RESOLVING HETEROGENEITY IN EPILEPSY WITH GENETIC MARKERS

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Juvenile myoclonic epilepsy (JME) or the syndrome of Janz, is a clinically well-defined benign form of epilepsy that starts in adolescence. It is characterized by small myoclonic jerks, clonic-tonic-clonic-seizures, and a characteristic EEG feature -4-6 Hz multispike-wave complexes (4-6 Hz mS&W). JME occurs more frequently in the relatives of JME patients than in the general population, as do other forms of epilepsy. In addition, the 4-6 Hz mS&W and other EEG abnormalities occur in family members without epilepsy. JME is a common form of epilepsy, thought to represent about 100% of all epilepsies. We recently reported the finding of strong evidence for linkage of JME traits seen in relatives to the HLA and BF loci on chromosome 6. The lod score is over 3.0 no matter what mode of inheritance is assumed when we classify the abnormal EEGs seen in unaffected family members as "affected". The lod score also remains over 3.0 no matter how family members with non-JME epilepsy are classified. Under the most conservative classification (non-JME epilepsy considered "unaffected") the lod score is over 4.0 under recessive inheritance. A preliminary segregation analysis showed a two locus model for JME could be rejected. The current study is designed to confirm and further investigate the genetics of both JME and the relationship of JME to other generalized epilepsy. JME probands will be identified in clinics in the New York area. We will investigate the inheritance of JME and the EEG traits by analysis of the linkage marker data as well as by segregation analysis. We will gather data from 125 JME families over five years. In addition to the JmE families, we will collect data on 30 families identified through a patient with juvenile absence and 30 through a patient with tonic-clonic seizures. These data will allow us to test for heterogeneity between JME and other forms of epilepsy and to test whether a subgroup of those non- JME families map to chromosome 6. We will use HLA typing and restriction fragment length polymorphisms (RFLP) for mapping, with RFLP probes derived initially from the around the HLA region. We will look for genetic linkage markers closer to the locus for JME and the EEG traits. The identification of a genetic marker for JME has given a new focus to basic studies on the classification and mechanisms of the epilepsies. The identification of a gene involved in the expression of a common form of epilepsy means that we can now use that gene locus as a probe to identify other epilepsies whose expression may be influenced by the same gene locus. This means that we now have a way of classifying the generalized epilepsies based on etiology rather than non-specific clinical symptoms. Also, the identification of a gene involved in abnormal EEGs means that, once the gene product is known, a basic aspect of the working of the brain can be investigated.