SCN2A sodium channel gene was analyzed in 2 families with probable benign familial neonatal-infantile seizures (BFNISs), 9 with possible BFNIS, 10 with benign familial infantile seizures, and in 93 additional families with various early childhood epilepsies, in a study at the University of Melbourne, Australia, and other international centers. Six different SCN2A mutations were found in 8 families and 56 affected individuals with BFNIS, and in no other family in the study. BFNIS is an autosomal dominant disorder that presents from day 2 to 7 months of age (mean, 11.2 +/- 9.2 weeks) with afebrile secondarily generalized partial seizures of varying frequency, from a few to clusters of many per day. Seizures completely remit by 12 months of age, with no recurrences in later childhood or adolescence. Interictal EEGs in the active phase were either normal or showed focal epileptiform discharges in posterior or central regions. Brain imaging was normal in 8 cases; one patient had a choroid plexus papilloma. SCN2A mutations are specific for BFNIS. [1]
COMMENT. Benign familial neonatal-infantile seizure disorder (BFNIS) with onset around 3 months is an intermediate variant of autosomal dominant benign epilepsies in the first year. Benign familial neonatal seizures (BFNS) begin around day 3 and benign familial infantile seizures (BFIS) begin around 6 months. BFNIS has now been linked to mutations in the sodium channel gene SCN2A (Heron et al, 2002; Berkovic 2004), BFNS is caused by defects in potassium channel genes KCNQ2 and KCNQ3 (Singh et al, 1998), and BFIS in one family is associated with a mutation in the ATP1A2 gene (Vanmolkot et al, 2003). BFNIS has characteristic clinical manifestations that allow early diagnosis and an excellent prognosis.
A total of 13 genes have been identified in human idiopathic epilepsies since 1995 [2]. Most of the known genes code for ion channels, but 2 are not channelopathies (MASS1/VLGR1 coding for a G-protein coupled receptor in one family with febrile and afebrile seizures, and LG11, a tumor suppressor gene, identified in several families with autosomal dominant (AD) familial lateral temporal lobe epilepsy) Other epilepsies with identified genes are AD familial nocturnal frontal lobe epilepsy (CHRNA4), generalized epilepsy with febrile seizures plus (SCN1A, SCN2A), severe myoclonic epilepsy of infancy (SCN1A), and juvenile myoclonic epilepsy (GABRA1). A large number of genetic factors probably contribute to seizure susceptibility.
The clinical spectrum of SCN1A mutations ranges from febrile seizures, febrile seizures plus, a mild and a classical form of severe myoclonic epilepsy in infancy (Dravet syndrome). [3]