Natural history of individuals with autism spectrum disorder and germline PTEN mutations

患有自闭症谱系障碍和种系 PTEN 突变的个体的自然史

• 批准号: 10242080
• 负责人: Charis Eng
• 金额: $ 38.93万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242080
• 关键词: Adolescent; Adult; Age; Behavior; Behavioral; Behavioral Symptoms; Biochemical; Biological Markers; Brain; Caring; Cell Proliferation; Characteristics; Child; Clinical Trials; Cognition; Cognitive; Comprehensive Health Care; Consensus; Consensus Development; Data; Data Collection; Development; Electroencephalography; Etiology; Evaluation; FRAP1 gene; Functional disorder; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genomics; Goals; Guidelines; Heritability; Heterogeneity; Human; Individual; Intervention Studies; Knockout Mice; Malignant Neoplasms; Medical; Megalencephaly; Modeling; Molecular; Mutation; National Comprehensive Cancer Network; Natural History; Neurocognitive; Neurodevelopmental Disorder; Neurons; Outcome; PI3K/AKT; PTEN gene; Pathway interactions; Pattern; Peripheral; Phenotype; Phosphoric Monoester Hydrolases; Practice Guidelines; Process; Proteins; Recommendation; Risk Management; Series; Signs and Symptoms; Specificity; Stratification; Structure; Subgroup; Symptoms; System; Tumor Suppressor Proteins; Validation; Variant; aged; autism spectrum disorder; biomarker identification; cancer risk; cell growth; cognitive function; cohort; differential expression; frontal lobe; individuals with autism spectrum disorder; molecular marker; mouse model; neural correlate; neurobehavior; neurobehavioral; neuropathology; neurophysiology; neuropsychiatric disorder; potential biomarker; precision genetics; psychologic; recruit; relating to nervous system; repetitive behavior; risk stratification; social communication; specific biomarkers; therapeutic target; transcriptome; treatment planning; white matter

Autism spectrum disorders (ASD) are an etiologically heterogeneous set of neurodevelopmental disorders marked by social communication/interaction deficits and restricted/repetitive behaviors. Genetic studies have identified a strong heritable component, yet >80% of ASD remains idiopathic. Marked heterogeneity has slowed attempts to identify pathophysiology and related therapeutic targets. One promising strategy to reduce complexity is to focus on subgroups with a specific genetic etiology, such as ASD associated with germline heterozygous PTEN mutations (PTEN-ASD, who are always macrocephalic). In the last 4 years, we characterized cross-sectional neurobehavioral and neurocognitive differences among PTEN-ASD, those with PTEN mutations but no ASD (PTEN-no ASD) and macrocephalic ASD without PTEN mutations (Macro-ASD) and begun longitudinal data collection in individuals aged 3-21. We propose a natural history study of the neurophenotypic and molecular characteristics of PTEN-ASD with the goals of understanding risk management and treatment planning as well as identifying sensitive biomarkers for intervention studies. We will recruit 170 (70 from current cohort) individuals with PTEN-ASD, Macro-ASD, and PTEN no-ASD, and expanding recruitment to aged 18 months to 45 years. Data collected will include: (a) cancer occurrence, (b) autism and other behavioral symptoms, (c) neurocognitive profiles, (d) adaptive function, (e) genomic modifiers, (f) protein levels from PI3K/AKT/mTOR/S6K pathway, and (g) EEG, in order to: (Aim 1) Determine cross-sectional and longitudinal neurobehavioral and medical differences between PTEN-ASD and other groups in an expanded age range. This aim seeks to describe initial levels and longitudinal changes in cancer occurrence, behavioral signs/symptoms, and cognitive function in PTEN-ASD; (Aim 2) Identify EEG and molecular biomarkers specific to PTEN-ASD and those shared with other groups. This aim seeks to identify biomarkers that may be treatment targets in intervention studies; and (Aim 3) Develop a comprehensive, multi-level, longitudinal model of PTEN-ASD to inform future clinical trials and the development of consensus care guidelines. We will use data from Aims 1 and 2 and from TSC Associated Neuropsychiatric Disorders (TAND) Checklist (after validation). This first comprehensive longitudinal evaluation of the phenotypic and molecular characteristics of PTEN ASD, to identify specific molecular pathway and correlated neural abnormalities responsible for ASD symptoms in these individuals, which can be ably compared to TSC and PMS. It is a crucial next step toward the development of personalized genetic treatment approaches for PTEN-ASD. Prior to initiating further clinical trials, it will be critical to identify treatment targets at the molecular, neurophysiological, and behavioral levels.

自闭症谱系障碍（ASD）是一组神经发育障碍的一组 以社会沟通/互动缺陷和受限制/重复行为为标志。遗传研究已有 确定了强大的可遗传成分，但> 80％的ASD仍然是特发性。明显的异质性已减慢 试图鉴定病理生理学和相关治疗靶标。减少的一种有希望的策略 复杂性是专注于具有特定遗传病因的亚组，例如与种系有关的ASD 杂合子PTEN突变（PTEN-ASD，始终是脑脑）。在过去的四年中，我们 PTEN-ASD的横截面神经行为和神经认知差异的表征 PTEN突变，但没有ASD（pten-no ASD）和脑头ASD，没有PTEN突变（宏ASD） 并开始在3-21岁的个体中收集纵向数据。我们提出了一项关于 PTEN-ASD的神经表型和分子特征，其目标是了解风险管理 以及治疗计划以及确定敏感生物标志物进行干预研究。我们将招募170 （当前队列的70个）患有PTEN-ASD，宏观ASD和PTEN NO-ASD的人，并扩大招聘 至18个月至45岁。收集的数据将包括：（a）癌症发生，（b）自闭症和其他行为 症状，（c）神经认知特征，（d）自适应功能，（e）基因组修饰剂，（f）来自 PI3K/AKT/MTOR/S6K途径，以及（G）EEG，以：（ AIM 1）确定横截面和纵向 PTEN-ASD与其他年龄范围内PTEN-ASD和其他群体之间的神经行为和医学差异。这 目的旨在描述癌症发生的初始水平和纵向变化，行为体征/症状， PTEN-ASD中的认知功能； （AIM 2）确定特定于PTEN-ASD的脑电图和分子生物标志物， 这些与其他群体共享。此目的旨在确定可能是治疗靶标的生物标志物 干预研究； （AIM 3）开发一个综合的，多层次的PTEN-ASD纵向模型 告知未来的临床试验和共识护理指南的制定。我们将使用目标1和 2并从TSC相关的神经精神疾病（TAND）清单（验证后）。第一个 PTEN ASD的表型和分子特征的全面纵向评估，以识别 特定的分子途径和相关的神经异常，负责ASD症状 个人，与TSC和PM相比，这是可以很好的。这是迈向发展的下一步 PTEN-ASD的个性化基因治疗方法。在启动进一步的临床试验之前，这将是至关重要的 确定分子，神经生理和行为水平的治疗靶标。