De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy.

Severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) is a rare disorder occurring in young children often without a family history of a similar disorder. The earliest disease manifestations are usually fever-associated seizures. Later in life, patients display different types of afebrile seizures including myoclonic seizures. Arrest of psychomotor development occurs in the second year of life and most patients become ataxic. Patients are resistant to antiepileptic drug therapy. Recently, we described de novo mutations of the neuronal sodium channel alpha-subunit gene SCN1A in seven isolated SMEI patients. To investigate the contribution of SCN1A mutations to the etiology of SMEI, we examined nine additional SMEI patients. We observed eight coding and one noncoding mutation. In contrast to our previous study, most mutations are missense mutations clustering in the S4-S6 region of SCN1A. These findings demonstrate that de novo mutations in SCN1A are a major cause of isolated SMEI.