Abstract

Introduction

Myotonic dystrophy type 1 (DM1 or Steinert´s disease; OMIM 160900) is the most frequent adult muscular dystrophy with a prevalence of about 5/100000 [1, 2]. DM1 clinical manifestations include prominent distal muscle weakness, myotonia and multiorgan involvement mainly affecting the heart, eye, brain, and endocrine system [3]. This autosomal dominant genetic disease is caused by an unstable trinucleotide CTG repeat expansion in the 3’ UTR of the DM protein kinase (DMPK) gene [4–7]. Unaffected individuals have 5–37 CTG repeats in this gene which remains stable over generations. In DM1, unstable >40 CTG repeats expansion tends to increase among the different tissues and in successive generations accounting for the anticipation phenomenon [8–10]. The CTG expansion length which correlates inversely with the disease age of onset is currently the only known predictor of some phenotypic manifestations. However, modifier gene or epigenetic factors causing conspicuous variability of DM1 multisystemic involvement in a given individual remain poorly understood.

Of note, large collections of DM1 patients are scant in the literature and usually focus on given manifestations, such as cardiac or endocrine symptoms [11–34]. The gender of the transmitting parent is known to affect CTG size in the offspring, causing preferential transmission of congenital forms by the mother [35–36]. However, gender has not been specifically studied and disease manifestations are considered similar in male and female patients. Here, by a cross-sectional analysis of a large cohort of DM1 patients enrolled in the DM-scope registry and two additional independent nationwide databases we identified the impact of gender on DM1 phenotype’s severity, socio-economic conditions and mortality.

Materials and Methods

Study design

Cross-sectional analysis of the DM-scope registry

We first analysed 1409 French adult DM1 patients (>18yrs) of the DM-scope registry (Fig 1), which collects in a standardized form relevant clinical and epidemiological data during routine medical evaluation performed in French neuromuscular reference centers. Analyses focused on two themes: patients’ genotype/phenotype and socio-economic conditions.

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Fig 1

Patient selection of DM-Scope registry.

Complementary study in two nationwide systems

We used two other independent national databases (Fig 2) for initial analysis validation and for complementary results (i) the French DM1 patients survey of patients’ health and medical care (FDM-S, n = 970) and (ii) the French National Health Service Database (PMSI—Programme de Médicalisation des Systèmes d'Information, n = 3301) to assess morbidity and mortality. In FDM-S survey, the AFM-Telethon foundation asked DM1 patients (>18yrs) to fulfill questionnaires about their socio-economic status, the main symptoms with their specific impact on the everyday life, medical care and genetic counselling. The PMSI database monitors and harmonizes medical care in hospitals in France. We analysed data collected on French adult DM1 patients (>18yrs) in 2010–2011, with emphasis on history of hospitalizations and death notification. The DM-scope, FDM-S and PMSI databases were approved by the data protection national authority; the DM-scope study was approved by ethics committee and participating patients granted their informed consent. The DM-scope study was approved in 2008 by the CNIL (National Commission on Informatics and Liberty, #1282122). As an information system restricted to standard medical use, no written consent is required by the CNIL and all participating patients received information letter and granted their verbal informed consent. Patient consent is documented in the database and in all centers. This consent procedure has been approved by the national ethic committee CCTIRS (Advisory Committee on Information Processing in Material Research in the Field of Health)

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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.

Results

Population characteristics

Among the 1409 adult DM1 patients enrolled since 2009 in the DM-Scope registry, a small majority (53.15%) were women, but age, CTG repeats expansion size, age-of-onset, and distribution into the 5 clinical forms were similar between men and women, allowing comparisons of genders in further analyses (Table 1). A strong correlation was found in both men and women between CTG repeat expansion size and the different clinical forms (Fig 3), supporting the robustness of the classification based on the age-of-onset.

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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).

Table 1

Characteristics of patients in the DM-scope registry.

	Mean age of patients in yrs (SD)	Mean age of onset (SD)	Mean CTG expansion (SD)	Congenital form in %	Infantile form in %	Juvenile form in %	Adult form in %	Late onset form in %
Female (749)	42.65 (12,8)	24.53 (14)	647.72 (452)	3.59	15.72	25.66	42.21	12.83
Male (660)	42.38 (13.4)	23.72 (15)	628.9 (433)	4.59	17.72	24.68	39.72	13.29
Overall (1409)	42.52 (13)	24.15 (14)	639.1 (443)	4.05	16.65	25.2	41.05	13.04
	NS	NS	NS	NS	NS	NS	NS	NS

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Gender of patients and clinical symptoms

The frequency of some symptoms differed, to various extents, between men and women. To illustrate the influence of gender on each symptom, relative risks for men and women were calculated and expressed in form of a forest plot (Fig 4). Men more frequently had developmental abnormalities, severe myotonia, severe cardiac and respiratory involvement and muscle weakness, as assessed by MRC testing (p = 0.001). Women had more frequently cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity.

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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.

By reference to the general French population, DM1 clinical manifestations were ascribed to 3 subgroups: (1) manifestations virtually not encountered in the general population but more frequent in a given gender in DM1: facial dysmorphism, myotonia, and delayed conduction at ECG in males; and dysphagia in females; (2) manifestations more frequent in a given gender in the French population but not in the DM1 population (similar frequency in DM1 males and females): higher risk ratio of diabetes in French males [39] was reduced and not significant in both genders in DM1 patients (RR of diabetes in males of the DM1 cohort 1.18 vs. 1.42 in the general population); (3) manifestations more prevalent in a given gender in both the general and DM1 population, with an accentuated gender effect in DM1 for thyroid disorders and obesity (RR of thyroid disorders in females of the DM1 cohort 2.15 vs. 1.12 in the general population; RR of obesity in females of the DM1 cohort 1.58 vs. 1.10 in the general population [40,41]).

Discussion

Our study revealed the multidimensional influence of gender in DM1. First, maternal inheritance was associated with longer repeat expansions and more severe phenotype, as previously reported [5, 6]. This has been attributed to marked DNA instability in the female germ cell lineage allowing additional triplets insertion during oogenesis [43]. Such instability also results to an anticipation in case of maternal inheritance, a phenomenon corresponding to earlier onset and more severe symptoms observed in successive generations [10]. Surprisingly, and in contrast to the general assumptions, we observed that fathers transmitted up to 9% of neonatal onset (mild or severe) forms and 50% of infantile forms, especially those with lower cognitive impairment. Another unexpected observation was that only a minority of overall DM1 patients (37%) had maternal inheritance, which is most unusual for an autosomal dominant inherited disease. It probably results from increased miscarriage and perinatal lethality observed in female DM1 transmitters.

The second gender difference implied an unequal prevalence of several DM1 signs and symptoms in men and women. These differences could not be accounted for overall quantitative male-to-female disproportion in our study population (considered in all statistical analysis), or for the age and genotype differences between the two groups. Men tended to have more obvious classical DM1 symptoms, combining cognitive impairment, marked myotonia, cardiac and respiratory involvement whereas women had more extra-muscular and late onset manifestations, less suggestive of DM1, such as cataracts, obesity, dysthyroidism, GI symptoms and sphincter dysfunction. The most poorly symptomatic patients were women, implicating occasional hidden DM1 transmissions by undiagnosed female mutation carriers. In practice, the sex-related differential risks of developing specific manifestations may require sex-orientated care management, which should be specifically adapted for men (at higher risk of mechanical ventilation, respiratory failure or cardiac conduction defects, which could provide more frequent hospitalization and increased mortality according PMSI database) as well as for women (at higher risk of dysthyroidism, obesity, sphincter dysfunction, and cataracts). This gender disproportion suggests that women could be more careful with their own health. This is underlined by FDM-S survey showing a similar number of annual routine visits to the cardiologist and pneumonologist for both genders, despite male have more cardiac and respiratory involvement, which should prompt more regular medical care. Altogether, the results highlight the importance of a greater awareness about preventive medical care in DM1 male individuals.

The major strengths of this study include (i) the unprecedented number of patients with genetically confirmed DM1 included in the DM-scope cohort, (ii) the prospective and standardized collection of data in the registry performed by expert physicians, (iii) the single country-based enrolment of patients allowing comparisons with the general population, and (iv) the validation of important results by analysis of two other national DM1 sources (FDM-S, PMSI). Similarly described in the litterature, cross sectional studies discussed in our work are inappropriate for the analysis of age-dependant symptoms in a given clinical form. This point deserves a follow-up study using complex ad hoc statistical approaches.

The exact mechanisms underlying gender-dependent differences remain unknown. More diffusely severe myopathy in male patients assessed by MRC testing was reminiscent of some other muscular diseases of autosomal inheritance, such as FSHD, hypokalemic periodic paralysis (HypoPP) or ANO5 mutation-related myopathy [44]. It has been experimentally established that both genetic background [45] and male gender may influence the severity of weakness in mouse autosomal muscular dystrophy. Male and female skeletal muscles display considerable differences in their metabolic properties and gene expression patterns [46,47]. In congenital myotonia, sexual steroid hormones influence severity of myotonia, reflecting testosterone modulation of CLCN1 chloride channel activity [48]. In cardiovascular diseases, it has been described a possible early-life sex-dependent vulnerability to oxidative stress [49]. Other gender-related cellular differences can be considered, as recently proposed [50].

Conclusion

In conclusion, the present study identified gender as a previously unrecognized factor influencing DM1 manifestations with sex-related distinctive clinical profiles and severity. Worse socio-economic consequences of the disease and higher morbidity and mortality were observed in DM1 males. Gender of DM1 patients should be considered in the design of both stratified medical management and clinical trials.

Acknowledgments

Abbreviations

Funding Statement

The study has been funded by AFM-Téléthon, http://www.afm-telethon.fr/, GB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability

Data are governed by ethical and legal restrictions. Data are from three databases: DM-Scope registry, whose authors may be contacted at [email protected]; the AFM-Téléthon DM1 survey, whose authors may be contacted at [email protected]; The French National Health Service database, whose authors may be contacted at [email protected].

References