Assessing Clinical Endpoints and Biomarkers in Myotonic Dystrophy Type-1 and Type 2

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are the most common inherited skeletal myopathies in adults. RNA toxicity is the core disease mechanism, good molecular targets have been identified and there has been rapid progress in developing targeted therapies. However, incomplete characterization and limited biologic understanding of phenotypic heterogeneity, and lack of reliable clinical endpoints and biomarkers remain major obstacle in the road to therapeutic success in these diseases. The present study seeks to overcome these roadblocks building on previous work of the Myotonic Dystrophy Clinical Research Network (DMCRN) (14-N-0132 study) with the following added features: 1) larger DM1 cohort including 11 - 70 year old individuals; 2) including DM2 individuals, 3) longer study duration; 4) allowing validation of NIH custombuilt devices for longitudinal measurements; and 5) including non-muscle endpoints and biomarkers specifically respiratory and central nervous system (CNS) function, which are important for survival and quality of life. The goal of the current study is to prospectively assess the disease progression over 2 years in individuals with DM1 and DM2. Selected tests, imaging and patient-reported outcomes will be assessed for ability to quantify disease burden, detect disease progression and predict changes. Additionally, we will examine muscle and cerebrospinal fluid (CSF) RNA alternative splice events as biomarkers of DM1 and DM2 severity and explore genetic modifiers of DM1 and DM2 severity by genome wide association (GWA) study.

Study population: This study plans to enroll up to 180 participants: 120 individuals with DM1 and 60 individuals with DM2 (open to both juvenile and adult individuals (11 to 70 years old, inclusive)) at the NIH Clinical Center.

Study Design: This will be a prospective observational study. No treatment will be administered as part of this study. Participants will receive standard of care as determined by their treating physician. Participants will report to the NIH Clinical Center for 3 visits each: at baseline (Visit 1), at 1-year from baseline (Visit 2), and at 2-years from baseline (Visit 3). To reduce fatigue and impact on results, each study visit be split into more than one trip to the NIH within a 30 day window) and may require the patient to be admitted to the clinical center. Each trip to the NIH for a study visit may last up to seven days. Study procedures for each visit are outlined in Section 4 and Appendix A. Data and samples will be shared with DMCRN investigators participating in Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type 1 (ENDDM1) study as indicated in Appendix B.

Outcome measures: No specific primary and secondary outcomes will be specified; however, the change in the following measures from baseline may be used to characterize the baseline status and disease progression over the course of the study: 1) muscle strength; 2) myotonia; 3) hand and upper arm functional tests; 4) measures of gait, balance and mobility; 5) skeletal muscle MRI measures of muscle mass and fatty degeneration; 6) skeletal muscle RNA biomarkers from biopsied tissue; 7) cognitive function; 8) brain MRI measures of gray matter volume, white matter hyperintensity volume, whole brain volume, integrity of white matter tracts measured as mean diffusivity and fractional anisotropy and resting state functional connectivity by functional MRI; 9) pulmonary function tests; 10) MRI measures of the diaphragm motion and contractility, myocardial function as well as myocardial fat and water composition and fibrosis; 11) clinical assessments of sleep, speech and swallow and gastrointestinal motility impairment; and 12) CSF RNA biomarkers and genetic modifiers of DM1 and DM2 severity from a GWA study in collaboration with other DMCRN researchers.