Genetic Testing in Benign Familial Epilepsy in the First Year of Life: Clinical and Diagnostic Significance

In the journal Epilepsia early view, Drs. Zara and colleagues, representing a large consortium of investigators throughout Italy, report the diagnostic and clinical significance of genetic testing for certain genes with the intent to assess the genetics of benign familial epilepsies that occur in the first year of life and assess the extent of the overlap between the benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS) and benign familial infantile seizures (BFIS).

Families with at least two first degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included in this study. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures of family members was between one and four months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after four months of age in all family members. SCN2A, KNCNQ2, KCNQ3, PPRT2 point mutations were analyzed with sequencing of DNA.

Forty-six (46) families including 165 affected individuals were evaluated and it led to identification of 41 mutations; 14 affecting KCNQ2, one affecting KCNQ3, five affecting SCN2A and 21 affecting PRRT2. In BFNS mutations specifically involved KCNQ2; in BFNIS two genes are involved, KCNQ2 and SCN2A; and BFIS families are the most genetically heterogenous with all four genes involved, although 70% of them carry PRRT2 mutations.

The investigators concluded the role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures is associated with KCNQ2 mutations and may represent a predictive factor. KCNQ3 mutations may be involved in families with infantile seizures. In summary, all that points to an important role of potassium channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6-8 months provides further confirmation that the gene is not specifically associated with BFNIS and also involved in families with a delayed age of onset. The data also indicated that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families. The age of onset of seizures is correlated with underlying genetics as about 90% atypical BFNS families are linked to KCNQ2 compared to only 3% of BFIS families for which PRRT2 represents the major gene.

This data is quite important. It helps to illuminate the genetic underpinnings of a complex set of epilepsies that occur in the very young. This highlights, once again, the importance of keeping up-to-date with various genetics discoveries as they quickly translate into the clinical sphere and secondly to understand that we also need to continue to work through how these genetic discoveries impact therapeutic choices with regards to the armamentarium of drugs that are currently available.