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

自闭症谱系障碍（ASD）是一种病因异质性的神经发育障碍 以社交/互动缺陷和限制/重复行为为特征。遗传学研究 虽然确定了一个很强的遗传成分，但>80%的ASD仍然是特发性的。显著的异质性已经减缓 试图确定病理生理学和相关的治疗目标。一个有希望的战略， 复杂性在于关注具有特定遗传病因的亚组，例如与生殖细胞相关的ASD 杂合子PTEN突变（PTEN-ASD，总是大头）。在过去的四年里，我们 PTEN-ASD之间的特征性横截面神经行为和神经认知差异， PTEN突变但无ASD（PTEN-no ASD）和无PTEN突变的大头ASD（Macro-ASD） 并开始在3-21岁的个体中进行纵向数据收集。我们提出了一个自然历史研究的 PTEN-ASD的神经表型和分子特征，目的是了解风险管理 和治疗计划，以及为干预研究确定敏感的生物标志物。我们将招募170名 (70来自当前队列）患有PTEN-ASD、Macro-ASD和PTENno-ASD的个体，并扩大招募 18个月至45岁。收集的数据将包括：（a）癌症发生率，（B）自闭症和其他行为 症状，（c）神经认知概况，（d）适应功能，（e）基因组修饰剂，（f）来自 PI 3 K/AKT/mTOR/S6 K通路，和（g）EEG，以便： PTEN-ASD和其他年龄组之间的神经行为和医学差异。这 aim旨在描述癌症发生，行为体征/症状， （目的2）鉴定PTEN-ASD特异性的EEG和分子生物标志物， 与其他群体共享的。这一目标旨在鉴定可能是治疗靶点的生物标志物， 干预研究;和（目标3）开发一个全面的，多层次的，纵向的PTEN-ASD模型， 为未来的临床试验和共识护理指南的制定提供信息。我们将使用目标1和 2和TSC相关神经精神障碍（TAND）检查表（验证后）。该第一 对PTEN ASD的表型和分子特征进行全面的纵向评价，以鉴定 这些患者中负责ASD症状的特定分子途径和相关神经异常 个人，这可以巧妙地比较TSC和PMS。这是发展的关键一步， PTEN-ASD的个性化基因治疗方法。在开始进一步的临床试验之前， 在分子、神经生理学和行为水平上确定治疗目标。

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.