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Case Reports
. 2013 Sep;54(9):e117-21.
doi: 10.1111/epi.12241. Epub 2013 Jun 12.

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

Stephan Lauxmann  1 , Nadia Boutry-Kryza, Clotilde Rivier, Stephan Mueller, Ulrike B S Hedrich, Snezana Maljevic, Pierre Szepetowski, Holger Lerche, Gaetan Lesca
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Free article
Case Reports

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

Stephan Lauxmann et al. Epilepsia. 2013 Sep.
Free article

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.

Keywords: Epilepsy; Genetics; Infantile seizures; Ion channel; Sodium channel.

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