The search for epilepsies ideal for clinical and molecular genetic studies.

Abstract

The first step in localizing the chromosomal site of specific epilepsies is to define their pattern of inheritance. This determination is now being carried out for benign juvenile myoclonic epilepsy; fifty multigenerational families are being studied in three separate epilepsy programs in Los Angeles, Winston-Salem, NC, and Berlin. Concurrent with these studies, investigators are combining the principles of classic linkage analysis, using 30 protein markers, with the use of restriction-fragment-length polymorphisms to determine the chromosomal location of juvenile myoclonic epilepsy. Two problems appear formidable, however. First, since the chromosomal location of specific epilepsies is unknown, the entire human genome must be screened. Second, once the location of a specific epilepsy gene is narrowed down to a region of 10(6) base pairs, the problem of identifying the actual molecular defect is difficult, especially if we have no assay or method to show that a given gene is culpable for producing epilepsy. An approach more likely to succeed is to use as markers the DNA fragments of proteins that are suspected to cause the disease in experimental models of genetic epilepsies; for example, the gamma-aminobutyric acid receptor genes, which are suspected to cause myoclonic epilepsy in experimental animals, can be tested in benign juvenile myoclonic epilepsy. At the same time, other marker proteins could be used to locate the chromosomal site of other specific epilepsies. Once the chromosomal site is determined, recombinant DNA technology will permit the measurement of the precise arrangement of the genes for these restriction-fragment-length polymorphisms and protein markers at a given locus of a chromosome.