Elena Gardella1,2, Felicitas Becker3, Rikke S Møller1,2, Julian Schubert3, Johannes R Lemke4, Line H G Larsen5, Hans Eiberg6, Michael Nothnagel7, Holger Thiele7, Janine Altmüller7, Steffen Syrbe8, Andreas Merkenschlager8, Thomas Bast9, Bernhard Steinhoff9, Peter Nürnberg7, Yuan Mang10, Louise Bakke Møller1, Pia Gellert1, Sarah E Heron11,12, Leanne M Dibbens11,12, Sarah Weckhuysen13,14, Hans Atli Dahl5, Saskia Biskup3, Niels Tommerup10, Helle Hjalgrim1,2, Holger Lerche3, Sándor Beniczky1,15, Yvonne G Weber3. 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.
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.
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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