Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation

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Item Type:	Article
Title:	Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation
Creators Name:	Gardella, E., Becker, F., Møller, R.S., Schubert, J., Lemke, J.R., Larsen, L.H.G., Eiberg, H., Nothnagel, M., Thiele, H., Altmüller, J., Syrbe, S., Merkenschlager, A., Bast, T., Steinhoff, B., Nürnberg, P., Mang, Y., Bakke Møller, L., Gellert, P., Heron, S.E., Dibbens, L.M., Weckhuysen, S., Dahl, H.A., Biskup, S., Tommerup, N., Hjalgrim, H., Lerche, H., Beniczky, S. and Weber, Y.G.
Abstract:	OBJECTIVE: Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination—known as infantile convulsions and paroxysmal choreoathetosis (ICCA)—are related autosomal dominant diseases. PRRT2 (proline-rich transmembrane protein 2 gene) has been identified as the major gene in all 3 conditions, found to be mutated in 80 to 90% of familial and 30 to 35% of sporadic cases. METHODS: We searched for the genetic defect in PRRT2-negative, unrelated families with BFIS or ICCA using whole exome or targeted gene panel sequencing, and performed a detailed cliniconeurophysiological workup. RESULTS: In 3 families with a total of 16 affected members, we identified the same, cosegregating heterozygous missense mutation (c.4447G>A; p.E1483K) in SCN8A, encoding a voltage-gated sodium channel. A founder effect was excluded by linkage analysis. All individuals except 1 had normal cognitive and motor milestones, neuroimaging, and interictal neurological status. Fifteen affected members presented with afebrile focal or generalized tonic–clonic seizures during the first to second year of life; 5 of them experienced single unprovoked seizures later on. One patient had seizures only at school age. All patients stayed otherwise seizure-free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or “shivering” attacks, triggered by stretching, motor initiation, or emotional stimuli. In 1 case, we recorded typical PKD spells by video-EEG-polygraphy, documenting a cortical involvement. INTERPRETATION: Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical–genetic spectrum of combined epileptic and dyskinetic syndromes.
Keywords:	Benign Neonatal Epilepsy, Chorea, Genetic Predisposition to Disease, Mutation, NAV1.6 Voltage-Gated Sodium Channel, Single Nucleotide Polymorphism
Source:	Annals of Neurology
ISSN:	0364-5134
Publisher:	Wiley
Volume:	79
Number:	3
Page Range:	428-436
Date:	March 2016
Official Publication:	https://doi.org/10.1002/ana.24580
PubMed:	View item in PubMed

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