Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation
Autor/innen
- 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
Journal
- Annals of Neurology
Quellenangabe
- Ann Neurol 79 (3): 428-436
Zusammenfassung
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.