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Epilepsia 07/2012; 53(7):1276. · 3.96 Impact Factor
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Hiltrud Muhle,
Ines Steinich,
Sarah von Spiczak,
Andre Franke, Yvonne Weber,
Holger Lerche,
Michael Wittig,
Simone Heidemann,
Arvid Suls,
Peter de Jonghe,
Carla Marini,
Renzo Guerrini,
Ingrid E Scheffer,
Samuel F Berkovic,
Ulrich Stephani,
Reiner Siebert,
Thomas Sander,
Ingo Helbig,
Holger Tönnies
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ABSTRACT: Early onset absence epilepsy (EOAE) starting before the age of 4 years constitutes a rare subgroup of the idiopathic generalized epilepsies (IGEs). A strong genetic component in IGE has been suggested by twin and family studies. We describe a boy with absence seizures starting at the age of 9 months whose parents both had childhood absence epilepsy. A 192-kb duplication in 1q21.3 was identified in the proband and his father, encompassing the gene CHRNB2 coding for the β-2 subunit of the nicotinic acetylcholine receptor and the gene ADAR coding for adenosine deaminase, an enzyme responsible for RNA editing. Both are candidate genes for seizure disorders. The duplication was not identified in 191 independent IGE patients (93 EOAE; 98 classical IGE) or in 1,157 population controls.
Epilepsia 12/2010; 51(12):2453-6. · 3.96 Impact Factor
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Hiltrud Muhle,
Sarah von Spiczak,
Verena Gaus,
Serife Kara,
Ingo Helbig,
Jochen Hampe,
Andre Franke, Yvonne Weber,
Holger Lerche,
Ailing A Kleefuss-Lie,
Christian E Elger,
Stefan Schreiber,
Ulrich Stephani,
Thomas Sander
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ABSTRACT: GRM4 encoding the group III metabotropic glutamate receptor 4 (mGluR4), is located on the chromosomal segment 6p21.3 where tentative susceptibility loci for Juvenile Myoclonic Epilepsy (JME) and Photoparoxysmal Response (PPR) have been mapped. The present candidate gene study examined if variation in GRM4 confers susceptibility to IGE.
The case-control association sample included 564 unrelated IGE patients and 733 population controls of German descent. Association analysis was carried out for 17 single nucleotide polymorphisms (SNPs) covering the genomic GRM4 sequence for all IGE patients as well as for two common IGE subsyndromes [Juvenile Myoclonic Epilepsy (JME, n=215) and Childhood Absence Epilepsy (CAE, n=175)]. Sequence analysis was performed in 85 IGE and 42 PPR cases and 44 controls.
Nominally significant associations were detected between IGE and seven GRM4 SNPs (with P-values ranging from 0.037 to 0.0036), between JME and five SNPs (P=0.042-0.0106), and between CAE and two SNPs (P=0.0466-0.0021). Four novel SNPs were identified by sequence analysis.
Our association findings support the hypothesis that GRM4 sequence variants might confer low-risk effects to the etiology of IGE. A minor pathogenetic contribution of the examined variants is possible. These exploratory findings warrant further replication analyses.
Epilepsy research 03/2010; 89(2-3):319-26. · 2.48 Impact Factor
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ABSTRACT: Ion channelopathies are caused by malfunction or altered regulation of ion channel proteins due to hereditary or acquired protein changes. In neurology, main phenotypes include certain forms of epilepsy, ataxia, migraine, neuropathic pain, myotonia, and muscle weakness including myasthenia and periodic paralyses. The total prevalence of monogenic channelopathies in neurology is about 35:100,000. Susceptibility-related mutations further increase the relevance of channel genes in medicine considerably. As many disease mechanisms have been elucidated by functional characterization on the molecular level, the channelopathies are regarded as model disorders for pathogenesis and treatment of non-monogenic forms of epilepsy and migraine. As more than 35% of marketed drugs target ion channels, there is a high chance to identify compounds that counteract the effects of the mutations.
Advances in experimental medicine and biology 01/2010; 686:305-34. · 1.09 Impact Factor
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ABSTRACT: Cranial MRI has been shown to be a safe procedure in patients with a vagus nerve stimulator (VNS), but body MRI may cause overheating of the stimulator lead. Here we report a case of a patient with an implanted vagus nerve stimulator who required a cervical spinal MRI due to a rapidly progressive paraparesis. The spinal MRI was performed in a 1.5T scanner without complications showing a nearly complete compression of the spinal cord.
Epilepsy research 04/2009; 84(2-3):273-5. · 2.48 Impact Factor
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Ingo Helbig,
Heather C Mefford,
Andrew J Sharp,
Michel Guipponi,
Marco Fichera,
Andre Franke,
Hiltrud Muhle,
Carolien de Kovel,
Carl Baker,
Sarah von Spiczak, [......],
Christian E Elger,
Peter Nürnberg,
Corrado Romano,
Alain Malafosse,
Bobby P C Koeleman,
Dick Lindhout,
Ulrich Stephani,
Stefan Schreiber,
Evan E Eichler,
Thomas Sander
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ABSTRACT: We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.
Nature Genetics 02/2009; 41(2):160-2. · 35.53 Impact Factor
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Arvid Suls,
Peter Dedeken,
Karolien Goffin,
Hilde Van Esch,
Patrick Dupont,
David Cassiman,
Judith Kempfle,
Thomas V Wuttke, Yvonne Weber,
Holger Lerche, [......],
Lieve R F Claes,
Liesbet Deprez,
Snezana Maljevic,
Alberto Vargas,
Tine Van Dyck,
Dirk Goossens,
Jurgen Del-Favero,
Koen Van Laere,
Peter De Jonghe,
Wim Van Paesschen
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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.
Brain 06/2008; 131(Pt 7):1831-44. · 9.46 Impact Factor
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ABSTRACT: Mutation screening and linkage disequilibrium mapping of the gene encoding the GABA(A) beta(3) subunit (GABRB3) identified a common genetic variant in the exon 1a promoter region (C-allele of rs4906902) which displayed a reduced transcriptional activity and showed a strong allelic association with childhood absence epilepsy (CAE). The present population-based association study tested whether the C-allele of rs4906902 confers susceptibility to CAE or other common syndromes of idiopathic generalized epilepsy (IGE) in a German sample.
Seven hundred and eighty unrelated German IGE patients (250 CAE, 123 juvenile absence epilepsy, 303 juvenile myoclonic epilepsy (JME), 104 epilepsy with generalized tonic-clonic seizures on awakening) and 559 healthy population controls were genotyped for the single nucleotide polymorphism (SNP) rs4906902.
The frequency of the risk-conferring C-allele did not differ significantly between CAE patients (f(C)=0.190) and controls (f(C)=0.183; P=0.376, one-tailed). Similarly, no evidence for an allelic association was found for 373 patients with idiopathic absence epilepsy, 303 JME patients, and the entire IGE sample (P>0.77, two-tailed).
Our study failed to replicate an association of the common GABRB3 exon 1a promoter SNP rs4906902 with CAE. Moreover, the present results do not provide evidence that the common functional C-variant confers a substantial epileptogenic effect to a broad spectrum of IGE syndromes in the German population.
Epilepsy Research 04/2007; 74(1):28-32. · 2.29 Impact Factor
