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 and investigated the role of profilin in this mechanism. (2) We characterized the biochemical effects and clinical and pathological manifestations of a mutation in the transport protein dynactin in an autosomal dominant form of motor neuron disease. (3) We further characterized the clinical manifestations of motor neuronopathy due to mutations in glycyl-tRNA synthetase. (4) We further characterized the effects of protein kinase C mutations in patients with spinocerebellar ataxia. (5) We completed studies of X-linked Charcot-Marie-Tooth disease in transgenic mice and described a patient with unusually severe manifestations of this disease. (6) We further characterized the effects of histone acetylation and histone deacetylase inhibitors on the expression of SMN, the gene that is mutated in spinal muscular atrophy. (7) We completed a phase 1b chronic high dose tolerability study of idebenone therapy in patients with Friedreich's ataxia and developed a phase 2 protocol comparing high dose, low dose, and placebo treatment. (8) We helped in the development of an ataxia scale for measuring the response to treatment of patients with Friedreich's ataxia and related diseases.