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

项目总结 最近的研究表明，多达2%的自闭症谱系障碍(ASD)患者和 智力障碍(ID)具有SHANK3基因的缺失或点突变，导致 费兰-麦克德米德综合征(PMS)，大约85%的PMS患者符合标准 对于ASD。SHANK3编码一种主要的支架蛋白，它形成了 谷氨酸能(兴奋性)突触的突触后密度及其在突触中的关键作用 功能。SHANK3和谷氨酸通路与多种形式的ASD有关，这 趋同意味着共享的生化途径与潜在的重叠治疗 目标。因此，将经前综合症中的SHANK3缺陷作为ASD的特定遗传原因允许 美国通知更广泛的特发性自闭症(IASD)的治疗。我们正在进行的研究提供了深入的 经前综合征的表型，指向特定的临床和电生理(EEG)特征。 然而，潜在的脑电生物标志物作为治疗反应的衡量标准的有效性仍然存在。 待定。 视觉诱发电位(VEP)检测皮质兴奋性的初步数据 突触后电位显示可能与经前综合征和间歇性自闭症的发病机制有关。 用于评估干预反应的生物标记物和新的临床方法也已被 在我们的站点成功地在经前综合征和IASD患者队列中试验。我们已经确定了一个 经前综合征兴奋性缺陷的独特VEP特征(P60-N75波幅显著降低)，即 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更大的 PMS中的样本和听域中的平行兴奋过程，以便分层 IASD患者和我们预测会对IGF-1有反应的人。 我们将招收150名儿童(60名经前综合症儿童；90名IASD儿童；5-12岁)，特别是招募 智力残疾和言语不多的儿童，因为这一特征在经前综合症中非常突出 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 提示经前综合征患者选择电生理标记物与IASD相关，并可预测 治疗反应。我们的长期目标是通过以下方式优化IASD的治疗选择 建立源自经前综合征的生物特征(S)：a)有助于预测治疗 应答者，以及b)对干预作出反应。这项研究的预期结果是 建立电生理生物标志物用于经前综合征和经前综合征临床试验的可行性 并定义将标记IASD患者子集的生物学特征 神经和临床对IGF-1的反应。

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.