title: The phenotypic spectrum of SCN8A encephalopathy.
abstract: OBJECTIVE
  SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations.
  
  
  METHODS
  We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data.
  
  
  RESULTS
  Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges.
  
  
  CONCLUSIONS
  SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent.
authors.forename: Jan
authors.initials: J
authors.lastname: Larsen
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Carvill
authors.forename: Elena
authors.initials: E
authors.lastname: Gardella
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kluger
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schmiedel
authors.forename: Nina
authors.initials: N
authors.lastname: Barisic
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Eva
authors.initials: E
authors.lastname: Brilstra
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mang
authors.forename: Jens Erik Klint
authors.initials: JE
authors.lastname: Nielsen
authors.forename: Martin
authors.initials: M
authors.lastname: Kirkpatrick
authors.forename: David
authors.initials: D
authors.lastname: Goudie
authors.forename: Rebecca
authors.initials: R
authors.lastname: Goldman
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Jähn
authors.forename: Birgit
authors.initials: B
authors.lastname: Jepsen
authors.forename: Deepak
authors.initials: D
authors.lastname: Gill
authors.forename: Miriam
authors.initials: M
authors.lastname: Döcker
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Jacinta M
authors.initials: JM
authors.lastname: McMahon
authors.forename: Bobby
authors.initials: B
authors.lastname: Koeleman
authors.forename: Mandy
authors.initials: M
authors.lastname: Harris
authors.forename: Kees
authors.initials: K
authors.lastname: Braun
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Nicola
authors.initials: N
authors.lastname: Specchio
authors.forename: Tania
authors.initials: T
authors.lastname: Djémié
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.forename: Monica
authors.initials: M
authors.lastname: Troncoso
authors.forename: Ledia
authors.initials: L
authors.lastname: Troncoso
authors.forename: Andrea
authors.initials: A
authors.lastname: Bevot
authors.forename: Markus
authors.initials: M
authors.lastname: Wolff
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
mesh_terms: D000293:Adolescent; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D038622:Internationality; D008297:Male; D009154:Mutation / Q000235:genetics*; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; C100681:SCN8A protein, human