Sex Shapes the Course of Myotonic Dystrophy, Landmark Registry Study Reveals

Myotonic dystrophy has long been described as a single disease with two genetic flavors, yet clinicians have quietly suspected for years that men and women do not experience it in the same way. A new nationwide study from Serbia now provides some of the strongest evidence to date that biological sex leaves a measurable imprint on virtually every organ system the disorder touches. Drawing on 587 genetically confirmed adult patients from the Serbian Registry for Myotonic Dystrophies, researchers compared men and women with myotonic dystrophy type 1 (DM1) and type 2 (DM2) across neuromuscular, cardiac, respiratory, endocrine, skeletal, and ophthalmologic domains. The findings, published in the Journal of Neurology, suggest that sex should be treated as a genuine modifier of disease expression rather than a demographic footnote, with implications for how patients are monitored, risk-stratified, and ultimately treated.

Myotonic dystrophies are autosomal dominant, multisystem disorders caused by toxic repeat expansions in DNA. DM1, the more common and generally more severe form, stems from an expanded CTG repeat in the DMPK gene, while DM2 arises from a CCTG expansion in intron 1 of the CNBP gene, formerly known as ZNF9. In both conditions, the mutant RNA accumulates in cell nuclei and sequesters RNA-binding proteins, producing a splicing defect that disrupts dozens of downstream genes. The result is a bewildering clinical spectrum: myotonia, the delayed relaxation of muscles after contraction; progressive weakness that in DM1 typically begins distally and in DM2 proximally; cataracts; cardiac conduction disturbances; respiratory insufficiency; endocrine dysfunction including diabetes and hypogonadism; and cognitive and gastrointestinal involvement. Because the molecular bottleneck is shared, both diseases overlap in many features, yet they differ markedly in age at onset, severity, and pace of progression, with DM2 often presenting as a milder, later-onset condition.

The Serbian team, led by Ana Azanjac Arsic and Stojan Peric, conducted a cross-sectional analysis of 391 patients with DM1 and 196 with DM2, all enrolled in a national registry whose establishment was approved by the relevant ethics committees. Each participant underwent a comprehensive workup: a detailed neuromuscular examination, electrophysiological testing, cardiac and respiratory evaluation, endocrine and laboratory assessment, skeletal and ophthalmologic examination, and measurement of functional status. Muscle strength was quantified using a modified Medical Research Council score, a standard grading system for assessing power in defined muscle groups. Because the study was explicitly exploratory, the investigators did not apply corrections for multiple statistical comparisons, a point they acknowledge; the results should therefore be viewed as hypothesis-generating signals that will need confirmation in independent cohorts.

In DM1, the sex distribution was nearly even, with a male-to-female ratio of 1.1 to 1, but the clinical burden was not. Men with DM1 carried a distinctly heavier neuromuscular load. They showed weaker grip and hand muscles in the distal upper limbs and weaker proximal lower limb muscles, and their myotonia lasted measurably longer on electrophysiological testing. Speech involvement in the form of dysarthria was more common in men, as was dysphagia, difficulty swallowing that carries a real risk of aspiration. Peripheral polyneuropathy, skeletal deformities, baldness, and infertility were all reported more frequently in male patients, and electrocardiographic abnormalities appeared more often as well. Taken together, the picture in DM1 is one of a more aggressive neuromuscular and cardiac disease in men, consistent with earlier hints from French national databases that male sex predicts greater severity and mortality in this disorder.

DM2 told a strikingly different story. Women outnumbered men in the cohort by a ratio of 1.5 to 1, an imbalance that echoes prior observations in European DM2 registries and remains one of the intriguing epidemiological puzzles of this disease. More importantly, the phenotypic axis of sex difference flipped. Women with DM2 displayed more pronounced weakness in the proximal muscles of the lower limbs, reduced respiratory capacity on pulmonary function testing, and a higher prevalence of cataracts. The cataract finding is particularly interesting because population studies have long suggested that estrogen protects the lens, and the loss of that protection after menopause may interact with the RNA toxicity that drives DM2 pathology. For women with DM2, the practical message is that breathing function and lens status deserve especially close surveillance.

Men with DM2 were not spared, however; their excess burden simply shifted to other systems. Male DM2 patients had longer myotonia duration, more frequent polyneuropathy, and higher rates of baldness and infertility, mirroring some of the male-predominant features seen in DM1. They also showed more hyperglycemia, pointing to a greater metabolic and endocrine load, and they required pacemaker implantation more often, a concrete marker of clinically significant cardiac conduction disease. The authors summarize this asymmetry elegantly: the greater neuromuscular burden falls on DM1 males and DM2 females, while cardiologic and endocrinologic or metabolic complications cluster in males across both disease types.

Why would sex sculpt the phenotype of an RNA-mediated disease so differently depending on which gene harbors the repeat? Several biological mechanisms offer plausible explanations. Sex hormones modulate muscle mass, insulin sensitivity, and cardiac electrophysiology, and estrogen in particular has documented protective effects on lens transparency and vascular function. Alternative splicing, the very process corrupted in myotonic dystrophy, is itself influenced by sex hormone-regulated splicing factors, meaning the toxic RNA may hijack different cellular programs in male and female tissues. Differences in repeat instability dynamics, X-chromosome-linked modifiers, and body composition could also contribute. None of these mechanisms has been definitively proven in humans, and the Serbian authors are careful to frame their study as descriptive; but the consistency of the male cardiac and metabolic signal across both DM1 and DM2 suggests a shared biological substrate rather than statistical noise.

The clinical implications are immediate and practical. A man with DM1, according to these data, warrants particularly vigilant monitoring of swallow function, speech, peripheral nerve status, and cardiac rhythm, with a low threshold for electrophysiological follow-up and pacemaker evaluation. A woman with DM2 should receive focused attention on proximal leg strength, respiratory function, and early cataract screening, while her male counterpart needs closer metabolic surveillance and cardiac follow-up. Risk stratification tools and clinical trial design have historically treated myotonic dystrophy cohorts as homogeneous; this study adds weight to the argument that sex must be incorporated as a stratifying variable, both to balance trial arms fairly and to detect treatment effects that might be masked or amplified in one sex. As antisense oligonucleotide and small-molecule therapies for myotonic dystrophy move toward the clinic, understanding which patients are most vulnerable to which complications could determine who benefits most and when.

The study also highlights the quiet power of national rare disease registries. No single center could have assembled 587 genetically confirmed myotonic dystrophy patients with this depth of phenotyping; a coordinated national effort spanning Belgrade, Kragujevac, Novi Sad, and Nis could. The cross-sectional design cannot establish whether sex differences emerge at disease onset or accumulate over time, and the absence of multiple-comparison correction means individual findings should be interpreted with appropriate caution. Yet the overall pattern, converging with prior reports from France, Germany, and international collaborations, paints a coherent picture: myotonic dystrophy is not one disease experienced identically by all patients, but a family of sex-modified trajectories. For the hundreds of thousands of people worldwide living with DM1 and DM2, that insight moves precision medicine one practical step closer, turning a demographic variable into a roadmap for personalized monitoring and care.

Subject of Research: Sex-related phenotypic differences in genetically confirmed myotonic dystrophy types 1 and 2 in a nationwide Serbian registry cohort

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

Article References: Azanjac Arsic, A., Andrejic, N., Viric, V., Gunjic, I., Sreckovic, S., Rajic, S., Jovin, Z., Bozovic, I., Djordjevic, G., Basta, I., & Peric, S. (2026). Sex-related phenotypic differences in myotonic dystrophy types 1 and 2: a nationwide registry study from Serbia. Journal of Neurology, 273(10), Article 645. https://doi.org/10.1007/s00415-026-14190-5

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14190-5

Keywords: myotonic dystrophy type 1, myotonic dystrophy type 2, sex differences, muscle strength, myotonia, cardiac conduction, polyneuropathy, cataracts, respiratory function, infertility, patient registry, Serbia