Genotype-Phenotype Relationships in Fragile X Families

描述(由申请人提供)：FMR1前突变患者的参与范围从童年的发育问题和成年后的精神病理到衰老中的神经退化；后者包括我们与我们的澳大利亚合作者确认的脆性X-相关颤动症共济失调综合征(FXTAS)。然而，一些携带前突变的个体没有明显的临床参与，而另一些人在童年、成年或衰老时经历了轻微或严重的缺陷。通常，发育问题被认为与FMRP缺陷有关，而衰老问题与RNA毒性继发于FMR1-mRNA的升高有关。我们将评估分子/细胞功能障碍的特定区域，包括线粒体功能障碍、组织间(淋巴细胞-成纤维细胞)嵌合体、隐匿性甲基化和疾病相关反义FMR1(ASFM1)亚型的增加，对携带突变前等位基因的儿童和成人的临床表型的性质和程度的影响。将使用特定的临床结果衡量标准，以记录神经认知、运动和精神领域的轻微到严重参与。我们将评估189名患者(10至30岁)，包括63名受影响的携带者、63名发育正常(无症状)的患者和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、运动和社交缺陷)的严重程度与特定分子异常的存在之间的关系(特定目标1)。我们将扩展这些研究，以表征具有前突变的成年人的分子功能障碍的性质和严重程度，这些人有精神和/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名患者(30至65岁)，分为有神经或精神问题的携带者、无症状的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平行，或者FXTAS的分子特征是否不同，以及是否可以确定早期生物标记物用于未来的治疗努力。最后，我们将利用敏感的神经成像技术(弥散张量成像；DTI)来评估患有前突变的成年人的参与程度，以确定与未受影响的携带者和对照组相比，有精神和/或神经问题的ADUL携带者白质纤维束完整性丧失和线粒体功能障碍的严重程度之间的一致性程度(特定目标3)。这项工作将继续包括澳大利亚团队，他们将对两个地点看到的所有患者的血液和成纤维细胞进行隐蔽的甲基化研究，以及AIMS 1和2的有限招募。我们的研究将提供早期参与的生物标记物，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.