Genetic Influences on Risk for Epilepsy

An inherited contribution to the etiology of epilepsy has been suspected for centuries. Until recently, however, little progress has been made in identifying the specific genetic influences on susceptibility to seizures. This slow progress is partly due to underlying complexity in the genetic contributions. The epilepsies are etiologically and clinically heterogeneous, and genetic influences appear to have primary importance in only a subset of patients. Moreover, many different genetic mechanisms may influence risk for epilepsy in different families or different syndromes. Some of these mechanisms involve major effects of single genes, producing simple patterns of inheritance in families (autosomal or X-linked, dominant or recessive). Other mechanisms probably involve the combined effects of multiple genes and environmental factors, each with a smaller effect on susceptibility to seizures. The important genetic mechanisms clearly differ across some clinically defined epilepsy syndromes, but the relationship between clinical syndrome and genetic mechanism is not straightforward. Risk for a single syndrome is sometimes influenced by different genetic mechanisms in different families; conversely, a single genetic mechanism may influence risk for different syndromes within the same family. Approximately 25 percent of prevalent epilepsy is associated with an antecedent central nervous system (CNS) injury (e.g., head trauma, stroke, or brain infection) and accordingly is classified as ‘‘symptomatic’’ (1). The remainder without identified cause is assigned into two broad classes by the current International Classification of Epileptic Syndromes (2): ‘‘idiopathic,’’ reserved for syndromes of presumed genetic origin, and ‘‘cryptogenic’’ for syndromes presumed to be nongenetic but with insufficient evidence to assign a specific etiology. The current system of classification is problematic, however, because idiopathic and cryptogenic epilepsies are not easily distinguishable in terms of the importance of genetic susceptibility. For most of the syndromes currently classified as ‘‘idiopathic,’’ clear evidence of a genetic basis, either from linkage studies or from demonstration of a specific mode of inheritance, is lacking. Similarly, in syndromes classified as ‘‘cryptogenic,’’ a genetic contribution to etiology cannot be ruled out.