Premium
An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold N a + current
Author(s) -
Lauxmann Stephan,
BoutryKryza Nadia,
Rivier Clotilde,
Mueller Stephan,
Hedrich Ulrike B. S.,
Maljevic Snezana,
Szepetowski Pierre,
Lerche Holger,
Lesca Gaetan
Publication year - 2013
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12241
Subject(s) - missense mutation , ictal , epilepsy , nonsense mutation , mutation , sodium channel , gating , medicine , neuroscience , biology , endocrinology , genetics , chemistry , sodium , organic chemistry , gene
Summary Missense mutations in SCN2A , encoding the brain sodium channel Na V 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 EEG s 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 V 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 N a + 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 N a + 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.