Mutation information:
NumberExon/IntronNucleotide change Protein changeLocation Mutation typeConsequencesPhenotype InheritanceReference
146226c.4943G>Ap.Arg1648HisDIVS4MissenseP/﹢→P/﹢(29); G-LOF GEFS+Familial(NA),P=5/5Escayg A.2000
SMEIFamilial(Paternal)Depienne C.2009

Functional information:
NumberNucleotide changeProtein changeLocationPhenotypeFunctional defect type Details of the major biophysical abnormalities.Reference
38c.4943G>Ap.Arg1648His(R1648H)DIVS4GEFS+ fG-LOF Moderate persistent current,slowed inactivation and increased recovery from inactivation Enhanced slow inactivation that may result in reduced current density during long depolarization or repetitive stimulation.Rhodes TH.2004; Lossin C.2002; Spampanato J.2001; Alekov A.2000

Inheritance information:
NumberNucleotide changeProtein changeMutation type Proband's phenotype1st transmitter's phenotype Mosaic Affected generationsPenetranceReference
139c.4943G>Ap.Arg1648His(DIVS4)MissenseGEFS+NA 5/5Escayg A.2000
SMEINA(Paternal) Depienne C.2009

[c.4943G>A] Clinical description

The age at examination of affected individuals (11 females, including spouse III-7, and three males) was 12-77 years; nine had histories of FS, with onset at age four months-three years, and seven of these nine later developed epilepsy. The number of FS episodes experienced by each patient was highly variable. Two patients (III-5 and IV-5) had complex FS with prolonged or multiple attacks over 24h periods. The occurrence of FS in the oldest patients (II-1, II-2, II-3, and III-6) could not be determined. Individual IV-7 never experienced FS. In the 12 patients who developed afebrile seizures, the epilepsy phenotype was variable. The age at which the first epileptic seizure occurred could be determined for four individuals (II-1, II-3, IV-1, and IV-7) and was 3-60 years. For the other patients (II-2, III-2, III-5, III-6, III-8, IV-3, IV-5, and IV-6), age at onset could not be reliably recorded, because of either lack of precise information or lack of a seizure-free interval between FS and onset of epilepsy (with seizures often precipitated by hyperthermia) or because of an early association of FS and afebrile seizures. Generalized tonic-clonic seizures (GTCSs) occurred in all the epileptic patients. These seizures were associated with absences in two individuals (IV-1 and IV-5) and with myoclonic seizures (precipitated by carbamazepine) in patient IV-5. In four patients (III-5, III-6, IV-1, and IV-6), the results of interictal EEG were suggestive of idiopathic generalized epilepsy (normal background, generalized 3-Hz spike-waves, and photosensitivity for individual III-6). For individual IV-5, generalized spike-waves were associated with a slow background. In two individuals, some characteristics of partial seizures were associated with the generalized electroclinical pattern: right hemiclonic seizures in patient IV-1 and left hemiclonic and versive seizures with an interictal frontal focus in individual III-5. In both patients, no focal lesions or brain asymmetries were found on neuroimaging. Four patients were intellectually impaired (severely in the case of  individual II-2 and moderately in the case of individuals III-5, IV-1, and IV-5), and one individual (IV-1) presented a pyramidal syndrome on the right side. There was considerable intrafamilial variation in the severity of the epileptic disease, with respect to the frequency of seizures, clinical evolution, and response to antiepileptic drugs. The clinical evolution of seven patients was favorable. They had been seizure free during the two years preceding our study. Three of these seven patients were no longer taking antiepileptic drugs (individuals III-2, III-8, and IV-3), two were receiving monotherapy (individuals II-1 and II-3), and two were receiving antiepileptic-drug polytherapy (individuals III-6 and IV-6). In three patients (II-2, III-5, IV-1), a few seizures persisted during antiepileptic polytherapy. Patient IV-5 had pharmacoresistant epilepsy with numerous seizures persisting during antiepileptic polytherapy. At-risk individuals III-3, III-4, III-10, IV-4, and IV-8were clinically normal at ages 44, 41, 56, 24, and 30 years, respectively, and were considered to be unaffected(Baulac S, et al. Am. J. Hum. Genet. 65:1078–1085, 1999. [10486327]).