TY - JOUR

T1 - Benign Infantile Seizures and Paroxysmal Dyskinesia Caused by an SCN8A Mutation

AU - Gardella, Elena

AU - Becker, Felicitas

AU - Moller, Rikke S.

AU - Schubert, Julian

AU - Lemke, Johannes R.

AU - Larsen, Line H. G.

AU - Eiberg, Hans

AU - Nothnagel, Michael

AU - Thiele, Holger

AU - Altmueller, Janine

AU - Syrbe, Steffen

AU - Merkenschlager, Andreas

AU - Bast, Thomas

AU - Steinhoff, Bernhard

AU - Nuernberg, Peter

AU - Mang, Yuan

AU - Moller, Louise Bakke

AU - Gellert, Pia

AU - Heron, Sarah E.

AU - Dibbens, Leanne M.

AU - Weckhuysen, Sarah

AU - Dahl, Hans Atli

AU - Biskup, Saskia

AU - Tommerup, Niels

AU - Hjalgrim, Helle

AU - Lerche, Holger

AU - Beniczky, Sandor

AU - Weber, Yvonne G.

PY - 2016/3

Y1 - 2016/3

N2 - 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.

AB - 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.

U2 - 10.1002/ana.24580

DO - 10.1002/ana.24580

M3 - Journal article

C2 - 26677014

VL - 79

SP - 428

EP - 436

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 3

ER -