Studies Of Hereditary Neurological Disease

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The purpose of the Neurogenetics Branch is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. Particular areas of research interest include the polyglutamine expansion diseases (Huntington's disease, Kennedy's disease, and spinocerebellar ataxia), spinal muscular atrophy, Charcot-Marie-Tooth disease, muscular dystrophy, hereditary motor neuron disease, and Friedreich's ataxia. The disease mechanisms are studied in cell culture and other model systems. A genetic outreach program is intended to identify and characterize patients and families with hereditary neurological diseases. A trial of idebenone treatment in Friedreich's ataxia is in progress. Further therapeutic trials are anticipated. Specific research accomplishments in the past year include the following: (1) We have further characterized the mechanism of neuronal death in cell culture and Drosophila models of polyglutamine disease. (2) We have completed an in vitro drug screen and identified treatments that mitigate polyglutamine toxicity in cell culture. (3) We have helped to narrow the search for the genetic defect responsible for an autosomal dominant form of motor neuronopathy mapped to chromosome 9. (4) We have helped in the identification of the gene responsible for hereditary axonal neuropathy (CMT2D). (5) We identified the gene for an autosomal dominant form of motor neuron disease. (6) We have carried out a phase 1 dose escalation and tolerability study of idebenone therapy in patients with Friedreich's ataxia. (7) We have identified an agent (valproate) that increases levels of the deficient protein SMN in cells from patients with spinal muscular atrophy.