Adult Neurological Phenotypes of Fragile X Gray Zone Expansion

描述（由申请人提供）：在美国有22.5人患有脆性X智力低下（FMR 1）基因灰区扩展或FMR 1中缺乏AGG散布。该基因的长期扩增与智力残疾、自闭症、不育、成年人神经退行性疾病（包括震颤和步态共济失调）有关。最近的研究表明，患有FMR1灰色区域扩展的老年人患帕金森病的风险更高，认知功能更低。然而，这种关联尚未得到最终界定。该项目将确定：1）在基于社区的样本中FMR 1灰区扩展与运动障碍和认知缺陷的存在的关联，2）FMR 1中正常AGG散布的丧失与这些神经学表型的关系，和3）在FMR 1灰区携带者中是否存在类似于在较大扩展携带者中所见的神经元核内包涵体。为了实现这些目标，本研究将分析两个大型流行病学队列（共2700例受试者）中收集的数据：宗教秩序研究（P30AG10161，R01AG15819）和记忆与衰老项目（R01AG17917）。将根据FMR 1灰区扩展状态的存在与否以及FMR 1三核苷酸重复序列中是否存在稳定AGG散布，分析与运动功能、运动障碍和认知测试相关的临床数据。在确定的FMR 1灰区携带者中，将检查脑切片中FMR 1携带者中常见的异常，包括核内包涵体，并与年龄和性别匹配的对照组进行比较。如果这项研究确实证实了神经系统体征、病理学发现和FMR 1灰区扩张或FMR 1 AGG散布丢失之间的关联，则长期目标是更简明地定义表型基因型关系和临床表现的分子贡献者，例如次级基因效应。这项研究的结果将改变FMR 1灰色地带扩展个体的遗传咨询。该项目涉及2008年NIH脆性X综合征和相关疾病研究计划的以下目标：FMR 1基因变异的流行病学（FXS），运动障碍人群的流行病学（FXTAS）以及对其他神经退行性疾病（FXTAS）的更广泛影响。

DESCRIPTION (provided by applicant): There are 22.5 people in the US who have a fragile X mental retardation (FMR1) gene gray zone expansion or lack AGG interspersions in FMR1. Longer expansions in this gene are associated with intellectual disability, autism, infertility, an neurodegenerative disorder in adults, to include tremor and gait ataxia. Recent studies have shown that older individuals with FMR1 gray zone expansions have a higher risk of parkinsonism and lower cognitive function. However, this association has not been conclusively defined. This project will determine: 1) the association of FMR1 gray zone expansions and the presence of movement disorders and cognitive deficits in a community based sample, 2) the relationship of loss of normal AGG interspersions in FMR1 and these neurological phenotypes, and 3) whether neuronal intranuclear inclusions similar to those seen in larger expansion carriers are present in the FMR1 gray zone carriers. To reach these aims, this study will involve analysis of data collected in two large epidemiological cohorts of 2700 subjects total from: the Religious Orders Study (P30AG10161, R01AG15819) and the Memory and Aging Project (R01AG17917). Clinical data related to motor function, movement disorders, and cognitive testing will be analyzed based on the presence or absence of FMR1 gray zone expansion status and the presence or absence of stabilizing AGG interspersions in the FMR1 trinucleotide repeat. In identified FMR1 gray zone carriers, brain sections will be examined for abnormalities typically seen in FMR1 carriers, to include intranuclear inclusions, and compared to age and sex matched controls. If this study does confirm an association between neurological signs, pathological findings, and FMR1 gray zone expansion or loss of FMR1 AGG interspersions, the long term objective is to more concisely define the phenotype genotype relationship and molecular contributors to clinical manifestations, such as secondary gene effects. Results of this study will change the genetic counseling for individuals with FMR1 gray zone expansions. This project addresses the following goals of the 2008 NIH Research Plan on Fragile X Syndrome and Associated Disorders: epidemiology of FMR1 gene variations (FXS), epidemiology in movement disorder populations (FXTAS), and broader implications for other neurodegenerative diseases (FXTAS).