Genetic heterogeneity in the epilepsies.

There is ample evidence for genetic and other heterogeneity in the mechanisms leading to epilepsy. Animal models of epilepsy show that genetic factors can influence the hypersensitivity of neurons. In the human, there are over 140 Mendelian traits (including disorders of amino acids, enzymes, hormones, and vasculature) that increase the risk of seizures. Furthermore, systems with an intermediate optimum (such as blood clotting and blood glucose) involve a number of mechanisms under independent genetic control, and it is reasonable to assume that the same principle applies to neuronal excitability. Finally, genetic variation can be expected in any of the factors that are altered in the origin of seizures: neuronal inhibition, inactivation of excitatory neurotransmitters, feedback control, and seizure generalization. One goal of future research is to define etiological subtypes on the basis of biochemical data or other factors. Meanwhile, it is possible to analyze currently available indicators of phenotypic variability (age at onset of seizures, family history of seizures, seizure type, EEG pattern, and history of antecedent factors such as fever or trauma) to address the following questions: Do any phenotypic groups have different sibling risks for seizures? How much phenotypic variability is seen among affected siblings of each defined group of probands (index cases)? Do any groups of probands show significant biochemical differences? Within a specific group, do isolated and familial cases show the same phenotype? Within a presumed single entity, will linkage marker studies show further heterogeneity? With such data in hand, certain strategies can be recommended. Complex segregation analysis of family data will permit a test of alternative models for genetic transmission. Linkage studies of selected large families (using recombinant DNA probes) will establish the genetic map location of any single-locus major factor. Selected samples of multiplex families (with several affected siblings) will concentrate the likelihood of genetic factors and will permit the detection of biochemical factors that might be significant in only a few families. Biochemical and other hypotheses can be tested in a panel of twin pairs concordant or discordant for epilepsy. The search for genetic heterogeneity clearly has implications for diagnosis, prognosis, therapy, and genetic counseling, as well as for other research studies on the basic mechanisms of the epilepsies.(ABSTRACT TRUNCATED AT 400 WORDS)