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Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia.
- Source :
-
Journal of neurology [J Neurol] 2016 Feb; Vol. 263 (2), pp. 334-343. Date of Electronic Publication: 2015 Dec 08. - Publication Year :
- 2016
-
Abstract
- Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na(+) current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.
- Subjects :
- Base Sequence
Blotting, Western
DNA Mutational Analysis
Female
Genotype
Humans
Infant, Newborn
Male
Molecular Sequence Data
Mutagenesis, Site-Directed
Patch-Clamp Techniques
Pedigree
Phenotype
Reverse Transcriptase Polymerase Chain Reaction
Ataxia genetics
Epilepsy genetics
Mutation, Missense
NAV1.2 Voltage-Gated Sodium Channel genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1432-1459
- Volume :
- 263
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of neurology
- Publication Type :
- Academic Journal
- Accession number :
- 26645390
- Full Text :
- https://doi.org/10.1007/s00415-015-7984-0