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Samuel F Berkovic

Publications and source records attributed to Samuel F Berkovic.

At least 19 recordsLinked to original sources
PubMed2026

Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.

Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analyzed surgical tissue from 25 consecutive cases recruited from adult and pediatric epilepsy surgery programs. We performed high-depth sequencing of lesional tissue, validated somatic variants using droplet digital PCR or amplicon sequencing, and investigated genotype-phenotype correlations. A pathogenic or likely pathogenic variant was detected in 64% (n = 16/25) of cases. Of these, five cases with FCDIIa or FCDIIb had germline variants in NPRL3 (n = 3) or DEPDC5 (n = 2). Somatic variants were identified in 44% (n = 11/25) of cases. The genetic yield for FCDIIb was 77% of cases having a pathogenic mTOR pathway variant detected (n = 10/13), and for FCDIIa 66% (n = 6/9). High depth sequencing approaches allowed detection of somatic variants with very low (down to 0.4%) variant allele fractions (VAFs). No pathogenic variants were detected in 3 cases with FCDI. 62% (n = 15/24) of the cases with ≥12 months follow up experienced a favourable seizure outcome (Engel 1-2) following surgery. Of note, n = 9 patients required repeat surgery to resect residual dysplasia. Determining a genetic diagnosis reveals aetiology and paves the way to precision therapies that may benefit those with FCD who do not respond to current treatments.

Humans↗
PubMed2006

What happens now? Ongoing outcome after post-temporal lobectomy seizure recurrence.

We studied outcome subsequent to the initial post-temporal lobectomy seizure recurrence (n = 202) or remission. Two years after recurrence, there was 74% (95% CI 67% to 79%) probability of further seizures. Two years after a 2-year seizure remission, there was 68% (95% CI 52% to 79%) probability of remaining seizure-free (n = 50). Remission after seizures had a significantly poorer outcome than an equivalent period of complete seizure freedom after surgery. Implications for outcome classification are discussed.

Epilepsy↗
PubMed2006

Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations.

SCN1B, the gene encoding the sodium channel beta 1 subunit, was the first gene identified for generalized epilepsy with febrile seizures plus (GEFS+). Only three families have been published with SCN1B mutations. Here, we present four new families with SCN1B mutations and characterize the associated phenotypes. Analysis of SCN1B was performed on 402 individuals with various epilepsy syndromes. Four probands with missense mutations were identified. Detailed electroclinical phenotyping was performed on all available affected family members including quantitative MR imaging in those with temporal lobe epilepsy (TLE). Two new families with the original C121W SCN1B mutation were identified; novel mutations R85C and R85H were each found in one family. The following phenotypes occurred in the six families with SCN1B missense mutations: 22 febrile seizures, 20 febrile seizures plus, five TLE, three other GEFS+ phenotypes, two unclassified and ten unaffected individuals. All individuals with confirmed TLE had the C121W mutation; two underwent temporal lobectomy (one with hippocampal sclerosis and one without) and both are seizure free. We confirm the role of SCN1B in GEFS+ and show that the GEFS+ spectrum may include TLE alone. TLE with an SCN1B mutation is not a contraindication to epilepsy surgery.

Adolescent↗
PubMed2006

A GABAA receptor mutation causing generalized epilepsy reduces benzodiazepine receptor binding.

Understanding the consequences of newly discovered single gene mutations causing human epilepsy has the potential to yield new insights into the underlying mechanisms of this disorder. A mutation of the gamma2 subunit of the GABA(A) receptor, which substitutes glutamine for arginine at position 43 (R43Q) has been found in a familial generalized epilepsy. We tested the hypothesis that individuals affected by the GABRG2(R43Q) mutation have reduced binding to the GABA(A) receptor complex using positron emission tomography (PET) and the benzodiazepine receptor ligand [(11)C]-flumazenil. Fourteen subjects with the GABRG2(R43Q) mutation and 20 controls were studied. Benzodiazepine receptor binding was reduced in subjects with the mutation (mean whole brain binding potential for [(11)C]-flumazenil: GABA(A) mutation 0.66+/-0.1; controls 0.89+/-0.1; P<0.003). The greatest change in benzodiazepine binding occurred anteriorly, with peak differences in insular and anterior cingulate cortices revealed by statistical parametric mapping. Our findings provide in vivo evidence of reduced benzodiazepine receptor binding in subjects with the mutation. As synaptic inhibition in the human brain is largely mediated by the GABA(A) receptor, these findings are likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.

Adult↗
PubMed2006

Febrile seizures: traffic slows in the heat.

Febrile seizures, which occur in young children, have long been known to have a major inherited component. Mutations in some genes that encode sodium channel and GABA(A) receptor subunits have been found in a few families affected by febrile seizures. These mutations account only for a minority of cases, and much remains to be learnt about the molecular architecture of febrile seizures. A rare inherited cause--a mutation in the GABA(A) receptor subunit GABRG2 gene--has been recently shown to cause a temperature-dependent intracellular trafficking defect. This is an important step in unravelling the molecular pathogenesis of this common childhood disorder.

Biological Transport↗
PubMed2006

SRPX2 mutations in disorders of language cortex and cognition.

The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.

Adult↗
PubMed2006

Distinguishing sleep disorders from seizures: diagnosing bumps in the night.

BACKGROUND: Abnormal paroxysmal events in sleep may be parasomnias or epileptic seizures. In nocturnal frontal lobe epilepsy (NFLE), the unusual seizure features often lead to diagnostic confusion with nonepileptic parasomnias; video-electroencephalography monitoring is usually required to make the diagnosis. OBJECTIVE: To examine the reliability of the clinical history in diagnosing NFLE, using the Frontal Lobe Epilepsy and Parasomnias (FLEP) scale. DESIGN: The FLEP scale, comprising specific questions reflecting the diagnostic features of NFLE and parasomnias, was developed by an expert panel following review of the literature. It was then validated in a sample of individuals with firmly diagnosed nocturnal events. SETTING: Patients were recruited after appropriate diagnostic workup in tertiary sleep and epilepsy referral centers in Melbourne, Australia. PARTICIPANTS: Sixty-two patients (45 males) [corrected] with paroxysmal nocturnal events. Intervention Two independent interviews were conducted in each case, with the patient and a witness, by researchers blinded to the diagnosis. MAIN OUTCOME MEASURE: The diagnosis obtained from scores on the FLEP scale was compared with the confirmed diagnosis in each patient. RESULTS: Nocturnal frontal lobe epilepsy was correctly diagnosed from the FLEP score in 31 of 31 patients, with a sensitivity of 1.0 (95% confidence interval [CI], 0.85-1.00), specificity of 0.90 (95% CI, 0.73-0.97), positive predictive value of 0.91 (95% CI, 0.75-0.97), and negative predictive value of 1.00 (95% CI, 0.85-1.00). CONCLUSIONS: A diagnosis of NFLE can be made reliably using the clinical features identified in the FLEP scale. This may reduce the requirement for tertiary referral and extensive inpatient monitoring.

Aged↗
PubMed2006

Human epilepsies: interaction of genetic and acquired factors.

Epilepsies, once regarded as due to demoniacal possession, can have both genetic and acquired causes, with interaction of these factors in many cases. To date, nearly all the genes discovered to be involved in human epilepsies encode subunits of ion channels, both voltage-gated and ligand-gated. Established acquired causes include serious brain trauma, stroke, tumours and infective lesions. Thus, in terms of exploring the neurobiology of "nature and nurture" in disease, the epilepsies are an excellent paradigm. Here, we review the evidence and discuss the possibility that ion channels are a common biological substrate for both genetic and acquired epilepsies. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).

Brain Neoplasms↗
PubMed2006

Update on pharmacogenetics in epilepsy: a brief review.

Recent developments in the pharmacogenetics of antiepileptic drugs provide new prospects for predicting the efficacy of treatment and potential side-effects. Epilepsy is a common, serious, and treatable neurological disorder, yet current treatment is limited by high rates of adverse drug reactions and lack of complete seizure control in a significant proportion of patients. The disorder is especially suitable for pharmacogenetic investigation because treatment response can be quantified and side-effects can be assessed with validated measures. Additionally, there is substantial knowledge of the pharmacodynamics and kinetics of antiepileptic drugs, and some candidate genes implicated in the disorder have been identified. However, recent studies of the association of particular genes and their genetic variants with seizure control and adverse drug reactions have not provided unifying conclusions. This article reviews the published work and summarises the state of research in this area. Future directions for research and the application of this technology to the clinical practice of individualising treatment for epilepsy are discussed.

Anticonvulsants↗
PubMed2006

De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study.

BACKGROUND: Vaccination, particularly for pertussis, has been implicated as a direct cause of an encephalopathy with refractory seizures and intellectual impairment. We postulated that cases of so-called vaccine encephalopathy could have mutations in the neuronal sodium channel alpha1 subunit gene (SCN1A) because of a clinical resemblance to severe myoclonic epilepsy of infancy (SMEI) for which such mutations have been identified. METHODS: We retrospectively studied 14 patients with alleged vaccine encephalopathy in whom the first seizure occurred within 72 h of vaccination. We reviewed the relation to vaccination from source records and assessed the specific epilepsy phenotype. Mutations in SCN1A were identified by PCR amplification and denaturing high performance liquid chromatography analysis, with subsequent sequencing. Parental DNA was examined to ascertain the origin of the mutation. FINDINGS: SCN1A mutations were identified in 11 of 14 patients with alleged vaccine encephalopathy; a diagnosis of a specific epilepsy syndrome was made in all 14 cases. Five mutations predicted truncation of the protein and six were missense in conserved regions of the molecule. In all nine cases where parental DNA was available the mutations arose de novo. Clinical-molecular correlation showed mutations in eight of eight cases with phenotypes of SMEI, in three of four cases with borderline SMEI, but not in two cases with Lennox-Gastaut syndrome. INTERPRETATION: Cases of alleged vaccine encephalopathy could in fact be a genetically determined epileptic encephalopathy that arose de novo. These findings have important clinical implications for diagnosis and management of encephalopathy and, if confirmed in other cohorts, major societal implications for the general acceptance of vaccination.

Adolescent↗
PubMed2006

Analyzing the etiology of benign rolandic epilepsy: a multicenter twin collaboration.

PURPOSE: Benign rolandic epilepsy (BRE) is considered a genetically determined idiopathic partial epilepsy. We analyzed a large sample of twins from four international twin registers to probe the genetics of BRE. We also aim to synthesize the apparently conflicting family and twin data into a model of BRE etiology. METHODS: Large population-based twin registries of epilepsies from Odense (Denmark), Richmond, Virginia (United States), and Oslo (Norway) were reviewed for BRE cases and added to our Australian twin data. Diagnosis of classic BRE was based on electroclinical criteria with normal neurologic development. Cases with a compatible electroclinical picture but abnormal neurologic development were termed non-classic BRE. RESULTS: Eighteen twin pairs were identified (10 monozygous; eight dizygous) of whom at least one twin was diagnosed with classic BRE among a total sample of 1,952 twin pairs validated for seizures, and all were discordant for BRE. The estimated monozygous pairwise concordance for BRE in this sample was 0.0 [95% confidence interval (CI), 0.0-0.3). Four twin pairs (one monozygous, three dizygous) had non-classic BRE, and all co-twins had seizures. CONCLUSIONS: The twin data showing an absence of any concordant twin pairs with classic BRE suggest that noninherited factors are of major importance in BRE. Modelling the data shows that the familial occurrence of centrotemporal spikes makes only a minor contribution to the familial aggregation of BRE. Genetic factors are probably more important in non-classic BRE. The etiology and mode(s) of inheritance of BRE are much more complicated than initially conceptualized.

Adult↗
PubMed2006

Paroxysmal motor disorders of sleep: the clinical spectrum and differentiation from epilepsy.

The diagnosis of paroxysmal events in sleep represents a significant challenge for the clinician, with the distinction of nocturnal epilepsy from nonepileptic sleep disorders often the primary concern. Diagnostic error or uncertainty is not uncommon in this situation, particularly with respect to nocturnal frontal lobe epilepsy (NFLE), which has a variable and often unusual presentation. Such errors can be minimized if the range of nonepileptic disorders with motor activity in sleep is fully appreciated. Here we review these disorders, before discussing the important clinical and electrographic features that allow their accurate differentiation from seizures. Particular emphasis is placed on the differentiation of nocturnal frontal lobe epilepsy from non-rapid eye movement (NREM) arousal disorders and other parasomnias. The value of recording episodes with video EEG polysomnography is discussed.

Adolescent↗
PubMed2006

Exploration of the genetic architecture of idiopathic generalized epilepsies.

PURPOSE: Idiopathic generalized epilepsy (IGE) accounts for approximately 20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures. METHODS: Genome-wide linkage scans were performed in 126 IGE-multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type-related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening. RESULTS: Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families. CONCLUSIONS: Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22-q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic-clonic seizures on awakening.

Chromosome Mapping↗
PubMed2005

Increased serotonin receptor availability in human sleep: evidence from an [18F]MPPF PET study in narcolepsy.

Data from animal studies suggest that serotonin release promotes wakefulness and suppresses REM sleep, but there are dangers in extrapolating these findings to humans. Binding of the radioligand [18F]MPPF to 5HT1A receptors is sensitive to levels of endogenous serotonin. In this study, we aimed to demonstrate changes in serotonin receptor availability in the human brain in wakefulness and sleep using [18F]MPPF and positron emission tomography. 14 subjects with narcolepsy cataplexy underwent [18F]MPPF PET scans in wakefulness and in sleep. Subjects who used the stimulant methylphenidate took their normal medication for the wake scan but omitted it prior to the sleep scan. The change in binding potential (BP) between the sleep and wake scans was examined using paired t test. Methylphenidate is thought to have little or no effect on serotonergic neurotransmission, and in order to confirm the absence of an effect on [18F]MPPF binding, a concurrent study was performed using a beta-microprobe technique to examine the effect of methylphenidate administration on [18F]MPPF binding in Sprague-Dawley rats. The human study showed a significant increase in [18F]MPPF binding in sleep compared to wakefulness in the whole brain and all regions of interest examined (temporal cortex, mesial temporal region and cingulate cortex). The beta-microprobe study confirmed that methylphenidate administration had no effect on [18F]MPPF binding. These findings indicate that serotonin receptor availability is increased in sleep compared to wakefulness in narcoleptic humans.

Adult↗
PubMed2005

Susceptibility genes for complex epilepsy.

Common idiopathic epilepsies are, clinically and genetically, a heterogeneous group of complex seizure disorders. Seizures arise from periodic neuronal hyperexcitability of unknown cause. The genetic component is mostly polygenic, where each susceptibility gene in any given individual is likely to represent a small component of the total heritability. Two susceptibility genes have been so far identified, where genetic variation is associated with experimentally demonstrated changes in ion channel properties, consistent with seizure susceptibility. Rare variants and a polymorphic allele of the T-type calcium channel CACNA1H and a polymorphic allele and a rare variant of the GABA(A) receptor delta subunit gene have differential functional effects. We speculate that these and other as yet undiscovered susceptibility genes for complex epilepsy could act as 'modifier' loci, affecting penetrance and expressivity of the mutations of large effect in those 'monogenic' epilepsies with simple inheritance that segregate through large families. Discovery of epilepsy-associated ion channel defects in these rare families has opened the door to the discovery of the first two susceptibility genes in epilepsies with complex genetics. The susceptibility genes so far detected are not commonly involved in complex epilepsy suggesting the likelihood of considerable underlying polygenic heterogeneity.

Alleles↗
PubMed2005

Assessment of the role of FDG PET in the diagnosis and management of children with refractory epilepsy.

PURPOSE: We performed a retrospective analysis of the results of FDG PET scans in children with refractory epilepsy referred to our centre over an 8-year period, with a view to ascertaining the impact of FDG PET on subsequent patient management. METHODS: A questionnaire was used to assess the impact of FDG PET scan on diagnosis, management and clinical decision-making processes for epilepsy surgery from the managing clinician's perspective. FDG PET scan results were also compared with MRI, EEG and SPECT results and coded according to whether the FDG PET scan provided independent information and localisation of epileptogenic regions. RESULTS: A total of 118 eligible patients under the age of 14 years were identified, with questionnaires being completed on 113 evaluable patients (96%). The pre-PET management plan consisted of consideration for surgery in 92 patients (81%) and medical therapy for the remaining 21 patients (19%). Managing physicians rated FDG PET as providing information additional to that obtained with other investigations regarding epileptogenic sites in 88 patients (77%). FDG PET had either a minor or a major impact on clinical management in 58 patients (51%), principally with regard to surgical candidacy. CONCLUSION: FDG PET has a definite role in the assessment of paediatric patients with refractory epilepsy who are being considered for surgery. In the future, analysis of FDG PET data in specific subpopulations of children with refractory epilepsy may lead to novel insights regarding aetiology.

Anticonvulsants↗