Studies Of Hereditary Neurological Disease

神经遗传学科的目的是研究遗传性神经疾病的病因，目标是开发有效的治疗方法。研究兴趣的特定领域包括多谷氨酰胺扩张性疾病（亨廷顿氏病、肯尼迪氏病和脊髓小脑性共济失调）、脊髓性肌萎缩症、腓骨肌萎缩症、肌肉萎缩症、遗传性运动神经元疾病和弗里德赖希共济失调。在细胞培养和其他模型系统中研究疾病机制。遗传外展计划允许识别和表征遗传神经疾病的患者和家庭。依地苯酮治疗弗里德赖希共济失调的试验正在进行中。预计将进行进一步的治疗试验。近一年来的具体研究成果包括：(1)进一步明确了细胞培养和多聚谷氨酰胺病果蝇模型中神经元死亡的机制，并探讨了profilin在这一机制中的作用。(2)我们描述了常染色体显性运动神经元疾病中运输蛋白动力蛋白突变的生化效应和临床病理表现。(3)进一步明确glyyl - trna合成酶突变引起的运动神经病变的临床表现。(4)我们进一步表征了蛋白激酶C突变在脊髓小脑性共济失调患者中的作用。(5)我们在转基因小鼠中完成了x -连锁腓骨肌萎缩症的研究，并描述了一名患有该疾病异常严重表现的患者。(6)我们进一步表征了组蛋白乙酰化和组蛋白去乙酰化酶抑制剂对脊髓性肌萎缩症中发生突变的SMN基因表达的影响。(7)我们完成了伊地苯酮治疗弗里德赖希共济失调患者的1b期慢性高剂量耐受性研究，并制定了比较高剂量、低剂量和安慰剂治疗的2期方案。(8)我们帮助开发了一种共济失调量表，用于测量弗里德里希共济失调及相关疾病患者对治疗的反应。

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.