Early Biomarkers of Autism Spectrum Disorders in infants with Tuberous Sclerosis

描述（由申请人提供）：自闭症谱系障碍（ASD）具有复杂和不同的病因。对潜在的分子和细胞机制缺乏了解是找到有效治疗方法的关键障碍。ASD患病率高的单基因疾病为研究自闭症的潜在生物学和测试治疗提供了独特的机会。硬化症（TSC）是一种遗传性疾病，其中约50%的个体也受到ASD的影响。重要的是，TSC可以在出生前或出生时诊断，因此患有TSC的婴儿使我们能够前瞻性地观察ASD的自然史，并开发更好的工具来早期检测自闭症。在分子水平上，TSC疾病表现是由两个TSC基因中的一个突变引起的mTOR的异常过度活性引起的。药理学mTOR抑制以纠正TSC中的细胞缺陷不再是未来的希望，而是一个令人兴奋的现实，其对各种TSC疾病表现具有已证实的功效。为了确定这些药物在治疗或预防ASD中的潜在益处，必须确定 研究人员还将研究TSC婴儿自闭症的早期标志物，以免将不会发展ASD的幼儿置于不必要的风险之中。越来越多的临床和基础科学证据表明，异常的白色物质连接代表了TSC生物标志物的合理候选者。TSC小鼠模型表现出轴突的特化、引导和髓鞘形成的缺陷。更重要的是，几个研究小组报告了TSC患者正常外观的白色物质的异常，这些异常可以通过MR成像识别，并且白色物质微结构完整性的丧失与神经和认知缺陷相关。此外，有初步数据表明，在动物模型和TSC患者中，白色物质的完整性可以通过用mTOR抑制剂治疗来改善。综上所述，这些发现导致了这样的假设，即通过先进的MRI和EEG分析，对TSC婴儿的白色物质完整性和神经连接的纵向评估可以用作这种遗传性疾病中后续ASD的早期生物标志物。该提案旨在建立一个由五家儿童医院组成的联盟，这些医院在地理上分布在美国各地，以招募生命第一年的TSC患者来验证这一假设。将使用3Tesla MR扫描仪的最新成像技术、先进的EEG技术、经验证的神经发育评估工具、遗传分析和36个月内的标准化临床措施。临床联盟将由具有另一种罕见疾病（神经胶质瘤病）经验的集中数据协调中心提供支持。与每个中心的神经发育和相关残疾（LEND）计划的领导力教育合作将提供ASD和TSC的额外跨学科研究培训和教育专业知识。作为这项研究的结果，更好地了解大脑连接及其与TSC中ASD的关系将为自闭症及其相关原因的新干预措施铺平道路。

DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASD) has complex and varying etiologies. A lack of understanding regarding the underlying molecular and cellular mechanisms is a key barrier in finding effective treatments. Single-gene disorders that have a high prevalence of ASD provide unique opportunities to investigate the underlying biology and test treatments for autism. Tuberous Sclerosis Complex (TSC) is a genetic disorder in which approximately 50% of individuals are also affected with ASD. Importantly, TSC can be diagnosed before or at the time of birth, and thus infants with TSC allow us to observe prospectively the natural history of ASD and develop better tools for early detection of autism. On a molecular level, TSC disease manifestations result from the aberrant hyperactivity of mTOR that is caused by mutation in one of two TSC genes. Pharmacologic mTOR inhibition to correct the cellular defects in TSC is no longer a hope for the future, but rather an exciting reality with proven efficacy against various TSC disease manifestations. To determine the potential benefit these agents may have in treating or preventing ASD, it is imperative to identify early markers of autism in infants with TSC, so as to not put young children who will not develop ASD at unnecessary risk. Accumulating clinical and basic science evidence suggests that aberrant white matter connectivity represents a rational candidate as a biomarker in TSC. TSC mouse models demonstrate defects in the specification, guidance, and myelination of axons. More importantly, several groups have reported abnormalities in the normal-appearing white matter of TSC patients that can be identified by MR imaging, and loss of white matter microstructural integrity is associated with neurological and cognitive deficits. Furthermore, there is preliminary data indicating that white matter integrity can be improved by treatment with mTOR inhibitors in both animal models and in TSC patients. Taken together, these findings lead to the hypothesis that longitudinal assessment of white matter integrity and neural connectivity in TSC infants, through advanced MRI and EEG analysis, can be used as an early biomarker of subsequent ASD in this genetic disease. This proposal aims to establish a consortium of five Children's Hospitals that are geographically-distributed throughout the US to recruit TSC patients in the first year of life to test this hypothesis. State of the art imaging with 3Tesla MR scanners, advanced EEG technology, validated neurodevelopmental assessment tools, genetic analysis, and standardized clinical measures through age 36 months will be utilized. The clinical consortium will be supported by a centralized Data Coordinating Center with experience in another rare disease (neurofibro- matosis). Collaboration with Leadership Education in Neurodevelopmental and Related Disabilities (LEND) programs at each center will provide additional interdisciplinary research training and education expertise in ASD and TSC. As a result of the research outlined in this proposal, better understanding of brain connectivity and it relationship to ASD in TSC will pave the way for new interventions for this and related causes of autism.