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Neurology. 2009 Sep 29;73(13):1046-53. doi: 10.1212/WNL.0b013e3181b9cebc.

De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies.

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  • 1Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Saitama, Japan.

Abstract

BACKGROUND:

Mutations of voltage-gated sodium channel alpha(II) gene, SCN2A, have been described in a wide spectrum of epilepsies. While inherited SCN2A mutations have been identified in multiple mild epilepsy cases, a de novo SCN2A-R102X mutation, which we previously reported in a patient with sporadic intractable childhood localization-related epilepsy, remains unique. To validate the involvement of de novo SCN2A mutations in the etiology of intractable epilepsies, we sought to identify additional instances.

METHODS:

We performed mutational analyses on SCN2A in 116 patients with severe myoclonic epilepsy in infancy, infantile spasms, and other types of intractable childhood partial and generalized epilepsies and did whole-cell patch-clamp recordings on Na(v)1.2 channels containing identified mutations.

RESULTS:

We discovered 2 additional de novo SCN2A mutations. One mutation, SCN2A-E1211K, was identified in a patient with sporadic infantile spasms. SCN2A-E1211K produced channels with altered electrophysiologic properties compatible with both augmented (an approximately 18-mV hyperpolarizing shift in the voltage dependence of activation) and reduced (an approximately 22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation) channel activities. The other de novo mutation, SCN2A-I1473M, was identified in a patient with sporadic neonatal epileptic encephalopathy. SCN2A-I1473M caused an approximately 14-mV hyperpolarizing shift in the voltage dependence of activation.

CONCLUSIONS:

The identified de novo mutations SCN2A-E1211K, -I1473M, and -R102X indicate that SCN2A is an etiologic candidate underlying a variety of intractable childhood epilepsies. The phenotypic variations among patients might be due to the different electrophysiologic properties of mutant channels.

Comment in

PMID:
19786696
[PubMed - indexed for MEDLINE]
PMCID:
PMC2754324
Free PMC Article
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