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 three conditions, found to be mutated in 80-90% of familial and 30-35% 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 clinico-neurophysiological workup.
RESULTS: In three families with a total of 16 affected members, we identified the same, co-segregating 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 but one 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-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 EEG was normal in all cases but two. Five/16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or "shivering" attacks, triggered by stretching, motor initiation or by emotional stimuli. In one 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. This article is protected by copyright. All rights reserved.