Investigators at Instituto G Gaslini, Genova, Italy and multiple other centers in Italy studied the genetics of benign familial epilepsies of the first year of life and assessed the extent of the genetic overlap between neonatal and infantile seizure syndromes. Families with at least two first-degree relatives affected by focal seizures with onset in the first year of life and normal development before seizure onset were included. A total of 46 families including 165 affected members were collected and were classified as benign familial neonatal seizures (BFNS) in 8 families, benign familial neonatal-infantile seizures (BFNIS) in 9 (1-4 months of age at onset), and benign familial infantile seizures (BFIS) in 29 (onset after 4 months of age in all family members). Genetic analysis identified 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in this cohort was 89%. Mutations specifically involve KCNQ2 in BFNS, KCNQ2 (6 families) and SCN2A (two families) in BFNIS. BFIS families are most genetically heterogeneous, with all 4 genes involved, 70% carrying a PRRT2 mutation. PRRT2 mutations are clustered in families with BFIS and also, with paroxysmal kinesigenic dyskinesia.

KCNQ2 mutation is frequently represented in the entire spectrum of disorders, progressively decreasing with age, and may be predictive of afebrile seizures during follow-up, beyond the typical neonatal seizures. Age of onset of seizures is significantly correlated with genetics: 90% of BFNS families are linked to KCNQ2 compared to only 3% of BFIS families. [1]

COMMENT. Mutational screening for neonatal and infantile seizures should involve KCNQ2 in both BFNS and BFNIS, and PRRT2 in BFIS families. A clear clinical classification of the seizure phenotype is an essential preliminary to genetic analysis. In addition to confirming a clinical diagnosis, a positive SCN1A mutation will influence treatment and improve seizure control. [2]