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)影响每68名儿童中就有一名(CDC，2014年)，已知遗传原因占病例的10%-15%(Devlin&Scherer，2012年；Gaugler等人，2014年)。大约2%的严重ASD儿童存在SHANK3基因的缺失或点突变，这会导致Phelan-Mcdermid综合征(PMS)(Betancur&Buxbaum，2013；Leblond等人，2014)。感觉反应性异常，如低反应性和高反应性，代表了ASD的新的DSM-5标准。虽然感觉反应性问题已经在特发性ASD中表现出来(Tomcheck&Dunn，1997；Tavassoli等，2012,2013)，但还没有研究调查严重影响儿童的感觉反应性异常，包括经前综合症儿童。识别感觉反应异常对这样的儿童尤其重要，因为他们不能用语言描述他们的感觉经历。此外，我们的初步研究表明，经前综合症儿童在视觉领域的低反应性是常见的。该项目旨在更广泛地发展对经前综合症和自闭症儿童视觉系统内行为和神经感觉反应的可靠测量。这项研究很重要，因为它寻求开发生物标记物，可以应用于其他临床人群的严重影响的个人。

 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.