PubMed1986
The complexity of the human genome creates special problems in understanding the genetic component of disease processes. An estimated 50,000 genes exist in the human genome, and it is reasonable to assume that mutation in any one of these genes may result in an inherited disorder. Because of the complex pattern of gene expression controlling the development and organization of the central nervous system (CNS), insights into the genetic component, if any, of diseases such as epilepsy are most accessible to analysis by genetic linkage studies. Advances in the manipulation of DNA have made possible more effective acquisition of genotypic information in humans by studying the inheritance of restriction fragment length polymorphisms (RFLPs) using cloned DNA probes. Two approaches exist to utilize this technology in studying inherited disorders. The first approach consists of genotypic determinations in affected families with cloned genes in which a mutation might result in the phenotype observed. Analysis of these data will show whether the inheritance of an allele of the candidate gene is linked to the disease. The second approach relies upon the construction with these probes of a linkage map for the human genome such that disease families can be screened in order to determine with which of these markers the phenotype is linked, indicating the map position of a gene associated with the inherited disorder. The use of these new approaches enables investigators to screen either specific biochemical defects in disease families or to identify the underlying genetic mechanisms in inherited disorders whose phenotype is expressed only in the intact human (84). 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; 50 multigenerational families are being studied in three separate epilepsy programs in Los Angeles, Winston-Salem, North Carolina, and Berlin. Concurrent with these studies, investigators are combining the principles of classic linkage analysis, using 30 protein markers, with the use of RFLPs 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.(ABSTRACT TRUNCATED AT 400 WORDS)