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

自闭症谱系障碍(Asd)是一组病因不同的神经发育障碍。 以社交沟通/互动不足和受限/重复行为为特征。基因研究已经 发现了一种很强的可遗传成分，但80%的ASD仍然是特发性的。显著的异质性已经放缓 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，以减少 复杂性是指集中于具有特定遗传病因的亚群，例如与生殖系相关的ASD PTEN杂合性突变(PTEN-ASD，通常为巨头症)。在过去的4年里，我们 PTEN-ASD患者的横断面神经行为和神经认知差异的特征 PTEN突变但无ASD(PTEN-NO ASD)和无PTEN突变的巨头型ASD(Macro-ASD) 并开始在3-21岁的个人中进行纵向数据收集。我们建议进行一项自然历史研究 PTEN-ASD的神经表型和分子特征及其对风险管理的认识 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人 (来自当前队列的70人)患有PTEN-ASD、宏观ASD和PTEN非ASD的个人，并正在扩大招募 至18个月至45岁。收集的数据将包括：(A)癌症发生情况；(B)自闭症和其他行为 症状，(C)神经认知特征，(D)适应功能，(E)基因组修饰，(F)来自 PI3K/AKT/mTOR/S6K通路和(G)EEG，以便：(目标1)确定横断面和纵向 在扩大的年龄范围内，PTEN-ASD组与其他组之间的神经行为和医学差异。这 AIM旨在描述癌症发生的初始水平和纵向变化，行为迹象/症状， 和认知功能；(目的2)鉴定PTEN-ASD和PTEN-ASD特异性的脑电和分子生物标志物 那些与其他组共享的内容。这一目标寻求识别可能成为治疗靶点的生物标志物 干预研究；以及(目标3)建立一个全面的、多层次的PTEN-ASD纵向模型，以 告知未来的临床试验和制定共识护理指南。我们将使用AIMS 1和 2和来自TSC相关神经精神障碍(TAND)检查表(验证后)。这是第一次 综合纵向评估PTEN ASD的表型和分子特征，以鉴定 导致ASD症状的特定分子途径和相关神经异常 个人，这可以巧妙地与TSC和经前综合症相比较。这是发展的关键的下一步 PTEN-ASD的个体化基因治疗方法。在启动进一步的临床试验之前，这将是至关重要的 在分子、神经生理和行为水平上确定治疗靶点。

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.