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

Missense mutations in SCN2A, encoding the brain sodium channel Na_V1.2, 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 Na_V1.2 (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. [ABSTRACT FROM AUTHOR]