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。一个相关的研究领域是雄激素对肌肉力量和运动神经元存活的影响机制。遗传外展计划旨在识别和表征遗传神经疾病的患者和家庭。一项庆大霉素治疗杜氏肌营养不良患者的试验最近完成，一项伊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。一年来的具体研究成果包括：(1)进一步明确了多谷氨酰胺病细胞培养模型中神经元死亡的机制。(2)我们已经完成了体外药物筛选，并确定了减轻细胞培养中聚谷氨酰胺毒性的治疗方法。(3)我们已经确定了减轻多谷氨酰胺病果蝇模型毒性的遗传因素。(4)我们已经帮助缩小了对9号染色体常染色体显性运动神经病变遗传缺陷的研究范围。(5)我们帮助鉴定了遗传性轴索神经病（CMT2D）的候选基因。(6)我们建立了遗传性神经病变和声带麻痹（Charcot-Marie-Tooth病2C型）家族的连锁定位。(7)我们在弗里德里希共济失调患者中进行了一项依地苯酮治疗的一期剂量递增和耐受性研究。(8)我们已经确定了一种药物（丙戊酸），可以增加脊髓性肌萎缩症患者细胞中缺陷蛋白SMN的水平。(9)在gwin - hardy博士的努力下，我们对帕金森病及相关疾病进行了广泛的临床和遗传研究。

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 related area of investigation has been the mechanism of androgen effects on muscle strength and motor neuron survival. A genetic outreach program is intended to identify and characterize patients and families with hereditary neurological diseases. A trial of gentamicin treatment in patients with Duchenne muscular dystrophy was recently completed, and a trial of idebenone treastment 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 a cell culture model 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 identified genetic factors that mitigate toxicity in a Drosophila model of polyglutamine disease. (4) We have helped to narrow the search for the genetic defect responsible for an autosomal dominant form of motor neuronopathy mapped to chromosome 9. (5) We have helped in the identification of a candidate gene for hereditary axonal neuropathy (CMT2D). (6) We have established linkage localization for families with hereditary neuropathy and vocal fold paralysis (Charcot-Marie-Tooth disease type 2C). (7) We have carried out a phase 1 dose escalation and tolerability study of idebenone therapy in patients with Friedreich's ataxia. (8) We have identified an agent (valproate) that increases levels of the deficient protein SMN in cells from patients with spinal muscular atrophy. (9) Through the efforts of Dr. Gwinn-Hardy, we have engaged in extensive clinical and genetic studies of Parkinson's disease and related disorders.