Familial dysautonomia (FD; Riley-Day syndrome) is the best know and most frequent of a group of congenital sensory neuropathies characterized by widespread sensory and variable autonomic dysfunction. First described in 1949. FD is devastating disorder that involves progressive neuronal degeneration with a broad impact on the operation of many of the body's systems leading to a vastly reduced quality of life and premature death. Affected individuals demonstrate lack of overflow tears, impaired temperature and pain sensation, and autonomic dysfunction, including labile blood pressure and uncoordinated swallowing. Despite recent advances in the management of FD, the disorder is inevitably fatal with only 50% of patients reaching 30 years of age. FD is due to a recessive genetic defect with a remarkably high carrier frequency in Ashkenazi Jews of 1 in 30, rivaling the gene frequencies of more widely recognized disorders such as Tay-Sachs disease and cystic fibrosis. FD's genetic characteristics make it ideally suite for molecular investigation. We have used genetic linkage to map the defective gene to chromosome 9q31 and have determined that its ethnic bias is due to a founder effect, with most disease alleles sharing a common ancestral mutation. This has provided a strategy for narrowing the location of the disease gene to a small stretch of genomic DNA. We are now poised to identify the nature of the genetic defect in FD and to characterize its mode of pathogenesis. The product of this work will be a knowledge of the cause of FD and its relationship to other sensory neuropathies, the ability to screen for carriers of the disorder, and the beginning to the exploration of the normal and abnormal function of the DYS gene in human and animal model systems. In the long-term we will contribute both to the fundamental understanding of development and maintenance of the sensory and autonomic nervous systems, and to the hope of FD patients for an effective treatment preventing progression of this devastating disorder.
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