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Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity

From the Department of Neuropsychiatry (Drs. Kanai, Iwasa, and Kaneko), Hirosaki University School of Medicine, Aomori; Department of Pediatrics (Drs. Hirose, Fukuma, Yasumoto, and Mitsudome), Fukuoka University; Department of Pediatrics (Dr. Oguni), Tokyo Women’s Medical University; Kobe City General Hospital (Dr. Shirasaka); Department of Pediatrics (Dr. Miyajima), Tokyo Medical University; Department of Occupational Therapy (Dr. Wada), School of Health Science, Hirosaki University; Department of Pediatrics (Dr. Matsuo), Saga Medical School; Department of Pediatrics (Dr. Ito), Shiga Medical Center for Children; and Department of Neurology (Dr. Kanai), Chiba University School of Medicine, Japan.

Address correspondence and reprint requests to Dr. Kazuaki Kanai, Department of Neuropsychiatry, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036–8562, Japan; e-mail: VZR03355{at}nifty.ne.jp

Background and Methods: Many missense mutations in the voltage-gated sodium channel subunit gene SCN1A were identified in patients with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI), although GEFS+ is distinct from SMEI in terms of clinical symptoms, severity, prognosis, and responses to antiepileptic drugs. The authors analyzed the localization of missense mutations in SCN1A identified in patients with GEFS+ and SMEI to clarify the phenotype-genotype relationships.

Results: Mutations in SMEI occurred more frequently in the "pore" regions of SCN1A than did those in GEFS+. These SMEI mutations in the "pore" regions were more strongly associated than mutations in other regions with the presence of ataxia and tendency to early onset of disease. The possibility of participation of ion selectivity dysfunction of the channel in the pathogenesis of SMEI was suggested by a mutation in the pore region (R946C) identified in a SMEI patient.

Conclusions: There was a significant phenotype-genotype relationship in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy with SCN1A missense mutations. More severe sodium channel dysfunctions including abnormal ion selectivity that are caused by mutations in the pore regions may be involved in the pathogenesis of SMEI.

Received September 17, 2003. Accepted in final form March 18, 2004.

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