title: Missense mutations in sodium channel SCN1A and SCN2A predispose children to encephalopathy with severe febrile seizures.
abstract: OBJECTIVE
  Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood encephalopathy following severe febrile seizures. The pathogenesis of AESD is considered to be fever-induced seizure susceptibility and excitotoxicity, which may be caused by sodium channel dysfunction in some cases. Here we studied whether mutations in genes encoding sodium channels, SCN1A and SCN2A, predispose children to AESD.
  
  
  METHODS
  We recruited 92 AESD patients in a nationwide survey of acute encephalopathy in Japan from 2008 to 2011. We collected their genomic DNA samples, and sequenced the entire coding region of SCN1A and SCN2A.
  
  
  RESULTS
  Five out of 92 patients (5.4%) had missense mutations either in SCN1A or SCN2A. After a preceding infection with fever, all the patients showed status epilepticus at the onset. Hemiconvulsion-hemiplegia was recognized in three patients during the acute/subacute phase. One patient had taken theophylline for the treatment of bronchial asthma just before the onset of AESD. Familial history was not remarkable except one patient with a SCN1A mutation (G1647S) whose mother had a similar episode of AESD in her childhood. A different substitution (G1674R) at the same amino acid position, as well as two other SCN1A mutations found in this study, had previously been reported in Dravet syndrome. Another SCN1A mutation (R1575C) had been detected in other types of acute encephahlitis/encephalopathy. One patient had SCN2A mutation, F328V, which had previously been reported in Dravet syndrome. Another SCN2A mutation, I172V, was novel. None of the patients were diagnosed with Dravet syndrome or genetic (generalized) epilepsy with febrile seizure plus in the following-up period.
  
  
  CONCLUSIONS
  Mutations in SCN1A and SCN2A are a predisposing factor of AESD. Altered channel activity caused by these mutations may provoke seizures and excitotoxic brain damage.
authors: Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: makisaito-tky@umin.ac.jp.
authors: Makiko
authors: M
authors: Saitoh
authors: Department of Pediatrics, Fukuoka University, Fukuoka, Japan.
authors: Atsushi
authors: A
authors: Ishii
authors: Department of Pediatrics, Fukuoka University, Fukuoka, Japan.
authors: Yukiko
authors: Y
authors: Ihara
authors: Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Ai
authors: A
authors: Hoshino
authors: Division of Neurology, National Center for Child Health and Development, Tokyo, Japan.
authors: Hiroshi
authors: H
authors: Terashima
authors: Division of Neurology, National Center for Child Health and Development, Tokyo, Japan.
authors: Masaya
authors: M
authors: Kubota
authors: Division of Neurology, Saitama Children's Medical Center, Saitama, Japan.
authors: Kenjiro
authors: K
authors: Kikuchi
authors: Department of Pediatrics, Tokyo Medical University, Tokyo, Japan.
authors: Gaku
authors: G
authors: Yamanaka
authors: Department of Pediatrics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
authors: Kaoru
authors: K
authors: Amemiya
authors: Department of Pediatrics, Fukuoka University, Fukuoka, Japan.
authors: Shinichi
authors: S
authors: Hirose
authors: Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Masashi
authors: M
authors: Mizuguchi
mesh_terms: D001927:Brain Diseases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; C568251:SCN2A protein, human
keywords: Acute encephalopathy; Status epilepticus; Voltage-gated sodium channels