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

 描述（由申请人提供）：先天性强直性肌营养不良是由于患有强直性肌营养不良的父母与其后代之间的致病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由于早期呼吸衰竭、智力残疾、虚弱和许多全身性并发症而导致显著的发病率和死亡率。在RNA被翻译成蛋白质之前，RNA被切割或剪接，以便根据年龄和其他因素形成正确的蛋白质形式。在患有强直性肌营养不良的成人中，CTG重复损害该过程，导致许多重要RNA转录物的异常剪接，这反过来又导致不同的疾病表现。目前尚不清楚在先天性强直性肌营养不良症中是否发生相同的疾病机制。随着强直性肌营养不良治疗方法的发展，必须了解这一过程是否也发生在先天性强直性肌营养不良中。该提案旨在更好地了解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。这些结果将有助于更好地了解疾病进展，并为接近治疗试验做好准备。我们假设RNA剪接的变化是儿童期疾病进展的原因。该研究的第二个目的是确定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。本研究利用了现有的先天性强直性肌营养不良纵向疾病进展队列。在这项研究中，患有先天性强直性肌营养不良的儿童有神经精神功能，肌肉功能，心脏传导，呼吸功能，言语和生活质量的措施。目前的提案旨在确定致病的RNA剪接变化。此外，这项研究将研究全球变化的翻译发生的结果，螯合的RNA结合蛋白。最后，本研究将确定RNA剪接和翻译的变化与疾病进展中的临床终点的相关性。这些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。这些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，本计画亦将提供RNA生物学基础研究之研究技术。

 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.