Development of Behavioral and Neural Biomarkers for Autism Spectrum Disorder Using a Genetically Defined Subtype

 描述（由申请人提供）：自闭症谱系障碍（ASD）影响68名儿童中的1名（CDC，2014），已知遗传原因占病例的10-15%（Devlin &谢勒，2012; Gaugler et al.，2014）。大约2%的严重受影响的ASD儿童在SHANK 3基因中具有缺失或点突变，这导致M-M综合征（PMS）（Betancur & Buxbaum，2013; Leblond等人，2014）。SHANK 3是谷氨酸突触中的支架蛋白（Bodzdagi等人，2013; Yang等人，2012年）。超过80%的PMS儿童符合ASD和智力残疾的精神障碍诊断和统计手册（DSM）标准，并且语言能力最低（Soorya等人，2013年）。感觉反应性异常，如低反应性和高反应性代表了ASD的新DSM-5标准。虽然在特发性ASD形式中已经显示出感觉反应性问题（Tomcheck和Dunn，1997; Tavassoli等人，2012年，2013年），没有研究调查了严重影响儿童的感觉反应异常，包括那些患有PMS的儿童。识别感觉反应异常对这些儿童尤其重要，因为他们不能用语言描述他们的感觉体验。在ASD的特发性形式中，视觉是研究最多的感觉形态（Simmons等人，2009; Tavassoli等人，2011; Weinger等人，2014）。此外，我们的初步研究表明，在视觉领域的低反应性是常见的经前综合征儿童。初步数据还表明，感觉反应的行为和电生理测量可能有能力客观区分患有（1）PMS，（2）特发性ASD和（3）典型发育对照的儿童。 拟议项目的目的是开发ASD感觉反应的行为和神经生物标志物，这些生物标志物在严重受影响的个体（包括PMS）中是可行的，并且可以翻译为其他遗传定义的亚型和跨感觉模式。该项目旨在更广泛地开发PMS和ASD儿童视觉系统内行为和神经感觉反应的可靠措施。所获得的知识将提供一个如何在PMS和ASD的感觉系统受到影响，同时评估与神经功能的关系增强的理解。这项研究很重要，因为它旨在开发可应用于其他严重受影响个体临床人群的生物标志物。

 DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) affects 1 in 68 children (CDC, 2014) with known genetic causes accounting for 10-15% of cases (Devlin & Scherer, 2012; Gaugler et al., 2014). Approximately 2% of severely affected children with ASD have deletions or point mutations in the SHANK3 gene, which results in Phelan- McDermid syndrome (PMS) (Betancur & Buxbaum, 2013; Leblond et al, 2014). SHANK3 is a scaffolding protein in glutamate synapses (Bodzdagi et al., 2013; Yang et al., 2012). Over 80% of children with PMS meet Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for ASD and intellectual disability and are minimally verbal (Soorya et al., 2013). Sensory reactivity abnormalities such as hypo- and hyper-reactivity represent a new DSM-5 criterion for ASD. While sensory reactivity issues have been shown in idiopathic forms of ASD (Tomcheck & Dunn, 1997; Tavassoli et al., 2012, 2013), no studies have investigated sensory reactivity abnormalities in severely affected children, including those with PMS. Identifying sensory reactivity abnormalities is especially important in such children as they cannot verbally describe their sensory experiences. In idiopathic forms of ASD, vision is the most researched sensory modality (Simmons et al., 2009; Tavassoli et al., 2011; Weinger et al., 2014). Moreover our pilot studies suggest that hyporeactivity in the visual domain is common in children with PMS. Preliminary data also show that behavioral and electrophysiological measures of sensory reactivity may have the capacity to objectively differentiate between children with (1) PMS, (2) idiopathic ASD, and (3) typically developing controls. The aim of the proposed project is to develop behavioral and neural biomarkers of sensory reactivity in ASD, which are feasible in severely affected individuals (including PMS) and can be translated to other genetically defined subtypes and across sensory modalities. This project aims to develop reliable measures of behavioral and neural sensory reactivity within the visual system of children with PMS and ASD more broadly. The knowledge gained will provide an enhanced understanding of how one sensory system is affected in PMS and ASD, while assessing the relationship with neural functioning. This study is important because it seeks to develop biomarkers that can be applied to other clinical populations of severely affected individuals.