2. Academic Validation
  3. Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation

Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation

  • Ann Neurol. 2016 Mar;79(3):428-36. doi: 10.1002/ana.24580.
Elena Gardella 1 2,  Felicitas Becker 3,  Rikke S Møller 1 2,  Julian Schubert 3,  Johannes R Lemke 4,  Line H G Larsen 5,  Hans Eiberg 6,  Michael Nothnagel 7,  Holger Thiele 7,  Janine Altmüller 7,  Steffen Syrbe 8,  Andreas Merkenschlager 8,  Thomas Bast 9,  Bernhard Steinhoff 9,  Peter Nürnberg 7,  Yuan Mang 10,  Louise Bakke Møller 1,  Pia Gellert 1,  Sarah E Heron 11 12,  Leanne M Dibbens 11 12,  Sarah Weckhuysen 13 14,  Hans Atli Dahl 5,  Saskia Biskup 3,  Niels Tommerup 10,  Helle Hjalgrim 1 2,  Holger Lerche 3,  Sándor Beniczky 1 15,  Yvonne G Weber 3
Affiliations

Affiliations

  • 1 Danish Epilepsy Center-Filadelfia, Dianalund, Denmark.
  • 2 Institute of Regional Health Research, University of South Denmark, Odense, Denmark.
  • 3 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 4 Institute of Human Genetics, University Hospitals, University of Leipzig, Leipzig, Germany.
  • 5 Amplexa Genetics, Odense, Denmark.
  • 6 RC-LINK, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
  • 7 Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • 8 Department of Woman and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
  • 9 Epilepsy Center Kork, Kork, Germany.
  • 10 Wilhelm Johannsen Center for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
  • 11 Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
  • 12 Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
  • 13 Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
  • 14 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 15 Department of Clinical Neurophysiology, Aarhus University, Aarhus, Denmark.
PMID: 26677014 DOI: 10.1002/ana.24580
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.

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