Molecular genetics of myotonic dystrophy and the evolution of therapeutic approaches.

Abstract

Myotonic dystrophy (DM) is the most common form of adult-onset muscular dystrophy, characterized by skeletal muscle symptoms such as myotonia and progressive muscle wasting, alongside a wide array of multisystemic manifestations affecting the cardiovascular, gastrointestinal, central nervous, endocrine, and ocular systems. DM is an autosomal dominant disorder caused by the unstable expansion of non-coding repeat sequences within the disease-causative genes. The mutant transcripts harboring these expanded repeats exert pathogenic effects via a toxic gain-of-function mechanism, most notably through RNA mediated toxicity that perturbs alternative splicing regulation and contributes to the diverse clinical phenotype. Beyond splicing defects, aberrant signal transduction and the activation of cellular senescence pathways have also been implicated in disease pathophysiology. This review summarizes current understanding of the molecular genetics and mechanistic basis of DM, outlines recent progress in therapeutic development-particularly RNA-targeted strategies involving nucleic acid-based therapeutics and small molecules-and explores emerging approaches aimed at modulating repeat expansions as a means to mitigate disease progression.