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151. Comprehensive NGS-Based Diagnostics in over 800 Patients with Epileptic Encephalopathy

Author

Prehl, I., primary, Reicherter, K., additional, Jüngling, J., additional, Hoffmann, J., additional, Döcker, M., additional, Riesch, E., additional, Puk, O., additional, Russ, A., additional, Fehr, S., additional, Stöbe, P., additional, Grau, T., additional, Singh, Y., additional, Battke, F., additional, Lemke, J., additional, Lerche, H., additional, Biskup, S., additional, and Hörtnagel, K., additional

Published
2015
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152. Absence epilepsies with widely variable onset are a key feature of autosomal dominant Glut1 deficiency

Author

Mullen, S.A., Suls, Arvid, Weber, Y., Lerche, H., De Jonghe, Peter, Berkovic, S.F., and Scheffer, I.E.

Subjects
Human medicine
Abstract

AB Background: Familial glucose transporter type 1 (GLUT1) deficiency due to autosomal dominant inheritance of SLC2A1 mutations is associated with paroxysmal exertional dyskinesia; epilepsy and intellectual disability occur in some family members. We recently demonstrated that GLUT1 deficiency occurs in over 10% of patients with early-onset absence epilepsy. Methods: This family study analyses the phenotypes in 2 kindreds segregating SLC2A1 mutations identified through probands with early-onset absence epilepsy. One comprised 9 individuals with mutations over 3 generations; the other had 6 individuals over 2 generations. Results: Of 15 subjects with SLC2A1 mutations, epilepsy occurred in 12. Absence seizures were the most prevalent seizure type (10/12), with onset from 3 to 34 years of age. Epilepsy phenotypes varied widely, including idiopathic generalized epilepsies (IGE) with absence (8/12), myoclonic-astatic epilepsy (2/12), and focal epilepsy (2/12). Paroxysmal exertional dyskinesia occurred in 7, and was subtle and universally undiagnosed prior to molecular diagnosis. There were 2 unaffected mutation carriers. Conclusions: GLUT1 deficiency is an important monogenic cause of absence epilepsies with onset from early childhood to adult life. Individual cases may be phenotypically indistinguishable from common forms of IGE. Although subtle paroxysmal exertional dyskinesia is a helpful diagnostic clue, it is far from universal. The phenotypic spectrum of GLUT1 deficiency is considerably greater than previously recognized. Diagnosis of GLUT1 deficiency has important treatment and genetic counseling implications.

Published
2010

153. Analysis of ELP4, SRPX2, and interacting genes in typical and atypical rolandic epilepsy

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Reinthaler, E., Lal, D., Jurkowski, Wiktor, Feucht, M., Steinböck, H., Gruber-Sedlmayr, U., Ronen, G., Geldner, J., Haberlandt, E., Neophytou, B., Hahn, A., Altmüller, J., Thiel, H., Toliat, M., Lerche, H., Nürnberg, Peter, Sander, T., Neubauer, B., Zimprich, F., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Reinthaler, E., Lal, D., Jurkowski, Wiktor, Feucht, M., Steinböck, H., Gruber-Sedlmayr, U., Ronen, G., Geldner, J., Haberlandt, E., Neophytou, B., Hahn, A., Altmüller, J., Thiel, H., Toliat, M., Lerche, H., Nürnberg, Peter, Sander, T., Neubauer, B., and Zimprich, F.

Abstract

Rolandic epilepsy (RE) and its atypical variants (atypical rolandic epilepsy, ARE) along the spectrum of epilepsy–aphasia disorders are characterized by a strong but largely unknown genetic basis. Two genes with a putative (ELP4) or a proven (SRPX2) function in neuronal migration were postulated to confer susceptibility to parts of the disease spectrum: the ELP4 gene to centrotemporal spikes and SRPX2 to ARE. To reexamine these findings, we investigated a cohort of 280 patients of European ancestry with RE/ARE for the etiological contribution of these genes and their close interaction partners. We performed next-generation sequencing and single-nucleotide polymorphism (SNP)–array based genotyping to screen for sequence and structural variants. In comparison to European controls we could not detect an enrichment of rare deleterious variants of ELP4, SRPX2, or their interaction partners in affected individuals. The previously described functional p.N327S variant in the X chromosomal SRPX2 gene was detected in two affected individuals (0.81%) and also in controls (0.26%), with some preponderance of male patients. We did not detect an association of SNPs in the ELP4 gene with centrotemporal spikes as previously reported. In conclusion our data do not support a major role of ELP4 and SRPX2 in the etiology of RE/ARE.

Published
2014

154. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance

Author

Dibbens, Lm, Mullen, S, Helbig, I, Mefford, Hc, Bayly, Ma, Bellows, S, Leu, C, Trucks, H, Obermeier, T, Wittig, M, Franke, A, Caglayan, H, Yapici, Z, Sander, T, Eichler, Ee, Scheffer, Ie, Mulley, Jc, Berkovic, Sf, De Jonghe, P, Suls, A, Hjalgrim, H, Madsen, Jm, Møller, Rs, Lehesjoki, Ae, Siren, A, Gaus, V, Janz, D, Schmitz, B, Elger, Ce, Hallmann, K, Kleefuß-Lie, Aa, Kunz, Ws, Raabe, A, Muhle, H, Ostertag, P, von Spiczak, S, Stephani, U, Lerche, H, Weber, Yg, Striano, P, Zara, F, Marini, C, Brilstra, Eh, Kastelijn-Nolst, Trenité, Koeleman, D, Bpc, de Kovel, Cgf, Lindhout, D, Swinkels, Mem, Yalcin, O, Baykan, B, Turkdogan, D, Dizdarer, G, Ozkara, C, Lee, Y, Müller-Quernheim, J, Fölster-Holst, R, Hofmann, S, Nebel, A., Schreiber, S, Schürmann, M, Rodriguez, E, Weidinger, S, Baurecht, H, Lie, Ba, Boberg, Km, Karlsen, Th., De Jonghe, Peter, Suls, Arvid, Dibbens, Leanne M, Mullen, Saul, Helbig, Ingo, Mefford, Heather C, Bayly, Marta A, Bellows, Susannah, Leu, Costin, Trucks, Holger, Obermeier, Tanja, Wittig, Michael, Franke, Andre, Caglayan, Hande, Yapici, Zuhal, Sander, Thomas, Eichler, Evan E, Scheffer, Ingrid E, Mulley, John C, and Berkovic, Samuel F

Subjects
Male, Proband, Clinical Sciences, idiopathic generalized epilepsy, European Continental Ancestry Group, Single-nucleotide polymorphism, Pedigree chart, family studies, Biology, White People, Cohort Studies, Idiopathic generalized epilepsy, Epilepsy, single nucleotide polymorphism, genetic inheritance, Genetics, medicine, inheritance, Humans, SNP, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), seizures, Chromosomes, Human, Pair 15, Articles, General Medicine, 5q13.3 deletions, medicine.disease, Penetrance, Pedigree, Female, Human medicine, microdeletion, Chromosome Deletion, Comparative genomic hybridization
Abstract

Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts, we first aimed to confirm the association of 15q13.3 deletions and IGE. We then set out to determine the relative occurrence of sporadic and familial cases and to examine the likelihood of having seizures for individuals with the microdeletion in familial cases. The 15q13.3 microdeletion was identified in 7 of 539 (1.3%) unrelated cases of IGE using quantitative PCR or SNP arrays and confirmed by array comparative genomic hybridization analysis using probes specific to the 15q13.3 region. The inheritance of this lesion was tracked using family studies. Of the seven microdeletions identified in probands, three were de novo, two were transmitted from an unaffected parent and in two cases the parents were unavailable. Non-penetrance of the microdeletion was identified in 4/7 pedigrees and three pedigrees included other family members with IGE who lacked the 15q13.3 deletion. The odds ratio is 68 (95% confidence interval 29-181), indicating a pathogenic lesion predisposing to epilepsy with complex inheritance and incomplete penetrance for the IGE component of the phenotype in multiplex families. Refereed/Peer-reviewed

Published
2009

155. Impaired Action Potential Initiation in GABAergic Interneurons Causes Hyperexcitable Networks in an Epileptic Mouse Model Carrying a Human NaV1.1 Mutation

Author

Hedrich, U. B. S., primary, Liautard, C., additional, Kirschenbaum, D., additional, Pofahl, M., additional, Lavigne, J., additional, Liu, Y., additional, Theiss, S., additional, Slotta, J., additional, Escayg, A., additional, Dihne, M., additional, Beck, H., additional, Mantegazza, M., additional, and Lerche, H., additional

Published
2014
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157. Comprehensive NGS-Based Diagnostics in More Than 1,000 Patients with Epileptic Disorders

Author

Jüngling, J., primary, Prehl, I, additional, Döcker, M., additional, Reicherter, K., additional, Hoffmann, J., additional, Grau, T., additional, Russ, A., additional, Fehr, S., additional, Singh, Y., additional, Stöbe, P., additional, Battke, F., additional, Lemke, J., additional, Lerche, H., additional, Biskup, S., additional, and Hörtnagel, K., additional

Published
2014
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160. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with dravet syndrome

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], ESF, European Science Foundation; WT089062, Wellcome Trust; 098051, Wellcome Trust; 261123, EC, European Commission; DFG, Deutsche Forschungsgemeinschaft [sponsor], Suls, A., Jaehn, J. A., Kecskés, A., Weber, Y., Weckhuysen, S., Craiu, D. C., Siekierska, A., Djémie, T., Afrikanova, T., Gormley, P., Von Spiczak, S., Kluger, G., Iliescu, C. M., Talvik, T., Talvik, I., Meral, C., Caglayan, H. S., Giraldez, B. G., Serratosa, J., Lemke, J. R., Hoffman-Zacharska, D., Szczepanik, E., Barisic, N., Komarek, V., Hjalgrim, H., Møller, R. S., Linnankivi, T., Dimova, P., Striano, P., Zara, F., Marini, C., Guerrini, R., Depienne, C., Baulac, S., Kuhlenbäumer, G., Crawford, Alexander Dettmar, Lehesjoki, A.-E., De Witte, P. A. M., Palotie, A., Lerche, H., Esguerra, C. V., De Jonghe, P., Helbig, I., Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], ESF, European Science Foundation; WT089062, Wellcome Trust; 098051, Wellcome Trust; 261123, EC, European Commission; DFG, Deutsche Forschungsgemeinschaft [sponsor], Suls, A., Jaehn, J. A., Kecskés, A., Weber, Y., Weckhuysen, S., Craiu, D. C., Siekierska, A., Djémie, T., Afrikanova, T., Gormley, P., Von Spiczak, S., Kluger, G., Iliescu, C. M., Talvik, T., Talvik, I., Meral, C., Caglayan, H. S., Giraldez, B. G., Serratosa, J., Lemke, J. R., Hoffman-Zacharska, D., Szczepanik, E., Barisic, N., Komarek, V., Hjalgrim, H., Møller, R. S., Linnankivi, T., Dimova, P., Striano, P., Zara, F., Marini, C., Guerrini, R., Depienne, C., Baulac, S., Kuhlenbäumer, G., Crawford, Alexander Dettmar, Lehesjoki, A.-E., De Witte, P. A. M., Palotie, A., Lerche, H., Esguerra, C. V., De Jonghe, P., and Helbig, I.

Abstract

Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and feversensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures. © 2013 by The American Society of Human Genetics. All rights reserved.

Published
2013

161. Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Author

Kasperaviciute, D, Catarino, CB, Matarin, M, Leu, C, Novy, J, Tostevin, A, Leal, B, Hessel, EVS, Hallmann, K, Hildebrand, MS, Dahl, H-HM, Ryten, M, Trabzuni, D, Ramasamy, A, Alhusaini, S, Doherty, CP, Dorn, T, Hansen, J, Kraemer, G, Steinhoff, BJ, Zumsteg, D, Duncan, S, Kaelviaeinen, RK, Eriksson, KJ, Kantanen, A-M, Pandolfo, M, Gruber-Sedlmayr, U, Schlachter, K, Reinthaler, EM, Stogmann, E, Zimprich, F, Theatre, E, Smith, C, O'Brien, TJ, Tan, KM, Petrovski, S, Robbiano, A, Paravidino, R, Zara, F, Striano, P, Sperling, MR, Buono, RJ, Hakonarson, H, Chaves, J, Costa, PP, Silva, BM, da Silva, AM, de Graan, PNE, Koeleman, BPC, Becker, A, Schoch, S, von Lehe, M, Reif, PS, Rosenow, F, Becker, F, Weber, Y, Lerche, H, Roessler, K, Buchfelder, M, Hamer, HM, Kobow, K, Coras, R, Blumcke, I, Scheffer, IE, Berkovic, SF, Weale, ME, Delanty, N, Depondt, C, Cavalleri, GL, Kunz, WS, Sisodiya, SM, Kasperaviciute, D, Catarino, CB, Matarin, M, Leu, C, Novy, J, Tostevin, A, Leal, B, Hessel, EVS, Hallmann, K, Hildebrand, MS, Dahl, H-HM, Ryten, M, Trabzuni, D, Ramasamy, A, Alhusaini, S, Doherty, CP, Dorn, T, Hansen, J, Kraemer, G, Steinhoff, BJ, Zumsteg, D, Duncan, S, Kaelviaeinen, RK, Eriksson, KJ, Kantanen, A-M, Pandolfo, M, Gruber-Sedlmayr, U, Schlachter, K, Reinthaler, EM, Stogmann, E, Zimprich, F, Theatre, E, Smith, C, O'Brien, TJ, Tan, KM, Petrovski, S, Robbiano, A, Paravidino, R, Zara, F, Striano, P, Sperling, MR, Buono, RJ, Hakonarson, H, Chaves, J, Costa, PP, Silva, BM, da Silva, AM, de Graan, PNE, Koeleman, BPC, Becker, A, Schoch, S, von Lehe, M, Reif, PS, Rosenow, F, Becker, F, Weber, Y, Lerche, H, Roessler, K, Buchfelder, M, Hamer, HM, Kobow, K, Coras, R, Blumcke, I, Scheffer, IE, Berkovic, SF, Weale, ME, Delanty, N, Depondt, C, Cavalleri, GL, Kunz, WS, and Sisodiya, SM

Abstract

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and

Published
2013

164. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Author

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, 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, and Sander, T

Abstract

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.

Published
2012

165. Antibody-mediated status epilepticus: a retrospective multicenter survey

Author

Holzer, F J, Rossetti, A O, Heritier-Barras, A C, Zumsteg, D, Roebling, R, Huber, R, Lerche, H, Kiphuth, I C, Bardutzky, J, Bien, C G, Tröger, M, Schoch, G, Prüss, H, Seeck, M, Holzer, F J, Rossetti, A O, Heritier-Barras, A C, Zumsteg, D, Roebling, R, Huber, R, Lerche, H, Kiphuth, I C, Bardutzky, J, Bien, C G, Tröger, M, Schoch, G, Prüss, H, and Seeck, M

Abstract

Background: In recent years, an increasing number of auto-antibodies (AB) have been detected in the CSF and serum of patients with new onset epilepsy. Some of these patients develop convulsive or nonconvulsive status epilepticus (AB-SE), necessitating intensive medical care and administration of multiple antiepileptic and immunomodulatory treatments of uncertain effectiveness. Objectives: In this retrospective multicenter survey we aimed to determine the spectrum of gravity, the duration and the prognosis of the disorder. In addition, we sought to identify the antibodies associated with this condition, as well as determine whether there is a most effective treatment regime. Methods: 12 European Neurology University Clinics, with extensive experience in the treatment of SE patients, were sent a detailed questionnaire regarding symptoms and treatment of AB-SE patients. Seven centers responded positively, providing a total of 13 patients above the age of 16. Results: AB-SE affects mainly women (12/13, 92%) with a variable age at onset (17-69 years, median: 25 years). The duration of the disease is also variable (10 days to 12 years, median: 2 months). Only the 3 oldest patients died (55-69 years). Most patients were diagnosed with anti NMDAR encephalitis (8/13) and had oligoclonal bands in the CSF (9/13). No specific treatment regimen (antiepileptic, immunomodulatory) was found to be clearly superior. Most of the surviving 10 patients (77%) recovered completely or nearly so within 2 years of index poststatus. Conclusion: AB-SE is a severe but potentially reversible condition. Long duration does not seem to imply fatal outcome; however, age older than 50 years at time of onset appears to be a risk factor for death. There was no evidence for an optimal antiepileptic or immunomodulatory treatment. A prospective multicenter study is warranted in order to stratify the optimal treatment algorithm, determine clear risk factors of unfavorable outcome and long-term prognosis.

Published
2012

166. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1

Author

Suls, A, Dedeken, P, Goffin, K, Van Esch, H, Dupont, P, Cassiman, D, Kempfle, J, Wuttke, TV, Weber, Y, Lerche, H, Afawi, Z, Vandenberghe, W, Korczyn, AD, Berkovic, SF, Ekstein, D, Kivity, S, Ryvlin, P, Claes, LRF, Deprez, L, Maljevic, S, Vargas, A, Van Dyck, T, Goossens, D, Del-Favero, J, Van Laere, K, De Jonghe, P, Paesschen, W, Suls, A, Dedeken, P, Goffin, K, Van Esch, H, Dupont, P, Cassiman, D, Kempfle, J, Wuttke, TV, Weber, Y, Lerche, H, Afawi, Z, Vandenberghe, W, Korczyn, AD, Berkovic, SF, Ekstein, D, Kivity, S, Ryvlin, P, Claes, LRF, Deprez, L, Maljevic, S, Vargas, A, Van Dyck, T, Goossens, D, Del-Favero, J, Van Laere, K, De Jonghe, P, and Paesschen, W

Abstract

Paroxysmal exercise-induced dyskinesia (PED) can occur in isolation or in association with epilepsy, but the genetic causes and pathophysiological mechanisms are still poorly understood. We performed a clinical evaluation and genetic analysis in a five-generation family with co-occurrence of PED and epilepsy (n = 39), suggesting that this combination represents a clinical entity. Based on a whole genome linkage analysis we screened SLC2A1, encoding the glucose transporter of the blood-brain-barrier, GLUT1 and identified heterozygous missense and frameshift mutations segregating in this and three other nuclear families with a similar phenotype. PED was characterized by choreoathetosis, dystonia or both, affecting mainly the legs. Predominant epileptic seizure types were primary generalized. A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients and a reduced glucose uptake by mutated transporters compared with the wild-type as determined in Xenopus oocytes confirmed a pathogenic role of these mutations. Functional imaging studies implicated alterations in glucose metabolism in the corticostriate pathways in the pathophysiology of PED and in the frontal lobe cortex in the pathophysiology of epileptic seizures. Three patients were successfully treated with a ketogenic diet. In conclusion, co-occurring PED and epilepsy can be due to autosomal dominant heterozygous SLC2A1 mutations, expanding the phenotypic spectrum associated with GLUT1 deficiency and providing a potential new treatment option for this clinical syndrome.

Published
2008

170. Epilepsie

Author

Klamer, S., primary, Weber, Y. G., primary, and Lerche, H., additional

Published
2012
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171. Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect

Author

Weber, Y. G., primary, Kamm, C., additional, Suls, A., additional, Kempfle, J., additional, Kotschet, K., additional, Schule, R., additional, Wuttke, T. V., additional, Maljevic, S., additional, Liebrich, J., additional, Gasser, T., additional, Ludolph, A. C., additional, Van Paesschen, W., additional, Schols, L., additional, De Jonghe, P., additional, Auburger, G., additional, and Lerche, H., additional

Published
2011
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172. Pharmakogenetik

Author

Becker, F., primary, Zimprich, F., additional, Sisodiya, S., additional, and Lerche, H., additional

Published
2011
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175. Understanding the climatic signal in the water stable isotope records from the NEEM shallow firn/ice cores in northwest Greenland

Author

Steen-Larsen, H. C., primary, Masson-Delmotte, V., additional, Sjolte, J., additional, Johnsen, S. J., additional, Vinther, B. M., additional, Bréon, F.-M., additional, Clausen, H. B., additional, Dahl-Jensen, D., additional, Falourd, S., additional, Fettweis, X., additional, Gallée, H., additional, Jouzel, J., additional, Kageyama, M., additional, Lerche, H., additional, Minster, B., additional, Picard, G., additional, Punge, H. J., additional, Risi, C., additional, Salas, D., additional, Schwander, J., additional, Steffen, K., additional, Sveinbjörnsdóttir, A. E., additional, Svensson, A., additional, and White, J., additional

Published
2011
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182. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

Author

de Kovel, C. G. F., primary, Trucks, H., additional, Helbig, I., additional, Mefford, H. C., additional, Baker, C., additional, Leu, C., additional, Kluck, C., additional, Muhle, H., additional, von Spiczak, S., additional, Ostertag, P., additional, Obermeier, T., additional, Kleefuss-Lie, A. A., additional, Hallmann, K., additional, Steffens, M., additional, Gaus, V., additional, Klein, K. M., additional, Hamer, H. M., additional, Rosenow, F., additional, Brilstra, E. H., additional, Kasteleijn-Nolst Trenite, D., additional, Swinkels, M. E. M., additional, Weber, Y. G., additional, Unterberger, I., additional, Zimprich, F., additional, Urak, L., additional, Feucht, M., additional, Fuchs, K., additional, Moller, R. S., additional, Hjalgrim, H., additional, De Jonghe, P., additional, Suls, A., additional, Ruckert, I.-M., additional, Wichmann, H.-E., additional, Franke, A., additional, Schreiber, S., additional, Nurnberg, P., additional, Elger, C. E., additional, Lerche, H., additional, Stephani, U., additional, Koeleman, B. P. C., additional, Lindhout, D., additional, Eichler, E. E., additional, and Sander, T., additional

Published
2009
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183. Genetics and differenzial developmental expression of the Na+ channel gene SCN2A reveal molecular correlates for early-onset (neonatal-infantile) seizures and late-onset episodic ataxia, myoclonus and pain

Author

Liao, Y, primary, Deprez, L, additional, Anttonen, AK, additional, Maljevic, S, additional, Claes, L, additional, Hristova, D, additional, Jordanova, A, additional, Ala-Mello, S, additional, Liukkonen, E, additional, Gaily, E, additional, Bellan-Koch, A, additional, Blazevic, D, additional, Schubert, S, additional, Thomas, EA, additional, Petrou, S, additional, Ahonen, VE, additional, De Joghe, P, additional, Lehesejoki, AE, additional, and Lerche, H, additional

Published
2009
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192. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1

Author

Suls, A., primary, Dedeken, P., additional, Goffin, K., additional, Van Esch, H., additional, Dupont, P., additional, Cassiman, D., additional, Kempfle, J., additional, Wuttke, T. V., additional, Weber, Y., additional, Lerche, H., additional, Afawi, Z., additional, Vandenberghe, W., additional, Korczyn, A. D., additional, Berkovic, S. F., additional, Ekstein, D., additional, Kivity, S., additional, Ryvlin, P., additional, Claes, L. R. F., additional, Deprez, L., additional, Maljevic, S., additional, Vargas, A., additional, Van Dyck, T., additional, Goossens, D., additional, Del-Favero, J., additional, Van Laere, K., additional, De Jonghe, P., additional, and Van Paesschen, W., additional

Published
2008
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196. The Wada-Test in 2000–2005at German, Swiss and Austrian and Dutch Epilepsy-Centres – the experience of the Arbeitsgemeinschaft für prächirurgische Epilepsiediagnostik und operative Epilepsietherapie e.V regarding 1421 procedures

Author

Haag, A, primary, Knake, S, additional, Hamer, HM, additional, Boesebeck, F, additional, Freitag, H, additional, Schulz, R, additional, Baum, P, additional, Helmstaedter, C, additional, Wellmer, J, additional, Urbach, H, additional, Hopp, P, additional, Mayer, T, additional, Hufnagel, A, additional, Jokeit, H, additional, Lerche, H, additional, Uttner, I, additional, Meencke, HJ, additional, Meierkord, H, additional, Pauli, E, additional, Runge, U, additional, Saar, J, additional, Trinka, E, additional, Benke, T, additional, Vulliemoz, S, additional, Wiegand, G, additional, Stephani, U, additional, Wieser, HG, additional, Rating, D, additional, Werhahn, K, additional, Noachtar, S, additional, Schulze-Bonhage, A, additional, Wagner, K, additional, Alpherts, W, additional, van Emde Boas, W, additional, and Rosenow, F, additional

Published
2007
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