title: Early onset epileptic encephalopathy caused by de novo SCN8A mutations.
abstract: OBJECTIVE
  De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs).
  
  
  METHODS
  A total of 163 patients with EOEEs without mutations in known genes, including 6 with malignant migrating partial seizures in infancy (MMPSI), and 60 with unclassified EOEEs, were analyzed by target capture (28 samples) or whole-exome sequencing (135 samples).
  
  
  RESULTS
  We identified de novo SCN8A mutations in 7 patients: 6 of 60 unclassified EOEEs (10.0%), and one of 6 MMPSI cases (16.7%). The mutations were scattered through the entire gene: four mutations were located in linker regions, two in the fourth transmembrane segments, and one in the C-terminal domain. The type of the initial seizures was variable including generalized tonic-clonic, atypical absence, partial, apneic attack, febrile convulsion, and loss of tone and consciousness. Onset of seizures was during the neonatal period in two patients, and between 3 and 7 months of age in five patients. Brain magnetic resonance imaging (MRI) showed cerebellar and cerebral atrophy in one and six patients, respectively. All patients with SCN8A missense mutations showed initially uncontrollable seizures by any drugs, but eventually one was seizure-free and three were controlled at the last examination. All patients showed developmental delay or regression in infancy, resulting in severe intellectual disability.
  
  
  CONCLUSIONS
  Our data reveal that SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified EOEEs, and rarely as MMPSI. Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy.
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan; Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ohba
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Terashima
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kawawaki
authors.forename: Mayumi
authors.initials: M
authors.lastname: Matsufuji
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kojima
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tateno
authors.forename: Hadassa
authors.initials: H
authors.lastname: Goldberg-Stern
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.forename: Dafna
authors.initials: D
authors.lastname: Marom
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D042241:Early Diagnosis; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D013036:Spasms, Infantile / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; C100681:SCN8A protein, human
keywords: De novo mutation; Early onset epileptic encephalopathies; SCN8A