Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation


  • E. Gardella
  • F. Becker
  • R.S. Møller
  • J. Schubert
  • J.R. Lemke
  • L.H.G. Larsen
  • H. Eiberg
  • M. Nothnagel
  • H. Thiele
  • J. Altmüller
  • S. Syrbe
  • A. Merkenschlager
  • T. Bast
  • B. Steinhoff
  • P. Nürnberg
  • Y. Mang
  • L. Bakke Møller
  • P. Gellert
  • S.E. Heron
  • L.M. Dibbens
  • S. Weckhuysen
  • H.A. Dahl
  • S. Biskup
  • N. Tommerup
  • H. Hjalgrim
  • H. Lerche
  • S. Beniczky
  • Y.G. Weber


  • Annals of Neurology


  • Ann Neurol 79 (3): 428-436


  • 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.