Familial dysautonomia (FD; Riley-Day syndrome) is the best known and most frequent of a group of congenital sensory neuropathies characterized by widespread sensory and variable autonomic dysfunction. First described in 1949, FD is a 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 percent 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 suited 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. During the initial period of this grant we have narrowed the location of the genetic defect to an 162 kb stretch of 9q31 and have generated the complete DNA sequence of this region. 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 the disorder to reduce the incidence of affected births, and an exploration of the normal and abnormal function of the FD gene in human an animal model systems. In the long-term this work 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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