Health Endpoints and Longitudinal Progression in Congenital Myotonic Dystrophy (HELP-CDM)

 描述(申请人提供)：先天性强直性肌营养不良是由于强直性肌营养不良的父母及其后代之间的CTG三核苷酸重复扩增迅速扩大，导致出生时出现症状。先天性强直性肌营养不良会导致严重的发病率和死亡率，原因是早年呼吸衰竭、智力残疾、虚弱和一些全身并发症。在RNA被翻译成蛋白质之前，RNA被切割或剪接，这样就可以根据年龄和其他因素制造出正确的蛋白质形式。在患有强直性肌营养不良的成年人中，CTG重复序列破坏了这一过程，导致许多重要的RNA转录本的异常剪接，进而导致疾病的多种表现。目前尚不清楚先天性强直性肌营养不良是否存在相同的发病机制。随着针对强直性肌营养不良的治疗方法的发展，了解这一过程是否也发生在先天性强直性肌营养不良中是非常重要的。这项建议旨在更好地了解CTG重复扩增如何导致先天性强直性肌营养不良儿童的疾病。这一结果将有助于更好地了解疾病的进展，并为即将到来的治疗试验做准备。我们假设，RNA剪接变化是儿童疾病进展的原因。这项研究的第二个目的是识别基于血液的生物标志物，如RNA剪接变异或其他观察到的蛋白质变化，这可能有助于未来的治疗试验。这项研究利用了现有的先天性强直性肌营养不良的纵向疾病进展队列。在这项研究中，先天性强直性肌营养不良的儿童进行了神经精神功能、肌肉功能、心脏传导、呼吸功能、言语和生活质量的测量。目前的提案试图确定导致疾病的RNA剪接变化。此外，这项研究还将检查由于RNA结合蛋白的隔离而发生的翻译的全球变化。最后，这项研究将确定RNA剪接和翻译的变化与疾病进展中的临床终点的相关性有多好。该结果将为先天性强直性肌营养不良疾病的进展提供一个完整的临床和生物学模型。这一关键信息将允许为治疗试验开发适当的临床和生物学终点。此外，该项目还将为RNA生物学的基础研究提供研究技术。

 DESCRIPTION (provided by applicant): Congenital myotonic dystrophy is due to the rapid enlargement of the disease-causing CTG trinucleotide repeat expansion between a parent with myotonic dystrophy and their offspring resulting in symptoms at birth. Congenital myotonic dystrophy causes significant morbidity and mortality due to early life respiratory failure, intellectual disability, weakness, and a number of systemic complications. Before RNA is translated into proteins, the RNA is cut, or spliced, so that the correct form of the protein is made based on age and other factors. In adults with myotonic dystrophy, the CTG repeat impairs this process resulting in abnormal splicing of many important RNA transcripts which in turn leads to the diverse disease manifestations. It is not known whether the same disease mechanism occurs in congenital myotonic dystrophy. As developing therapies for myotonic dystrophy target this mechanism, it is imperative to understand if this process also occurs in congenital myotonic dystrophy. This proposal seeks to better understand how the CTG repeat expansion causes disease in children with congenital myotonic dystrophy. The results will lead to a better understanding of disease progression and prepare for approaching therapeutic trials. We hypothesize that RNA splicing changes are responsible for disease progression in childhood. A secondary aim of the study is to identify blood-based biomarkers such as RNA splice variation or other observed protein changes, which could facilitate future therapeutic trials. This study utilizes an existing longitudinal disease progression cohort with congenital myotonic dystrophy. In this study, children with congenital myotonic dystrophy have measures of neuropsychiatric function, muscle function, cardiac conduction, respiratory function, speech, and quality of life. The current proposal seeks to identify disease-causing RNA splicing changes. In addition, this study will examine global changes in translation that occur as the result of sequestration of RNA-binding proteins. Finally, this study will identify how well the changes in RNA splicing and translation correlate with the clinical endpoints in the disease progression. The results will provide a complete clinical and biological model for congenital myotonic dystrophy disease progression. This critical information will permit development of appropriate clinical and biological endpoints for therapeutic trials. In addition, this project wil provide the investigator techniques in fundamental research in RNA biology.