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型智力迟钝（FMR1）基因灰色区扩增或在FMR1中缺乏AGG散点。该基因的长时间扩增与智力残疾、自闭症、不孕症、成人神经退行性疾病（包括震颤和步态共济失调）有关。最近的研究表明，FMR1灰色区域扩张的老年人患帕金森病的风险更高，认知功能更低。然而，这种联系还没有得到明确的定义。该项目将确定：1)FMR1灰色区扩展与社区样本中运动障碍和认知缺陷的存在之间的关联，2)FMR1中正常AGG分布的丢失与这些神经表型之间的关系，以及3)FMR1灰色区携带者中是否存在与较大扩展携带者相似的神经元核内包涵体。为了达到这些目标，本研究将涉及分析两个大型流行病学队列中收集的2700名受试者的数据：宗教秩序研究（P30AG10161, R01AG15819）和记忆与衰老项目（R01AG17917）。我们将根据FMR1三核苷酸重复序列中是否存在稳定化AGG穿插，以及是否存在FMR1灰色区扩展状态，来分析与运动功能、运动障碍和认知测试相关的临床数据。在确定的FMR1灰色地带携带者中，将检查大脑切片，以检查FMR1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。如果本研究确实证实了神经学症状、病理表现与FMR1灰色地带扩展或FMR1 AGG散布体缺失之间的关联，那么长期目标是更简洁地定义表型-基因型关系和影响临床表现的分子因素，如继发基因效应。本研究结果将改变FMR1灰色区扩增个体的遗传咨询。该项目涉及2008年NIH脆性X综合征及相关疾病研究计划的以下目标：FMR1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的更广泛影响（FXTAS）。

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).