Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder caused by a CTG(n) repeat expansion in the 3'-untranslated region of the DMPK gene. The repeat tract becomes unstable when exceeding approximately 35 to 50 CTG triplets, expanding both intergenerationally and throughout a patient's lifetime. Somatic instability is age-dependent, tissue-specific, and expansion-biased, with higher levels of expansion correlating with increased disease severity and faster progression. In blood, the estimated progenitor allele length (ePAL) serves as a predictive biomarker for age of onset, while in muscle, the modal repeat length is associated with the degree of muscle impairment. Somatic expansion is driven by DNA mismatch repair (MMR) proteins such as MSH3, and variation in MMR genes have emerged as modifiers of somatic instability and contributors to phenotypic variability. In this review, we evaluate techniques for quantifying repeat dynamics, highlight findings for patient-derived tissues, and discuss insights from animal and cellular models. Together, these advances contribute to a nuanced understanding of DM1 pathogenesis and offer future strategies for disease monitoring and intervention.
Hoekman et al. (Fri,) studied this question.