Genetics of demyelinating diseases.

Multiple sclerosis (MS), the prototypic demyelinating disease in humans, is the most common cause of acquired neurological dysfunction arising between early to mid adulthood. MS is an inflammatory disorder and is believed to result from an autoimmune response, directed against myelin proteins and perhaps other antigens, resulting in demyelination and dense astrogliosis. A genetic component in MS is indicated by an increased relative risk to siblings compared to the general population (lambda s) of 20-40, and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have yielded a considerable number of reports showing significant genetic effects for the major histocompatibility complex (MHC), immunoglobulin heavy chain, T cell antigen receptor, and myelin basic protein loci. With the exception of the MHC, however, these results have been difficult to replicate or apply beyond isolated populations. Recently, a multi-analytical genomic screen effort was completed to identify genomic regions potentially harboring MS susceptibility genes. Nineteen such regions were identified. The data confirm the reported genetic effect of the MHC region. However, no single locus generated overwhelming evidence of linkage. These results suggest a multifactorial etiology, including both environmental and multiple genetic factors of moderate effect.