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

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 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.