Medicine (Austin & Northern Health) - Research Publications
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ItemNo Preview AvailableClinical genetic study of the epilepsy-aphasia spectrumTsai, M-H ; Vears, DF ; Turner, SJ ; Smith, RL ; Berkovic, SF ; Sadleir, LG ; Scheffer, IE (WILEY-BLACKWELL, 2013-02-01)PURPOSE: To characterize the frequency and nature of the family history of seizures in probands with epilepsy falling within the epilepsy-aphasia spectrum (EAS) in order to understand the genetic architecture of this group of disorders. METHODS: Patients with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), Landau-Kleffner syndrome (LKS), atypical benign partial epilepsy (ABPE), and intermediate epilepsy-aphasia disorders (IEAD) were recruited. All affected and available unaffected relatives up to three degrees of relatedness underwent phenotyping using a validated seizure questionnaire. Pedigrees were constructed for all families. The proportion of affected relatives according to each degree of relatedness was calculated. The epilepsy phenotypes in close relatives were analyzed. The data were compared to the families of probands with benign childhood epilepsy with centrotemporal spikes (BECTS) using the same methodology. KEY FINDINGS: Thirty-one probands, including five ECSWS, three LKS, one ABPE, and 22 IEAD were recruited. The mean age of seizure onset was 3.9 (range 0.5-7) years. A male predominance was seen (68%, 21/31) . Sixteen (51.6%) of 31 had a positive family history of seizures. Among 1,254 relatives, 30 (2.4%) had a history of seizures: 13 (10.2%) of 128 first-degree relatives, 5 (1.7%) of 291 second-degree relatives, and 12 (1.4%) of 835 third-degree relatives. Thirteen had febrile seizures, including two who had both febrile seizures and epilepsy. Of the 19 relatives with epilepsy, 4 had BECTS, 4 epilepsies with focal seizures of unknown cause, 3 IEAD, and 7 unclassified. One had genetic generalized epilepsy. In the families of the BECTS probands, 9.8% of first-degree, 3% of second-degree, and 1.5% of third-degree relatives had seizures, which was not significantly different from the EAS cohort families. SIGNIFICANCE: The frequencies of seizures in relatives of probands with EAS suggest that the underlying genetic influence of EAS is consistent with complex inheritance and similar to BECTS. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures. These findings suggest that a shared genetic predisposition to focal epilepsies underpins the epilepsy-aphasia spectrum.
ItemNo Preview AvailableEarly onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiencyArsov, T ; Mullen, SA ; Damiano, JA ; Lawrence, KM ; Huh, LL ; Nolan, M ; Young, H ; Thouin, A ; Dahl, H-HM ; Berkovic, SF ; Crompton, DE ; Sadleir, LG ; Scheffer, IE (WILEY-BLACKWELL, 2012-12-01)Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike-waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in-frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE.
ItemNo Preview AvailableSodium channels and the neurobiology of epilepsyOliva, M ; Berkovic, SF ; Petrou, S (WILEY, 2012-11-01)Voltage-gated sodium channels (VGSCs) are integral membrane proteins. They are essential for normal neurologic function and are, currently, the most common recognized cause of genetic epilepsy. This review summarizes the neurobiology of VGSCs, their association with different epilepsy syndromes, and the ways in which we can experimentally interrogate their function. The most important sodium channel subunit of relevance to epilepsy is SCN1A, in which over 650 genetic variants have been discovered. SCN1A mutations are associated with a variety of epilepsy syndromes; the more severe syndromes are associated with truncation or complete loss of function of the protein. SCN2A is another important subtype associated with epilepsy syndromes, across a range of severe and less severe epilepsies. This subtype is localized primarily to excitatory neurons, and mutations have a range of functional effects on the channel. SCN8A is the other main adult subtype found in the brain and has recently emerged as an epilepsy gene, with the first human mutation discovered in a severe epilepsy syndrome. Mutations in the accessory β subunits, thought to modulate trafficking and function of the α subunits, have also been associated with epilepsy. Genome sequencing is continuing to become more affordable, and as such, the amount of incoming genetic data is continuing to increase. Current experimental approaches have struggled to keep pace with functional analysis of these mutations, and it has proved difficult to build associations between disease severity and the precise effect on channel function. These mutations have been interrogated with a range of experimental approaches, from in vitro, in vivo, to in silico. In vitro techniques will prove useful to scan mutations on a larger scale, particularly with the advance of high-throughput automated patch-clamp techniques. In vivo models enable investigation of mutation in the context of whole brains with connected networks and more closely model the human condition. In silico models can help us incorporate the impact of multiple genetic factors and investigate epistatic interactions and beyond.
ItemEpi4K: Gene discovery in 4,000 genomesBerkovic, S ; Cossette, P ; Delanty, N ; Dlugos, D ; Eichler, E ; Epstein, M ; Glauser, T ; Goldstein, D ; Heinzen, E ; Johnson, MR ; Kuzniecky, R ; Lowenstein, D ; Marson, T ; Mefford, H ; O'Brien, T ; Ottman, R ; Poduri, A ; Scheffer, I ; Sherr, E ; Shianna, K (WILEY, 2012-08-01)A major challenge in epilepsy research is to unravel the complex genetic mechanisms underlying both common and rare forms of epilepsy, as well as the genetic determinants of response to treatment. To accelerate progress in this area, the National Institute of Neurological Disorders and Stroke (NINDS) recently offered funding for the creation of a "Center without Walls" to focus on the genetics of human epilepsy. This article describes Epi4K, the collaborative study supported through this grant mechanism and having the aim of analyzing the genomes of a minimum 4,000 subjects with highly selected and well-characterized epilepsy.