Are generalized and localization-related epilepsies genetically distinct?

BACKGROUND Whether the genetic influences are distinct for generalized and localization-related epilepsies or whether some susceptibility genes raise the risk for both types of epilepsy is uncertain. OBJECTIVE To evaluate genetic heterogeneity in epilepsy. METHODS We used Cox proportional hazards analysis to compute rate ratios (RRs) for generalized and localization-related idiopathic or cryptogenic epilepsy in the first-degree relatives of 1498 adult probands with idiopathic or cryptogenic epilepsy ascertained from voluntary organizations. The reference group comprised the first-degree relatives of 362 probands from the same study with postnatal symptomatic epilepsy in whom the genetic contributions appear to be minimal. RESULTS In the parents and siblings, the risk for all idiopathic or cryptogenic epilepsy was greater if the proband's epilepsy was generalized than if it was localization-related (RR, 4.7 vs 2.4). However, in the parents and siblings of each group of probands, the increased risk was not restricted to the same type of epilepsy as in the proband. The results differed in offspring, with a greater risk for all types of epilepsy if the proband's epilepsy was localization-related than if it was generalized (RR, 4.2 vs 1.6) and a greater risk for localization-related epilepsy than for generalized epilepsy (RR, 7.8 vs 1.8) if the proband's epilepsy was localization-related. CONCLUSIONS These findings in parents and siblings suggest that some susceptibility genotypes raise the risk for both generalized and localization-related epilepsies but are more common in persons affected with generalized epilepsy. The different findings in offspring may reflect a different influence on susceptibility in that subgroup.