Studies Of Hereditary Neurological Disease

神经遗传学分支的目的是调查遗传性神经系统疾病的原因，目的是为这些疾病开发有效的治疗方法。特别感兴趣的研究领域包括多聚谷氨酰胺扩增疾病（亨廷顿病、肯尼迪病和脊髓小脑性共济失调）、脊髓性肌萎缩、夏科-马里-图思病、肌营养不良、遗传性运动神经元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描述遗传性神经系统疾病的患者和家庭。艾地苯醌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。具体研究成果包括：（1）在细胞培养和果蝇多聚谷氨酰胺病模型中进一步研究了神经元死亡的机制，并探讨了profilin在其中的作用。(2)我们的特点是生化作用和临床和病理表现的突变的转运蛋白dynactin的常染色体显性形式的运动神经元疾病。(3)我们进一步描述了甘氨酰-tRNA合成酶突变引起的运动神经元病的临床表现。(4)我们进一步研究了蛋白激酶C突变对脊髓小脑性共济失调患者的影响。(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，并描述了一名患有这种疾病的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SMN表达的影响，SMN是脊髓性肌萎缩症中突变的基因。(7)我们完成了艾地苯醌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，用于测量弗里德赖希共济失调和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.