Sex-related phenotypic differences in myotonic dystrophy types 1 and 2: a nationwide registry study from Serbia

Myotonic dystrophies (DM) are autosomal dominant, multisystem disorders with variable clinical expressions. DM1 and DM2 share overlapping features, such as myotonia and muscle weakness, but differ in age at onset, severity, progression and multisystem features. Emerging evidence suggests that biological sex influences disease manifestations, progression, and outcomes.

To assess sex-specific differences among patients with genetically confirmed DM1 and DM2.

This cross-sectional study included 587 adult patients (391 DM1, 196 DM2) from the Serbian Registry for Myotonic Dystrophies. Comprehensive assessments included neuromuscular examination, electrophysiological testing, systemic evaluation (cardiac, respiratory, endocrine, skeletal, and ophthalmologic), laboratory analysis, and functional status. Muscle strength was measured using a modified Medical Research Council score. Statistical analyses compared male and female patients within each DM type. Given the exploratory nature of the study, no adjustment for multiple comparisons was applied.

In DM1, the male-to-female ratio was 1.1:1. Males exhibited more severe neuromuscular involvement, including less strength in distal upper limb and proximal lower limb, longer myotonia duration, higher prevalence of dysarthria, dysphagia, polyneuropathy, skeletal deformities, baldness, and infertility, as well as more common impairment on ECG. In DM2, females predominated (ratio 1.5:1) and showed more pronounced weakness in proximal lower limb, reduced respiratory capacity, and more common cataracts. DM2 males had longer myotonia, higher prevalence of polyneuropathy, baldness, infertility, hyperglycemia, and more frequent pacemaker implantation.

Sex is associated with distinct phenotypic profiles in DM1 and DM2. Greater neuromuscular burden was seen in DM1 males and DM2 females. On the other hand, male patients generally exhibit more cardiologic and endocrinological/metabolic burden in both DM1 and DM2. Incorporating sex as a variable in clinical evaluation, risk stratification, and therapeutic planning may be essential for personalized management of DM patients in future.