Congenital myotonic dystrophy, the most severe form of myotonic dystrophy, causes weakness, breathing problems, and feeding problems at birth. During childhood, children often have intellectual impairment, fatigue, behavioral concerns and weakness. Importantly, many of the symptoms are distinct from those adults with myotonic dystrophy. In adults with myotonic dystrophy, a toxic RNA repeat expansion leads to global misregulation of RNA splicing. It is not clear if the same mechanism is involved in congenital myotonic dystrophy. Such information is critical since new treatments for myotonic dystrophy target this issue. This proposal is designed to evaluate the pathogenesis of congenital myotonic dystrophy. The investigators will evaluate changes in RNA splicing and gene expression in muscle samples and then validate these changes in a DM1 cell model by enrolling 100 children below the age of 15 with congenital myotonic dystrophy. Children will be evaluated with measures of physical function and cognition at the baseline visit and a fine needle aspirate of the muscle will be collected. Children with congenital myotonic dystrophy will return for a clinical evaluation at 12 months. These children will be compared to 30 histopathologically normal muscle biopsies.
In Aim 1, we will initially evaluate changes in RNA splicing and correlate these with the clinical outcome measures to identify those specific transcripts that most directly correlate with symptoms. Key RNA splicing events will be evaluated as predictors of clinical function at the 12-month visit.
In Aim 2, we will also evaluate secondary gene expression changes in a similar manner, which has not been done in myotonic dystrophy. Once key gene expression and RNA splicing signatures have been identified, Aim 3 will evaluate them in a DM1 cell model to assess the role of MBNL1 sequestration and other splicing regulators for a particular splice event. This is a key pathogenic mechanism in DM1. At the completion of this project, we will have identified key biomarkers and performed preliminary experiments to understand the role of these events in the mechanism of disease. By better understanding the pathogenesis of congenital myotonic dystrophy, we allow these children access to disease modifying therapies in myotonic dystrophy, as well as identify new therapeutic targets for drug development.
This proposal seeks to understand the relationship between the biological changes that cause congenital myotonic dystrophy and the symptoms that develop. This is a necessary step to extend the targeted, disease modifying, therapies developed for adults with myotonic dystrophy into this population. This understanding of the disease pathogenesis will also develop new biomarkers and potential treatment targets. The long-term goal is to reduce the disability for children with this disease.
