN2B, and the second GEFS(+) family with an SCN1B mutation is described here. The family had 19 affected in iduals: 16 with typical GEFS(+) phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS(+), and the authors found no evidence to implicate SCN2B in this syndrome.
Publisher: Elsevier BV
Date: 02-1994
DOI: 10.1016/S0140-6736(94)91463-X
Abstract: We describe a distinctive epilepsy syndrome in six families, which is the first partial epilepsy syndrome to follow single gene inheritance. The predominant seizure pattern had frontal lobe seizure semiology with clusters of brief motor attacks occurring in sleep. Onset was usually in childhood, often persisting through adult life. Misdiagnosis as night terrors, nightmares, hysteria, or paroxysmal nocturnal dystonia was common, and the inheritance pattern was often not appreciated. This autosomal dominant epilepsy syndrome is ideal for identification of partial epilepsy genes.
Publisher: Defense Technical Information Center
Date: 2015
DOI: 10.21236/ADA621217
Publisher: Wiley
Date: 21-06-2011
DOI: 10.1111/J.1528-1167.2011.03134.X
Abstract: Cases of severe childhood epilepsies in temporal association with vaccination have great impact on the acceptance of vaccination programs by parents and health care providers. However, little is known about the type and frequency of seizures and epilepsy syndromes following vaccination. This study aims to describe the clinical features of children presenting with seizures after vaccination using a register-based cohort. We surveyed the national German database of adverse events following immunization (AEFI) for reported seizures and epilepsies in children aged 0-6 years. All cases reported in 2006-2008 were analyzed retrospectively available clinical information was reevaluated and classified by seizure type and epilepsy syndrome. In total, 328 cases reported between 2006 and 2008 were included. Data supportive of seizures or epilepsy were present in 247 (75.3%) of 328 patients with a mean interval between the vaccination and the epileptic event of 24 h and 7.5 days for inactivated and attenuated vaccines, respectively. Fifty-one (15.5%) of 328 patients presented with syncope, hypotonic-hyporesponsive episodes, or other nonepileptic events. Information was insufficient for classification into epileptic versus nonepileptic events in 30 (11.3%) of 328 patients. For cases with confirmed seizures, febrile seizures were present in 121 (49%) of 247 cases, and 38 (15.4%) of 247 patients had single afebrile seizures. Status epilepticus was described in 21 (8.5%) of 247 patients. Thirty-one (12.6%) of 247 patients presented with various pediatric epilepsy syndromes. Severe childhood epilepsies (Dravet syndrome, West syndrome, Lennox-Gastaut syndrome, or Doose syndrome) were diagnosed in 29 (11.7%) of 247 patients, with the vaccination-associated event being the first documented seizure in 15 (51.7%) of 29 patients. Vaccination-associated seizures present in the setting of various epilepsy syndromes, including severe childhood epilepsies in >10% of cases. Early diagnosis of the corresponding epilepsy syndromes and confirmation of an underlying etiology is important for treatment decisions, genetic counseling, and public health evaluation of vaccine safety.
Publisher: Elsevier BV
Date: 10-1998
DOI: 10.1086/302047
Publisher: Wiley
Date: 18-11-2022
DOI: 10.1002/EPI4.12553
Abstract: Recessive variants in RARS2 , a nuclear gene encoding a mitochondrial protein, were initially reported in pontocerebellar hypoplasia. Subsequently, a recessive RARS2 early‐infantile ( weeks) developmental and epileptic encephalopathy was described with hypoglycaemia and lactic acidosis. Here, we describe two unrelated patients with a novel RARS2 phenotype and reanalyse the published RARS2 epilepsy phenotypes and variants. Our novel cases had infantile‐onset myoclonic developmental and epileptic encephalopathy, presenting with a progressive movement disorder from 9 months on a background of normal development. Development plateaued and regressed thereafter, with mild to profound impairment. Multiple drug‐resistant generalized and focal seizures occurred with episodes of non‐convulsive status epilepticus. Seizure types included absence, atonic, myoclonic, and focal seizures. Electroencephalograms showed diffuse slowing, multifocal, and generalised spike‐wave activity, activated by sleep. Both patients had compound heterozygous RARS2 variants with likely impact on splicing and transcription. Remarkably, of the now 52 RARS2 variants reported in 54 patients, our reanalysis found that 44 (85%) have been shown to or are predicted to affect splicing or gene expression leading to protein truncation or nonsense‐mediated decay. We expand the RARS2 phenotypic spectrum to include infantile encephalopathy and suggest this gene is enriched for pathogenic variants that disrupt splicing.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-10-1999
Abstract: Congenital brain lesions producing focal seizures may be accompanied by reorganization of the areas responsible for motor and sensory functions within the brain due to a phenomenon that has been termed "neuronal plasticity." This can be studied using functional MRI (fMRI) and transcranial magnetic stimulation (TMS). Using either method, the motor cortex can be localized noninvasively, but to date there have been few studies correlating the level of agreement between the two techniques. We used fMRI and TMS to localize the motor cortex in a young woman with intractable focal seizures, congenital left arm weakness, and a dysplastic right hemisphere on MRI. There was excellent agreement in the localization of motor representation for each hand. Both were predominantly located in the left hemisphere. fMRI also showed an area of posterior activation in the right hemisphere, but there was no evidence of descending corticospinal projections from this site using TMS, direct cortical stimulation, and Wada testing. Functional MRI (fMRI) and transcranial magnetic stimulation (TMS) were successfully used to localize cortical motor function before epilepsy surgery. Each technique demonstrated migration of motor function for the left hand to the left motor cortex. After resection of the dysplastic right precentral gyrus there was no permanent increase in weakness or disability. The two techniques are complementary fMRI indicates all cortical areas activated by the motor task, whereas TMS identifies only those areas giving rise to corticospinal projections.
Publisher: American Chemical Society (ACS)
Date: 22-02-2017
DOI: 10.1021/JACS.6B12185
Abstract: Potassium-ion batteries (PIBs) are interesting as one of the alternative metal-ion battery systems to lithium-ion batteries (LIBs) due to the abundance and low cost of potassium. We have herein investigated Sn
Publisher: Wiley
Date: 24-11-2017
DOI: 10.1111/EPI.13957
Publisher: American Medical Association (AMA)
Date: 09-2011
DOI: 10.1001/ARCHNEUROL.2011.102
Abstract: To determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. Genetic analysis. Ambulatory and hospitalized care. Eighty-four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe lification. Any identified mutations were then screened in controls. Any SLC2A1 mutations. Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe lification analysis did not reveal any genomic rearrangements in 75 of the remaining cases 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder.
Publisher: Wiley
Date: 17-06-2019
DOI: 10.1002/ACN3.50815
Publisher: Wiley
Date: 12-06-2022
DOI: 10.1111/APA.16422
Abstract: Critically review research methods used to elicit children and young people's views and experiences in the first year of COVID‐19, using an ethical and child rights lens. A systematic search of peer‐reviewed literature on children and young people's perspectives and experiences of COVID‐19. LEGEND ( Let Evidence Guide Every New Decision ) tools were applied to assess the quality of included studies. The critical review methodology addressed four ethical parameters: (1) Duty of care (2) Children and young people's consent (3) Communication of findings and (4) Reflexivity. Two phases of searches identified 8131 studies 27 studies were included for final analysis, representing 43,877 children and young people's views. Most studies were from high‐income countries. Three major themes emerged: (a) Whose voices are heard (b) How are children and young people heard and (c) How do researchers engage in reflexivity and ethical practice? Online surveys of children and young people from middle‐class backgrounds dominated the research during COVID‐19. Three studies actively involved children and young people in the research process two documented a rights‐based framework. There was limited attention paid to some ethical issues, particularly the lack of inclusion of children and young people in research processes. There are equity gaps in accessing the experiences of children and young people from disadvantaged settings. Most children and young people were not involved in shaping research methods by soliciting their voices.
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.NEULET.2009.02.038
Abstract: Rare GABA(A) receptor gamma2 and alpha1 subunit mutations of pathogenic effect have been described segregating in families with "monogenic" epilepsies. We now report globally on the genetic variation contained within all 16 neuronal GABA(A) receptor subunit genes from the one patient cohort. The cohort consists of GEFS(+), FS, and IGE subgroups as either sporadic cases or index cases from small families, with one index case from one large IGE family. The rarity of mutations and coding variation in general across all of the subunits suggests a low tolerance for mutations affecting GABA mediated neuronal inhibition. Characterization of the broader channelopathy load associated with susceptibility to these common epilepsies mostly with complex genetics will need to be expanded beyond the family of GABA(A) receptor subunits to all families of neuronal ion channels and their interacting molecules by systematic mutation detection associated with functional investigation of their naturally occurring genetic variations.
Publisher: Wiley
Date: 18-02-2022
DOI: 10.1111/EPI.17173
Abstract: Epilepsy is common in patients with PIGN diseases due to biallelic variants however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic–atonic (1/26), and generalized tonic–clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug‐resistant epilepsy, compared to 4/6 ID+E patients, who were seizure‐free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty‐seven of 34 variants were novel. Variants were truncating ( n = 7), intronic and predicted to affect splicing ( n = 7), and missense or inframe indels ( n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-06-2010
Publisher: Oxford University Press (OUP)
Date: 2021
DOI: 10.1093/BRAINCOMMS/FCAA235
Abstract: Brain somatic mutations are an increasingly recognized cause of epilepsy, brain malformations and autism spectrum disorders and may be a hidden cause of other neurodevelopmental and neurodegenerative disorders. At present, brain mosaicism can be detected only in the rare situations of autopsy or brain biopsy. Liquid biopsy using cell-free DNA derived from cerebrospinal fluid has detected somatic mutations in malignant brain tumours. Here, we asked if cerebrospinal fluid liquid biopsy can be used to detect somatic mosaicism in non-malignant brain diseases. First, we reliably quantified cerebrospinal fluid cell-free DNA in 28 patients with focal epilepsy and 28 controls using droplet digital PCR. Then, in three patients we identified somatic mutations in cerebrospinal fluid: in one patient with subcortical band heterotopia the LIS1 p. Lys64* variant at 9.4% frequency in a second patient with focal cortical dysplasia the TSC1 p. Phe581His*6 variant at 7.8% frequency and in a third patient with ganglioglioma the BRAF p. Val600Glu variant at 3.2% frequency. To determine if cerebrospinal fluid cell-free DNA was brain-derived, whole-genome bisulphite sequencing was performed and brain-specific DNA methylation patterns were found to be significantly enriched (P = 0.03). Our proof of principle study shows that cerebrospinal fluid liquid biopsy is valuable in investigating mosaic neurological disorders where brain tissue is unavailable.
Publisher: Elsevier BV
Date: 02-2002
DOI: 10.1086/338710
Publisher: Elsevier BV
Date: 2018
Publisher: Wiley
Date: 07-2017
DOI: 10.1111/EPI.13800
Publisher: Elsevier BV
Date: 12-2010
Publisher: Elsevier BV
Date: 12-2019
Publisher: Elsevier BV
Date: 06-2017
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.TINS.2006.05.009
Abstract: Epilepsies, once regarded as due to demoniacal possession, can have both genetic and acquired causes, with interaction of these factors in many cases. To date, nearly all the genes discovered to be involved in human epilepsies encode subunits of ion channels, both voltage-gated and ligand-gated. Established acquired causes include serious brain trauma, stroke, tumours and infective lesions. Thus, in terms of exploring the neurobiology of "nature and nurture" in disease, the epilepsies are an excellent paradigm. Here, we review the evidence and discuss the possibility that ion channels are a common biological substrate for both genetic and acquired epilepsies. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (inmednet.com/).
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.EPLEPSYRES.2017.11.015
Abstract: This review discusses the updated classifications of seizures and the epilepsies, which were recently published by the International League Against Epilepsy (ILAE). While it is always a challenge to learn a new classification system, particularly one that has remained essentially unchanged for over three decades, these new classifications allow for the inclusion of some previously unclassifiable seizure types and utilize more intuitive terminology. In this review, we specifically discuss the use of these new classifications for patients, clinicians, and researchers.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2013
DOI: 10.1038/NATURE12439
Publisher: Modelling and Simulation Society of Australia and New Zealand (MSSANZ), Inc.
Date: 12-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2017
DOI: 10.1212/WNL.0000000000004762
Abstract: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel litude and variable blockade by quinidine. Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.
Publisher: BMJ
Date: 06-03-2013
DOI: 10.1136/JMEDGENET-2012-101448
Abstract: Recent advances in molecular genetics have translated into the increasing utilisation of genetic testing in the routine clinical practice of neurologists. There has been a steady, incremental increase in understanding the genetic variation associated with epilepsies. Genetic testing in the epilepsies is not yet widely practiced, but the advent of new screening technologies promises to exponentially expand both knowledge and clinical utility. To maximise the value of this new genetic insight we need to rapidly extrapolate genetic findings to inform patients of their diagnosis, prognosis, recurrence risk and the clinical management options available for their specific genetic condition. Comprehensive, highly specific and sensitive genetic test results improve the management of patients by neurologists and clinical geneticists. Here we discuss the latest developments in clinical genetic testing for epilepsy and describe new molecular genetics platforms that will transform both genetic screening and novel gene discovery.
Publisher: The Endocrine Society
Date: 02-2008
DOI: 10.1210/JC.2007-1611
Abstract: Pulsatile GH secretion from the anterior pituitary is a key mediator of human growth regulation and is affected by a number of genetic and environmental factors. Activation of neuronal nicotinic acetylcholine (nACh) receptors promotes GH release, but the role of these receptors in growth regulation is unknown. Our aim was to assess the effect of a mutation in the alpha4 subunit of the nACh receptor on cholinergic-mediated GH release. Forty-one healthy volunteers (24 male, age 36.2 +/- 12.2 yr, mean +/- sd) and 13 subjects with the alpha4-Ser248Phe mutation (four male, age 43.2 +/- 16.8 yr) were studied. Serum levels of GH, LH, FSH, prolactin, TSH, free T(4), and cortisol were measured at baseline and at regular intervals after infusion of physostigmine. Height and weight were recorded in all participants as well as from additional family members with (n = 11, four male) and without (n = 16, seven male) the mutation. Subjects with the mutation were shorter (1.62 +/- 0.08 vs. 1.72 +/- 0.09 m, P < 0.05) and had a greater body mass index (31 +/- 6 vs. 24 +/- 3 kg/m(2), P 0.2 vs. control). These findings suggest a role of the nACh receptor in human growth regulation.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2020
DOI: 10.1038/S41467-020-19289-5
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.EPLEPSYRES.2017.02.001
Abstract: Driven by advances in genomic technology and reduction in costs, next-generation sequencing (NGS) is venturing into routine clinical care. The 'real-world' clinical utility of NGS remains to be determined in focal epilepsies, which account for 60% of all epilepsies and for which the importance of genetic factors is just beginning to emerge. We investigated the diagnostic yield and management implications of whole exome sequencing (WES)-based screening of selected genes in the routine care of common focal epilepsies suspected to have a genetic basis. We performed WES, followed by targeted analysis of 64 epilepsy genes, on 40 consecutive children and adults enrolled prospectively from routine clinical practice who had MRI-negative focal epilepsy and a family history of febrile seizures or any type of epilepsy in at least one first- or second-degree relative. Exclusion criteria were previous genetic testing, severe intellectual disability and benign focal epilepsies of childhood. 5/40 (12.5%) patients had a pathogenic or likely pathogenic variant, detected in SCN1A, DEPDC5, PCDH19, GABRG2 or NPRL2. Identifying a pathogenic SCN1A variant in a patient with drug-resistant epilepsy prompted to halt presurgical investigations due to concern of unfavorable post-surgical outcome. It also led in the same patient to discontinue long-standing carbamazepine therapy (a potentially aggravating drug in epilepsies due to SCN1A mutations), resulting in complete seizure control. Patients with pathogenic or likely pathogenic variants had a younger median age of seizure onset (range) compared to those without [18 months (8 months-18 years) vs 18 years (18 months-70 years), p=0.02]. Our data demonstrate that WES with targeted gene analysis is an effective diagnostic tool for patients with common focal epilepsies in whom a genetic etiology is suspected. It can also influence clinical decision-making, including antiepileptic drug selection and consideration of epilepsy surgery, hence supporting its incorporation in the routine clinical care of this patient group.
Publisher: Wiley
Date: 24-11-2003
DOI: 10.1046/J.1440-1754.2003.00270.X
Abstract: There is increasing awareness of the importance of assessing physical, psychological, social and behavioural well-being in chronic disease. The aim of this study was to examine the health-related quality of life (HRQoL) of children with common epilepsy syndromes and to explore if there are HRQoL differences between those syndromes. Each child had their epilepsy syndrome defined according to the International League Against Epilepsy classification. Epilepsy syndromes included symptomatic frontal, temporal, parietal/occipital lobe and partial unlocalized epilepsy, and two idiopathic epilepsies, childhood absence epilepsy (CAE) and benign rolandic epilepsy (BRE). Seizure semiology and ictal/interictal electroencephalogram (EEG) were determined for symptomatic partial epilepsy syndromes by video-EEG monitoring. HRQoL was evaluated with an epilepsy-specific instrument, the Quality of Life in Childhood Epilepsy Questionnaire, and two generic instruments, the Child Health Questionnaire and Child Behavior Checklist. Children with symptomatic partial epilepsy syndromes were affected by epilepsy in a similar way and did not have unique HRQoL profiles. However, these children had significantly lower HRQoL scores compared to those with CAE or BRE. All children with epilepsy regardless of syndrome had a higher frequency of behavioural problems compared to normative data. These results indicate that children with epilepsy regardless of syndrome require evaluation of the psychosocial implications. There is a greater impact on HRQoL in symptomatic epilepsy compared to idiopathic epilepsy. Specific symptomatic partial syndromes did not differ in the degree they affect HRQoL. These findings have important implications for clinicians caring for children with epilepsy.
Publisher: American Association for Cancer Research (AACR)
Date: 14-09-2018
DOI: 10.1158/0008-5472.CAN-18-0951
Abstract: Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue s les from 68 in iduals and 6,124 cross-tissue s les from 369 in iduals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P & 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P & 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res 78(18) 5419–30. ©2018 AACR.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2017
DOI: 10.1038/EJHG.2017.29
Publisher: Public Library of Science (PLoS)
Date: 19-01-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2017
DOI: 10.1212/WNL.0000000000004769
Abstract: To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1 . A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 ided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial. Prolonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 μg/mL, reference range 1.3–5.0 μg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10–18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval −1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction. Quinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks. Australian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151). This study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1 , quinidine does not significantly reduce seizure frequency.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2005
DOI: 10.1007/S00259-005-1844-6
Abstract: We performed a retrospective analysis of the results of FDG PET scans in children with refractory epilepsy referred to our centre over an 8-year period, with a view to ascertaining the impact of FDG PET on subsequent patient management. A questionnaire was used to assess the impact of FDG PET scan on diagnosis, management and clinical decision-making processes for epilepsy surgery from the managing clinician's perspective. FDG PET scan results were also compared with MRI, EEG and SPECT results and coded according to whether the FDG PET scan provided independent information and localisation of epileptogenic regions. A total of 118 eligible patients under the age of 14 years were identified, with questionnaires being completed on 113 evaluable patients (96%). The pre-PET management plan consisted of consideration for surgery in 92 patients (81%) and medical therapy for the remaining 21 patients (19%). Managing physicians rated FDG PET as providing information additional to that obtained with other investigations regarding epileptogenic sites in 88 patients (77%). FDG PET had either a minor or a major impact on clinical management in 58 patients (51%), principally with regard to surgical candidacy. FDG PET has a definite role in the assessment of paediatric patients with refractory epilepsy who are being considered for surgery. In the future, analysis of FDG PET data in specific subpopulations of children with refractory epilepsy may lead to novel insights regarding aetiology.
Publisher: Hindawi Limited
Date: 31-01-2019
DOI: 10.1002/HUMU.23699
Publisher: Wiley
Date: 15-06-2020
DOI: 10.1111/DMCN.14588
Publisher: Springer Science and Business Media LLC
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 29-11-2022
DOI: 10.1038/S41431-022-01232-5
Abstract: We aimed to determine whether SNP-microarray genomic testing of saliva had a greater diagnostic yield than blood for pathogenic copy number variants (CNVs). We selected patients who underwent CMA testing of both blood and saliva from 23,289 blood and 21,857 saliva s les. Our cohort comprised 370 in iduals who had testing of both, 224 with syndromic intellectual disability (ID) and 146 with isolated ID. Mosaic pathogenic CNVs or aneuploidy were detected in saliva but not in blood in 20/370 (4.4%). All 20 in iduals had syndromic ID, accounting for 9.1% of the syndromic ID sub-cohort. Pathogenic CNVs were large in size (median of 46 Mb), and terminal in nature, with median mosaicism of 27.5% (not exceeding 40%). By contrast, non-mosaic pathogenic CNVs were 100% concordant between blood and saliva, considerably smaller in size (median of 0.65 Mb), and predominantly interstitial in location. Given that salivary microarray testing has increased diagnostic utility over blood in in iduals with syndromic ID, we recommend it as a first-tier testing in this group.
Publisher: Cold Spring Harbor Laboratory
Date: 20-08-2017
DOI: 10.1101/178822
Abstract: X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, Protocadherin 19 ( PCDH19 ) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to highly specific combinatorial adhesion codes such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between WT PCDH19- and null PCDH19-expressing cells in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining specific adhesion codes during cortical development and how disruption of these codes is associated with the unique X-linked inheritance of PCDH19 epilepsy.
Publisher: Cambridge University Press (CUP)
Date: 04-2003
Publisher: American Medical Association (AMA)
Date: 11-1994
DOI: 10.1001/ARCHNEUR.1994.00540230063014
Abstract: To determine whether the syndrome of benign familial neonatal convulsions in a large family was linked to markers on chromosome 20q and to study the seizure patterns in affected in iduals. A clinical and molecular biologic study of a single large family in which the probands were identical twins with benign familial neonatal convulsions. Thirteen living affected family members and 27 living unaffected family members were evaluated. Multipoint linkage analysis with use of the chromosome 20q markers CMM6 and RMR6 gave a maximum lod score of 3.13 at theta = 0.063, indicating linkage in this family. Of the 13 affected members, 10 had known neonatal seizures. Four subjects had febrile seizures, of whom only two had known neonatal seizures. Two members had afebrile seizures later, one of whom had not previously suffered neonatal or febrile seizures. The phenotypic heterogeneity in this family, with an epilepsy syndrome determined by a single gene, was striking. This suggests that molecular genetic approaches to the common forms of idiopathic epilepsy, involving patients with clinically similar phenotypes from unrelated families, may be inappropriate.
Publisher: Wiley
Date: 04-2010
DOI: 10.1111/J.1528-1167.2010.02522.X
Abstract: The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy. Generalized and focal are redefined for seizures as occurring in and rapidly engaging bilaterally distributed networks (generalized) and within networks limited to one hemisphere and either discretely localized or more widely distributed (focal). Classification of generalized seizures is simplified. No natural classification for focal seizures exists focal seizures should be described according to their manifestations (e.g., dyscognitive, focal motor). The concepts of generalized and focal do not apply to electroclinical syndromes. Genetic, structural-metabolic, and unknown represent modified concepts to replace idiopathic, symptomatic, and cryptogenic. Not all epilepsies are recognized as electroclinical syndromes. Organization of forms of epilepsy is first by specificity: electroclinical syndromes, nonsyndromic epilepsies with structural-metabolic causes, and epilepsies of unknown cause. Further organization within these isions can be accomplished in a flexible manner depending on purpose. Natural classes (e.g., specific underlying cause, age at onset, associated seizure type), or pragmatic groupings (e.g., epileptic encephalopathies, self-limited electroclinical syndromes) may serve as the basis for organizing knowledge about recognized forms of epilepsy and facilitate identification of new forms.
Publisher: Oxford University Press (OUP)
Date: 04-2021
Publisher: Oxford University Press (OUP)
Date: 2019
DOI: 10.1093/BRAIN/AWZ208
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.WATRES.2019.04.001
Abstract: Natural source zone depletion (NSZD) of light non-aqueous phase liquids (LNAPLs) includes partitioning, transport and degradation of LNAPL components. NSZD is being considered as a site closure option during later stages of active remediation of LNAPL contaminated sites, and where LNAPL mass removal is limiting. To ensure NSZD meets compliance criteria and to design enhanced NSZD actions if required, residual risks posed by LNAPL and its long term behaviour require estimation. Prediction of long-term NSZD trends requires linking physicochemical partitioning and transport processes with bioprocesses at multiple scales within a modelling framework. Here we expand and build on the knowledge base of a recent review of NSZD, to establish the key processes and understanding required to model NSZD long term. We describe key challenges to our understanding, inclusive of the dominance of methanogenic or aerobic biodegradation processes, the potentially changeability of rates due to the weathering profile of LNAPL product types and ages, and linkages to underlying bioprocesses. We critically discuss different scales in subsurface simulation and modelling of NSZD. Focusing on processes at Darcy scale, 36 models addressing processes of importance to NSZD are investigated. We investigate the capabilities of models to accommodate more than 20 subsurface transport and transformation phenomena and present comparisons in several tables. We discuss the applicability of each group of models for specific site conditions.
Publisher: Wiley
Date: 13-08-2020
DOI: 10.1002/EPI4.12414
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-11-2009
Publisher: Cold Spring Harbor Laboratory
Date: 20-11-2020
DOI: 10.1101/2020.11.18.20233916
Abstract: Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental, and developmental factors. While usually benign, in a minority of cases, febrile seizures precede later development of epilepsy. Here, we conducted a genome-wide association study of febrile seizures with 7,635 cases and 93,966 controls identifying and replicating seven new loci, all with P 5 × 10 −10 . Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10 , and four other loci harbored genes ( BSN, ERC2, GABRG2, HERC1 ) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. GABRG2 is a well-established epilepsy gene comprising variants associated with febrile seizures, and overall we found positive genetic correlations with epilepsies ( r g = 0.39, P = 1.68 × 10 −4 ). Finally, a polygenic risk score based on all genome-wide significant loci was associated within patients with number of hospital admissions with febrile seizures and age at first admission, suggesting potential clinical utility of improved genetic understanding of febrile seizure genesis.
Publisher: Elsevier BV
Date: 2023
Publisher: Wiley
Date: 20-11-2012
DOI: 10.1111/DMCN.12030
Abstract: Aim Genetic testing in the epilepsies is becoming an increasingly accessible clinical tool. Mutations in the sodium channel alpha 1 subunit ( SCN1A ) gene are most notably associated with Dravet syndrome. This is the first study to assess the impact of SCN1A testing on patient management from both carer and physician perspectives. Method Participants were identified prospectively from referrals to the Epilepsy Genetics Service in Glasgow and contacted via their referring clinicians. Questionnaires exploring the consequences of SCN1A genetic testing for each case were sent to carers and physicians. Results Of the 244 in iduals contacted, 182 (75%) carried a SCN1A mutation. Carers of 187 (77%) patients responded (90 females, 97 males mean age at referral 4y 10mo interquartile range 9y 1mo). Of those participants whose children tested positive for a mutation, 87% reported that genetic testing was helpful, leading to treatment changes resulting in fewer seizures and improved access to therapies and respite care. Out of 187 physicians, 163 responded (87%), of whom 48% reported that a positive test facilitated diagnosis earlier than with clinical and electroencephalography data alone. It prevented additional investigations in 67% of patients, altered treatment approach in 69%, influenced medication choice in 74%, and, through medication change, improved seizure control in 42%. Interpretation In addition to confirming a clinical diagnosis, a positive SCN1A test result influenced treatment choice and assisted in accessing additional therapies, especially in the very young.
Publisher: Wiley
Date: 29-01-2010
DOI: 10.1111/J.1528-1167.2009.02317.X
Abstract: We identified a patient with electrophysiologically verified neonatal long QT syndrome (LQTS) and neonatal seizures in the presence of a controlled cardiac rhythm. To find a cause for this unusual combination of phenotypes, we tested the patient for mutations in seven ion channel genes associated with either LQTS or benign familial neonatal seizures (BFNS). Comparative genome hybridization (CGH) was done to exclude the possibility of a contiguous gene syndrome. No mutations were found in the genes (KCNQ2, KCNQ3) associated with BFNS, and CGH was negative. A previously described mutation and a known rare variant were found in the LQTS-associated genes SCN5A and KCNE2. Both are expressed in the brain, and although mutations have not been associated with epilepsy, we propose a pathophysiologic mechanism by which the combination of molecular changes may cause seizures.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41467-019-12671-Y
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7 . The ATTTC expansions segregate in 158/158 in iduals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.
Publisher: Oxford University Press (OUP)
Date: 07-05-2015
DOI: 10.1093/HMG/DDV171
Publisher: SAGE Publications
Date: 11-2015
Publisher: Wiley
Date: 12-06-2012
Publisher: Wiley
Date: 18-08-2021
DOI: 10.1111/EPI.17036
Abstract: Add‐on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double‐blind, placebo‐controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long‐term open‐label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient‐reported outcomes from GWPCARE5. Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2‐week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day. Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open‐label extension. Median treatment duration was 444 days (range = 18–1535), with a mean modal dose of 22 mg/kg/day patients received a median of three concomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23% moderate, 50% severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty‐eight (9%) patients discontinued due to AEs. Sixty‐nine (22%) patients had liver transaminase elevations × upper limit of normal 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12‐week periods up to Week 156 was 45%–74% for convulsive seizures and 49%–84% for total seizures. Across all visit windows, ≥83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition. We show that long‐term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment‐resistant DS.
Publisher: Wiley
Date: 14-06-2023
DOI: 10.1111/DMCN.15308
Abstract: To assess the clinical utility of exome sequencing for patients with developmental and epileptic encephalopathies (DEEs). Over 2 years, patients with DEEs were recruited for singleton exome sequencing. Parental segregation was performed where indicated. Of the 103 patients recruited (54 males, 49 females aged 2 weeks–17 years), the genetic aetiology was identified in 36 out of 103 (35%) with management implications in 13 out of 36. Exome sequencing revealed pathogenic or likely pathogenic variants in 30 out of 103 (29%) patients, variants of unknown significance in 39 out of 103 (38%), and 34 out of 103 (33%) were negative on exome analysis. After the description of new genetic diseases, a molecular diagnosis was subsequently made for six patients or through newly available high‐density chromosomal microarray testing. We demonstrate the utility of exome sequencing in routine clinical care of children with DEEs. We highlight that molecular diagnosis often leads to changes in management and informs accurate prognostic and reproductive counselling. Our findings reinforce the need for ongoing analysis of genomic data to identify the aetiology in patients in whom the cause is unknown. The implementation of genomic testing in the care of children with DEEs should become routine in clinical practice. The cause was identified in 35% of patients with developmental and epileptic encephalopathies. KCNQ2 , CDKL5 , SCN1A , and STXBP1 were the most frequently identified genes. Reanalysis of genomic data found the cause in an additional six patients. Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset. Finding the molecular cause led to management changes in 36% of patients with DEEs.
Publisher: Elsevier BV
Date: 2001
DOI: 10.1086/316946
Publisher: Springer Science and Business Media LLC
Date: 14-09-2014
DOI: 10.1038/NG.3092
Publisher: Wiley
Date: 12-02-2023
DOI: 10.1111/DMCN.15546
Abstract: To determine indications and prescribing patterns for antiseizure medications (ASMs) in children by age, sex, and socioeconomic status. This retrospective study searched the New Zealand database of ASM prescriptions dispensed to in iduals aged 18 years or under during 2015 in three regions of New Zealand (48% paediatric population). Medical records were reviewed by a paediatric neurologist for indication. ASMs were grouped into old or new (1993 onwards). In total, 2594 children (0 to 18 years, mean age 11 years 2 months, median 12 years 51% male) were dispensed 3557 ASMs for seizures (76%), pain (6%), headache (5%), mental health (3%), and movement disorders (2%). After 10 years of age, lamotrigine was more likely and valproate less likely to be prescribed in females than males. No sex difference was observed for valproate prescriptions for non‐seizure indications. Topiramate prescriptions increased in adolescent females. Prescriptions for non‐seizure indications increased from 7% in children aged 6 years or under to 31% in 16‐ to 18‐year‐olds. The proportion of children receiving a new ASM compared to an old ASM was greater in children from higher than lower socioeconomic areas. Our results highlight a need for focused ASM teratogenicity messaging to clinicians prescribing ASMs for non‐seizure indications. In addition, to improve equity of epilepsy care, it is critical for health policies to consider socioeconomic factors that impact on ASM prescribing.
Publisher: Wiley
Date: 12-05-2022
DOI: 10.1111/EPI.17274
Abstract: This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently approved, DS‐specific therapies and emerging disease‐modifying treatments. A core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease‐modifying therapies) and nominated the 31‐member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS. There was strong consensus that infants 2–15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first‐ to third‐line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease‐modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians. This International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease‐modifying therapies.
Publisher: Elsevier BV
Date: 11-1999
DOI: 10.1016/S0967-5868(99)90007-3
Abstract: Cost-benefit analysis in neurology practice deserves continual reassessment. One ex le is the duration of a routine electroencephalography (EEG) required to optimise accuracy of diagnosis. Recommended guidelines of recording a routine EEG for 20 or more minutes are not based on scientific evidence. In many countries, EEG is not economically viable with costs outweighing financial remuneration. We prospectively studied 420 consecutive routine EEGs to see if a shorter record decreased diagnostic accuracy. A carefully structured 15 min routine EEG protocol produced comparable results with the 25 min recording. Shorter routine EEGs would make EEG more cost effective without compromising diagnostic accuracy.
Publisher: Wiley
Date: 07-2015
DOI: 10.1002/ANA.24457
Publisher: Elsevier BV
Date: 03-2016
Publisher: Oxford University Press (OUP)
Date: 09-07-2008
DOI: 10.1093/BRAIN/AWN138
Abstract: The early and late benign occipital epilepsies of childhood (BOEC) are described as two discrete electro-clinical syndromes, eponymously known as Panayiotopoulos and Gastaut syndromes. Our aim was to explore the clinical features, classification and clinical genetics of these syndromes using twin and multiplex family studies to determine whether they are indeed distinct. Sixteen probands including seven twins were studied. Non-twin probands (n = 9) with a family history of epilepsy were included. Electroclinical seizure semiology was characterized and probands were classified into BOEC syndromes. Detailed phenotyping of relatives was performed and phenotypic patterns within families were analysed. One-third of the children in this selected series of BOEC did not have a pure syndrome, rather a mixed syndrome with features of both Panayiotopoulos and Gastaut syndromes. Monozygotic twin pairs did not show a higher concordance rate than dizygotic twin pairs suggesting that BOEC may not be a purely genetic disorder. In relatives with epilepsy, there was a mixed pattern of focal and generalized epilepsies with focal epilepsies predominating. BOEC is an electro-clinical spectrum with Panayiotopoulos and Gastaut syndromes at either end many cases show mixed features. Clinical genetic studies highlight the multifactorial aetiology of BOEC as monozygotic twins have low concordance suggesting that non-conventional genetic influences or environmental factors play a major role. Family studies show both focal and generalized epilepsies reinforcing that these are not discrete categories of idiopathic epilepsies and are likely to share genetic determinants.
Publisher: Wiley
Date: 02-2000
DOI: 10.1002/1531-8249(200002)47:2<265::AID-ANA22>3.0.CO;2-N
Publisher: Wiley
Date: 21-05-2018
DOI: 10.1002/EPI4.12225
Publisher: Wiley
Date: 17-08-2022
DOI: 10.1002/AJMG.A.62950
Abstract: Verheij syndrome (VRJS) is a rare craniofacial spliceosomopathy presenting with craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay. It is caused by single nucleotide variants (SNVs) in PUF60 or interstitial deletions of the 8q24.3 region. PUF60 encodes a splicing factor which forms part of the spliceosome. To date, 36 patients with a sole diagnosis of VRJS due to disease-causing PUF60 SNVs have been reported in peer-reviewed publications. Although the depth of their phenotyping has varied greatly, they exhibit marked phenotypic heterogeneity. We report 10 additional unrelated patients, including the first described patients of Khmer, Indian, and Vietnamese ethnicities, and the eldest patient to date, with 10 heterozygous PUF60 variants identified through exome sequencing, 8 previously unreported. All patients underwent deep phenotyping identifying variable dysmorphism, growth delay, neurodevelopmental delay, and multiple congenital anomalies, including several unique features. The eldest patient is the only reported in idual with a germline variant and neither neurodevelopmental delay nor intellectual disability. In combining these detailed phenotypic data with that of previously reported patients (n = 46), we further refine the known frequencies of features associated with VRJS. These include neurodevelopmental delay/intellectual disability (98%), axial skeletal anomalies (74%), appendicular skeletal anomalies (73%), oral anomalies (68%), short stature (66%), cardiac anomalies (63%), brain malformations (48%), hearing loss (46%), microcephaly (41%), colobomata (38%), and other ocular anomalies (65%). This case series, incorporating three patients from previously unreported ethnic backgrounds, further delineates the broad pleiotropy and mutational spectrum of PUF60 pathogenic variants.
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2019
DOI: 10.1101/525683
Abstract: Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected in iduals and 8,364 controls of European ancestry. We focused on three phenotypic groups the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, in iduals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among in iduals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2 , and GABRG2 for GGE and LGI1, TRIM3 , and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.
Publisher: Wiley
Date: 08-2000
DOI: 10.1002/1531-8249(200008)48:2<264::AID-ANA20>3.0.CO;2-B
Publisher: European Respiratory Society (ERS)
Date: 07-1994
DOI: 10.1183/09031936.94.07071260
Abstract: Although asthma self-management plans are widely recommended as essential in the long-term treatment of adult asthma, there have been few studies examining their use. Our objective was to assess the effect of a "credit card" adult asthma self-management plan in a community experiencing major health problems from asthma, by means of a before and after intervention trial of the efficacy of the "credit card" plan, when introduced through community-based asthma clinics. The participants were 69 Maori people with asthma. The "credit card" plan consisted of written guidelines for the self-management of asthma, based on self-assessment of asthma severity, printed on a plastic card. On one side, management guidelines were based on the interpretation of peak expiratory flow rate (PEFR) recordings, whilst the reverse side was based on symptoms. The outcome measures used were before and after comparison of markers of asthma morbidity and requirement for acute medical treatment and a structured questionnaire assessing the acceptability and use of the credit card plan. Following the introduction of the plan, the mean PEFR increased from 347 to 389 l.min-1, the percentage of nights woken fell from 30.4 to 16.9%, and the number of days "out of action" fell from 3.8 to 1.7%. The requirements for acute medical treatment also fell during the intervention period. Most participants commented favourably on the content and usefulness of the plan. In the situation of worsening asthma, 28% of subjects found the peak flow side of the card most helpful, 7% the symptoms side, and 48% found both sides equally helpful.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Wiley
Date: 04-2003
DOI: 10.1046/J.1528-1157.2003.20102.X
Abstract: Mutations in genes coding for the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN. All affected family members underwent a detailed clinical evaluation and review of available EEG, neuroimaging, and videotapes of seizures. The molecular study of family D is reported here family S has a previously reported mutation in the beta 2 subunit of CHRN. A total of 16 in iduals with ADNFLE were identified in the two families. In both families, seizure semiology, age at seizure onset, and the natural history of the seizure disorder was similar. Intrafamilial variation in terms of severity of epilepsy syndrome was present in both families. A significant number of in iduals from each family had a history of psychological problems. The molecular study of family D revealed a Ser248Phe mutation in the alpha 4 subunit of CHRN. The epilepsy phenotype is not distinguishable in the two families who have ADNFLE as a result of mutations in genes coding for different CHRN subunits. This is likely to be due to the similar functional consequences of each mutation on the CHRN receptor.
Publisher: Elsevier BV
Date: 11-2007
Publisher: Springer Science and Business Media LLC
Date: 12-2018
DOI: 10.1007/S11154-018-9480-1
Abstract: The pituitary gland and the hypothalamus can be affected by autoimmune-mediated structural and functional disruption. These autoimmune-mediated diseases occur more commonly in females and are often found during pregnancy or in the post-partum period. Autoimmune diseases can either affect parts of the pituitary or hypothalamus, or can involve both sellar and suprasellar structures. Most of these cases comprise primary hypophysitis (PRH). Over the years, there has been a tremendous increase in the number of reported PRH cases and related disorders, including hypophysitis induced by immune checkpoint inhibitors. With this increasing data, more light is being shed on the spectrum of clinical presentations, biochemical and imaging abnormalities of these disorders. Regardless, these disorders are still relatively rare. The clinical presentation can vary vastly, based on the type of pituitary cell or the area of the suprasellar region affected. The severity can range from clinically silent disease to progressive and rapid deterioration and death, likely due to unrecognized central adrenal insufficiency. Although biopsy remains a gold standard for diagnosing these disorders, the current standard of practice is biochemical assessment for hormonal deficiencies and imaging studies. In several instances, these disorders spontaneously resolve, but medical or surgical intervention might be necessary to treat symptomatic disease. Due to the subtlety and a vast spectrum of clinical manifestations which could often be asymptomatic, and the rarity of the occurrence of these diseases in clinical practice, the diagnosis can be easily missed which could potentially lead to substantial morbidity or mortality. Therefore, it is crucial to have a strong clinical suspicion and pursue timely biochemical and imaging studies to initiate prompt treatment. In this article, we review the various autoimmune conditions that affect the sellar and suprasellar structures, their diagnostic approach and management of these disorders.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2015
DOI: 10.1158/1055-9965.EPI-14-0317
Abstract: Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify in iduals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 in iduals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev 24(7) 1121–9. ©2015 AACR.
Publisher: Wiley
Date: 15-01-2022
DOI: 10.1111/EPI.17166
Abstract: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with in iduals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. We performed a case–control whole exome sequencing study in unrelated in iduals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry‐matched controls. The association of ultra‐rare variants (URVs in 18 834 protein‐coding genes) with epilepsy was examined in 1928 in iduals with GGE (vs. 8578 controls), then separately in 945 in iduals with familial GGE (vs. 8626 controls), and finally in 1005 in iduals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ‐aminobutyric acid type A [GABA A ] receptors, 113 genes representing the GABAergic pathway). GABRG2 was associated with GGE ( p = 1.8 × 10 −5 ), approaching study‐wide significance in familial GGE ( p = 3.0 × 10 −6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABA A receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9–7.8, false discovery rate [FDR]‐adjusted p = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3–6.7, FDR‐adjusted p = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3–2.5, FDR‐adjusted p = .0024) but not with sporadic GGE (OR = 1.3, 95% CI = .9–1.9, FDR‐adjusted p = .19). URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.
Publisher: Wiley
Date: 03-07-2015
DOI: 10.1002/ACN3.224
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.EPLEPSYRES.2021.106743
Abstract: Dravet syndrome (DS) is still seen as a "pediatric disease", where patients receive excellent care in pediatric centers, but care is less than optimal in adult health care systems (HCS). This creates a barrier when young adults need to leave the family-centered pediatric system and enter the adult, patient-centered HCS. Here we create a guide to help with the transition from pediatric to adult for patients with DS. Experts in Dravet syndrome flagged the main barriers in caring for adults with DS and created a 2-page transition summary guide based on their expertise and a literature review. The 2-page guide addresses: DS diagnosis in children and adults clinical manifestations, including the differences in seizures types and frequencies between children and adults with DS the natural history of intellectual disability, behavior, gait, motor disorders and dysautonomia a review of optimal treatments (including medications not commonly used in adult epilepsy settings such as stiripentol and fenfluramine), as well as emergency seizure management avoidance of triggers, preventive measures, and vaccine administration in adults with DS. Several young adults with DS are still followed by their child neurologist. This 2-page transition guide should help facilitate the transition of patients with DS to the adult HCS and should be given to families as well as adult health care providers that may not be familiar with DS.
Publisher: SAGE Publications
Date: 29-09-2021
Abstract: Whether genetic factors contribute to acquired epilepsies has long been controversial. Supporters observe that, among in iduals exposed to seemingly the same brain insult, only a minority develops unprovoked seizures. Yet, only in relatively recent years have studies started to build a case for genetic contributions. Here, we appraise this emerging evidence, by providing a critical review of studies published in the field.
Publisher: Wiley
Date: 22-07-2019
DOI: 10.1002/EPI4.12350
Publisher: Wiley
Date: 31-08-2023
DOI: 10.1002/ANA.26765
Abstract: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippoc al sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in in iduals with FMTLE. We studied 134 families with ≥ 2 first or second‐degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one in idual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13–28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug‐resistance and/or hippoc al sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007) in contrast, no enrichment for the febrile seizure PRS was observed. FMTLE is a generally mild drug‐responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub‐genome‐wide significant focal epilepsy genome‐wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023
Publisher: Wiley
Date: 08-2014
DOI: 10.1111/EPI.12707
Abstract: There are many monogenic disorders associated with epilepsy that begin in childhood and persist into adult life. Each of these disorders raises specific issues for transition, in addition to common issues facing this group of patients as they move from pediatric to adult care. Such comorbidities include psychiatric and movement disorders. Epileptic encephalopathies may be caused by monogenic disorders, with Dravet syndrome being the best characterized. Although some patients have a relatively good adult outcome, others have persisting severe epilepsy complicated by autistic spectrum disorder and problems with gait. When reevaluating a patient as they transition to adult care, a thorough reconsideration of the genetic etiology of their epilepsy should be performed. This should be followed by genetic counseling for the patient and their family members.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2019
DOI: 10.1038/S41467-018-08054-4
Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer ( r g = 0.57, p = 4.6 × 10 −8 ), breast and ovarian cancer ( r g = 0.24, p = 7 × 10 −5 ), breast and lung cancer ( r g = 0.18, p =1.5 × 10 −6 ) and breast and colorectal cancer ( r g = 0.15, p = 1.1 × 10 −4 ). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-08-2006
DOI: 10.1212/01.WNL.0000228257.60184.82
Abstract: To accurately define the electroclinical features of absence seizures in children with newly diagnosed, untreated childhood absence epilepsy (CAE). The authors searched an EEG database for absence seizures in normal children with new onset untreated absence epilepsy. Seventy consecutive children were classified into IGE syndromes. The clinical and EEG features of the seizures in the children with CAE were analyzed using video-EEG recordings. The authors analyzed 339 absence seizures in 47 children with CAE. The average seizure duration was 9.4 seconds and clinical features consisted of arrest of activity, loss of awareness, staring, and 3-Hz eyelid movements, but there was in idual variation. Ictal EEG predominantly showed regular 3-Hz generalized spike and wave (GSW) with one or two spikes per wave however, disorganization of discharges was common and three or more spikes per wave occurred rarely. Postictal slowing was frequent. Interictal abnormalities included fragments of GSW, posterior bilateral delta activity, and focal discharges. Although all 47 children met the current criteria for CAE, only 5 fulfilled the recently proposed criteria for CAE. The heterogeneous nature of each clinical and EEG feature of untreated absence seizures is of critical importance when determining criteria for childhood absence epilepsy.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2016
DOI: 10.1038/EJHG.2016.80
Publisher: Wiley
Date: 20-04-2022
DOI: 10.1111/EPI.17250
Abstract: Vaccination against the SARS‐CoV‐2 virus is a primary tool to combat the COVID‐19 pandemic. However, vaccination is a common seizure trigger in in iduals with Dravet syndrome (DS). Information surrounding COVID‐19 vaccine side effects in patients with DS would aid caregivers and providers in decisions for and management of COVID‐19 vaccination. A survey was emailed to the Dravet Syndrome Foundation's Family Network and posted to the Dravet Parent & Caregiver Support Group on Facebook between May and August 2021. Deidentified information obtained included demographics and vaccination status for in iduals with DS. Vaccine type, side effects, preventative measures, and changes in seizure activity following COVID‐19 vaccination were recorded. For unvaccinated in iduals, caregivers were asked about intent to vaccinate and reasons for their decision. Of 278 survey responses, 120 represented vaccinated in iduals with DS (median age = 19.5 years), with 50% reporting no side effects from COVID‐19 vaccination. Increased seizures following COVID‐19 vaccination were reported in 16 in iduals, but none had status epilepticus. Of the 158 in iduals who had not received a COVID‐19 vaccination, 37 were older than 12 years (i.e., eligible at time of study), and only six of these caregivers indicated intent to seek vaccination. The remaining 121 responses were caregivers to children younger than 12 years, 60 of whom indicated they would not seek COVID‐19 vaccination when their child with DS became eligible. Reasons for vaccine hesitancy were fear of increased seizure activity and concerns about vaccine safety. These results indicate COVID‐19 vaccination is well tolerated by in iduals with DS. One main reason for vaccine hesitancy was fear of increased seizure activity, which occurred in only 13% of vaccinated in iduals, and none had status epilepticus. This study provides critical and reassuring insights for caregivers and health care providers making decisions about the safety of COVID‐19 vaccinations for in iduals with DS.
Publisher: Elsevier BV
Date: 2012
Publisher: Wiley
Date: 28-12-2015
DOI: 10.1002/AJMG.A.37527
Abstract: Mutations in COL4A1 are well described and result in brain abnormalities manifesting with severe neurological deficits including cerebral palsy, intellectual disability, and focal epilepsy. Families with mutations in COL4A2 are now emerging with a similar phenotype. We describe a family with an autosomal dominant disorder comprising porencephaly, focal epilepsy, and lens opacities, which was negative for mutations in COL4A1. Using whole exome sequencing of three affected in iduals from three generations, we identified a rare variant in COL4A2. This COL4A2 (c.2399G>A, p.G800E, CCDS41907.1) variant was predicted to be damaging by multiple bioinformatics tools and affects an invariable glycine residue that is essential for the formation of collagen IV heterotrimers. The cataracts identified in this family expand the phenotypic spectrum associated with mutations in COL4A2 and highlight the increasing overlap with phenotypes associated with COL4A1 mutations.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-08-2008
DOI: 10.1212/01.WNL.0000316192.52731.77
Abstract: Mutations of the neuronal nicotinic acetylcholine (nACh) receptor identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) lead to increased sensitivity to ACh. As activation of presynaptic nicotinic receptors augments the release of dopamine in the striatum and the prefrontal regions, we tested the hypothesis that that the alpha4-Ser248Phe mutation affects dopaminergic transmission. We measured D(1) receptor binding using [(11)C]-SCH23390 and PET in 12 subjects with the alpha4-Ser248Phe mutation (3 men, mean age 41 +/- 16 years) and 19 controls (8 men, mean age 36 +/- 13 years) matched for gender, smoking status, and age. Parametric images were produced using the simplified reference region method. Both MRI-based regions of interest and voxel based analyses were used. Reduced striatal [(11)C]-SCH23390 binding occurred with the mutation (controls 1.1 +/- 0.1 ADNFLE 0.97 +/- 0.2 p < 0.01). Statistical parametric mapping confirmed a region of reduced [(11)C]-SCH23390 binding in the right putamen in alpha4-Ser248Phe subjects compared to controls (309 voxels, local maxima 20 16 -2 mm Z(score) 3.57, p < 0.05). Reduced D(1) receptor binding may represent increased extracellular dopamine levels or, more likely, receptor downregulation. Alterations in mesostriatal dopaminergic circuits may contribute to nocturnal paroxysmal motor activity in autosomal dominant nocturnal frontal lobe epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-01-2015
Publisher: Cold Spring Harbor Laboratory
Date: 08-03-2022
DOI: 10.1101/2022.03.04.22271462
Abstract: Germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders. Heterozygous missense variants at a hotspot encoding a canonical degron lead to SETBP1 accumulation and Schinzel-Giedion syndrome (SGS), a rare severe developmental disorder involving multisystem malformations. Heterozygous loss-of-function variants result in SETBP1 haploinsufficiency disorder which is phenotypically much milder than SGS. Following an initial description of four in iduals with atypical SGS carrying heterozygous missense variants adjacent to the degron, a few in idual cases of variants outside the degron were reported. Due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of the roles of the gene in brain development, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remain elusive, imposing challenges for diagnosis and patient care. Here, we present a comprehensive investigation of the largest cohort to-date of in iduals carrying SETBP1 missense variants outside the degron (n=18, including one in-frame deletion). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1 haploinsufficiency disorder, and primarily characterised by intellectual disability, epilepsy, speech and motor impairment. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding and transcription. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care and aetiology of SETBP1-related disorders.
Publisher: Wiley
Date: 02-08-2021
DOI: 10.1111/EPI.17015
Abstract: The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6‐month‐old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year. SCN1A pathogenic variants are found in % of patients. Many patients have atypical features resulting in diagnostic delay and inappropriate therapy. We aimed to provide an evidence‐based definition of SCN1A ‐Dravet syndrome in readiness for precision medicine trials. Epilepsy patients were recruited to the University of Melbourne Epilepsy Genetics Research Program between 1995 and 2020 by neurologists from around the world. Patients with SCN1A pathogenic variants were reviewed and only those with Dravet syndrome were included. Clinical data, including seizure and developmental course, were analyzed in all patients with SCN1A ‐Dravet syndrome. Two hundred and five patients were studied at a median age of 8.5 years (range 10 months to 60 years) 25 were deceased. The median seizure‐onset age was 5.7 months (range 1.5–20.6 months). Initial seizures were tonic‐clonic (52%) and hemiclonic (35%), with only 55% being associated with fever. Only 34% of patients presented with status epilepticus (seizure lasting ≥30 minutes). Median time between first and second seizure was 30 days (range 4 hours to 8 months), and seven patients (5%) had at least 6 months between initial seizures. Median ages at onset of second and third seizure types were 9.1 months (range 3 months–25.4 years) and 15.5 months (range 4 months–8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%. An evidence‐based definition of SCN1A ‐Dravet syndrome is essential for early diagnosis. We refine the spectrum of Dravet syndrome, based on patterns of seizure onset, type, and progression. Understanding of the full spectrum of SCN1A ‐Dravet syndrome presentation is essential for early diagnosis and optimization of treatment, especially as precision medicine trials become available.
Publisher: American Medical Association (AMA)
Date: 05-2020
Publisher: Wiley
Date: 22-04-2022
DOI: 10.1111/EPI.17254
Abstract: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in epilepsy. The underlying pathological mechanisms are likely to be multifactorial. Cardiac arrhythmia has been suggested as a cause of death in some patients with SUDEP. SCN5A encodes the cardiac Na v 1.5 sodium channel. SCN5A variants that result in either loss or gain of channel function cause cardiac arrhythmias. Rare SCN5A variants have been reported in SUDEP cases, but the impact of these variants on channel function is unknown. Here, we use whole‐cell voltage cl recordings to perform functional analyses of rare SCN5A SUDEP variants, p.V223G, p.I397V, and p.R523C. Expression and biophysical properties, including activation, inactivation, and recovery from inactivation, were probed. Each SCN5A variant significantly impacted human Na V 1.5 channel function, indicating that they could cause cardiac arrhythmias. The patient carrying the p.R523C variant was on lamotrigine, an antiseizure medication implicated in SUDEP. Therapeutic concentration of lamotrigine caused a slowing of the rate of recovery from inactivation and a hyperpolarizing shift in the voltage of inactivation of human Na V 1.5 wild‐type, but not p.R523C channels, implicating a gene‐by‐drug interaction. These data suggest that SCN5A arrhythmogenic variants may confer increased risk of sudden death in in iduals with epilepsy.
Publisher: Wiley
Date: 15-07-2020
DOI: 10.1111/NAN.12638
Publisher: Oxford University Press (OUP)
Date: 2010
DOI: 10.1093/BRAIN/AWP332
Publisher: Elsevier BV
Date: 10-2017
Publisher: Wiley
Date: 09-2010
DOI: 10.1111/J.1528-1167.2010.02558.X
Abstract: A family with dominantly inherited neonatal seizures and intellectual disability was atypical for neonatal and infantile seizure syndromes associated with potassium (KCNQ2 and KCNQ3) and sodium (SCN2A) channel mutations. Microsatellite markers linked to KCNQ2, KCNQ3, and SCN2A were examined to exclude candidate locations, but instead revealed a duplication detected by observation of three alleles for two markers flanking SCN2A. Characterization revealed a 1.57 Mb duplication at 2q24.3 containing eight genes including SCN2A, SCN3A, and the 3¢ end of SCN1A. The duplication was partially inverted and inserted within or near SCN1A, probably affecting the expression levels of associated genes, including sodium channels. Rare or unique microchromosomal copy number mutations might underlie familial epilepsies that do not fit within the clinical criteria for the established syndromes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
Publisher: Wiley
Date: 02-02-2016
DOI: 10.1002/ANA.24596
Abstract: The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.
Publisher: Elsevier BV
Date: 1997
DOI: 10.1016/S0387-7604(96)00060-5
Abstract: Single gene disorders offer the best opportunity for identification of genetic linkage and of abnormal genes. Epilepsies with single gene inheritance include symptomatic epilepsies where there is associated diffuse brain dysfunction, and idiopathic epilepsies where seizures are the major neurological abnormality. There are over 200 single gene symptomatic epilepsies most are rare. Gene identification has been achieved in a number of these conditions but these important advances have not yet led to a better understanding of epileptogenesis, because of the associated brain disease. Idiopathic single gene epilepsies include benign familial neonatal convulsions, where genetic linkage to chromosomes 20q and 8q has been found in different families, and benign familial infantile convulsions where linkage is presently unknown. Recently, four autosomal dominant partial epilepsies have been described. In autosomal dominant nocturnal frontal lobe epilepsy a genetic defect in the alpha 4 subunit of the nicotinic acetylcholine receptor was found in one family. This is the first genetic defect described in an idiopathic epilepsy. The other three syndromes are autosomal dominant partial epilepsy with variable foci, autosomal dominant rolandic epilepsy with speech dyspraxia, and familial temporal lobe epilepsy. In the latter condition, linkage to chromosome 10q has been reported in one family, but the genetic defect is unknown. It is likely that other idiopathic single gene epilepsies will be identified. Molecular genetic study of these disorders is likely to lead to discovery of other epilepsy genes. This will lead to an improved understanding of human epileptogenesis with implications for clinical diagnosis, genetic counselling, pharmacological therapy and possibly prevention of epilepsy.
Publisher: Massachusetts Medical Society
Date: 26-04-2018
DOI: 10.1056/NEJMC1714579
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/EJHG.2017.61
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.YEBEH.2012.09.039
Abstract: In an ongoing open-label extension (OV-1004), patients with Lennox-Gastaut syndrome who had completed 1 of 2 randomized controlled trials (OV-1002 [Phase II] or OV-1012 [Phase III]) are receiving clobazam at dosages ≤2.0 mg/kg/day (≤80 mg/day). Of 306 eligible patients from OV-1002 or OV-1012, 267 entered the open-label extension. As of the interim date, July 1, 2010, 213 patients (79.8%) had remained in the trial, and 189 had received clobazam for ≥12 months, 128 for ≥18 months, and 94 for ≥24 months. Median percentage decreases in average weekly rates of drop seizures were 71.1% and 91.6% at Months 3 and 24. Mean modal and mean maximum daily dosages were 0.94 mg/kg and 1.22 mg/kg for those who had received clobazam for ≥1 year. The 4 most common adverse events were upper respiratory tract infection (18.4%), fall (14.2%), pneumonia (13.9%), and somnolence (12.7%). Clobazam's adverse event profile was consistent with its profile in controlled trials.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2020
Publisher: Wiley
Date: 12-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2017
DOI: 10.1212/WNL.0000000000003635
Abstract: To analyze the oral motor, speech, and language phenotype in 20 children and adults with Dravet syndrome (DS) associated with mutations in SCN1A . Fifteen verbal and 5 minimally verbal DS patients with SCN1A mutations (aged 15 months-28 years) underwent a tailored assessment battery. Speech was characterized by imprecise articulation, abnormal nasal resonance, voice, and pitch, and prosody errors. Half of verbal patients had moderate to severely impaired conversational speech intelligibility. Oral motor impairment, motor planning rogramming difficulties, and poor postural control were typical. Nonverbal in iduals had intentional communication. Cognitive skills varied markedly, with intellectual functioning ranging from the low average range to severe intellectual disability. Language impairment was congruent with cognition. We describe a distinctive speech, language, and oral motor phenotype in children and adults with DS associated with mutations in SCN1A. Recognizing this phenotype will guide therapeutic intervention in patients with DS.
Publisher: Wiley
Date: 23-12-2020
DOI: 10.1111/DMCN.14428
Abstract: Epilepsy of infancy with migrating focal seizures (EIMFS), one of the most severe developmental and epileptic encephalopathy syndromes, is characterized by seizures that migrate from one hemisphere to the other. EIMFS is genetically heterogeneous with 33 genes. We report five patients with EIMFS caused by recessive BRAT1 variants, identified via next generation sequencing. Recessive pathogenic variants in BRAT1 cause the rigidity and multifocal seizure syndrome, lethal neonatal with hypertonia, microcephaly, and intractable multifocal seizures. The epileptology of BRAT1 encephalopathy has not been well described. All five patients were profoundly impaired with seizure onset in the first week of life and focal seizure migration between hemispheres. We show that BRAT1 is an important recessive cause of EIMFS with onset in the first week of life, profound impairment, and early death. Early recognition of this genetic aetiology will inform management and reproductive counselling.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2016
Publisher: Springer Science and Business Media LLC
Date: 07-2021
Publisher: Wiley
Date: 05-2000
DOI: 10.1111/J.1528-1157.2000.TB00205.X
Abstract: To describe the clinical features of a family from Northern Norway in which autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is associated with a Ser248Phe amino acid exchange in the second transmembrane domain of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4). We also tested for evidence of a de novo mutation or founder effect by comparing haplotypes with the original Australian family where the Ser248Phe mutation was first described. Clinical details were obtained from 19 family members. Personal interviews and genetic analysis were carried out in 17. Parts of the coding region of CHRNA4 were sequenced, and two known polymorphisms (bp555/FokI, bp594/CfoI) were typed by restriction analysis. Eleven in iduals had ADNFLE. The haplotypes of the mutation-carrying alleles of affected in iduals from the Northern Norwegian and the Australian ADNFLE family are different. The phenotypic expressions are remarkably similar. The Ser248Phe mutation occurred independently in both families. Given the rarity of the disease, this suggests that not only the position of a mutation in the coding sequence but also the type of an amino acid exchange is important for the etiology of ADNFLE. The phenotypic similarity of these two families with different genetic backgrounds suggests that the Ser248Phe mutation largely determines the phenotype, with relatively little influence of other background genes.
Publisher: Wiley
Date: 21-05-2022
DOI: 10.1111/EPI.17263
Abstract: This study was undertaken to evaluate efficacy and long‐term safety of triheptanoin in patients year old, not on a ketogenic diet, with drug‐resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS). UX007G‐CL201 was a randomized, double‐blind, placebo‐controlled trial. Following a 6‐week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8‐week placebo‐controlled period, all patients received open‐label triheptanoin through Week 52. The study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure frequency was observed in the triheptanoin arm relative to baseline, and a 13.5% difference was observed relative to placebo ( p = .58). In patients with absence seizures only ( n = 9), a median 62.2% reduction in seizure frequency was observed in the triheptanoin arm relative to baseline. Only one patient with absence seizures only was present in the control group, preventing comparison. No statistically significant differences in seizure frequency were observed. Common treatment‐emergent adverse events included diarrhea, vomiting, abdominal pain, and nausea, mostly mild or moderate in severity. No serious adverse events were considered to be treatment related. One patient discontinued due to status epilepticus. Triheptanoin did not significantly reduce seizure frequency in patients with Glut1DS not on the ketogenic diet. Treatment was associated with mild to moderate gastrointestinal treatment‐related events most resolved following dose reduction or interruption and/or medication for treatment. Triheptanoin was not associated with any long‐term safety concerns when administered at dose levels up to 35% of total daily caloric intake for up to 1 year.
Publisher: Informa UK Limited
Date: 08-2011
DOI: 10.1080/17470919.2010.547085
Abstract: It has been proposed that the human mirror neuron system (MNS) plays an integral role in mediating empathy. In this review, we critically examine evidence from three bodies of research that have been cited as supporting this notion: (1) behavioral studies that have examined the relationship between imitation and empathy, (2) findings from functional neuroimaging studies that report a positive correlation between MNS activation and self-report on an empathy questionnaire, and (3) observations of impaired imitation and empathy in autism spectrum disorders (ASD). In addition, we briefly review lesion studies of the neural correlates of imitation and empathy. Current evidence suggests that the MNS is broadly involved in empathy, but at this stage there has been limited consideration of its various forms, including motor, emotional, and cognitive empathy. There are also various forms of imitation, encompassing emotional and non-emotional, automatic, and voluntary actions. We propose that the relationship between imitation and empathy may vary depending on the specific type of each of these abilities. Furthermore, these abilities may be mediated by partially distinct neural networks, which involve the MNS to a variable degree.
Publisher: Elsevier BV
Date: 2017
Publisher: Wiley
Date: 04-2014
DOI: 10.1002/ANA.24128
Publisher: Wiley
Date: 18-08-2022
DOI: 10.1002/ETC.5425
Abstract: Per‐ and poly‐fluoroalkyl substances (PFAS) in water are typically present in their ionic (nonvolatile) forms however, these can transition to their nonionic (volatile) forms when in contact with organic solvents and organic matrices. In particular, when PFAS are dissolved in organic solvents such as residues left from firefighting foams, fuels, and bitumen present in asphalt, the equilibrium between ionic and nonionic forms can trend toward more volatile nonionic forms of PFAS. We assessed the volatility of common PFAS based on calculated and available experimental data across ambient temperature ranges experienced by airfield pavements and at elevated temperatures associated with reworking asphalts for reuse. Volatilities are shown to be comparable to hydrocarbons in the semivolatile range, suggesting that volatilization is a viable loss mechanism for some PFAS that are nonvolatile in water. The present study points to future investigative needs for this unexplored mass loss mechanism and potential exposure pathway. Environ Toxicol Chem 2022 :2202–2208. © 2022 Commonwealth of Australia. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
Publisher: Elsevier BV
Date: 10-2018
Publisher: Wiley
Date: 12-12-2022
DOI: 10.1002/ANA.26546
Publisher: Annual Reviews
Date: 06-01-2022
DOI: 10.1146/ANNUREV-PHARMTOX-052120-084449
Abstract: Epilepsy is an etiologically heterogeneous condition however, genetic factors are thought to play a role in most patients. For those with infantile-onset developmental and epileptic encephalopathy (DEE), a genetic diagnosis is now obtained in more than 50% of patients. There is considerable motivation to utilize these molecular diagnostic data to help guide treatment, as children with DEEs often have drug-resistant seizures as well as developmental impairment related to cerebral epileptiform activity. Precision medicine approaches have the potential to dramatically improve the quality of life for these children and their families. At present, treatment can be targeted for patients with diagnoses in many genetic causes of infantile-onset DEE, including genes encoding sodium or potassium channel subunits, tuberous sclerosis, and congenital metabolic diseases. Precision medicine may refer to more intelligent choices of conventional antiseizure medications, repurposed agents previously used for other indications, novel compounds, enzyme replacement, or gene therapy approaches.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-06-2018
Abstract: Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science , this issue p. eaap8757
Publisher: Wiley
Date: 14-04-2014
DOI: 10.1002/ANA.24126
Abstract: We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 in idual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.JCONHYD.2022.104007
Abstract: Long-term estimates of natural source zone depletion (NSZD) rates for petroleum LNAPL (light non-aqueous phase liquid) sites are not available. One-off measurements are often thought valid over the lifetime of LNAPL sites. In the context of site-wide LNAPL mass estimates, we report site-specific gasoline and diesel NSZD rates spanning 21-26 years. Using depth profiles of soil gases (oxygen, carbon dioxide, methane, volatiles) above LNAPL, NSZD rates were estimated in 1994, 2006 and 2020 for diesel and 1999, 2009 and 2020 for gasoline. Each date also had soil-core mass estimates, which together with NSZD rates allow estimation of the longevity for LNAPL presence. Site-wide coring (in 1992, 2002, 2007) estimated LNAPL mass reductions of 12,000 t. For diesel NSZD, the ratio of NSZD rates for 2006 (16,000-49,000 L/ha/y) to those in 2020 (2600-14,000 L/ha/y) was ~3-6. By 2020, the 1994 diesel NSZD rates would have predicted the entire removal of measured mass (16-42 kg/m
Publisher: Wiley
Date: 06-2011
Publisher: Georg Thieme Verlag KG
Date: 09-2019
Publisher: Elsevier BV
Date: 11-2018
Location: Australia
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
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Funder: National Health and Medical Research Council
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Funder: Medical Research Future Fund: Genomics Health Futures Mission Project Grant
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Funder: University of Melbourne
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Funder: Apex Foundation For Research Into Intellectual Disability
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Funder: Epilepsy Foundation of Victoria
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Funder: Wellington Medical Research Foundation
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Funder: Health Research Council of New Zealand
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: Einstein Stiftung Berlin
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Funder: Health Research Council of New Zealand
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