An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na+ current

• Published in: Epilepsia (Copenhagen) Vol. 54; no. 9; pp. e117 - e121
• Main Authors: Lauxmann, Stephan, Boutry‐Kryza, Nadia, Rivier, Clotilde, Mueller, Stephan, Hedrich, Ulrike B. S., Maljevic, Snezana, Szepetowski, Pierre, Lerche, Holger, Lesca, Gaetan
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2013
• Subjects: Action Potentials - genetics; Action Potentials - physiology; Electroencephalography - methods; Epilepsy; Epilepsy, Benign Neonatal - genetics; Epilepsy, Benign Neonatal - physiopathology; Female; Genetic Predisposition to Disease; Genetics; Humans; Infant; Infantile seizures; Ion channel; Madagascar; Male; Mutation, Missense - genetics; NAV1.2 Voltage-Gated Sodium Channel - genetics; Pedigree; Sodium channel; Madagascar; Genetics; Infantile seizures; Sodium channel; Ion channel; Epilepsy
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.12241

Summary Missense mutations in SCN2A, encoding the brain sodium channel NaV1.2, 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 NaV1.2 (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.