title: A missense mutation in SCN1A in brothers with severe myoclonic epilepsy in infancy (SMEI) inherited from a father with febrile seizures.
abstract: Severe myoclonic epilepsy in infancy (SMEI) is an age-dependent epileptic encephalopathy occurring in the first year of life and is one of the intractable epilepsies. Heterozygous mutations in the voltage-gated sodium channel alpha subunit type1 gene (SCN1A) are frequently identified in patients with SMEI; two-thirds of these mutations are truncation mutations (non-sense and frameshift), and one-third are missense mutations. Although most reported SMEI cases arise as sporadic mutations, close relatives of SMEI patients have also been shown to manifest other types of epilepsies at a higher rate than that in the general population. Here, we report a familial case of SMEI, in which two brothers were affected with SMEI while their father had previously experienced simple febrile seizures. A gene-based analysis identified a novel missense mutation in the SCN1A gene (c.5138G>A, S1713N) in both brothers and in their father. Clinically, both siblings showed failure in locomotion, an impairment of the sleep-wake cycle after late infancy, and the subsequent appearance of frontal foci. The similarity in clinical manifestations in both brothers suggests that the impairment of elements of the brainstem, particularly aminergic neurons, develops after late infancy in SMEI. However, the siblings differed in age at onset of SMEI and of myoclonic seizures, as well as in the severity of speech delay. Our molecular and clinical findings suggest that different genetic backgrounds and/or environmental factors may critically affect the clinical features of patients with SCN1A mutations, consistent with the heterogeneity prevalent in this disorder.
authors.affiliation: Segawa Neurological Clinic for Children, 2-8 Surugadai Kanda, Chiyoda-ku, Tokyo 101-0062, Japan. segawa@t3.rim.or.jp
authors.forename: Kazue
authors.initials: K
authors.lastname: Kimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugawara
authors.forename: Emi
authors.initials: E
authors.lastname: Mazaki-Miyazaki
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hoshino
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nomura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tateno
authors.forename: Kei
authors.initials: K
authors.lastname: Hachimori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamakawa
authors.forename: Masaya
authors.initials: M
authors.lastname: Segawa
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics*; D005220:Fathers; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D003294:Seizures, Febrile / Q000235:genetics*; D012720:Severity of Illness Index; D035781:Siblings; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels