Genotype-Phenotype Relationships in Fragile X Families

描述(由申请人提供)：在前一个项目期间，我们对脆性X家族的基因-表型研究描述了脆性X综合征和具有前突变的表型谱，导致在过去五年中发表了60多篇论文。结合详细的临床表型，在跨越三代的家庭背景下，导致在具有前突变(55-200个CGG重复)的患者中发现FMR1-mRNA升高，随后在2001年发现了脆性X相关颤动/共济失调综合征(FXTAS)。以震颤、共济失调、脑萎缩和认知功能下降为特征的FXTAS改变了脆性X领域的临床护理和遗传咨询，并公布了一种新的参与机制-RNA功能获得毒性模型。我们的初步数据记录了儿童时期与前突变有关的问题，以及成人的一系列神经和神经精神问题。虽然FXTAS在有前突变的男性中更常见，但老年女性表现出一系列神经、神经精神和激素问题，我们建议进一步研究。我们在这次竞争性更新中的目的是探索前突变对儿童和成人的神经发育和神经退行性变化的影响。我们此次更新的总人数将包括500名患有前突变的成年人和150名儿童，并将重点放在两个特定的年龄段。我们将研究8至16岁之间有前突变的男孩，因为我们的初步数据显示，在这个年龄段，注意力缺陷多动障碍和包括自闭症谱系障碍在内的社交缺陷都存在问题。此外，40岁以上的男性和女性，来自前突变携带者和年龄/教育匹配的对照人群，将被包括在我们的老龄化相关变化研究中。我们将利用CATsys系统对运动问题进行详细的神经学检查和定量测量。此外，我们将使用精神病学测量、神经心理测试和MRI定量成像来评估与携带者的关系。在拟议的项目期间，我们在加州和澳大利亚之间的富有成效的合作将继续下去。我们发现，庞大的组合数据集增加了我们分析的能力，激发了两个大陆上前突变携带者和FXTA参与的意识，并增强了我们对前突变参与不同种族群体的知识。

DESCRIPTION (provided by applicant): In the previous project period, our Genotype-Phenotype study of Fragile X families characterized the spectrum of phenotypic involvement in fragile X syndrome and in those with the premutation, leading to over 60 publications in the past five years. The combination of detailed clinical phenotyping, in the context of families spanning three generations, led to the finding of elevated FMR1-mRNA in those with the premutation (55-200 CGG repeats) and the subsequent discovery of Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) in 2001. FXTAS, which is characterized by tremor, ataxia, brain atrophy, and cognitive decline, has changed the fragile X field regarding clinical care and genetic counseling, and has promulgated a new mechanism of involvement, an RNA gain-of-function toxicity model. Our preliminary data documents problems in childhood related to the premutation, in addition to a broad array of neurological and neuropsychiatric problems in adults. Although FXTAS is more common in males with the premutation, aging females demonstrate a spectrum of neurological, neuropsychiatric, and hormonal problems that we propose to study further. Our aims in this competitive renewal are to explore both the neurodevelopmental and neurodegenerative effects of the premutation in both children and adults with the premutation. Our total numbers in this renewal will include 500 adults and 150 children with the premutation and controls with a focus on two specific age groups. We will study boys with the premutation between the ages of 8 to 16 years, as our preliminary data demonstrate problems with both Attention Deficit Hyperactivity Disorder and social deficits, including Autism Spectrum Disorders, in that age range. In addition, males and females over 40 years, from both premutation carrier and age- /education-matched control populations, will be included in our study of aging-related changes. We will utilize a detailed neurological examination and quantitative measurement of movement problems using the CATSYS system. In addition, we will employ psychiatric measures, neuropsychological testing, and MRI quantitative imaging to assess involvement in carriers. Our productive collaboration between California and Australia will continue during the proposed project period. We have found that the large combined data set has increased the power of our analyses, stimulated awareness of involvement of premutation carriers and FXTAS on both continents, and enhanced our knowledge of premutation involvement in diverse racial groups.