Recent advances in the neurosciences, in seizure classification procedures and in genetic methodologies have provided important new tools for elucidating the importance of genetic, maternal and environmental factors in risk for epilepsy. While it has been possible to conclusively demonstrate that genetic factors influence seizure susceptibility in three forms of epilepsy (benign neonatal, juvenile myoclonic and progressive myoclonus), the contribution of genotype to seizure risk for most forms of epilepsy is unknown. Objectives of the proposed study are to identify and resolve the roles of genetic, maternal and environmental factors in the etiology of seizures and specific epileptic syndromes and to examine the role of the epilepsy phenotype in risk for congenital malformations among offspring of seizure-affected individuals utilizing data on seizure history and history of congenital malformations among the offspring of twin pairs included in the population-based Virginia Twin Registry and Norwegian Twin Panel. These registries, developed from vital records, currently contain information on over 21 ,000 adult twin pairs and their families. The proposed study will focus on the over 800 adult twin pairs reporting seizures in one or both pair members, the estimated 350 young twins to be identified by surveying their parents, the over 800 twin kindreds reporting seizures in one or more offspring of twins but not in the twins themselves and a group of age, sex, race, and zygosity matched controls. Data pertinent to the occurrence of seizures in controls and to the occurrence and type of seizures occurring in affected individuals will be collected for analysis. Detailed information on reproductive history in affected twin pairs, including that on congenital malformations in offspring will also be collected. Cases will be coded for family membership and validated using medical records. Coded cases will be classified for seizure/epilepsy type using the International Classifications of Seizures and of Epilepsy and Epileptic Syndromes. The unique family structure of the data set to be collected will permit the use of several different methodological approaches in evaluating the hypotheses put forth in this study. Standard epidemiologic methods will be used to examine the role of specific demographic factors on seizure occurrence. The importance of genetic and maternal factors in determining risk for epilepsy and specific epileptic syndromes and the role of the epilepsy phenotype in risk for congenital malformations in offspring will be assessed using classical twin and cotwin control studies. Logistic regression techniques will be used in more detailed analyses of the importance of genetic, maternal and environmental factors on seizure risk.
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