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ABSTRACT: The neuronal voltage-gated sodium channel Na(v)1.1 encoded by the SCN1A gene plays an important role in the generation and propagation of action potentials in the central nervous system. Altered function of this channel due to mutations in SCN1A leads to hypersynchronous neuronal discharges resulting in seizures or migrainous attaques. A large number of distinct sequence variants in SCN1A are associated with diverse epilepsy and migraine syndromes. We developed an online and freely available database containing all reported sequence variants in SCN1A (http://www.molgen.ua.ac.be/SCN1AMutations/). We verified 623 distinct sequence variants, listed them using standard nomenclature for description and classified them according to their putative pathogenic nature. We provided links to relevant publications and information on the associated phenotype. The database can be queried using cDNA or protein position, phenotype, variant type or publication. By listing all SCN1A variants in a comprehensive manner, this database will facilitate interpretation of newly identified sequence variants and provide better insight into the genotype-phenotype relations of the growing number of SCN1A mutations.
Human Mutation 08/2009; 30(10):E904-20. · 5.69 Impact Factor
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ABSTRACT: The neuronal voltage-gated sodium channel Nav1.1 encoded by the SCN1A gene plays an important role in the generation and propagation of action potentials in the central nervous system. Altered function of this channel due to mutations in SCN1A leads to hypersynchronous neuronal discharges resulting in seizures or migrainous attaques. A large number of distinct sequence variants in SCN1A are associated with diverse epilepsy and migraine syndromes. We developed an online and freely available database containing all reported sequence variants in SCN1A (http://www.molgen.ua.ac.be/SCN1AMutations/). We verified 623 distinct sequence variants, listed them using standard nomenclature for description and classified them according to their putative pathogenic nature. We provided links to relevant publications and information on the associated phenotype. The database can be queried using cDNA or protein position, phenotype, variant type or publication. By listing all SCN1A variants in a comprehensive manner, this database will facilitate interpretation of newly identified sequence variants and provide better insight into the genotype-phenotype relations of the growing number of SCN1A mutations. © 2009 Wiley-Liss, Inc.
Human Mutation 07/2009; 30(10):E904 - E920. · 5.69 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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Liesbet Deprez,
Sarah Weckhuysen,
Katelijne Peeters,
Tine Deconinck,
Kristl G Claeys,
Lieve R F Claes,
Arvid Suls, Tine Van Dyck,
André Palmini,
Gert Matthijs,
Wim Van Paesschen,
Peter De Jonghe
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ABSTRACT: Mutations in the ATP1A2 gene have been described in families with familial hemiplegic migraine (FHM). FHM is a variant of migraine with aura characterized by the occurrence of hemiplegia during the aura. Within several FHM families, some patients also had epileptic seizures. In this study we tested the hypothesis that mutations in ATP1A2 may be common in patients presenting with epilepsy and migraine.
We selected 20 families with epilepsy and migraine and performed mutation analysis of ATP1A2 in the probands by direct sequencing of all exons and splice-site junctions.
Novel ATP1A2 mutations were found in two of the 20 families (10%). The p.Gly900Arg mutation was present in a family with epilepsy and FHM, and the p.Cys702Tyr mutation occurred in a family with occipitotemporal epilepsy and migraine with and without visual aura. In the two families together, six mutation carriers had the combination of epilepsy and migraine, two had only epilepsy, and six had only migraine.
This study shows that a history of migraine and a family history of both epilepsy and migraine should be obtained in all patients presenting with epilepsy in the epilepsy clinic. It may be worthwhile to screen patients with a combination of epilepsy and migraine and a positive family history of either migraine or epilepsy for mutations in the ATP1A2 gene.
Epilepsia 04/2008; 49(3):500-8. · 3.96 Impact Factor
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Arvid Suls,
Kristl G Claeys,
Dirk Goossens,
Boris Harding,
Rob Van Luijk,
Stefaan Scheers,
Liesbet Deprez,
Dominique Audenaert, Tine Van Dyck,
Sabine Beeckmans,
Iris Smouts,
Berten Ceulemans,
Lieven Lagae,
Gunnar Buyse,
Nina Barisic,
Jean-Paul Misson,
Jan Wauters,
Jurgen Del-Favero,
Peter De Jonghe,
Lieve R F Claes
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ABSTRACT: Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI.
Human Mutation 10/2006; 27(9):914-20. · 5.69 Impact Factor
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ABSTRACT: Febrile seizures (FS) represent the most common seizure disorder in childhood and contribution of a genetic predisposition has been clearly proven. In some families FS is associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical febrile seizures (FS+) and afebrile generalized and partial seizures. Mutations in the genes SCN1B, SCN1A and GABRG2 were identified in GEFS+ families. GEFS+ is genetically heterogeneous and mutations in these three genes were detected in only a minority of the families. We performed a 10 cM density genome-wide scan in a multigenerational family with febrile seizures and epilepsy and obtained a maximal multipoint LOD score of 3.12 with markers on chromosome 5q14.3-q23.1. Fine mapping and segregation analysis defined a genetic interval of approximately 33 cM between D5S2103 and D5S1975. This candidate region overlapped with a previously reported locus for febrile seizures (FEB4) in the Japanese population, in which MASS1 was proposed as disease gene. Mutation analysis of the exons and exon-intron boundaries of MASS1 in our family did not reveal a disease causing mutation. Our linkage data confirm for the first time that a locus on chromosome 5q14-q23 plays a role in idiopathic epilepsies. However, our mutation data is negative and do not support a role for MASS1 suggesting that another gene within or near the FEB4 locus might exist.
Human Genetics 02/2006; 118(5):618-25. · 5.07 Impact Factor
