title: Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Danish Epilepsy Center-Filadelfia, Dianalund, Denmark.|Institute of Regional Health Research, University of South Denmark, Odense, Denmark.
authors.forename: Elena
authors.initials: E
authors.lastname: Gardella
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Becker
authors.affiliation: Danish Epilepsy Center-Filadelfia, Dianalund, Denmark.|Institute of Regional Health Research, University of South Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schubert
authors.affiliation: Institute of Human Genetics, University Hospitals, University of Leipzig, Leipzig, Germany.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.affiliation: Amplexa Genetics, Odense, Denmark.
authors.forename: Line H G
authors.initials: LH
authors.lastname: Larsen
authors.affiliation: RC-LINK, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Department of Woman and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Syrbe
authors.affiliation: Department of Woman and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Merkenschlager
authors.affiliation: Epilepsy Center Kork, Kork, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bast
authors.affiliation: Epilepsy Center Kork, Kork, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Steinhoff
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Wilhelm Johannsen Center for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mang
authors.affiliation: Danish Epilepsy Center-Filadelfia, Dianalund, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Bakke Møller
authors.affiliation: Danish Epilepsy Center-Filadelfia, Dianalund, Denmark.
authors.forename: Pia
authors.initials: P
authors.lastname: Gellert
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Heron
authors.affiliation: Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.affiliation: Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Amplexa Genetics, Odense, Denmark.
authors.forename: Hans Atli
authors.initials: HA
authors.lastname: Dahl
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.affiliation: Wilhelm Johannsen Center for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: Danish Epilepsy Center-Filadelfia, Dianalund, Denmark.|Institute of Regional Health Research, University of South Denmark, Odense, Denmark.
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: Danish Epilepsy Center-Filadelfia, Dianalund, Denmark.|Department of Clinical Neurophysiology, Aarhus University, Aarhus, Denmark.
authors.forename: Sándor
authors.initials: S
authors.lastname: Beniczky
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Weber
mesh_terms: D002648:Child; D002675:Child, Preschool; D002819:Chorea / Q000175:diagnosis / Q000235:genetics*; D020936:Epilepsy, Benign Neonatal / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; C100681:SCN8A protein, human