Disease Progression Curves of Muscular Strength, Motor and Respiratory Muscle Function in Congenital, Childhood, and Adult Forms of Myotonic Dystrophy Type 1

Background: Natural history data are crucial for supporting clinical trial readiness in muscular dystrophies. Multisystemic and slowly progressive diseases, such as myotonic dystrophy type 1 (DM1), require significant efforts to define the different aspects of evolution across multiple systems. Methods: Our study aimed to model the progression of different functions (namely, muscular, motor, and respiratory) over more than 20 years in 3 different DM1 subtypes (congenital, childhood, and adult forms) related to disease duration. Results: We defined disease progression curves of different functions (muscular assessed through MRC scale during 565 visits, motor assessed through MFM scale during 409 visits, and respiratory assessed through spirometry and nocturnal saturation during 533 visits) in 9 congenital, 25 childhood, and 45 adult form, related to disease duration through a linear mixed model. The shape and slope of the progression curves differ across phenotypes, with some functional domains showing earlier and steeper declines. Conclusion: The progression curves confirm some clinical observations: (1) the decline of the upper limbs’ strength is more evident in the distal portion; (2) the decline of the lower limbs is due to ankle muscles; (3) the lung restriction and nocturnal oxygen desaturation parallel obesity onset. In addition, they show that the D1 sub- scale of the MFM scale is the most affected functional motor parameter, with a trend of decline similar to the ankle strength and the 6-minute walking test. Taken together, our data provide important guidance for the design of future clinical studies in DM1.