ORCID Profile
0000-0002-9148-085X
Current Organisation
University of South Australia
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Publisher: IEEE
Date: 10-2022
Publisher: Elsevier BV
Date: 06-2021
Publisher: IEEE Comput. Soc
Date: 2003
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: Springer Science and Business Media LLC
Date: 16-03-2202
Publisher: IEEE
Date: 10-2007
Publisher: Wiley
Date: 19-11-2019
DOI: 10.1002/ANA.25619
Publisher: ACM
Date: 25-01-2006
Publisher: IEEE
Date: 2006
Publisher: Wiley
Date: 04-07-2023
DOI: 10.1002/EPD2.20090
Abstract: A 24‐year‐old man with non‐lesional bitemporal lobe epilepsy since age 16 years was found dead in bed around midday. He was last seen the previous night when he was witnessed to have a tonic–clonic seizure. Before his death, he was experiencing weekly focal impaired awareness seizures and up to two focal‐to‐bilateral tonic–clonic seizures each year. He had trialed several antiseizure medications and was on levetiracetam 1500 mg/day, lamotrigine 400 mg/day, and clobazam 10 mg/day at the time of death. Other than epilepsy, his medical history was unremarkable. Of note, he had an older brother with a history of febrile seizures and a paternal first cousin with epilepsy. No cause of death was identified following a comprehensive postmortem investigation. The coroner classified the death as “sudden unexpected death in epilepsy” (SUDEP), and it would qualify as “definite SUDEP” using the current definitions. 1 This left the family with many questions unanswered in particular, they wish to know what caused the death and whether it could happen to other family members. Could postmortem genetic testing identify a cause of death, provide closure to the family, and facilitate cascade genetic testing of first‐degree family members who may be at risk of sudden death? While grieving family members struggle with uncertainty about the cause of death, we as clinicians also face similar uncertainties about genetic contributions to SUDEP, especially when the literature is sparse, and the utility of genetic testing is still being worked out. We aim to shed some light on this topic, highlighting areas where data is emerging but also areas where uncertainty remains, keeping our case in mind as we examine this clinically important area.
Publisher: Springer Science and Business Media LLC
Date: 10-2003
Publisher: IEEE
Date: 03-2011
Publisher: Wiley
Date: 18-11-2019
DOI: 10.1002/ANA.25625
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: 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: ACM
Date: 20-07-2013
Publisher: IEEE
Date: 03-2011
Publisher: Elsevier BV
Date: 03-2020
Publisher: Association for Computing Machinery (ACM)
Date: 10-2012
Abstract: Visual mixed and augmented realities have historically been applied to the gaming application domain. This article provides a survey of visual mixed and augmented reality gaming in both the academic and commercial contexts. There is an exploration of both indoor and outdoor mixed and augmented reality gaming. The different games are presented via the three major display technologies: head-mounted display, handheld display, and spatial immersive display. A number of academic mixed and augmented reality research projects are described that provide an overview of the current state of the art. A set of ex le commercial games are also examined to provide the context for the state of the games on the market.
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: IEEE
Date: 03-2014
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.YEBEH.2022.108960
Abstract: People with epilepsy have a higher prevalence of medical and psychiatric comorbidities compared to the general population. Comorbidities are associated with poor epilepsy outcomes, and there have been recommendations for screening and early identification to improve clinical management. Data from 'First Seizure Clinics' (FSCs) with expert epileptological review can inform about disorders already present at the point of diagnosis of epilepsy or unprovoked seizures. Here, we aimed to describe pre-existing conditions with a focus on psychiatric, substance use, cardiac, neurological, and cancer health domains. We included 1383 adults who received a new diagnosis of epilepsy or unprovoked seizures at Austin Hospital (AH) or Royal Melbourne Hospital (RMH) (Australia) FSCs from 2000 to 2010. Data were audited from FSC records, primarily detailed interviews undertaken by epileptologists. Logistic regression examined age distribution and other risk factors. The median age at FSC presentation was 37 years (IQR 26-53, range 18-94). Pre-existing conditions were reported by 40 % from 32 % in the youngest group (18-30 years) to 53 % in the oldest (65+ years). Psychiatric (18 %) and substance use (16 %) disorders were most common, with higher prevalence among patients 18 to 65 years of age compared to those older than 65 years (p < 0.001). Cardiac, neurological, or cancer conditions were reported by 3-6 %, most often amongst those older than 65 years (p 1 health domain. The commonest combination was a psychiatric condition with substance use disorder. Of the sixty-two patients reporting this combination, 61 were ≤65 years of age. Pre-existing health conditions are present in a substantial proportion of patients diagnosed with epilepsy or unprovoked seizures. Disorders are highest amongst elders, but one-third of younger adults also reported positive histories. These are predominantly psychiatric and/or substance use disorders, conditions strongly associated with poor outcomes in the general population. These findings inform post-diagnosis planning and management, as well as research examining post-diagnostic outcomes and associations between comorbidities and epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-11-2021
DOI: 10.1212/NXG.0000000000000641
Abstract: To assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort. Of 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.” Sixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS , CACNA2D2 , STUB1 , AFG3L2 , CLN6 , NAXE , and CHD2 . Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories. The application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield %, PME is one of the best genetically defined epilepsy syndromes.
Publisher: IEEE Comput. Soc
Date: 2003
Publisher: Cold Spring Harbor Laboratory
Date: 14-06-2022
DOI: 10.1101/2022.06.08.22276120
Abstract: Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here, we report a trans-ethnic GWAS including 29,944 cases, stratified into three broad- and seven sub-types of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants substantially close the missing heritability gap for GGE. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analysis of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current anti-seizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
Publisher: Wiley
Date: 30-10-2019
DOI: 10.1111/JON.12673
Publisher: ACM
Date: 22-06-2021
Publisher: Wiley
Date: 16-07-2020
DOI: 10.1002/JSID.947
Publisher: American Medical Association (AMA)
Date: 08-07-2022
DOI: 10.1001/JAMANETWORKOPEN.2022.20189
Abstract: Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking. To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy. A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018. Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years. Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period. A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants 390-mg cannabidiol, 62 participants placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days least squares mean difference, 0.014 95% CI, −0.175 to 0.203 P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days least squares mean difference, 0.096 95% CI, −0.093 to 0.285 P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, −6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension. Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery. ACTRN12616000510448 (double-blind) ACTRN12616001455459 (open-label).
Publisher: Wiley
Date: 12-2020
DOI: 10.1002/ALZ.041347
Publisher: Cold Spring Harbor Laboratory
Date: 07-06-2021
DOI: 10.1101/2021.06.01.21257500
Abstract: The vacuolar H + -ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1 , the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four in iduals. Here we identified 17 in iduals from 14 unrelated families with both with new and previously characterised variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 in iduals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in C. elegans . Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1 -related conditions.
Publisher: ACM
Date: 02-05-2019
Publisher: Elsevier BV
Date: 2023
Publisher: ACM
Date: 19-04-2023
Publisher: IEEE
Date: 10-2013
Publisher: ACM Press
Date: 2015
Publisher: Cold Spring Harbor Laboratory
Date: 15-01-2022
DOI: 10.1101/2022.01.14.22269323
Abstract: Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative ‘non-progressor’, ‘phenocopy’ mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. Cerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow up information, patients were categorised as Progressors. Non-Progressors were subtyped in to Phenocopy Non-Progressors (non-neurological/neurodegenerative final diagnosis), and Static Non-Progressors (static deficits, not fully explained by non-neurological/neurodegenerative causes). Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Phenocopy, 8 Static), 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M=554pg/mL, 95%CI:[461, 675], Phenocopy Non-Progressors M=459pg/mL, 95%CI:[385, 539], Static Non-Progressors M=730pg/mL, 95%CI:[516, 940]), compared to bvFTD Progressors (M=2397pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Static Non-Progressors tended to have higher T-tau and P-tau levels compared to Phenocopy Non-Progressors. This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from phenocopy non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, as well as for healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL
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: Elsevier BV
Date: 02-2018
Publisher: Cold Spring Harbor Laboratory
Date: 13-10-2023
Publisher: IEEE Comput. Soc
Date: 2003
Publisher: Wiley
Date: 17-07-2022
DOI: 10.1111/EPI.17332
Abstract: The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics increased access to genetic testing and counseling fuller understanding of natural histories agility and rigor in preclinical research, including strategic use of emerging model systems and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable ex les of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.
Publisher: IEEE
Date: 10-2017
Publisher: IEEE
Date: 02-2007
Publisher: ACM Press
Date: 2006
Publisher: IEEE
Date: 03-2010
Publisher: Springer International Publishing
Date: 2018
Publisher: IEEE Comput. Soc
Date: 2003
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: IEEE
Date: 10-2010
Publisher: ACM
Date: 23-11-2009
Publisher: Springer International Publishing
Date: 2018
Publisher: IEEE
Date: 10-2022
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: 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: IEEE
Date: 10-2011
Publisher: IEEE
Date: 11-2021
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2014
DOI: 10.1109/TVCG.2014.25
Publisher: IEEE
Date: 11-2012
Publisher: MDPI AG
Date: 14-02-2023
DOI: 10.3390/MTI7020020
Abstract: Collaborative virtual environments allow people to work together while being distant. At the same time, empathic computing aims to create a deeper shared understanding between people. In this paper, we investigate how to improve the perception of distant collaborative activities in a virtual environment by sharing users’ activity. We first propose several visualization techniques for sharing the activity of multiple users. We selected one of these techniques for a pilot study and evaluated its benefits in a controlled experiment using a virtual reality adaptation of the NASA MATB-II (Multi-Attribute Task Battery). Results show (1) that instantaneous indicators of users’ activity are preferred to indicators that continuously display the progress of a task, and (2) that participants are more confident in their ability to detect users needing help when using activity indicators.
Publisher: Elsevier BV
Date: 12-2019
Publisher: ACM
Date: 02-05-2019
Publisher: IEEE
Date: 09-2016
Publisher: Wiley
Date: 25-03-2022
DOI: 10.1111/EPI.17217
Abstract: Around 30% of patients undergoing surgical resection for drug‐resistant mesial temporal lobe epilepsy (MTLE) do not obtain seizure freedom. Success of anterior temporal lobe resection (ATLR) critically depends on the careful selection of surgical candidates, aiming at optimizing seizure freedom while minimizing postoperative morbidity. Structural MRI and FDG‐PET neuroimaging are routinely used in presurgical assessment and guide the decision to proceed to surgery. In this study, we evaluate the potential of machine learning techniques applied to standard presurgical MRI and PET imaging features to provide enhanced prognostic value relative to current practice. Eighty two patients with drug resistant MTLE were scanned with FDG‐PET pre‐surgery and T1‐weighted MRI pre‐ and postsurgery. From these images the following features of interest were derived: volume of temporal lobe (TL) hypometabolism, % of extratemporal hypometabolism, presence of contralateral TL hypometabolism, presence of hippoc al sclerosis, laterality of seizure onset volume of tissue resected and % of temporal lobe hypometabolism resected. These measures were used as predictor variables in logistic regression, support vector machines, random forests and artificial neural networks. In the study cohort, 24 of 82 (28.3%) who underwent an ATLR for drug‐resistant MTLE did not achieve Engel Class I (i.e., free of disabling seizures) outcome at a minimum of 2 years of postoperative follow‐up. We found that machine learning approaches were able to predict up to 73% of the 24 ATLR surgical patients who did not achieve a Class I outcome, at the expense of incorrect prediction for up to 31% of patients who did achieve a Class I outcome. Overall accuracies ranged from 70% to 80%, with an area under the receiver operating characteristic curve (AUC) of .75–.81. We additionally found that information regarding overall extent of both total and significantly hypometabolic tissue resected was crucial to predictive performance, with AUC dropping to .59–.62 using presurgical information alone. Incorporating the laterality of seizure onset and the choice of machine learning algorithm did not significantly change predictive performance. Collectively, these results indicate that "acceptable" to "good" patient‐specific prognostication for drug‐resistant MTLE surgery is feasible with machine learning approaches utilizing commonly collected imaging modalities, but that information on the surgical resection region is critical for optimal prognostication.
Publisher: International Association for Automation and Robotics in Construction (IAARC)
Date: 14-10-2020
Publisher: IEEE
Date: 2005
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 21-04-2016
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: IEEE
Date: 10-2023
Publisher: Elsevier BV
Date: 10-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-10-2021
DOI: 10.1212/WNL.0000000000012773
Abstract: Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in GLI3 and other patterning genes are involved in HH pathogenesis. About 50%–80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.
Publisher: Cold Spring Harbor Laboratory
Date: 26-12-2022
Publisher: IEEE
Date: 11-2014
Publisher: Springer Science and Business Media LLC
Date: 03-03-2005
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: IEEE
Date: 03-2022
Publisher: IEEE
Date: 03-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-08-2023
DOI: 10.1212/CPJ.0000000000200187
Abstract: Myoclonus is often approached in different ways by epileptologists and movement disorder specialists, leading to confusion in the literature. Multiplicity and inconsistency over the past 2 centuries resulted in a lack of precision and ambiguity of the terminology. We show that this is a current problem in which one phenomenon has been described with many terms and vice versa. Of more importance, we discuss the conceptualization of myoclonus from perspectives of both fields and focus on the borderland that exists, especially in the spectrum of cortical and epileptic myoclonus. By giving 2 ex les, we illustrate the conundrum: the spectrum of progressive myoclonus epilepsies and progressive myoclonic ataxias and “cortical tremor” observed in familial cortical myoclonic tremor with epilepsy or familial adult myoclonic epilepsy. We attempt to facilitate to bridge these subspecialties and form the base for a uniform understanding to take this issue forward toward future classifications, discussions, and scientific research.
Publisher: IEEE
Date: 03-2022
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: Wiley
Date: 03-11-2022
DOI: 10.1002/ACN3.51687
Abstract: The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA‐PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement. Clinical features of 6 patients with SMA‐PME were assessed by retrospective chart review, and a literature review of 24 previously published cases was performed. Leukocyte enzyme activity of acid ceramidase was assessed with a fluorescence‐based assay. Skin fibroblast ceramide content and was assessed by high performance liquid chromatography, electrospray ionization tandem mass spectroscopy. Enzyme replacement was assessed using recombinant human acid ceramidase (rhAC) in vitro. The six new patients showed the hallmark features of SMA‐PME, with variable initial symptom and age of onset. Five of six patients carried at least one of the recurrent SMA‐PME variants observed in two specific codons of ASAH1 . A review of 30 total cases revealed that patients who were homozygous for the most common c.125C T variant presented in the first decade of life with limb‐girdle weakness as the initial symptom. Sensorineural hearing loss was associated with the c.456A C variant. Leukocyte acid ceramidase activity varied from 4.1%–13.1% of controls. Ceramide species in fibroblasts were detected and total cellular ceramide content was elevated by 2 to 9‐fold compared to controls. Treatment with rhAC normalized ceramide profiles in cultured fibroblasts to control levels within 48 h. This study details the genotype–phenotype correlations observed in SMA‐PME and shows the impact of rhAC to correct the abnormal cellular ceramide profile in cells.
Publisher: ACM
Date: 26-05-2010
Publisher: Frontiers Media SA
Date: 18-03-2022
DOI: 10.3389/FNEUR.2022.858333
Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Although lots of effort has been made in identifying clinical risk factors for SUDEP in the literature, there are few validated methods to predict in idual SUDEP risk. Prolonged postictal EEG suppression (PGES) is a potential SUDEP biomarker, but its occurrence is infrequent and requires epilepsy monitoring unit admission. We use machine learning methods to examine SUDEP risk using interictal EEG and ECG recordings from SUDEP cases and matched living epilepsy controls. This multicenter, retrospective, cohort study examined interictal EEG and ECG recordings from 30 SUDEP cases and 58 age-matched living epilepsy patient controls. We trained machine learning models with interictal EEG and ECG features to predict the retrospective SUDEP risk for each patient. We assessed cross-validated classification accuracy and the area under the receiver operating characteristic (AUC) curve. The logistic regression (LR) classifier produced the overall best performance, outperforming the support vector machine (SVM), random forest (RF), and convolutional neural network (CNN). Among the 30 patients with SUDEP [14 females mean age (SD), 31 (8.47) years] and 58 living epilepsy controls [26 females (43%) mean age (SD) 31 (8.5) years], the LR model achieved the median AUC of 0.77 [interquartile range (IQR), 0.73–0.80] in five-fold cross-validation using interictal alpha and low gamma power ratio of the EEG and heart rate variability (HRV) features extracted from the ECG. The LR model achieved the mean AUC of 0.79 in leave-one-center-out prediction. Our results support that machine learning-driven models may quantify SUDEP risk for epilepsy patients, future refinements in our model may help predict in idualized SUDEP risk and help clinicians correlate predictive scores with the clinical data. Low-cost and noninvasive interictal biomarkers of SUDEP risk may help clinicians to identify high-risk patients and initiate preventive strategies.
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: 05-11-2021
DOI: 10.1002/ANA.25941
Abstract: Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected in iduals from both families shared a rare, homozygous c.191A G variant affecting a splice site in SLC7A6OS . Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss‐of‐function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021 :402–407
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: IGI Global
Date: 2006
DOI: 10.4018/978-1-59904-066-0.CH018
Abstract: Entertainment systems are one of the successful utilisations of augmented reality technologies to real world applications. This chapter provides my personal insights into the future directions of the use of augmented reality with gaming applications. This chapter explores a number of advances in technologies that may enhance augmented reality gaming. The features for both indoor and outdoor augmented reality are examined in context of their desired attributes for the gaming community. A set of concept games for outdoor augmented reality are presented to highlight novel features of this technology.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2009
DOI: 10.1109/MPRV.2009.38
Publisher: IEEE
Date: 09-2015
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: 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: IEEE
Date: 10-2022
Publisher: IEEE
Date: 06-2012
DOI: 10.1109/ISWC.2012.26
Publisher: Elsevier BV
Date: 04-2021
Publisher: IEEE
Date: 11-2017
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 09-2015
DOI: 10.1109/MITP.2015.87
Publisher: IEEE
Date: 03-2011
Publisher: ACM
Date: 08-12-2021
Publisher: Springer New York
Date: 2011
Publisher: Wiley
Date: 12-03-2020
DOI: 10.1111/EPI.16475
Publisher: Wiley
Date: 14-11-2022
DOI: 10.1111/EPI.17440
Abstract: Anterior temporal lobectomy (ATL) for medication‐resistant localized epilepsy results in ablation or reduction of seizures for most patients. However, some in iduals who attain an initial extended period of postsurgical seizure freedom will experience a later seizure recurrence. In this study, we examined the prevalence and some risk factors for late recurrence in an ATL cohort with extensive regular follow‐up. Included were 449 patients who underwent ATL at Austin Health, Australia, from 1978 to 2008. Postsurgical follow‐up was undertaken 2–3 yearly. Seizure recurrence was tested using Kaplan–Meier analysis, log‐rank test, and Cox regression. Late recurrence was qualified as a first disabling seizure years postsurgery. We examined risks within the ATL cohort according to broad pathology groups and tested whether late recurrence differed for the ATL cohort compared to patients who had resections outside the temporal lobe ( n = 98). Median post‐ATL follow‐up was 22 years (range = .1–38.6), 6% were lost to follow‐up, and 12% had died. Probabilities for remaining completely seizure‐free after surgery were 51% (95% confidence interval [CI] = 53–63) at 2 postoperative years, 36% (95% CI = 32–41) at 10 years, 32% (95% CI = 27–36) at 20 years, and 30% (95% CI = 25–34) at 25 years. Recurrences were reported up to 23 years postoperatively. Late seizures occurred in all major ATL pathology groups, with increased risk in the "normal" and "distant lesion" groups ( p ≤ .03). Comparison between the ATL cohort and patients who underwent extratemporal resection demonstrated similar patterns of late recurrence ( p = .74). Some first recurrences were very late, reported decades after ATL. Late recurrences were not unique to any broad ATL pathology group and did not differ according to whether resections were ATL or extratemporal. Reports of these events by patients with residual pathology suggest that potentially epileptogenic abnormalities outside the area of resection may be implicated as one of several possible underlying mechanisms.
Publisher: Springer Science and Business Media LLC
Date: 04-2002
Publisher: IEEE
Date: 03-2022
Publisher: Springer Science and Business Media LLC
Date: 02-2002
Publisher: The Eurographics Association
Date: 2019
Publisher: IEEE
Date: 09-2015
Publisher: Oxford University Press (OUP)
Date: 03-2022
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2014
DOI: 10.1109/MCG.2014.117
Publisher: Wiley
Date: 09-03-2023
DOI: 10.1111/EPI.17557
Abstract: The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome‐wide molecular studies on remaining, well‐selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole‐exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype–phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.
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: IEEE
Date: 09-2015
Publisher: ACM
Date: 03-12-2008
Publisher: Cold Spring Harbor Laboratory
Date: 23-02-2023
Publisher: IEEE
Date: 2004
Publisher: IEEE
Date: 07-2009
Publisher: World Scientific Pub Co Pte Lt
Date: 09-2015
Publisher: Association for Computing Machinery (ACM)
Date: 14-11-2022
DOI: 10.1145/3567741
Abstract: When collaborating face-to-face, people commonly use the surfaces and spaces around them to perform sensemaking tasks, such as spatially organising documents, notes or images. However, when people collaborate remotely using desktop interfaces they no longer feel like they are sharing the same space. This limitation may be overcome through collaboration in immersive environments, which simulate the physical in-person experience. In this paper, we report on a between-groups study comparing collaborations on image organisation tasks, in an immersive Virtual Reality (VR) environment to more conventional desktop conferencing. Collecting data from 40 subjects in groups of four, we measured task performance, user behaviours, collaboration engagement and awareness. Overall, the VR and desktop interface resulted in similar speed, accuracy and social presence rating, but we observed more conversations and interaction with objects, and more equal contributions to the interaction from participants within groups in VR. We also identified differences in coordination and collaborative awareness behaviours between VR and desktop platforms. We report on a set of systematic measures for assessing VR collaborative experience and a new analysis tool that we have developed to capture user behaviours in collaborative setting. Finally, we provide design considerations and directions for future work.
Publisher: IEEE
Date: 03-2019
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: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2010
DOI: 10.1109/MPRV.2010.35
Publisher: IEEE Comput. Soc
Date: 2001
Publisher: Springer Science and Business Media LLC
Date: 29-07-2013
Publisher: Elsevier BV
Date: 06-2023
Publisher: Wiley
Date: 15-04-2020
DOI: 10.1002/ANA.25724
Publisher: IEEE Comput. Soc
Date: 2001
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2009
DOI: 10.1109/MPRV.2009.59
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 10-2021
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2019
Publisher: Springer Science and Business Media LLC
Date: 19-10-2021
Publisher: Elsevier BV
Date: 03-2019
Publisher: Springer International Publishing
Date: 2017
Publisher: Institute of Electrical Engineers of Japan (IEE Japan)
Date: 2013
Publisher: ACM
Date: 06-05-2021
Publisher: Springer London
Date: 2010
Publisher: ACM
Date: 15-02-2007
Publisher: Elsevier BV
Date: 02-2021
Publisher: ACM
Date: 29-01-2006
Publisher: IEEE
Date: 10-2018
Publisher: ACM
Date: 21-04-2020
Publisher: Elsevier BV
Date: 11-2022
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.SEIZURE.2022.09.006
Abstract: To explore the cortical morphological associations of the psychoses of epilepsy. Psychosis of epilepsy (POE) has two main subtypes - postictal psychosis and interictal psychosis. We used automated surface-based analysis of magnetic resonance images to compare cortical thickness, area, and volume across the whole brain between: (i) all patients with POE (n = 23) relative to epilepsy-without psychosis controls (EC n = 23), (ii) patients with interictal psychosis (n = 10) or postictal psychosis (n = 13) relative to EC, and (iii) patients with postictal psychosis (n = 13) relative to patients with interictal psychosis (n = 10). POE is characterised by cortical thickening relative to EC, occurring primarily in nodes of the cognitive control network (rostral anterior cingulate, caudal anterior cingulate, middle frontal gyrus), and the default mode network (posterior cingulate, medial paracentral gyrus, and precuneus). Patients with interictal psychosis displayed cortical thickening in the left hemisphere in occipital and temporal regions relative to EC (lateral occipital cortex, lingual, fusiform, and inferior temporal gyri), which was evident to a lesser extent in postictal psychosis patients. There were no significant differences in cortical thickness, area, or volume between the postictal psychosis and EC groups, or between the postictal psychosis and interictal psychosis groups. However, prior to correction for multiple comparisons, both the interictal psychosis and postictal psychosis groups displayed cortical thickening relative to EC in highly similar regions to those identified in the POE group overall. The results show cortical thickening in POE overall, primarily in nodes of the cognitive control and default mode networks, compared to patients with epilepsy without psychosis. Additional thickening in temporal and occipital neocortex implicated in the dorsal and ventral visual pathways may differentiate interictal psychosis from postictal psychosis. A novel mechanism for cortical thickening in POE is proposed whereby normal synaptic pruning processes are interrupted by seizure onset.
Publisher: ACM
Date: 19-11-2018
Publisher: IEEE
Date: 2008
Publisher: IEEE
Date: 03-2015
Publisher: IEEE
Date: 03-2022
Publisher: IEEE
Date: 06-2011
DOI: 10.1109/ISWC.2011.25
Publisher: IEEE
Date: 03-2019
Publisher: IEEE
Date: 09-2008
Publisher: IEEE
Date: 2017
Publisher: IEEE
Date: 2006
Publisher: Springer Science and Business Media LLC
Date: 22-09-2020
DOI: 10.1038/S41467-020-18367-Y
Abstract: Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery s le comprises 22,824 in iduals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
Publisher: IEEE
Date: 10-2013
Publisher: IEEE
Date: 11-2016
Publisher: Elsevier BV
Date: 10-2023
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: IEEE
Date: 09-2008
Publisher: IEEE
Date: 10-2013
Publisher: American Medical Association (AMA)
Date: 03-08-2022
Publisher: IEEE
Date: 2005
DOI: 10.1109/ISWC.2005.20
Publisher: ACM
Date: 11-11-2014
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2020
Publisher: IEEE
Date: 09-2008
Publisher: IEEE
Date: 2006
Publisher: IEEE
Date: 09-2016
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: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2018
Publisher: IEEE
Date: 03-2015
Publisher: IEEE
Date: 10-2013
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: ACM
Date: 03-12-2008
Publisher: IEEE
Date: 2005
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-12-2021
DOI: 10.1212/WNL.0000000000012946
Abstract: We compared heart rate variability (HRV) in sudden unexpected death in epilepsy (SUDEP) cases and living epilepsy controls. This international, multicenter, retrospective, nested case–control study examined patients admitted for video-EEG monitoring (VEM) between January 1, 2003, and December 31, 2014, and subsequently died of SUDEP. Time domain and frequency domain components were extracted from 5-minute interictal ECG recordings during sleep and wakefulness from SUDEP cases and controls. We identified 31 SUDEP cases and 56 controls. Normalized low-frequency power (LFP) during wakefulness was lower in SUDEP cases (median 42.5, interquartile range [IQR] 32.6–52.6) than epilepsy controls (55.5, IQR 40.7–68.9 p = 0.015, critical value = 0.025). In the multivariable model, normalized LFP was lower in SUDEP cases compared to controls (contrast −11.01, 95% confidence interval [CI] −20.29 to 1.73 p = 0.020, critical value = 0.025). There was a negative correlation between LFP and the latency to SUDEP, where each 1% incremental reduction in normalized LFP conferred a 2.7% decrease in the latency to SUDEP (95% CI 0.95–0.995 p = 0.017, critical value = 0.025). Increased survival duration from VEM to SUDEP was associated with higher normalized high-frequency power (HFP p = 0.002, critical value = 0.025). The survival model with normalized LFP was associated with SUDEP ( c statistic 0.66, 95% CI 0.55–0.77), which nonsignificantly increased with the addition of normalized HFP ( c statistic 0.70, 95% CI 0.59–0.81 p = 0.209). Reduced short-term LFP, which is a validated biomarker for sudden death, was associated with SUDEP. Increased HFP was associated with longer survival and may be cardioprotective in SUDEP. HRV quantification may help stratify in idual SUDEP risk. This study provides Class III evidence that in patients with epilepsy, some measures of HRV are associated with SUDEP.
Publisher: ACM
Date: 21-04-2020
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: Cold Spring Harbor Laboratory
Date: 20-04-2021
DOI: 10.1101/2021.04.20.21255696
Abstract: De novo missense variants in KCNQ5 , encoding the voltage-gated K + channel K V 7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-cl recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) K V 7.5 or K V 7.5 and K V 7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P 2 - interaction, presumably in the non-conducting preopen-closed state. Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional, rather than trafficking deficits. LOF of K V 7.5 channels will reduce the M-current, likely resulting in increased excitability of K V 7.5- expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.
Publisher: ACM
Date: 27-10-2008
Publisher: IEEE
Date: 10-2013
Publisher: Wiley
Date: 29-11-2020
DOI: 10.1002/ACN3.51258
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/ALZ.12549
Abstract: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total‐tau (t‐tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt‐Jakob registry (Creutzfeldt‐Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t‐tau in most real‐life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.
Publisher: ACM
Date: 11-12-2011
Publisher: IEEE
Date: 11-2016
Publisher: IEEE
Date: 10-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-07-2021
DOI: 10.1212/CPJ.0000000000001114
Abstract: To explore the impact of psychiatric comorbidities on all-cause mortality in adults with epilepsy from a cohort of patients admitted for video-EEG monitoring (VEM) over 2 decades. A retrospective medical record audit was conducted on 2,709 adults admitted for VEM and diagnosed with epilepsy at 3 Victorian comprehensive epilepsy programs from 1995 to 2015. A total of 1,805 patients were identified in whom the record of a clinical evaluation by a neuropsychiatrist was available, excluding 27 patients who died of a malignant brain tumor known at the time of VEM admission. Epilepsy and lifetime psychiatric diagnoses were determined from consensus opinion of epileptologists and neuropsychiatrists involved in the care of each patient. Mortality and cause of death were determined by linkage to the Australian National Death Index and National Coronial Information System. Compared with the general population, mortality was higher in people with epilepsy (PWE) with a psychiatric illness (standardized mortality ratio [SMR] 3.6) and without a psychiatric illness (SMR 2.5). PWE with a psychiatric illness had greater mortality compared with PWE without (hazard ratio 1.41, 95% confidence interval 1.02–1.97) after adjusting for age and sex. No single psychiatric disorder by itself conferred increased mortality in PWE. The distribution of causes of death remained similar between PWE with psychiatric comorbidities and those without. The presence of comorbid psychiatric disorders in adults with epilepsy is associated with increased mortality, highlighting the importance of identifying and treating psychiatric comorbidities in these patients.
Publisher: Research Square Platform LLC
Date: 22-09-2023
Publisher: Wiley
Date: 10-02-2023
DOI: 10.1111/EPI.17519
Abstract: Familial adult myoclonus epilepsy/benign adult familial myoclonic epilepsy (FAME/BAFME) has emerged as a specific and recognizable epilepsy syndrome with autosomal dominant inheritance found around the world. Here, we trace the history of this syndrome. Initially, it was likely conflated with other familial myoclonus epilepsies, especially the progressive myoclonus epilepsies. As the progressive myoclonus epilepsies became better understood clinically and genetically, this group began to stand out and was first recognized as such in Japan. Subsequently, families were recognized around the world and there was debate as to whether they represented one or multiple disorders. Clarification came with the identification of pentanucleotide repeats in Japanese families, and FAME/BAFME was quickly shown to be due to pentanucleotide expansions in at least six genes. These have geographic predilections and appear to have been caused by historically ancient initial mutations. Within and between families, there is some variation in the phenotype, explained in large part by expansion size, but whether there are features specific to in idual genes remains uncertain.
Publisher: IEEE Comput. Soc
Date: 2002
Publisher: Elsevier BV
Date: 02-2020
Publisher: Wiley
Date: 21-05-2021
DOI: 10.1002/ACN3.51374
Abstract: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of in iduals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. We performed exome sequencing of 1,128 in iduals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 in iduals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.
Publisher: IEEE
Date: 11-2012
Publisher: ACM
Date: 27-07-2014
Publisher: IEEE Comput. Soc. Press
Date: 1988
Publisher: Wiley
Date: 06-09-2023
DOI: 10.1002/EPD2.20152
Abstract: Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome characterised by the development of progressively worsening myoclonus, ataxia and seizures. A molecular diagnosis can now be established in approximately 80% of in iduals with PME. Almost fifty genetic causes of PME have now been established, although some remain extremely rare. Herein we provide a review of clinical phenotypes and genotypes of the more commonly encountered PMEs. Using an illustrative case ex le, we describe appropriate clinical investigation and therapeutic strategies to guide the management of this often relentlessly progressive and devastating epilepsy syndrome.
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: 12-2021
Publisher: IEEE
Date: 2003
Publisher: MDPI AG
Date: 31-08-2020
DOI: 10.3390/IJMS21176333
Abstract: The CACNA1G gene encodes the low-voltage-activated Cav3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Cav3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Cav3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca2+ current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with CACNA1G mutations, corroborating further the causal association with distinct complex phenotypes.
Publisher: Wiley
Date: 04-08-2023
DOI: 10.1111/EPI.17727
Abstract: Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12–60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient , and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1‐weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = −.007 to −.002, p = .0003). Each 10‐year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = −.007 to −.005, p .0001). For male participants, the ratio was .011 less than for female participants (95% CI = −.014 to −.007, p .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-01-2020
Abstract: GABA (γ-aminobutyric acid) is the brain’s predominant inhibitory neurotransmitter and exerts a strong inhibitory influence through extrasynaptic GABA A receptors. This form of neurotransmission is known as tonic inhibition. Tonic inhibition is usually thought to reduce the excitability of all neurons, but here we show that it can selectively modulate the excitability of different types of neurons. Surprisingly, tonic inhibition can increase excitability in a common subtype of interneuron, and modeling results suggest this is achieved through the neuron’s electrophysiological, or functional, properties. These results provide insight into the impact of tonic inhibition upon neural activity and suggest a mechanism through which GABA may modulate the excitability of neurons in a selective manner.
Publisher: Elsevier BV
Date: 10-2022
Publisher: Wiley
Date: 12-2021
DOI: 10.1002/ALZ.058647
Abstract: Accurate, timely diagnosis of neurodegenerative disorders, in particular distinguishing primary psychiatric from neurological disorders and in younger people, can be challenging. There is a need for biomarkers to reduce the diagnostic odyssey and improve outcomes. Neurofilament light (NfL) has shown promise as a diagnostic biomarker in a wide range of disorders. Our Markers in Neuropsychiatric Disorders (MiND) Study builds on our pilot (Eratne et al, ANZJP, 2020), to explore the diagnostic and broader utility of plasma and cerebrospinal fluid (CSF) NfL and other novel markers such as phosphorylated tau 181 (p‐tau181), in a broad range of psychiatric and neurodegenerative/neurological disorders, with a view of translation into routine clinical practice. We assessed plasma and/or CSF NfL and p‐tau181 concentrations in broad cohorts, including: patients assessed for neurocognitive sychiatric symptoms at Neuropsychiatry and Melbourne Young‐Onset Dementia services and other services, in a wide range of disorders including Alzheimer disease, frontotemporal dementia, schizophrenia, bipolar disorder, depression, Niemann‐Pick Type C, epilepsy, functional neurological disorders. The most recent primary consensus diagnosis informed by established diagnostic criteria was categorised: primary psychiatric disorder (PPD), neurodegenerative/neurological disorder (ND), or healthy controls (HC). Findings from over 500 patients articipants will be presented, which indicate that CSF and plasma NfL levels are significantly elevated in a broad range of ND compared to a broad range of PPD, and HC, and bvFTD progressors from phenocopy syndromes, differentiating with areas under the curve of .90, sensitivity and specificity %. Plasma P‐tau181 levels distinguished Alzheimer disease (mainly younger sporadic), compared to other neurodegenerative disorders, with AUC 0.90, 90% sensitivity and specificity. As recruitment, s le analysis, data collection is ongoing, the most up to date results will be presented. NfL shows great promise as a diagnostic test to assist with the common, challenging diagnostic dilemma of distinguishing neurodegenerative from non‐neurodegenerative and primary psychiatric disorders. Plasma p‐tau181 shows strong diagnostic utility in younger‐onset Alzheimer disease. A significantly elevated NfL in someone with a psychiatric diagnosis should prompt consideration of neurodegenerative differentials. Plasma NfL could dramatically alter clinical care of patients with neuropsychiatric and neurological symptoms, improving outcomes for patients, their families, the healthcare system, and clinical trials.
Publisher: Elsevier BV
Date: 2020
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 12-2015
Publisher: IEEE
Date: 2002
Publisher: IEEE
Date: 10-2007
Publisher: Wiley
Date: 22-06-2023
DOI: 10.1002/EPD2.20026
Abstract: The self‐limited (familial) epilepsies with onset in neonates or infants, formerly called benign familial neonatal and/or infantile epilepsies, are autosomal dominant disorders characterized by neonatal‐ or infantile‐onset focal motor seizures and the absence of neurodevelopmental complications. Seizures tend to remit during infancy or early childhood and are therefore called “self‐limited”. A positive family history for epilepsy usually suggests the genetic etiology, but incomplete penetrance and de novo inheritance occur. Here, we review the phenotypic spectrum and the genetic architecture of self‐limited (familial) epilepsies with onset in neonates or infants. Using an illustrative case study, we describe important clues in recognition of these syndromes, diagnostic steps including genetic testing, management, and genetic counseling.
Publisher: IEEE
Date: 11-2007
Publisher: IEEE
Date: 03-2019
Publisher: IEEE
Date: 2004
Publisher: Frontiers Media SA
Date: 08-09-2020
Publisher: IEEE
Date: 2002
Publisher: IEEE
Date: 03-2015
Publisher: IEEE
Date: 10-2013
Publisher: IEEE
Date: 09-2008
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2017
Publisher: Springer New York
Date: 14-08-2012
Publisher: Elsevier BV
Date: 10-2016
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2018
Publisher: Springer Netherlands
Date: 2009
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: 18-11-2021
DOI: 10.1111/EPI.16766
Publisher: Springer Science and Business Media LLC
Date: 16-01-2022
Publisher: Elsevier BV
Date: 2021
Publisher: IEEE
Date: 10-2018
Publisher: IEEE
Date: 10-2018
Publisher: IEEE
Date: 03-2011
Publisher: IEEE
Date: 2004
Publisher: IEEE
Date: 03-2019
Publisher: ACM
Date: 23-11-2009
Publisher: Wiley
Date: 02-01-2023
DOI: 10.1002/ANA.26581
Abstract: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug‐resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippoc al sclerosis and ≥2‐year postsurgical follow‐up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. Nine centers from 3 continents contributed 206 patients operated for drug‐resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss‐of‐function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9–3.5, p = 1.3E‐09) and in genes encoding voltage‐gated cation channels (OR = 2.4, 95% CI = 1.4–3.8, p = 2.7E‐04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between‐group differences. Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision‐making and counseling. ANN NEUROL 2023 :752–761
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: 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: ACM
Date: 04-10-2014
Publisher: Wiley
Date: 18-08-2021
DOI: 10.1002/ANA.26191
Publisher: ACM
Date: 27-11-2017
Publisher: Cold Spring Harbor Laboratory
Date: 09-09-2022
DOI: 10.1101/2022.09.08.22279663
Abstract: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. We collected longitudinal diagnostic information (mean=36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other), and PSY. We pre-specified NfL pg/mL as indicative of ND/MCI/other. Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
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: Society for Imaging Science & Technology
Date: 14-02-2016
Publisher: MDPI AG
Date: 06-07-2020
DOI: 10.3390/MTI4030037
Abstract: Three-dimensional rendering technologies have long been utilized for explanatory purposes in scientific visualization and related areas. Their applications to wider fields, however, have often been limited. In this paper, we explore the use of 3D model and animation techniques, combined with narrative techniques, for recreating event-based information to aid understanding. An empirical experiment was conducted which examined the effectiveness of 3D model images and 3D animation videos compared to reading narratives in textual form. The results indicated that both forms of 3D graphical techniques positively supported users in terms of cognitive load, recall, and engagement over reading text.
Publisher: IEEE
Date: 09-2016
Publisher: IEEE
Date: 10-2010
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: Public Library of Science (PLoS)
Date: 15-10-2021
DOI: 10.1371/JOURNAL.PCBI.1009521
Abstract: Inhibitory interneurons shape the spiking characteristics and computational properties of cortical networks. Interneuron subtypes can precisely regulate cortical function but the roles of interneuron subtypes for promoting different regimes of cortical activity remains unclear. Therefore, we investigated the impact of fast spiking and non-fast spiking interneuron subtypes on cortical activity using a network model with connectivity and synaptic properties constrained by experimental data. We found that network properties were more sensitive to modulation of the fast spiking population, with reductions of fast spiking excitability generating strong spike correlations and network oscillations. Paradoxically, reduced fast spiking excitability produced a reduction of global excitation-inhibition balance and features of an inhibition stabilised network, in which firing rates were driven by the activity of excitatory neurons within the network. Further analysis revealed that the synaptic interactions and biophysical features associated with fast spiking interneurons, in particular their rapid intrinsic response properties and short synaptic latency, enabled this state transition by enhancing gain within the excitatory population. Therefore, fast spiking interneurons may be uniquely positioned to control the strength of recurrent excitatory connectivity and the transition to an inhibition stabilised regime. Overall, our results suggest that interneuron subtypes can exert selective control over excitatory gain allowing for differential modulation of global network state.
Publisher: Wiley
Date: 13-01-2021
DOI: 10.1002/EPI4.12460
Abstract: ‘First seizure’ clinics (FSCs) aim to achieve early expert assessment for in iduals with possible new‐onset epilepsy. These clinics also have substantial potential for research into epilepsy evolution, outcomes, and costs. However, a paucity of FSCs details has implications for interpretation and utilization of this research. We reviewed investigation findings over 11 years (2000‐2010) from two established independent FSCs at Austin Health (AH) and Royal Melbourne Hospital (RMH), Australia. These adult clinics are in major public hospitals and operate with similar levels of expertise. Organizational differences include screening and dedicated administration at AH. Included were N = 1555 patients diagnosed with new‐onset unprovoked seizures/epilepsy (AH n = 901, RMH n = 654). Protocol‐driven interviews and investigations had been recorded prospectively and were extracted from medical records for study. Median patient age was 37 (IQR 26‐52, range 18‐94) years (AH 34 vs RMH 42 years P .001). Eighty‐six percent of patients attended FSC within three weeks postindex seizure (median AH 12 vs RMH 25 days P .01). By their first appointment, 42% had experienced ≥2 seizures. An EEG was obtained within three weeks postindex seizure in 73% of patients, demonstrating epileptiform discharges in 25% (AH 33% vs RMH 15%). Seventy‐six percent of patients had an MRI within 6 weeks. Of those with imaging (n = 1500), 19% had potentially epileptogenic abnormalities (RMH 28% vs AH 12% P .01). At both sites, changes due to previous stroke/hemorrhage were the commonest lesions, followed by traumatic brain injury. ≥WHO level 1 brain tumors diagnosed at presentation comprised a very small proportion ( %) at each clinic. At both sites, epilepsy type could be determined in 60% of patients RMH had more focal and AH more generalized epilepsy diagnoses. Differences between the clinics’ administrative and screening practices may contribute to differences in investigation findings. Insight into these differences will facilitate interpretation and utilization, and planning of future research.
Publisher: Wiley
Date: 23-10-2020
DOI: 10.1111/EPI.16732
Publisher: IEEE
Date: 10-2013
Publisher: ACM
Date: 16-02-2014
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: IEEE
Date: 03-2023
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: ACM
Date: 06-05-2021
Publisher: Elsevier BV
Date: 06-2022
Publisher: Oxford University Press (OUP)
Date: 04-2002
Publisher: Springer US
Date: 2003
Publisher: Elsevier BV
Date: 09-2023
Publisher: IEEE Comput. Soc
Date: 2000
Publisher: IGI Global
Date: 2006
Publisher: American Medical Association (AMA)
Date: 14-12-2022
Publisher: IEEE
Date: 11-2017
Publisher: IEEE
Date: 09-2009
DOI: 10.1109/ISWC.2009.17
Publisher: MDPI AG
Date: 28-01-2022
DOI: 10.3390/BUILDINGS12020140
Abstract: This article presents our findings from a three-stage research project, which consists of the identification, development, and evaluation of a defect management Augmented Reality (AR) prototype that incorporates Building Information Modelling (BIM) technologies. Within the first stage, we conducted a workshop with four construction-industry representatives to capture their opinions and perceptions of the potentials and barriers associated with the integration of BIM and AR in the construction industry. The workshop findings led us to the second stage, which consisted of the development of an on-site BIM-based AR defect management (BIM-ARDM) system for construction inspections. Finally, a study was conducted to evaluate BIM-ARDM in comparison to the current paper-based defect management inspection approach employed on construction sites. The findings from the study revealed BIM-ARDM significantly outperformed current approaches in terms of usability, workload, performance, completion time, identifying defects, locating building elements, and assisting the user with the inspection task.
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: Frontiers Media SA
Date: 04-09-2019
Publisher: IEEE
Date: 11-2017
Publisher: IEEE
Date: 09-2009
DOI: 10.1109/ISWC.2009.15
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2022
Publisher: ACM
Date: 02-12-2018
Publisher: Springer New York
Date: 2011
Publisher: Elsevier BV
Date: 04-2020
Publisher: IEEE
Date: 10-2023
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: Wiley
Date: 22-07-2019
DOI: 10.1002/EPI4.12350
Publisher: SAGE Publications
Date: 17-11-2022
DOI: 10.1177/00048674211058684
Abstract: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of erse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for ex le with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine ( We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2] parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.
Publisher: ACM
Date: 19-04-2023
Publisher: ACM
Date: 29-10-2009
Publisher: Frontiers Media SA
Date: 27-07-2016
Publisher: MDPI AG
Date: 11-06-2020
DOI: 10.3390/APP10114049
Abstract: This article presents a user study into user perception of an object’s size when presented in virtual reality. Critical for users understanding of virtual worlds is their perception of the size of virtual objects. This article is concerned with virtual objects that are within arm’s reach of the user. Ex les of such virtual objects could be virtual controls such as buttons, dials and levers that the users manipulate to control the virtual reality application. This article explores the issue of a user’s ability to judge the size of an object relative to a second object of a different colour. The results determined that the points of subjective equality for height and width judgement tasks ranging from 10 to 90 mm were all within an acceptable value. That is to say, participants were able to perceive height and width judgements very close to the target values. The results for height judgement task for just-noticeable difference were all less than 1.5 mm and for the width judgement task less than 2.3 mm.
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: IEEE
Date: 03-2019
Publisher: IEEE
Date: 10-2009
Publisher: IEEE
Date: 10-2007
Publisher: ACM
Date: 13-09-2014
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: ACM
Date: 17-11-2013
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: Modelling and Simulation Society of Australia and New Zealand
Date: 12-2019
Publisher: IEEE
Date: 10-2019
Publisher: Wiley
Date: 10-2022
Abstract: Epilepsy genetics is a rapidly developing field, in which novel disease‐associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre‐ and post‐test counseling, and follow‐up after genetic testing is completed. We acknowledge that the resources vary across different settings but highlight that genetic diagnostic testing for epilepsy should be prioritized when the likelihood of an informative finding is high. Results of genetic testing, in particular the identification of causative genetic variants, are likely to improve in idual care. We emphasize the importance of genetic testing for in iduals with epilepsy as we enter the era of precision therapy.
Publisher: IEEE
Date: 2002
Publisher: Elsevier BV
Date: 03-2005
Publisher: Annual Reviews
Date: 31-08-2020
DOI: 10.1146/ANNUREV-GENOM-120219-074937
Abstract: Epilepsy encompasses a group of heterogeneous brain diseases that affect more than 50 million people worldwide. Epilepsy may have discernible structural, infectious, metabolic, and immune etiologies however, in most people with epilepsy, no obvious cause is identifiable. Based initially on family studies and later on advances in gene sequencing technologies and computational approaches, as well as the establishment of large collaborative initiatives, we now know that genetics plays a much greater role in epilepsy than was previously appreciated. Here, we review the progress in the field of epilepsy genetics and highlight molecular discoveries in the most important epilepsy groups, including those that have been long considered to have a nongenetic cause. We discuss where the field of epilepsy genetics is moving as it enters a new era in which the genetic architecture of common epilepsies is starting to be unraveled.
Publisher: Wiley
Date: 04-10-2019
DOI: 10.1002/MDS.27828
Publisher: IEEE
Date: 03-2019
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.JNS.2022.120439
Abstract: Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative 'non-progressor' mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. Cerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow-up information, patients were categorised as Progressors or Non-Progressors: further subtyped into Non-Progressor Revised (non-neurological/neurodegenerative final diagnosis), and Non-Progressor Static (static deficits, not fully explained by non-neurological/neurodegenerative causes). Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Non-Progressor Revised, 8 Non-Progressor Static), and 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M = 554 pg/mL, 95%CI:[461, 675], Non-Progressor Revised M = 459 pg/mL, 95%CI:[385, 539], and Non-Progressor Static M = 730 pg/mL, 95%CI:[516, 940]), compared to Progressors (M = 2397 pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Non-Progressor Static tended to have higher T-tau and P-tau levels compared to Non-Progressor Revised Diagnoses. This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2023
Publisher: IEEE
Date: 03-2021
Publisher: IEEE
Date: 03-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-07-2020
DOI: 10.1212/WNL.0000000000009855
Abstract: To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population. This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports. A total of 5,508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1,595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% confidence interval [CI] 2.0–3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI 3.4–19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and “epilepsy” was recorded as the cause of death in 24%. Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.
Publisher: Springer International Publishing
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 24-02-2023
DOI: 10.1101/2023.02.22.23286310
Abstract: Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date to investigate rare variants that confer risk for a spectrum of epilepsy syndromes. With an unprecedented s le size of ,000 human exomes, composed of 20,979 deep-phenotyped patients with epilepsy and 33,444 controls, we replicate previous gene findings at exome-wide significance using a hypothesis-free approach, we identify potential novel associations. Most discoveries are specific to a particular subtype of epilepsy, highlighting distinct genetic contributions to different epilepsies. Combining evidence from rare single nucleotide/short indel-, copy number-, and common variants, we find convergence of different genetic risk factors at the level of in idual genes. Further comparing to other exome-sequencing studies, we implicate shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our study also demonstrates the value of collaborative sequencing and deep-phenotyping efforts, which will continue to unravel the complex genetic architecture underlying the heterogeneity of epilepsy.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.SEIZURE.2022.02.004
Abstract: Between 16-77% of patients with newly diagnosed epilepsy report seizures before diagnosis but little is known about the risk factors for diagnostic delay. Here, we examined the association between prior seizures and neuroimaging findings in newly diagnosed focal epilepsy. Adults diagnosed with focal epilepsy at First Seizure Clinics (FSC) at the Royal Melbourne Hospital or Austin Health, Melbourne, Australia, between 2000 and 2010 were included. Medical records were audited for seizure history accrued from the detailed FSC interview. Potentially epileptogenic brain abnormality type, location and extent was determined from neuroimaging. Statistical analysis comprised multivariate logistic regression. Of 735 patients, 44% reported seizure/s before the index seizure. Among the 260 in iduals with a potentially epileptogenic brain imaging abnormality, 34% reported prior seizures. Of 475 in iduals with no abnormality, 50% reported prior seizures (p 50 years had lower odds compared to those 18-30 years (OR 0.5, p = 0.01). A history of prior seizures is less common in patients with newly diagnosed focal epilepsy associated with antecedent stroke or high-grade tumor than in those without a lesion, and is also less common in older in iduals. These findings may be related to age, biological mechanisms or aspects of diagnosis and assessment of these events.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-03-2020
Abstract: The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 in iduals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. We identified 369 nominally genome-wide significant loci ( P 5 × 10 −8 ) associated with cortical structure in a discovery s le of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P 8.3 × 10 −10 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain s les, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on in idual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY (C) M. R. GLASS
Publisher: Mary Ann Liebert Inc
Date: 12-2003
DOI: 10.1089/109493103322725405
Abstract: Post-surgical pain has been consistently reported in pediatrics as being difficult to manage and limiting to surgical outcomes. Pain management of children is not ideal, and some children unable to tolerate traditional pharmacological agents. Virtual reality (VR) is a new and promising form of non-pharmacologic analgesia. This case study explored the use of VR analgesia with a 16-year-old patient with cerebral palsy participating in a twice-daily physiotherapy program following Single Event Multi-Level Surgery. Over 6 days, the patient spent half of his physiotherapy sessions using VR and the other half without (order randomized). Traditional pharmacological pain management was administered throughout the trial. Using a subjective pain scale (five faces denoting levels of pain), the patient's overall pain ratings whilst in the VR (experimental) condition were 41.2% less than those in the no-VR (control) condition. This case report provides the first evidence that VR may serve as a powerful non-pharmacologic analgesic for children following surgery.
Publisher: Wiley
Date: 15-02-2023
DOI: 10.1002/EPI4.12693
Abstract: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti‐seizure medication (NaM‐ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. This retrospective, nested case–control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM‐ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. Proportions of cases and controls prescribed lamotrigine ( P = 0.166), one NaM‐ASM ( P = 0.80), or ≥2NaM‐ASMs ( P = 0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR] = 0.56 P = 0.054), one NaM‐ASM (aHR = 0.8 P = 0.588) or ≥2 NaM‐ASMs (aHR = 0.49 P = 0.139) at EMU admission were not at increased SUDEP risk up to 16 years following admission. Active tonic–clonic seizures at EMU admission associated with ‐fold SUDEP risk, irrespective of lamotrigine (aHR = 2.24 P = 0.031) or NaM‐ASM use (aHR = 2.25 P = 0.029). Sensitivity analyses accounting for incomplete ASM data at follow‐up suggest undetected changes to ASM use are unlikely to alter our results. This study provides additional evidence that lamotrigine and other NaM‐ASMs are unlikely to be associated with an increased long‐term risk of SUDEP, up to 16 years post‐EMU admission.
Publisher: IEEE
Date: 10-2009
Publisher: ACM
Date: 14-02-2021
Publisher: Springer Science and Business Media LLC
Date: 25-07-2016
Publisher: Oxford University Press (OUP)
Date: 04-2002
Publisher: Association for Computing Machinery (ACM)
Date: 12-2010
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 02-2023
Publisher: Wiley
Date: 23-10-2020
DOI: 10.1111/EPI.16729
No related grants have been discovered for Bruce Thomas.