De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy

Severe myoclonic epilepsy of infancy (SMEI) is a rare disorder that occurs in isolated patients. The disease is characterized by generalized tonic, cl onic, and tonic-clonic seizures that are initially induced by fever and beg in during the first year of life. Later, patients also manifest other seizu re types, including absence, myoclonic, and simple and complex partial seiz ures. Psychomotor development stagnates around the second year of life. Mis sense mutations in the gene that codes for a neuronal voltage-gated sodium- channel alpha -subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ is a mild type of epile psy associated with febrile and afebrile seizures. Because both GEFS+ and S MEI involve fever-associated seizures, we screened seven unrelated patients with SMEI for mutations in SCN1A. We identified a mutation in each patient : four had frameshift mutations, one had a nonsense mutation, one had a spl ice-donor mutation, and one had a missense mutation. All mutations are de n ovo mutations and were not observed in 184 control chromosomes.