Developmental Synaptopathies Associated with TSC, PTEN and SHANK3 Mutations

与 TSC、PTEN 和 SHANK3 突变相关的发育性突触病

• 批准号: 10381912
• 负责人: MUSTAFA SAHIN
• 金额: $ 22.12万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381912
• 关键词: Adult; Advisory Committees; Affect; Age; Biochemical; Biochemical Pathway; Biological Markers; Brain; Caring; Child; Clinic; Clinical; Clinical Trials; Collaborations; Communities; Consensus; Consensus Development; Data; Data Set; Development; Diagnosis; Disability phenotype; Disabled Persons; Disease; Early identification; Early treatment; Electroencephalography; Electrophysiology (science); Enrollment; Epilepsy; Etiology; FRAP1 gene; Family; Foundations; Functional disorder; Funding; Future; Genes; Genetic; Genetic Diseases; Genetic Translation; Goals; Guidelines; Heterogeneity; Incidence; Individual; Infant; Infrastructure; Institution; Institutional Review Boards; Intellectual functioning disability; Junior Physician; Knowledge; Lead; Light; Longevity; Medical; Mentors; Modeling; Molecular; Mutation; Natural History; Neurodevelopmental Disorder; Outcome; PTEN gene; Pathway interactions; Patient advocacy; Patients; Pediatric cohort; Penetrance; Persons; Pharmaceutical Preparations; Phelan-McDermid syndrome; Phenotype; Physicians; Pilot Projects; Predisposition; Protein Biosynthesis; Proteins; Psychologist; Public Health; Rare Diseases; Research; Research Personnel; Resources; Safety; Scientist; Severity of illness; Site; Strategic Planning; Structure; Subgroup; Support Groups; Synapses; Syndrome; System; TSC1 gene; TSC1/2 gene; TSC2 gene; Therapeutic; Time; Training; Translational Research; Tuberous sclerosis protein complex; United States National Institutes of Health; Vigabatrin; Work; advocacy organizations; autism spectrum disorder; base; biomarker discovery; career; clinical practice; cohort; comparative; cost estimate; data acquisition; disorder risk; early childhood; experience; genetic counselor; individuals with autism spectrum disorder; inhibitor/antagonist; interest; life time cost; longitudinal design; molecular marker; neurobehavioral; novel; novel strategies; patient advocacy group; pediatric patients; predictive marker; prevent; prospective; severe intellectual disability; specific biomarkers; synaptic function; targeted treatment; therapeutic target; tool; treatment strategy

Advances in genetics have illustrated that autism spectrum disorder (ASD) and intellectual disability (ID) include a spectrum of rare disorders, and that mutations in hundreds of genes may result in susceptibility to ASD/ID. This heterogeneity represents significant challenges, but at the same time unique opportunities for research in the field of ASD/ID. Many of the genes implicated in ASD/ID appear to converge on a few common pathways, suggesting that there may be a common dysfunction at the cellular or systems level. Deeper understanding of the shared pathophysiology of these diseases may serve as gateways for understanding mechanisms of other causes of ASD/ID and for shared treatment possibilities. The Developmental Synaptopathies Consortium (DSC) was formed and funded in 2014 in order to perform mechanistic analysis of three genetic disorders with high penetrance of ASD/ID, and shed light on molecular pathways and mechanism-based therapeutic targets relevant to ASD/ID. We propose to continue our focus on three genetic syndromes with abnormal synapse structure or function and that are associated with high penetrance for ASD/ID: TSC1/2 (Tuberous Sclerosis Complex or TSC), PTEN (PTEN Hamartoma Tumor Syndrome or PHTS) and SHANK3 (Phelan McDermid Syndrome or PMS) mutations. Specific aims for TSC are: 1) Characterize the phenotype of ASD and ID in a large cohort of pediatric and adult patients with TSC in a prospective, multi-center longitudinal design; 2) Identify electrophysiological biomarkers of synaptic function and connectivity associated with ASD and ID in TSC; and 3) Evaluate the suitability of the TAND Checklist as TSC-specific research tool for assessing clinically-meaningful outcomes in future ASD and ID clinical trials. Specific aims for PHTS are: 1) Determine cross-sectional and longitudinal neurobehavioral and medical differences between PTEN-ASD and other groups in an expanded age range; 2) Identify EEG and molecular biomarkers specific to PTEN-ASD and those shared with other groups; and 3) Validate TAND and develop a comprehensive, multi-level, longitudinal model of PTEN-ASD using data from Aims 1 and 2 and TAND scores, in order to inform future clinical trials and the development of consensus care guidelines. Specific aims for PMS are: 1) Comprehensively characterize PMS across the lifespan and track the natural history; 2) Validate electrophysiological biomarkers of PMS; and 3) Develop a comprehensive clinical model of PMS to inform assessment and future clinical trials. As detailed in the Resources sections, this Consortium involves experienced physician-researchers from premier academic institutions with strong institutional and patient advocacy group support, along with impressive mentors for training of future physician- researchers and genetic counselors focused on translational research in neurodevelopmental disorders. We will continue to work closely with the patient advocacy groups to engage and inform the families affected with these disorders. Knowledge gained from this project will inform clinical practice and spur the development of novel treatments.

遗传学的进步表明，自闭症谱系障碍（ASD）和智力障碍（ID）包括 一系列罕见疾病以及数百个基因的突变可能会导致对ASD/ID的敏感性。 这种异质性代表了重大挑战，但同时进行研究的独特机会 ASD/ID的字段。与ASD/ID有关的许多基因似乎在几种常见的途径上收敛， 表明在细胞或系统水平上可能存在常见的功能障碍。更深入的理解 这些疾病的共同病理生理学可能是理解其他机制的门户 ASD/ID的原因以及共同的治疗可能性。发育突触疗法财团（DSC） 于2014年成立和资助，以对三种遗传疾病进行机械分析 ASD/ID的渗透，并阐明分子途径和基于机制的治疗靶标相关 到ASD/ID。我们建议继续关注具有异常突触结构或 功能且与ASD/ID的高渗透率有关：TSC1/2（结节硬化症复合物或 TSC），PTEN（PTEN Hamartoma肿瘤综合征或PHT）和Shank3（Phelan McDermid综合征或 PMS）突变。 TSC的具体目的是：1）在大量队列中表征ASD和ID的表型 在预期的多中心纵向设计中患有TSC的小儿和成年患者； 2）识别 与TSC中ASD和ID相关的突触功能和连通性的电生理生物标志物；和 3）评估TAND清单作为TSC特定研究工具的适用性，用于评估临床上的含量 未来的ASD和ID临床试验中的结果。 PHT的具体目的是：1）确定横截面和 PTEN-ASD与其他群体之间的纵向神经行为和医学差异 范围; 2）确定针对PTEN-ASD的脑电图和分子生物标志物以及与其他群体共享的脑电图； 3）使用数据验证并开发PTEN-ASD的全面，多层次的纵向模型 从目标1和2和TAND分数中，以告知未来的临床试验和共识的发展 护理指南。 PMS的具体目的是：1）全面表征PMS的寿命和轨道 自然历史； 2）验证PMS的电生理生物标志物； 3）开发全面的临床 PM的模型，以告知评估和未来的临床试验。如资源部分所详述，这 财团涉及来自主要学术机构的经验丰富的医师研究者 机构和患者倡导小组的支持，以及令人印象深刻的导师，以培训未来的医生 - 研究人员和遗传咨询师致力于神经发育障碍的转化研究。我们将 继续与患者倡导小组紧密合作，以接触并告知受影响的家庭 疾病。从该项目中获得的知识将为临床实践提供信息，并刺激新颖的发展 治疗。