Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study

Abstract

Background: Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity.

Methods: We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18 y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301).

Results: Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate.

Conclusion: Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.

Fig 1. Patient selection of DM-Scope registry.

Fig 2. Design of cross-sectional observational study and respective contribution of three national databases: DM-Scope, FDM-S, PMSI Relevant clinical and epidemiological data from French DM1 adult patients (n = 1409), enrolled in DM-Scope registry, were compared to two complementary independent databases, AFM French DM1 survey of patients health and medical care (FDM-S, n = 970 patients) and the National Health Service Database (PMSI, n = 3301), according to similar criteria (age>18y, standardized nationwide collection).

Analyses focused on gender effect as a modifying factor of DM1 clinical phenotype, socio-economic status, morbidity and mortality.

Fig 3. CTG repeat expansion size in male and female individuals according to DM1 clinical forms.

Analyses assessed robustness of the conventional age of onset-based classification of DM1 with regard to the triplet expansion size. Inside each clinical form, no difference in CTG expansion size was observed between male and female groups. Performed tests: multiple comparison of mean (non parametric Kruskal Wallis test and post hoc test; * p<0.05, ** p<0.001, ***p<0.0001).

Fig 4. Gender impact on severity of symptoms expressed as risk ratio on 95% confidence interval.

This diagram represents the gender relative risk ratio value for each symptom with its 95% confidence interval (segment). A risk ratio is significant if the confidence interval does not cross the vertical line at value 1. The width of confidence interval depends on estimate standard deviation and consequently on observations number.