Genotype-Phenotype Relationships in Fragile X Families

描述（由申请人提供）：在之前的项目期间，我们对脆性X家族的基因型-表型研究表征了脆性X综合征和具有前置突变的人的表型参与谱，在过去的五年里发表了60多篇论文。在跨越三代的家庭背景下，结合详细的临床表型，导致在具有预突变（55-200个CGG重复序列）的人中发现FMR1-mRNA升高，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、认知能力下降为特征，改变了脆性X的临床护理和遗传咨询领域，并提出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的问题与突变前兆有关，以及成人中广泛的神经和神经精神问题。虽然FXTAS在有先兆突变的男性中更常见，但衰老的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。我们在这个竞争性更新的目的是探索在儿童和成人的预突变的神经发育和神经退行性影响。这次更新的总人数将包括500名成人和150名患有突变前和对照的儿童，重点关注两个特定年龄组。我们将研究年龄在8到16岁之间的男孩，因为我们的初步数据表明，在这个年龄范围内，注意缺陷多动障碍和社交缺陷，包括自闭症谱系障碍都存在问题。此外，40岁以上的男性和女性，来自突变前携带者和年龄/教育程度匹配的对照人群，将包括在我们的衰老相关变化研究中。我们将使用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，我们将采用精神病学测量、神经心理学测试和MRI定量成像来评估携带者的参与情况。在拟议的项目期间，加州和澳大利亚之间将继续开展富有成效的合作。我们发现，庞大的组合数据集提高了我们分析的能力，激发了我们对两大洲的预突变携带者和FXTAS参与的认识，并增强了我们对不同种族群体的预突变参与的认识。

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.