This investigation will advance our knowledge of inherited and degenerative brain and spinal cord disorders. Familial Spastic Paraparesis (FSP) includes a group of clinically and genetically diverse disorders that share progressive lower extremity spasticity beginning in childhood, adolescence or adulthood. Walking is progressively impaired, wheelchairs are often required, and urinary bladder disturbance and other neurologic deficits may occur. Neuropathologic studies show greatest degeneration in distal portions of the longest axons in the central nervous system: descending terminals of corticospinal tracts and ascending terminals of fasciculus gracilus. The underlying molecular basis of FSP is not known and specific treatments are not available. Genetic linkage analysis and positional cloning hold exciting promise for understanding the pathophysiology of FSP and related neurodegenerative disorders. Recently, autosomal dominant FSP was shown to be genetically heterogeneous. The disorder was tightly linked to chromosome 14q 11.2 in an extended French kindred. This locus was in other FSP families. We established an inter- institutional, multidisciplinary investigation aimed at defining the phenotypic spectrum of FSP and genetic mapping and positional cloning of FSP genes. We have evaluated more than 10 FSP kindreds in our Neurogenetic Disorders Clinic. This investigation will define the clinical spectrum of autosomal dominant FSP by performing detailed neurologic, neuro-ophthalmologic, electrophysiologic and neuro-imaging evaluations of FSP patients from a total of 22 kindreds. 126 members of one autosomal dominant FSP kindred including 32 living affected subjects were examined and videotaped. Using genetic linkage analysis, chromosome l4ql I .2 (the F5P1 locusl was excluded as the disease locus. A genome- wide search for the disease locus in this family was initiated in collaboration with the University of Utah Human Genome Center. Identifying the chromosomal locus and subsequently the gene responsible for FSP in this kindred will greatly advance our understanding of FSP. This information will permit accurate genetic counseling and diagnosis and facilitate the rationale design of treatments to prevent, retard or reverse this debilitating condition. Moreover, understanding the molecular basis of FSP will provide important insight into the pathophysiology of other inherited and degenerative brain and spinal cord disorders particularly those characterized by axonal degeneration.
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