A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Na(v)1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control ch...

Generalized epilepsy with febrile seizures-plus (GEFS+) is a benign Mendelian syndrome characterized by childhood-onset febrile and afebrile seizures. Three point mutations within two voltage-gated sodium channel genes have been identified so far: in GEFS+ type 1 a mutation in the beta1-subunit gene SCN1B, and in GEFS+ type 2 two mutations within the neuronal alpha-subunit gene SCN1A. Functiona...

SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis. Epilepsia 2009; 50: 1670–8. Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, et al. Na(v)1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying a Scn1a gene mutation. J Neurosci 2007; 27: 5903–14. Oguni H, Haya...

Commentary Advances in cellular reprogramming have made it possible to generate virtually any cell type from pluripotent stem cells. Initially, embryonic stem cells were the only source of truly plu-ripotent cells. However, in 2007, it was reported that induced pluripotent stem cells (iPSCs) could be generated from human somatic cells (1, 2). This discovery enabled iPSCs generated from patients...

21 Genetic epilepsy with febrile seizures plus (GEFS+) is an inherited epilepsy 22 which can result from mutations in at least four ion channel subunits. The majority of 23 the known GEFS+ mutations have been identified in SCN1A, the gene encoding 24 Nav1.1 α subunit. Protein kinases as critical modulators of sodium channels have been 25 closely related to the genesis of epilepsy. However, litt...

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel alpha1 subunit (NaV1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously ex...

Technological improvements shifted sequencing from low-throughput, work-intensive, gel-based systems to high-throughput capillary systems. This resulted in a broad use of genomic resequencing to identify sequence variations in genes and regulatory, as well as extended genomic regions. We describe a software package, novoSNP, that conscientiously discovers single nucleotide polymorphisms (SNPs) ...

Heterozygous loss-of-function mutations in the brain sodium channel Na(V)1.1 cause Dravet syndrome (DS), a pharmacoresistant infantile-onset epilepsy syndrome with comorbidities of cognitive impairment and premature death. Previous studies using a mouse model of DS revealed reduced sodium currents and impaired excitability in GABAergic interneurons in the hippocampus, leading to the hypothesis ...

In 1978, Charlotte Dravet described thècryptogenic' epilepsy syndrome severe myoclonic epilepsy of infancy (SMEI) (Dravet, 1978). This severe generalized epileptic encephalopathy begins at around 6 months of age with febrile hemiclonic or generalized status epilepticus. Hemiclonic status typically recurs involving each side independently. After 1 year of age, other seizure types appear includin...