Electrophysiological Markers for Interventions in Phelan-McDermid Syndrome and Idiopathic Autism

项目摘要 最近的研究表明，高达2%的自闭症谱系障碍（ASD）患者和 在SHANK 3基因中具有缺失或点突变的智力残疾（ID），导致 经前综合征（PMS），大约85%的PMS患者符合标准 自闭症SHANK 3编码一个主要的支架蛋白，在细胞内形成一个关键的框架。 突触后密度的神经元（兴奋性）突触，并发挥关键作用，在突触 功能SHANK 3和谷氨酸途径与多种形式的ASD有关， 融合意味着共享的生化途径， 目标的因此，将PMS中的SHANK 3缺陷作为ASD的特定遗传原因， 我们为更广泛的特发性ASD（iASD）的治疗提供信息。我们正在进行的研究提供了深入的 PMS的表型，指向特定的临床和电生理（EEG）概况。 然而，潜在的EEG生物标志物作为治疗反应的测量的功效仍然存在。 有待确定。 使用视觉诱发电位（VEP）检查皮层兴奋性的初步数据 突触后电位显示出与PMS和iASD疾病机制的有希望的联系。 用于评估对干预的反应的生物标志物和新的临床措施也已被 在我们的研究中心成功地在PMS和iASD患者队列中进行了试点。我们已经确定了一 PMS中兴奋性缺陷的独特VEP特征（P60-N75振幅显著降低）， 也存在于iASD儿童的子集中。在这里，我们建议将这项工作扩展到一个更大的 样本在PMS和平行兴奋过程中的听觉域，为了分层 iASD患者，并选择我们预测将对IGF-1产生反应的患者。 我们将招募150名儿童（60名PMS; 90名iASD;年龄5-12岁），特别招募 考虑到这一特征在经前综合症中的突出地位，智障和言语障碍儿童 以及在更广泛的ASD研究中解决这一群体的迫切需要。我们的短期目标是 显示PMS中所选电生理学标记物与iASD相关， 治疗反应。我们的长期目标是优化iASD的治疗选择， 建立源自PMS的生物特征，其：a）用于预测治疗 应答者，和B）对干预有应答。这项研究的预期结果是， 确立电生理学生物标志物用于PMS临床试验的可行性， iASD并定义生物学特征，该特征将标记可能显示iASD的患者子集 对IGF-1的神经和临床反应。

PROJECT SUMMARY Recent work suggests that up to 2% of individuals with autism spectrum disorder (ASD) and intellectual disability (ID) have deletions or point mutations in the SHANK3 gene, resulting in Phelan-McDermid syndrome (PMS), and approximately 85% of people with PMS meet criteria for ASD. SHANK3 codes for a master scaffolding protein that forms a key framework in the postsynaptic density of glutamatergic (excitatory) synapses and plays a critical role in synaptic function. SHANK3 and glutamate pathways are implicated in multiple forms of ASD and this convergence implies shared biochemical pathways with potentially overlapping therapeutic targets. Thus, targeting SHANK3 deficiency in PMS as a specific genetic cause of ASD allows us to inform treatment in broader idiopathic ASD (iASD). Our ongoing studies provide in-depth phenotyping of PMS, pointing toward a specific clinical and electrophysiological (EEG) profile. However, the efficacy of potential EEG biomarkers as a measure of treatment response remains to be determined. Preliminary data using visual evoked potentials (VEPs) to examine cortical excitatory postsynaptic potentials demonstrate promising links to disease mechanisms in PMS and iASD. Biomarkers and novel clinical measures for evaluating response to intervention have also been piloted successfully at our site in cohorts of patients with PMS and iASD. We have identified a unique VEP profile of excitatory deficits in PMS (markedly reduced P60-N75 amplitude) that is also present in a subset of children with iASD. Here, we propose to extend this work to a larger sample in PMS and to parallel excitatory processes in the auditory domain, in order to stratify individuals with iASD and select those we predict will show response to IGF-1. We will enroll 150 children (60 PMS; 90 iASD; age 5-12 years), specifically recruiting intellectually disabled and minimally verbal children given the prominence of this profile in PMS and the critical need to address this group in broader ASD research. Our short-term goal is to show that select electrophysiological markers in PMS are relevant to iASD and predictive of treatment response. Our long-term goal is to optimize treatment selection in iASD by establishing biological signature(s) derived from PMS that are: a) useful for predicting treatment responders, and b) responsive to intervention. The expected outcome of this study is to establish the feasibility of electrophysiological biomarkers for use in clinical trials in PMS and iASD and to define a biological profile that will mark a subset of patients with iASD likely to show neural and clinical response to IGF-1.