Studies Of Hereditary Neurological Disease

神经遗传学分部的目的是调查遗传性神经疾病的原因，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聚谷氨酰胺扩张性疾病(亨廷顿病、肯尼迪病和脊髓小脑性共济失调)、脊髓性肌萎缩症、夏科-玛丽-牙病、肌营养不良、遗传性运动神经元病和弗里德里希共济失调。在细胞培养和其他模型系统中对疾病机制进行了研究。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描述患有遗传性神经疾病的患者和家庭的特征。庆大霉素治疗Duchenne肌营养不良症的试验最近已经完成，艾地苯酮治疗Friedreich‘s共济失调的试验正在进行中。预计还会有更多的治疗试验。过去一年的具体研究成果包括：(1)我们进一步表征了聚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多聚谷氨酰胺毒性的治疗方法。(3)在聚谷氨酰胺病的果蝇模型中，我们确定了减轻毒性的遗传因素。(4)我们帮助缩小了对定位于9号染色体的常染色体显性遗传性运动神经病的遗传缺陷的搜索范围。(5)我们帮助确定了遗传性轴索神经病(CMT2D)的候选基因。(6)建立了遗传性神经病和声带麻痹(2C型)家系的连锁定位。(7)我们对Friedreich‘s共济失调患者进行了艾地苯酮治疗的第1期剂量递增和耐受性研究。(8)我们已经确定了一种药物(丙戊酸盐)，它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)通过Gwinn-Hardy博士的努力，我们对帕金森氏症及相关疾病进行了广泛的临床和遗传学研究。

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.