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- Title
Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation.
- Authors
Gardella, Elena; Becker, Felicitas; Møller, Rikke S.; Schubert, Julian; Lemke, Johannes R.; Larsen, Line H. G.; Eiberg, Hans; Nothnagel, Michael; Thiele, Holger; Altmüller, Janine; Syrbe, Steffen; Merkenschlager, Andreas; Bast, Thomas; Steinhoff, Bernhard; Nürnberg, Peter; Mang, Yuan; Bakke Møller, Louise; Gellert, Pia; Heron, Sarah E.; Dibbens, Leanne M.
- Abstract
<bold>Objective: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Interpretation: </bold>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.
- Subjects
DIAGNOSIS of epilepsy; CHOREA; DISEASE susceptibility; EPILEPSY; GENETIC polymorphisms; GENETIC mutation; MEMBRANE transport proteins; DIAGNOSIS
- Publication
Annals of Neurology, 2016, Vol 79, Issue 3, p428
- ISSN
0364-5134
- Publication type
journal article
- DOI
10.1002/ana.24580