Genetics of the epilepsies: Genetic twists in the channels and other tales

Abstract

Recent studies of the genetics of the epilepsies have identified surprising mechanisms and novel patterns of inheritance. The greatest challenge is to solve the genetics of the common idiopathic generalized epilepsies (IGEs). The common IGEs follow complex inheritance, where multiple genes are likely to contribute and environmental factors may also play a role. Little is known about the susceptibility genes contributing to complex inheritance, although there is evidence that the calcium channel subunit gene, CACNA1H, and another gene whose function is poorly understood, EFHC1, play a role (Helbig et al., 2008). In contrast, the 19 or so genes identified for idiopathic epilepsies have largely been found in monogenic epilepsies, often in large multiplex families. Most of these encode ion channels encompassing both voltage-gated and ligand-gated ion channel subunits. More recently, unexpected inheritance patterns have emerged. The most important is that a severe epileptic encephalopathy of infancy, Dravet syndrome, has turned out to be a monogenic disease. Second, an unrecognized, major group of IGEs called genetic epilepsy with febrile seizures plus (GEFS+) has become a model of ‘‘complex monogenic’’ epilepsy, exemplified in large dominant families in which genes have been found. The dominant genes are not the whole story in these families, as the heterogenous phenotypes are likely to be due to additional genetic factors. Third, the molecular basis for a fascinating novel mode of inheritance in epilepsy has been discovered for a familial epilepsy in which only females are affected. This X-linked inheritance pattern requires clinicians to think differently about the family histories they obtain.