ORCID Profile
0000-0001-8759-6748
Current Organisation
University of Adelaide
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-08-2014
Publisher: Elsevier BV
Date: 2012
Publisher: Rynnye Lyan Resources
Date: 03-07-2019
Publisher: Wiley
Date: 29-01-2010
DOI: 10.1111/J.1528-1167.2009.02317.X
Abstract: We identified a patient with electrophysiologically verified neonatal long QT syndrome (LQTS) and neonatal seizures in the presence of a controlled cardiac rhythm. To find a cause for this unusual combination of phenotypes, we tested the patient for mutations in seven ion channel genes associated with either LQTS or benign familial neonatal seizures (BFNS). Comparative genome hybridization (CGH) was done to exclude the possibility of a contiguous gene syndrome. No mutations were found in the genes (KCNQ2, KCNQ3) associated with BFNS, and CGH was negative. A previously described mutation and a known rare variant were found in the LQTS-associated genes SCN5A and KCNE2. Both are expressed in the brain, and although mutations have not been associated with epilepsy, we propose a pathophysiologic mechanism by which the combination of molecular changes may cause seizures.
Publisher: Rynnye Lyan Resources
Date: 26-02-2020
DOI: 10.26656/FR.2017.4(3).418
Abstract: This research was aimed to evaluate the quality of long-jawed mackerel fish flour, resulted from four different treatments, based on specific criteria, namely water content, protein, fat and calcium. This was a True Experimental Design Post test-Only Control Design research with a completely randomized design (CRD). The experimental method consisted of four treatments. Data regarding protein content was obtained by using Kjehdal method, water content using oven method, fat content using Soxhlet while calcium content using the Atomic Absorption Spectrophotometry method. The research data were processed statistically for ANOVA (Analysis of Variance) and continued with the LSD (Least Significance Different) test. ANOVA test analysis results showed that the water content (p = 0.02), protein (p = 0.00), fat (p = 0.00), and calcium (p = 0.00) significantly different between the four treatments. The fish flour produced meets quality standard based on Indonesian standard of fish flour registered by number Indonesian National Standard (SNI) 2715: 2013 in terms of water content, protein and fat.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.PEDIATRNEUROL.2009.05.009
Abstract: Potassium channel subunits encoded by several genes of the KCNQ family underlie the M-current. Specifically, KCNQ2 and KCNQ3 play a major role at most neuronal sites. Mutations in KCNQ2 or KCNQ3 that reduce the M-current are responsible for benign familial neonatal seizures, a rare autosomal dominant idiopathic epilepsy of the newborn. The aim of this study was to investigate a single family with benign familial neonatal seizures for mutations in KCNQ genes and to analyze the association of mutation type with disease prognosis. A family in which members in several generations had signs and symptoms compatible with a diagnosis of benign familial neonatal seizures had DNA testing with single-stranded conformation polymorphism analysis for various mutations known to cause benign familial neonatal seizures. A novel KCNQ2 mutation c.63-66delGGTG (p.K21fsX40), causing a framework shift and early chain termination, was identified in the affected family members. In all cases, there was complete remission of the seizures after the neonatal period. This KCNQ2 mutation has implications for diagnosis and prognosis of familial neonatal seizures. Its presence suggests a benign disease with good prognosis and its identification can spare patients and physicians the need for extensive investigations or prolonged therapy.
Publisher: Virtus Interpress
Date: 2007
DOI: 10.22495/COCV5I1P6
Abstract: The ASX Corporate Governance Council’s Principles of Good Corporate Governance and Best Practice Recommendations (Released March 2003) has been criticised as unduly prescriptive and potentially costly, particularly for small firms. Using a s le of 518 West Australia and Queensland based ASX listed companies, we show that small companies are less likely to comply with several of the ASX recommendations than large companies. We also show that some agency controls largely ignored in the recommendations, such as substantial shareholders, may substitute for some of the corporate governance mechanisms recommended by the ASX. We also consider the effect that the extent of director interlocking may have on compliance, and find that it is minimal. Overall, the results of this research provide a timely reminder that when it comes to corporate governance, one size does not fit all.
Publisher: Wiley
Date: 21-03-2004
DOI: 10.1002/ANA.20029
Abstract: We recently reported mutations in the sodium channel gene SCN2A in two families with benign familial neonatal-infantile seizures (BFNISs). Here, we aimed to refine the molecular-clinical correlation of SCN2A mutations in early childhood epilepsies. SCN2A was analyzed in 2 families with probable BFNIS, 9 with possible BFNIS, 10 with benign familial infantile seizures, and in 93 additional families with various early childhood epilepsies. Mutations effecting changes in conserved amino acids were found in two of two probable BFNIS families, in four of nine possible BFNIS families, and in none of the others. Our eight families had six different SCN2A mutations one mutation (R1319Q) occurred in three families. BFNIS is an autosomal dominant disorder presenting between day 2 and 7 months (mean, 11.2 +/- 9.2 weeks) with afebrile secondarily generalized partial seizures neonatal seizures were not seen in all families. The frequency of seizures varied some in iduals had only a few attacks without treatment and others had clusters of many per day. Febrile seizures were rare. All cases remitted by 12 months. Ictal recordings in four subjects showed onset in the posterior quadrants. SCN2A mutations appear specific for BFNIS the disorder can now be strongly suspected clinically and the families can be given an excellent prognosis.
Publisher: Elsevier BV
Date: 2001
DOI: 10.1086/316946
Publisher: BMJ
Date: 14-09-2007
Publisher: Wiley
Date: 14-08-2007
DOI: 10.1002/ANA.21169
Abstract: The relationship between genetic variation in the T-type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which CACNA1H variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures. Exons 3 to 35 of CACNA1H were screened for variants in 240 epilepsy patients (167 unrelated) and 95 control subjects by single-stranded conformation analysis followed by direct sequencing. Cascade testing of families was done by sequencing or single-stranded conformation analysis. Selected variants were introduced into the CACNA1H protein by site-directed mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired. More than 100 variants were detected, including 19 novel variants leading to amino acid changes in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy. Electrophysiological analysis of 11 variants showed that 9 altered channel properties, generally in ways that would be predicted to increase calcium current. Variants in CACNA1H that alter channel properties are present in patients with various generalized epilepsy syndromes. We propose that these variants contribute to an in idual's susceptibility to epilepsy but are not sufficient to cause epilepsy on their own. The genetic architecture is dominated by rare functional variants therefore, CACNA1H would not be easily identified as a susceptibility gene by a genome-wide case-control study seeking a statistical association.
Publisher: Elsevier BV
Date: 09-2002
Publisher: Wiley
Date: 09-2010
DOI: 10.1111/J.1528-1167.2010.02558.X
Abstract: A family with dominantly inherited neonatal seizures and intellectual disability was atypical for neonatal and infantile seizure syndromes associated with potassium (KCNQ2 and KCNQ3) and sodium (SCN2A) channel mutations. Microsatellite markers linked to KCNQ2, KCNQ3, and SCN2A were examined to exclude candidate locations, but instead revealed a duplication detected by observation of three alleles for two markers flanking SCN2A. Characterization revealed a 1.57 Mb duplication at 2q24.3 containing eight genes including SCN2A, SCN3A, and the 3¢ end of SCN1A. The duplication was partially inverted and inserted within or near SCN1A, probably affecting the expression levels of associated genes, including sodium channels. Rare or unique microchromosomal copy number mutations might underlie familial epilepsies that do not fit within the clinical criteria for the established syndromes.
Publisher: Wiley
Date: 10-07-2012
DOI: 10.1111/J.1528-1167.2012.03585.X
Abstract: We aimed to refine the phenotypic spectrum and map the causative gene in two families with familial focal epilepsy with variable foci (FFEVF). A new five-generation Australian FFEVF family (A) underwent electroclinical phenotyping, and the original four-generation Australian FFEVF family (B) (Ann Neurol, 44, 1998, 890) was re-analyzed, including new affected in iduals. Mapping studies examined segregation at the chromosome 22q12 FFEVF region. In family B, the original whole genome microsatellite data was reviewed. Five subjects in family A and 10 in family B had FFEVF with predominantly awake attacks and active EEG studies with a different phenotypic picture from other families. In family B, reanalysis excluded the tentative 2q locus reported. Both families mapped to chromosome 22q12. Our results confirm chromosome 22q12 as the solitary locus for FFEVF. Both families show a subtly different phenotype to other published families extending the clinical spectrum of FFEVF.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2012
DOI: 10.1038/NG.2440
Abstract: We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies.
Publisher: Wiley
Date: 02-05-2007
Publisher: Elsevier BV
Date: 06-1997
Publisher: BMJ
Date: 03-2004
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: Wiley
Date: 03-2011
Publisher: SAGE Publications
Date: 23-03-2012
Abstract: Benign neonatal sleep myoclonus is an uncommon, nonepileptic disorder characterized by myoclonic jerks appearing in the neonatal period that occur predominantly during sleep. Although self-limiting, the disorder is frequently confused with epileptic neonatal seizures. A few familial cases have been reported however the genetics has not been studied. We ascertained 3 families with 2 or more affected in iduals and analyzed the pedigrees. We used microsatellite markers to determine if the disorder was possibly linked to KCNQ2 or KCNQ3, the 2 genes that cause most cases of benign familial neonatal seizures, a disorder that it could be easily confused with. The 3 pedigrees, including one with 4 affected in iduals, were suggestive of autosomal dominant inheritance. The loci for KCNQ2 and KCNQ3 were excluded in the 2 larger families. We conclude that benign neonatal sleep myoclonus can show autosomal dominant inheritance and is not allelic with benign familial neonatal seizures.
Publisher: Wiley
Date: 12-2008
DOI: 10.1111/J.1528-1167.2008.01652.X
Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a relatively benign epilepsy syndrome with few comorbidities. Here we describe two families with unusually severe ADNFLE, with associated psychiatric, behavioral, and cognitive features. Detailed clinical data on 17 affected in iduals were obtained, and genotyping of microsatellite markers, linkage analysis, and sequencing of candidate genes was performed. The severe ADNFLE phenotype in these families was often refractory to treatment, with status epilepticus occurring in 24% of subjects. Psychiatric or behavioral disorders occurred in 53%, with intellectual disability in 24%, and developmental regression in two in iduals. No mutations were identified in alpha4, alpha2, or beta2 nAChR subunits. In one family there was evidence of linkage to a region of 15q24 without nAChR subunit genes. In conclusion, severe ADNFLE has significant medical, psychiatric, and intellectual morbidity. The molecular basis of severe ADNFLE is unknown but may involve non-nAChR-related mechanisms.
Publisher: Wiley
Date: 27-04-2005
DOI: 10.1111/J.1528-1167.2005.49004.X
Abstract: gamma-Aminobutyric acid (GABA)-receptor genes are prime candidates for a role in seizure susceptibility. An association between the c.1465G-->A variant in the GABA(B) receptor 1 gene (GABBR1) and susceptibility to temporal lobe epilepsy (TLE) has been reported in an Italian cohort. We sought to replicate this association in an independent Australian cohort. The 234 patients with TLE and 164 healthy controls were genotyped for the c.1465G-->A variant, by using inclusion criteria identical to those of the first study. The c.1465G-->A variant was found in one TLE patient and one control subject. Genotype and allele frequencies did not differ between groups. We did not replicate the reported associations between the c.1465G-->A variant and susceptibility to TLE. We suggest that the initial positive association may be due to undetected population stratification the importance of genomic control is emphasized. Population-specific effects also may play a role, and we highlight the need to demonstrate an in vitro functional effect to give biologic meaning to any proposed association.
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.NEUROSCIENCE.2007.05.038
Abstract: Two novel mutations (R85C and R85H) on the extracellular immunoglobulin-like domain of the sodium channel beta1 subunit have been identified in in iduals from two families with generalized epilepsy with febrile seizures plus (GEFS+). The functional consequences of these two mutations were determined by co-expression of the human brain NaV1.2 alpha subunit with wild type or mutant beta1 subunits in human embryonic kidney (HEK)-293T cells. Patch cl studies confirmed the regulatory role of beta1 in that relative to NaV1.2 alone the NaV1.2+beta1 currents had right-shifted voltage dependence of activation, fast and slow inactivation and reduced use dependence. In addition, the NaV1.2+beta1 current entered fast inactivation slightly faster than NaV1.2 channels alone. The beta1(R85C) subunit appears to be a complete loss of function in that none of the modulating effects of the wild type beta1 were observed when it was co-expressed with NaV1.2. Interestingly, the beta1(R85H) subunit also failed to modulate fast kinetics, however, it shifted the voltage dependence of steady state slow inactivation in the same way as the wild type beta1 subunit. Immunohistochemical studies revealed cell surface expression of the wild type beta1 subunit and undetectable levels of cell surface expression for both mutants. The functional studies suggest association of the beta1(R85H) subunit with the alpha subunit where its influence is limited to modulating steady state slow inactivation. In summary, the mutant beta1 subunits essentially fail to modulate alpha subunits which could increase neuronal excitability and underlie GEFS+ pathogenesis.
Publisher: Elsevier BV
Date: 05-2007
Publisher: Wiley
Date: 26-01-2004
DOI: 10.1111/J.0013-9580.2004.04303.X
Abstract: We describe seven Italian families with generalized epilepsy with febrile seizures plus (GEFS+), in which mutations of SCN1A, SCN1B, and GABRG2 genes were excluded and compare their clinical spectrum with that of previously reported GEFS+ with known mutations. We performed a clinical study of seven families (167 in iduals). The molecular study included analysis of polymerase chain reaction (PCR) fragments of SCN1A and SCN1B exons by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of GABRG2 in all families. We excluded SCN1A, SCN1B, and GABRG2 genes with linkage analysis in a large pedigree and directly sequenced SCN2A in a family with neonatal-infantile seizures onset. We compared the epilepsy phenotypes observed in our families with those of GEFS+ families harboring mutations of SCN1A, SCN1B, and GABRG2 and estimated the percentage of mutations of these genes among GEFS+ cases by reviewing all published studies. Inheritance was autosomal dominant with 69% penetrance. Forty-one in iduals had epilepsy: 29 had a phenotype consistent with GEFS+ seven had idiopathic generalized epilepsy (IGE) in three, the epilepsy type could not be classified and two were considered phenocopies. Clinical phenotypes included FS+ (29.2%), FS (29.2%), IGE (18.2%), FS+ with focal seizures (13%) or absence seizures (2.6%), and FS with absence seizures (2.6%). Molecular study of SCN1A, SCN2A, SCN1B, and GABRG2 did not reveal any mutation. Results of our study and literature review indicate that mutations of SCN1A, SCN2A, SCN1B, and GABRG2 in patients with GEFS+ are rare. The most frequently observed phenotypes matched those reported in families with mutations of the SCN1A, SCN1B, and GABRG2 genes. IGE and GEFS+ may overlap in some families, suggesting a shared genetic mechanism. The observation that 13% of affected in iduals had focal epilepsy confirms previously reported rates and should prompt a reformulation of the "GEFS+" concept to include focal epileptogenesis.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 02-08-2016
DOI: 10.1002/AJMG.A.37853
Abstract: Recessive mutations in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome, a phenotype characterized by neonatal microcephaly, hypertonia, and refractory epilepsy with premature death by age 2 years. Recently, attenuated disease variants have been described, suggesting that a wider clinical spectrum of BRAT1-associated neurodegeneration exists than was previously thought. Here, we report two affected siblings with compound heterozygous truncating mutations in BRAT1 and intra-familial phenotypic heterogeneity, with a less severe disease course in the female sibling. This phenotypic variability should be taken into account when treating patients with BRAT1-associated neurodegenerative disease. Mildly affected in iduals with BRAT1 mutations show that BRAT1 must be considered as a cause in childhood refractory epilepsy and microcephaly with survival beyond infancy. © 2016 Wiley Periodicals, Inc.
Publisher: Wiley
Date: 15-05-2015
DOI: 10.1111/EPI.13020
Abstract: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. Detailed clinical data were collected from 36 families comprising two or more in iduals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE) 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of in iduals with KCNQ2 mutations later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability a molecular lesion was identified in two the other family remains unsolved. Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.
Publisher: Springer Science and Business Media LLC
Date: 04-2007
DOI: 10.1016/J.NURT.2007.01.009
Abstract: Approximately 70% of all patients with epilepsy lack an obvious extraneous cause and are presumed to have a predominantly genetic basis. Both familial and de novo mutations in neuronal voltage-gated and ligand-gated ion channel subunit genes have been identified in autosomal dominant epilepsies. However, patients with dominant familial mutations are rare and the majority of idiopathic epilepsy is likely to be the result of polygenic susceptibility alleles (complex epilepsy). Data on the identity of the genes involved in complex epilepsy is currently sparse but again points to neuronal ion channels. The number of genes and gene families associated with epilepsy is rapidly increasing and this increase is likely to escalate over the coming years with advances in mutation detection technologies. The genetic heterogeneity underlying idiopathic epilepsy presents challenges for the rational selection of therapies targeting particular ion channels. Too little is currently known about the genetic architecture of the epilepsies, and genetic testing for the known epilepsy genes remains costly. Pharmacogenetic studies have yet to explain why 30% of patients do not respond to the usual antiepileptic drugs. Despite this, the recognition that the idiopathic epilepsies are a group of channelopathies has, to a limited extent, explained the therapeutic action of the common antiepileptic drugs and has assisted clinical diagnosis of some epilepsy syndromes.
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.MCN.2007.03.003
Abstract: Seizure susceptibility is high in human infants compared to adults, presumably because of developmentally regulated changes in neural excitability. Benign familial neonatal-infantile seizures (BFNIS), characterized by both early onset and remission, are caused by mutations in the gene encoding a human sodium channel (NaV1.2). We analyzed neonatal and adult splice forms of NaV1.2 with a BFNIS mutation (L1563V) in human embryonic kidney cells. Computer modeling revealed that neonatal channels are less excitable than adult channels. Introduction of the mutation increased excitability in the neonatal channels to a level similar to adult channels. By contrast, the mutation did not affect the adult channel variant. This "adult-like" increased excitability is likely to be the mechanism underlying BFNIS in infants with this mutation. More generally, developmentally regulated NaV1.2 splicing may be one mechanism that counters the normally high excitability of neonatal neurons and helps to reduce seizure susceptibility in normal human infants.
Publisher: Wiley
Date: 26-03-2007
DOI: 10.1111/J.1528-1167.2007.01049.X
Abstract: Mutations of the sodium channel subunit gene SCN2A have been described in families with benign familial neonatal-infantile seizure (BFNIS). We describe two large families with BFNIS and novel SCN2A mutations. The families had 12 and 9 affected in iduals, respectively, with phenotypes consistent with BFNIS. Two mutations were discovered in SCN2A (E430Q I1596S). Both families had in iduals with neonatal onset but the typical age of onset was in the early infantile period (mean 3.0 months). One mutation positive in idual, with an otherwise typical clinical pattern, had seizures beginning at 13 months. Two in iduals with SCN2A mutations were identified with seizures in later life. In each family a single in idual with infantile seizures was mutation negative and thus represented phenocopies. This study extends the age range of presentation of BFNIS, confirms that neonatal and early infantile onsets are characteristic, and emphasizes the role of molecular diagnosis to confirm the etiology.
Publisher: BMJ
Date: 23-01-2013
DOI: 10.1136/JMEDGENET-2012-101406
Abstract: Mutations in the gene PRRT2 encoding proline-rich transmembrane protein 2 have recently been identified as the cause of three clinical entities: benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis (ICCA) syndrome, and paroxysmal kinesigenic dyskinesia (PKD). Patients with ICCA have both BFIE and PKD and families with ICCA may contain in iduals who exhibit all three phenotypes. These three phenotypes were all mapped by linkage analyses to the pericentromeric region of chromosome 16, and were hypothesised to have the same genetic basis due to the co-occurrence of the disorders in some families. Despite considerable effort, the gene or genes for BFIE, ICCA, and PKD were not identified for many years after the linkage region was identified. Mutations in the gene PRRT2 were identified in several Chinese families with PKD, suggesting that the gene may also be responsible for ICCA and BFIE in families linked to the chromosome 16 locus. This was demonstrated to be the case, with the majority of families with ICCA and BFIE found to have PRRT2 mutations. The vast majority of these mutations are truncating and are predicted to lead to haploinsufficiency. PRRT2 is a largely uncharacterised protein. It is expressed in the brain and has been demonstrated to interact with SNAP-25, a component of the molecular machinery involved in the release of neurotransmitters at the presynaptic membrane. Therefore, the PRRT2 protein may play a role in this process. However, the molecular mechanisms underlying the remarkable pleiotropy associated with PRRT2 mutations have still to be determined.
Publisher: Public Library of Science (PLoS)
Date: 20-03-2015
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/917565
Abstract: Sixty cases of febrile seizures from a Chinese cohort had previously been reported with a strong association between variants in the seizure-related ( SEZ ) 6 gene and febrile seizures. They found a striking lack of genetic variation in their controls. We found genetic variation in SEZ6 at similar levels at the same DNA sequence positions in our 94 febrile seizure cases as in our 96 unaffected controls. Two of our febrile seizure cases carried rare variants predicted to have damaging consequences. Combined with some of the variants from the Chinese cohort, these data are compatible with a role for SEZ6 as a susceptibility gene for febrile seizures. However, the polygenic determinants underlying most cases of febrile seizures with complex inheritance remain to be determined.
Publisher: BMJ
Date: 06-01-2016
DOI: 10.1136/JMEDGENET-2015-103508
Abstract: Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date. Mutations in KCNT1 have also been described in eight unrelated cases of sporadic and familial autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients have a high frequency of associated intellectual disability and psychiatric features. Two mutations in KCNT1 have been associated with both ADNFLE and MMFSI, suggesting that the genotype-phenotype relationship for KCNT1 mutations is not straightforward. Mutations have also been described in several patients with infantile epileptic encephalopathies other than MMFSI. Notably, all mutations in KCNT1 described to date are missense mutations, and electrophysiological studies have shown that they result in increased potassium current. Together, these genetic and electrophysiological studies raise the possibility of delivering precision medicine by treating patients with KCNT1 mutations using drugs that alter the action of potassium channels to specifically target the biological effects of their disease-causing mutation. Such trials are now in progress. Better understanding of the mechanisms underlying KCNT1-related disease will produce further improvements in treatment of the associated severe seizure disorders.
Publisher: Wiley
Date: 2012
DOI: 10.1002/ANA.22644
Abstract: KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists. We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail. We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80 10%) 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved. KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.
Publisher: EMBO
Date: 25-03-2014
Publisher: Wiley
Date: 22-03-2004
DOI: 10.1002/ANA.20028
Publisher: Wiley
Date: 09-2011
Publisher: Springer Science and Business Media LLC
Date: 17-11-2015
DOI: 10.1038/NG.3144
Publisher: Wiley
Date: 14-04-2014
DOI: 10.1002/ANA.24126
Abstract: We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 in idual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway.
Publisher: Wiley
Date: 05-2004
Publisher: Wiley
Date: 13-02-2016
DOI: 10.1002/ANA.24580
Abstract: Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination-known as infantile convulsions and paroxysmal choreoathetosis (ICCA)-are related autosomal dominant diseases. PRRT2 (proline-rich transmembrane protein 2 gene) has been identified as the major gene in all 3 conditions, found to be mutated in 80 to 90% of familial and 30 to 35% of sporadic cases. We searched for the genetic defect in PRRT2-negative, unrelated families with BFIS or ICCA using whole exome or targeted gene panel sequencing, and performed a detailed cliniconeurophysiological workup. In 3 families with a total of 16 affected members, we identified the same, cosegregating heterozygous missense mutation (c.4447G>A p.E1483K) in SCN8A, encoding a voltage-gated sodium channel. A founder effect was excluded by linkage analysis. All in iduals except 1 had normal cognitive and motor milestones, neuroimaging, and interictal neurological status. Fifteen affected members presented with afebrile focal or generalized tonic-clonic seizures during the first to second year of life 5 of them experienced single unprovoked seizures later on. One patient had seizures only at school age. All patients stayed otherwise seizure-free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or "shivering" attacks, triggered by stretching, motor initiation, or emotional stimuli. In 1 case, we recorded typical PKD spells by video-EEG-polygraphy, documenting a cortical involvement. Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical-genetic spectrum of combined epileptic and dyskinetic syndromes.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Sarah Heron.