Action tremor & dementia in male carriers of fragile X

描述（由申请人提供）：本申请的目的是定义一种新发现的进行性神经系统疾病的临床特征，包括意向性震颤、共济失调和痴呆，伴有全身性脑萎缩和包涵体，发生于脆性X前突变的老年男性。脆性X综合征（FXS）是一种发育障碍，涉及脆性X智力低下1基因（FMR 1）中的三核苷酸重复扩增（CGG）。完全突变与男性的智力迟钝和女性的轻度认知障碍有关。FXS基因携带者被认为具有前突变，即较小的三核苷酸扩增（55至200个CGG重复）。前突变通常与正常或接近正常的认知和解剖表型相关，但最近的数据表明，前突变表型可能包括微妙的发育异常。我们在过去两年的研究表明，一个亚组的成年男性与前突变发展的神经系统疾病类似的一些脊髓小脑共济失调。当男性50多岁或60多岁时，它首次出现在临床上，其特征是动作震颤和其他运动表现、痴呆和全身性脑萎缩。这种疾病的患病率尚未确定，但我们的数据表明，它可能在每10万男性20至78人之间，这是很常见的，它将代表一个重要的公共卫生问题。自从我们之前提交本申请以来，我们已经获得了一些额外患者的神经学、放射学、神经心理学和神经病理学数据，该疾病已成为美国其他研究者的研究重点。国内外拟议的研究将比较患有震颤性共济失调疾病的FXS携带者男性样本与年龄和教育匹配的无震颤或其他神经系统疾病体征的携带者男性样本以及无FXS参与的健康男性匹配组。采用的措施包括全面的标准化神经系统评估、神经心理学检查、功能评估、大脑MRI和基础分子研究。将在基线、18个月和36个月随访时收集数据。数据分析将包括组间和重复测量方法。这项研究的结果将提供关于这种以前未鉴定的疾病的临床特征的重要信息，包括其进展速度及其与FXS前突变的关系。进一步了解这种表型的性质及其与FMR 1基因的相关性，对于老年男性运动障碍的鉴别诊断、管理和适当治疗具有重要的临床意义。

DESCRIPTION (provided by applicant): The purpose of this application is to define the clinical features of a newly identified, progressive neurologic disorder consisting of intention tremor, ataxia, and dementia, with generalized brain atrophy and inclusion bodies, among older men with the fragile X premutation. Fragile X syndrome (FXS) is a developmental disorder involving a trinucleotide repeat expansion (CGG) in the fragile X mental retardation 1 gene (FMR1). The full mutation is associated with mental retardation among males and milder impairment of cognition among females. Carriers of the FXS gene are said to possess the premutation, a smaller trinucleotide expansion (55 to 200 CGG repeats). The premutation generally has been associated with a normal or nearly normal cognitive and anatomic phenotype, but recent data suggest the premutation phenotype may include subtle developmental anomalies. Our research over the past two years suggests that a subgroup of adult males with the premutation develop a neurologic disorder resembling some of the spinocerebellar ataxias. It is first clinically apparent when the men are in their fifties or sixties, and is characterized by action tremor and other motor findings, dementia, and generalized brain atrophy. The prevalence of this disorder has not been definitively established, but our data suggest it may be between 20 and 78 per I00,000 males, which is common enough that it would represent an important public health problem. Since our previous submission of this application, we have obtained neurologic, radiologic, neuropsychological, and neuropathologic data on a number of additional patients, and the condition has become the focus of study for other investigators in the United States. and abroad. The proposed study will compare a sample of FXS carrier males with this tremor-ataxia disorder to an age- and education-matched sample of carrier males without tremor or other signs of neurologic disorder, and a matched group of healthy men without FXS involvement. The measures used include a comprehensive standardized neurological evaluation, neuropsychological examination, functional assessment, MRI of the brain, and basic molecular studies. Data will be collected at baseline, and at 18-month and 36-month follow-up points. Data analysis will include between-groups and repeated measures methods. The results of this study will provide important information on the clinical features of this previously unidentified disorder, including its rate of progression and its relationship to the FXS premutation. Further knowledge of the nature of this phenotype, and of its association with the FMR1 gene, is of substantial clinical importance for the differential diagnosis, management, and appropriate treatment of movement disorders among older males.