title: An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na(+) current.
abstract: Missense mutations in SCN2A, encoding the brain sodium channel NaV 1.2, have been described in benign familial neonatal-infantile seizures (BFNIS), a self-limiting disorder, whereas several SCN2A de novo nonsense mutations have been found in patients with more severe phenotypes including epileptic encephalopathy. We report a family with BFNIS originating from Madagascar. Onset extended from 3 to 9 months of age. Interictal EEGs were normal. In two patients, ictal electroencephalography (EEG) studies showed partial seizure patterns with secondary generalization in one. Seizures remitted before 18 months of age, with or without medication. Intellectual development was normal. A novel missense mutation of SCN2A, c.4766A>G/p.Tyr1589Cys, was found in a highly conserved region of NaV 1.2 (D4/S2-S3). Functional studies using heterologous expression in tsA201 cells and whole-cell patch clamping revealed a depolarizing shift of steady-state inactivation, increased persistent Na(+) current, a slowing of fast inactivation and an acceleration of its recovery, thus a gain-of-function. Using an action potential waveform in a voltage-clamp experiment we indicated an increased inward Na(+) current at subthreshold voltages, which can explain a neuronal hyperexcitability. Our results suggest that this mutation induces neuronal hyperexcitability, resulting in infantile epilepsy with favorable outcome.
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Lauxmann
authors.forename: Nadia
authors.initials: N
authors.lastname: Boutry-Kryza
authors.forename: Clotilde
authors.initials: C
authors.lastname: Rivier
authors.forename: Stephan
authors.initials: S
authors.lastname: Mueller
authors.forename: Ulrike B S
authors.initials: UB
authors.lastname: Hedrich
authors.forename: Snezana
authors.initials: S
authors.lastname: Maljevic
authors.forename: Pierre
authors.initials: P
authors.lastname: Szepetowski
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D004569:Electroencephalography / Q000379:methods; D020936:Epilepsy, Benign Neonatal / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008270:Madagascar; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics; D010375:Pedigree
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human
keywords: Epilepsy; Genetics; Infantile seizures; Ion channel; Sodium channel