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 allows the identification and characterization of 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 further characterized the mechanism of neuronal death in cell culture and Drosophila models of polyglutamine disease. (2) We completed an in vitro drug screen and identified treatments that mitigate polyglutamine toxicity in cell culture. (3) We helped to identify the genetic defect responsible for an autosomal dominant form of motor neuronopathy (ALS4). (4) We helped in the characterization of the gene responsible for hereditary axonal neuropathy (CMT2D). (5) We characterized the effects of a mutation in the transport protein dynactin in an autosomal dominant form of motor neuron disease. (6) We completed a phase 1a dose escalation and tolerability study of idebenone therapy in patients with Friedreich's ataxia and began a chronic high dose tolerability study (phase 1b). (7) We identified an agent (valproic acid) that increases levels of the deficient protein SMN in cells from patients with spinal muscular atrophy and characterized the effect of other histone deacetylase inhibitors on SMN gene experssion.