Brain, Vol. 126, No. 3, 531-546,
March 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg053
Mutations of sodium channel 
subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic–clonic seizures
1 National Epilepsy Centre, Shizuoka Medical Institute of Neurological Disorders, Shizuoka, 2 Laboratory for Neurogenetics, RIKEN, Brain Science Institute, Saitama and 3 Department of Pediatrics, Gifu Prefectural Gifu Hospital, Gifu, Japan
Correspondence to: Yushi Inoue, MD, PhD, National Epilepsy Center, Shizuoka Medical Institute of Neurological Disorders, 886 Urushiyama, Shizuoka, 420–8688, Japan E-mail: shizuoka{at}szec.hosp.go.jp or Kazuhiro Yamakawa, PhD, Laboratory for Neurogenetics, RIKEN Brain Science Institute, Hirosawa 2–1, Wako-shi, Saitama 351–0198, Japan E-mail: yamakawa{at}brain.riken.go.jp
A group of infant onset epilepsies manifest very frequent generalized tonic–clonic seizures (GTC) intractable to medical therapy, which may or may not be accompanied by minor seizures such as myoclonic seizures, absences and partial seizures. They include severe myoclonic epilepsy in infancy (SMEI) and intractable childhood epilepsy with GTC (ICEGTC). They are commonly associated with fever-sensitivity, family history of seizure disorders and developmental decline after seizure onset. Mutations of the neuronal voltage-gated sodium channel 
subunit type 1 gene (SCN1A) were recently reported in SMEI patients. To clarify the genotypic differences in this group of epilepsies, we searched for SCN1A abnormalities in 25 patients with SMEI and 10 with ICEGTC, together with the family members of 15 patients. Frameshift mutations in SCN1A were observed in four patients, nonsense mutations in five patients, missense mutations in 21 patients, other mutations in two patients and no mutation in five patients. SMEI patients showed nonsense mutations, frameshifts, or missense mutations, while ICEGTC patients showed only missense mutations. Study of both parents of 11 patients revealed that the mutations in these patients were de novo. However, two mothers had the same missense mutations as their ICEGTC children, and they had generalized epilepsy with febrile seizures plus. Here we suggest that SMEI and ICEGTC represent a continuum with minor phenotypic and genotypic differences.
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