Genotype-Phenotype Relationships in Fragile X Families

描述（由申请人提供）：在前一个项目期间，我们的脆性X家族基因型-表型研究表征了脆性X综合征和前突变的表型参与谱，在过去五年中发表了60多篇论文。在跨越三代的家族背景下，详细的临床表型组合导致在具有前突变（55-200 CGG重复）的那些中发现FMR 1-mRNA升高，并且随后在2001年发现脆性X相关震颤/共济失调综合征（FXTAS）。FXTAS以震颤、共济失调、脑萎缩和认知能力下降为特征，改变了临床护理和遗传咨询方面的脆弱X领域，并公布了一种新的参与机制，即RNA功能获得性毒性模型。我们的初步数据记录了儿童时期与前突变相关的问题，以及成人中广泛的神经和神经精神问题。虽然FXTAS是更常见的男性与前突变，老年女性表现出一系列的神经，神经精神和激素的问题，我们建议进一步研究。我们的目标是在这个竞争性的更新是探索在儿童和成人的前突变的神经发育和神经退行性病变的影响。我们在这次更新中的总人数将包括500名成人和150名儿童的前突变和控制，重点是两个特定的年龄组。我们将研究8至16岁之间具有前突变的男孩，因为我们的初步数据表明，在该年龄范围内，注意缺陷多动障碍和社交缺陷，包括自闭症谱系障碍。此外，40岁以上的男性和女性，来自突变前携带者和年龄/教育匹配的对照人群，将被纳入我们的衰老相关变化研究。我们将利用详细的神经系统检查和定量测量的运动问题，使用CATALYST系统。此外，我们将采用精神病学的措施，神经心理学测试，和MRI定量成像，以评估参与运营商。我们在加州和澳大利亚之间富有成效的合作将在拟议项目期间继续进行。我们发现，大型合并数据集增加了我们分析的力量，激发了对两大洲前突变携带者和FXTAS参与的认识，并增强了我们对不同种族群体前突变参与的了解。

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.