Genotype-Phenotype Relationships in Fragile X Families

描述（由申请人提供）：FMR 1前突变患者的参与范围很广，从儿童期的发育问题和成年期的精神病理学到衰老期的神经变性;后者包括我们与澳大利亚合作者一起确定的脆性X相关震颤共济失调综合征（FXTAS）。然而，一些具有前突变的个体没有明显的临床参与，而另一些个体在儿童期、成年期或衰老期经历轻度或严重的缺陷。通常，发育问题被认为与FMRP缺陷有关，而衰老问题与继发于FMR 1-mRNA升高的RNA毒性有关。我们将评估特定领域的分子/细胞功能障碍的影响，包括线粒体功能障碍，组织间（淋巴细胞-成纤维细胞）镶嵌，隐匿性甲基化，以及疾病相关的反义FMR 1（ASFM 1）亚型的增加对儿童和成人前突变等位基因携带者的临床表型的性质和程度。将使用特定的临床结局指标，记录神经认知、运动和精神领域的轻度至重度受累。我们将评估189例患者（10至30岁），包括63名受影响的携带者，63名发育正常（无症状）和63名年龄和性别匹配的正常对照，以确定突变前发育问题（包括认知，运动和社会缺陷）的严重程度与特定分子异常（特定目标1）之间的关系。我们将扩展这些研究，以表征具有前突变的成年人中分子功能障碍的性质和严重程度，这些成年人具有精神和/或神经功能障碍，但不符合FXTAS的临床标准（特定目标2）;我们将招募201例患者（30至65岁），分为受神经或精神问题影响的携带者、无症状携带者和年龄和性别匹配的对照组。我们将确定突变前成人的临床参与谱是否与分子失调的严重程度相关，或者FXTAS的分子特征是否不同，以及是否可以识别早期生物标志物用于未来的治疗努力。最后，我们将利用灵敏的神经成像技术（扩散张量成像; DTI）来评估成人前突变的参与程度，以确定与未受影响的携带者和对照组相比，患有精神和/或神经问题的成人携带者中白色物质中纤维束完整性丧失与线粒体功能障碍严重程度之间的一致性程度（具体目标3）。这项工作将继续包括澳大利亚团队，除了目标1和2的有限招募外，他们将对两个研究中心的所有患者进行血液和成纤维细胞的隐性甲基化研究。我们的研究将提供早期参与的生物标志物，并为基于线粒体的干预，低FMRP的靶向治疗或早期阻断RNA毒性的药物等治疗奠定基础。

DESCRIPTION (provided by applicant): There is a spectrum of involvement in those with the FMR1 premutation that ranges from developmental problems in childhood and psychopathology in adulthood to neurodegeneration in aging; the latter includes the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) that we have identified with our Australian collaborators. However, some individuals with the premutation have no overt clinical involvement, whereas others experience mild or severe deficits in childhood, adulthood or aging. Typically, the developmental problems are thought to be related to FMRP deficits, whereas the aging problems to RNA toxicity secondary to elevated FMR1-mRNA. We will assess the influence of specific domains of molecular/cellular dysfunction, including mitochondrial dysfunction, inter-tissue (lymphocyte-fibroblast) mosaicism, occult methylation, and increases of disease-associated antisense FMR1 (ASFM1) isoforms on the nature and degree of the clinical phenotypes in both children and adults who are carriers of premutation alleles. Specific clinical outcome measures will be used that can document mild to severe involvement in the neurocognitive, motor and psychiatric realms. We will assess 189 patients (10 to 30 years) including 63 carriers who are affected, 63 who have normal development (asymptomatic) and 63 normal controls matched on age and sex to define the relationship between the severity of premutation developmental problems, including cognitive, motor and social deficits, and the presence of specific molecular abnormalities (Specific Aim 1). We will extend these studies to characterize the nature and severity of molecular dysfunction in adults with the premutation who have psychiatric and/or neurological dysfunction but do not meet clinical criteria for FXTAS (Specific Aim 2); we will recruit 201 patients (30 to 65y), divided between carriers who are affected with neurological or psychiatric problems, asymptomatic carriers, and controls matched for age and sex. We will determine whether the spectrum of clinical involvement in premutation adults is paralleled by severity of molecular dysregulation or whether the molecular features of FXTAS are distinct, and whether early biomarkers can be identified to use in future treatment endeavors. Lastly we will utilize sensitive neuroimaging techniques (diffusion tensor imaging; DTI) to assess involvement in adults with the premutation to determine the degree of concordance between the loss of integrity of fiber tracts in white matter and the severity of the mitochondrial dysfunction in adul carriers with psychiatric and/or neurological problems compared to unaffected carriers and controls (Specific Aim 3). This work will continue to include the Australia team, who will carry ou the occult methylation studies on blood and fibroblasts for all patients seen at both sites, in addition to limited recruitment for Aims 1 and 2. Our studies will provide biomarkers of early involvement and lay the basis for treatments such as mitochondrial based interventions, targeted treatment for low FMRP, or medications that block RNA toxicity early on.