Medicine (Austin & Northern Health) - Research Publications

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Author: Berkovic, Samuel × Author: Mullen, Saul × Author: Scheffer, Ingrid × End date: 2012 × Start date: 2010 × Type: Journal Article ×

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    Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency
    Arsov, 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)
    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.
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    Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32
    Steffens, M ; Leu, C ; Ruppert, A-K ; Zara, F ; Striano, P ; Robbiano, A ; Capovilla, G ; Tinuper, P ; Gambardella, A ; Bianchi, A ; La Neve, A ; Crichiutti, G ; de Kovel, CGF ; Trenite, DK-N ; de Haan, G-J ; Lindhout, D ; Gaus, V ; Schmitz, B ; Janz, D ; Weber, YG ; Becker, F ; Lerche, H ; Steinhoff, BJ ; Kleefuss-Lie, AA ; Kunz, WS ; Surges, R ; Elger, CE ; Muhle, H ; von Spiczak, S ; Ostertag, P ; Helbig, I ; Stephani, U ; Moller, RS ; Hjalgrim, H ; Dibbens, LM ; Bellows, S ; Oliver, K ; Mullen, S ; Scheffer, IE ; Berkovic, SF ; Everett, KV ; Gardiner, MR ; Marini, C ; Guerrini, R ; Lehesjoki, A-E ; Siren, A ; Guipponi, M ; Malafosse, A ; Thomas, P ; Nabbout, R ; Baulac, S ; Leguern, E ; Guerrero, R ; Serratosa, JM ; Reif, PS ; Rosenow, F ; Moerzinger, M ; Feucht, M ; Zimprich, F ; Kapser, C ; Schankin, CJ ; Suls, A ; Smets, K ; De Jonghe, P ; Jordanova, A ; Caglayan, H ; Yapici, Z ; Yalcin, DA ; Baykan, B ; Bebek, N ; Ozbek, U ; Gieger, C ; Wichmann, H-E ; Balschun, T ; Ellinghaus, D ; Franke, A ; Meesters, C ; Becker, T ; Wienker, TF ; Hempelmann, A ; Schulz, H ; Rueschendorf, F ; Leber, M ; Pauck, SM ; Trucks, H ; Toliat, MR ; Nuernberg, P ; Avanzini, G ; Koeleman, BPC ; Sander, T (OXFORD UNIV PRESS, 2012-12-15)
    Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.