Friedreich's ataxia (FA) is an autosomal recessive degenerative disease characterized by relentlessly progressive gait and limb ataxia, absent tendon reflexes in the legs, and electrophysiological evidence of axonal sensory neuropathy. Age of onset is usually before 25. With progression of the disease loss of position sense, dysarthria, areflexia, pyramidal weakness of the legs, and extensor plantar responses add to the clinical picture. Evidence of hypertrophic cardiomyopathy is found in almost all patients. Scoliosis and pes cavus are common. Additional symptoms in some cases include optic atrophy, hearing loss, distal amyotrophy, and glucose intolerance or diabetes mellitus. Almost all patients are chairbound by age 45, and no cure exists. The primary biochemical defect is unknown. The FA gene (FRDA) was mapped by linkage to 9q13-q21.1, and a candidate region has been defined to a 350-kb interval between two flanking markers, that the applicant has cloned in YACs and cosmids. The long term objective of the study is to understand the molecular basis of FA. The applicant obtained DNA samples and in selected cases cell lines from 85 families with members affected with FRDA. Patients have been subjected to a detailed clinical, electrophysiological, biochemical and neuroimaging evaluation. These families have been genotyped for the closely linked markers. Additional patients to be included in the study will be identified. Genes localized in the FRDA candidate region will be isolated by cDNA direct selection, by exon amplification, and by large- scale sequencing of cosmid clones. These genes will be analyzed for mutations in affected and carrier subjects to identify the FRDA gene. After the FRDA gene is identified, its genomic structure will be defined and a systematic search for mutations will be carried out in all available patients. Correlations between variations in the clinical phenotype and specific mutations will be evaluated. Successful completion of the proposed studies will allow the isolation of the altered gene in FA and its characterization. Disease-causing mutations will be identified, and information will be obtained about their correlation with the clinical phenotype.
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