Myotonic dystrophy type 1: clinical diversity, molecular insights and therapeutic perspectives

Myotonic dystrophy type 1 (DM1) is the most prevalent muscular dystrophy in adulthood and is one of the most clinically diverse monogenic diseases. Although it is classified as a neuromuscular disease, DM1 is a multisystem disorder that affects nearly all organ systems, particularly skeletal and smooth muscles, the central nervous system and the heart. Its phenotypic variability extends beyond a continuum of severity, encompassing differences in age of onset and organ involvement. DM1 is caused by a trinucleotide (CTG) repeat expansion within the 3' untranslated region of the DMPK gene, leading to a toxic RNA gain-of-function mechanism that disrupts RNA splicing, causing widespread cellular dysfunction. Despite progress in understanding DM1 pathogenesis, gaps remain in elucidating genotype-phenotype correlations, genetic modifiers and mechanisms that influence disease progression. Breakthroughs in the past five to ten years have uncovered important insights into the molecular underpinnings of DM1 and accelerated therapeutic innovation. Targeted interventions such as small molecules, antisense oligonucleotides and gene-editing technologies are progressing into clinical trials. Additionally, emerging research on somatic instability, epigenetic modifications and novel biomarkers suggests approaches for precision medicine. This Review synthesizes recent clinical and molecular discoveries, highlighting implications for therapy development. By integrating clinical heterogeneity with mechanistic insights, we provide a framework for future translational research and therapeutic innovation in this life-limiting disease.