Toward Trial Readiness in Congenital Myotonic Dystrophy

Background and Objectives: Congenital myotonic dystrophy (CDM) is a life-limiting genetic disorder present at birth, marked by profound motor and cognitive impairments. CDM is the most severe form of myotonic dystrophy type 1 (DM1), both caused by a cytosine-thymine-guanine (CTG) repeat expansion in the DM1 protein kinase gene. Clinical trials targeting the shared disease mechanism in DM1 adults have shown promise. However, a lack of validated clinical end points in early childhood and a limited understanding of the variable disease progression are challenges to trial design in CDM. This longitudinal cohort study identifies predictors of motor function in children with CDM to inform future clinical trials. Methods: , a biomarker of splicing dysregulation, and the achievement of motor milestones was evaluated in a subset of participants who provided muscle biopsy samples. Results: = 0.001). Discussion: The severity of clinical course in infancy and age of independent walking are key predictors of motor function across childhood in CDM. However, baseline motor performance is the strongest predictor of 1-year change and should be a central consideration in clinical trial design. Larger, prospective studies are needed to assess the responsiveness of early motor milestones as indicators of treatment response.