Adult Neurological Phenotypes of Fragile X Gray Zone Expansion

描述(申请人提供)：美国有22.5人患有脆性X智力低下(FMR1)基因灰区扩大或缺乏FMR1的agg散布。该基因较长的扩增与智力残疾、自闭症、不孕不育、成年人的一种神经退行性疾病有关，包括震颤和步态共济失调。最近的研究表明，患有FMR1灰区扩大的老年人患帕金森症的风险更高，认知功能更低。然而，这种联系还没有得到最终的定义。该项目将确定：1)在基于社区的样本中，FMR1灰区扩张与运动障碍和认知障碍的存在之间的关联；2)FMR1中正常AGG散布丢失与这些神经表型的关系；以及3)FMR1灰区携带者中是否存在与较大扩张携带者中看到的类似的神经元内包涵体。为了达到这些目的，本研究将对两个大型流行病学队列中收集的数据进行分析，共2700名受试者：宗教教派研究(P30AG10161，R01AG15819)和记忆与衰老项目(R01AG17917)。与运动功能、运动障碍和认知测试相关的临床数据将根据FMR1灰区扩展状态的存在或不存在以及FMR1三核苷酸重复中是否存在稳定的AGG点缀进行分析。在已确定的FMR1灰区携带者中，将检查大脑切片是否存在FMR1携带者中常见的异常，以包括核内包涵体，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体征、病理结果与FMR1灰区扩大或丢失FMR1 agg间隔区之间的关联，长期目标是更简明地定义表型和临床表现的分子因素，如次要基因效应。这项研究的结果将改变FMR1灰区扩张个体的遗传咨询。该项目涉及2008年美国国立卫生研究院脆性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(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).