A Prospective Natural History Study of Angelman Syndrome: A Fresh Approach to a 10-year Longitudinal Study to Facilitate Development of Novel Therapeutic Products

安杰曼综合症的前瞻性自然史研究：为期 10 年的纵向研究的新方法，以促进新型治疗产品的开发

• 批准号: 9373337
• 负责人: Wen-Hann Tan
• 金额: $ 200万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9373337
• 关键词: Prospective; Natural; History; Study; Angelman

Project Summary Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, seizures, disturbed behavior and little/no speech. Robust longitudinal, prospectively collected, natural history data are the bedrock for the design of clinical trials, including selection of appropriate outcome measures. This AS Natural History Study seeks to address the unmet needs listed below by introducing new outcome measures, including those suggested by pharmaceutical company actively developing treatments for AS: (i) Current outcome measures do not adequately assess communication skills of individuals with AS, including the use of augmentative and alternative communication (AAC) devices. (ii) Anxiety, a debilitating symptom in some individuals with AS, has not been examined systematically. (iii) The motor and language impairments faced by individuals with AS negatively impacts their scores on the most widely-used assessment tool (Bayley Scales of Infant Development, BSID) and results in an underestimation of their abilities. (iv) Evaluation of treatment effects is limited by an inadequate number of validated outcome measures. (v) The natural history of AS in adults is poorly understood due to small number of adult participants. The overall goal is to increase understanding of the long-term natural history of AS and obtain AS-specific norms for outcome measures that can be used in clinical trials, to ultimately improving their care. The specific aims are: Aim 1: To conduct a prospective, longitudinal natural history study of AS in both children and adults, using investigator-observed and parent-reported outcome measures that will be useful for future clinical trials. Aim 2: Adapt the BSID for the AS population, by lessening the bias introduced by motor and language impairments, and pilot its use. Exploratory Aim: To assess the feasibility of using video recordings obtained by caregivers in the participant's natural environment to study the abilities of individuals with AS to use AAC devices. Participants will be enrolled (at 3 physical sites and via remote participation) for annual assessments including medical/developmental history, physical examination (on-site participants), and a battery of developmental and behavioral measures. For participants at the physical sites, a modified version of the BSID, which removes the penalty in the cognitive domain introduced by fine motor impairments and speed of accomplishment, and credits non-verbal communication modalities in the expressive language domain, will be administered. Video recordings of participants will be edited and scored by an expert in the use of AAC devices.

项目摘要 Angelman综合征（AS）是一种神经发育障碍，其特征是智障，癫痫发作， 行为干扰，很少/没有言语。强大的纵向，前瞻性收集的自然历史数据是 设计临床试验的基岩，包括选择适当的结果指标。这是 自然历史研究旨在通过引入新的结果指标来满足以下未满足的需求， 包括制药公司建议的那些主动为以下方式开发治疗方法： （i）当前的结果措施不能充分评估AS的个人的沟通技巧，包括 使用增强和替代通信（AAC）设备。 （ii）焦虑是某些患有AS的人的衰弱症状，尚未系统地检查。 （iii）个人面临的运动和语言障碍，其分数对他们的分数产生了影响 大多数广泛使用的评估工具（Bayley的婴儿发育量表，BSID），导致 低估了他们的能力。 （iv）评估治疗效果受到验证的结果指标数量不足的限制。 （v）由于少数成年参与者的数量，成年人的自然历史对成年人的了解很少。 总体目标是提高对AS的长期自然历史的理解并获得特定的 可以在临床试验中使用的结果措施的规范，以最终改善其护理。具体 目的是： 目的1：在儿童和成人中进行AS的前瞻性，纵向自然历史研究，使用 研究者观察和父母报告的结果指标将对以后的临床试验有用。 AIM 2：通过减少运动和语言引入的偏见来适应AS人群的BSID 损害，并试行其使用。 探索目的：评估使用参与者在参与者的看护人获得的视频记录的可行性 自然环境研究使用AAC设备的个人的能力。 参与者将入学（在3个实体站点，通过远程参与）进行年度评估，包括 医学/发育历史，体格检查（现场参与者）以及一系列发育和 行为措施。对于物理站点的参与者，BSID的修改版本 通过精细运动障碍和成就速度引入的认知领域的处罚，以及 将管理表达语言领域中的非语言交流方式。视频 参与者的录音将由AAC设备的使用专家进行编辑和评分。

项目成果

Methylation analysis and developmental profile of two individuals with Angelman syndrome due to mosaic imprinting defects.

• DOI: 10.1016/j.ejmg.2022.104456
• 发表时间: 2022-04
• 期刊: EUROPEAN JOURNAL OF MEDICAL GENETICS
• 影响因子: 1.9
• 作者: Baker, Emma K.;Merton, Catherine F.;Tan, Wen-Hann;Dudding-Byth, Tracy;Godler, David E.;Sadhwani, Anjali
• 通讯作者: Sadhwani, Anjali