RESOLVING HETEROGENEITY IN EPILEPSY WITH GENETIC MARKERS

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This study will use linkage analysis to investigate the genetics of idiopathic generalized epilepsy (IGE), which accounts for more than 40% of all epilepsy. We will investigate three specific forms of IGE: juvenile myoclonic epilepsy (JME), epilepsy with awakening grand mal (AGM), and epilepsy with random grand mal (RGM). JME has been shown to be genetically linked to the HLA region of chromosome 6. This JME locus has been designated EJM-1. Because of the family characteristics of JME, it was thought that several other forms of IGC would be also be linked to the HLA locus. We tested this hypothesis during the last grant period. We found that RGM is apparently not linked to the HLA locus. However, AGM, although different from JME clinically, may be genetically identical. We have the following four goals for our further work on the genetics of IGE: 1. To test the hypothesis, developed in the last grant period, that AGM is linked to the HLA locus on chromosome 6. 2. To search for a gene locus that causes epilepsy with random grand mal (RGM) which we have shown to be genetically different from the clinically similar AGM and JME. 3. Simultaneously, to look for a second locus involved in the expression of all three forms of IGC. 4. To find flanking markers for the EJM-1 locus. We will recruit families identified through JME, RGM and AGM patients; collect blood, EEGs, and family histories from all family members; and type the subjects for markers throughout the genome. We will test for linkage of AGM to the HLA locus and test all three forms, but especially RGM, for linkage to a genetic marker. We will test specific candidate loci for linkage to any or all three forms of IGE. Our findings during the last grant period--that AGM may be linked to EJM- 1 and RGM is not linked -- show that genetic linkage data can be used to unravel clinical heterogeneity. They demonstrate that differentiating the different forms of epilepsy--one of the most difficult problems in both research and clinical practice -- can be resolved by searching for the genetic cause of disease. They also show that definition of the proper phenotype is critical for genetic studies of common complex disease.