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

Celine Dogan (1) , Marie de Antonio (1, 2, 3) , Dalil Hamroun (4) , Hugo Varet (1) , Marianne Fabbro (1) , Felix Rougier (1) , Khadija Amarof (5) , Marie-Christine Arne Bes (6) , Anne-Laure Bedat-Millet (7) , Anthony Behin (8) , Remi Bellance (9) , Françoise Bouhour (10) , Celia Boutte (11) , François Boyer (12, 13) , Emmanuelle Salort-Campana (14, 15) , Françoise Chapon (16, 17) , Pascal Cintas (18) , Claude Desnuelle (19) , Romain Deschamps (9) , Valérie Drouin-Garraud (7) , Xavier Ferrer (20) , Helene Gervais-Bernard (10) , Karima Ghorab (21, 22) , Pascal Laforêt (23) , Armelle Magot (24, 25) , Laurent Magy (26, 27) , Dominique Menard (28) , Marie-Christine Minot (28) , Aleksandra Nadaj-Pakleza (29) , Sybille Pellieux (30) , Yann Péréon (31, 32) , Marguerite Preudhomme (33) , Jean Pouget (34, 14) , Sabrina Sacconi (35, 19) , Guilhem Sole (20) , Tanya Stojkovich (23) , Vincent Tiffreau (33) , Andoni Urtizberea (36) , Christophe Vial (37) , Fabien Zagnoli (38) , Gilbert Caranhac , Claude Bourlier , Gerard Riviere , Alain Geille , Romain K. Gherardi (1) , Bruno Eymard (39) , Jack Puymirat , Sandrine Katsahian (2) , Guillaume Bassez (1)

1 IMRB - Institut Mondor de Recherche Biomédicale
2 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
3 UPD5 - Université Paris Descartes - Paris 5
4 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
5 CHU de Fort de France
6 CRMN - AOC - Centre de Reference des Maladies Neuromusculaires - Atlantique Occitanie Caraïbe
7 CHU Rouen
8 Institut de Myologie
9 CHU de la Martinique [Fort de France]
10 Groupement Hospitalier Est
11 CHU - Centre Hospitalier Universitaire [Grenoble]
12 SPVQVRSF - Santé publique, vieillissement, qualité de vie et réadaptation des sujets fragiles - EA 3797
13 Service de Médecine Physique Neurologique-Traumatologique [Reims]
14 GMGF - Génétique Médicale et Génomique Fonctionnelle
15 Centre de référence des maladies neuromusculaires et de la SLA
16 CHU Caen
17 COMETE - Mobilités : Attention, Orientation et Chronobiologie
18 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
19 CHU Nice - Centre Hospitalier Universitaire de Nice
20 CHU Bordeaux [Bordeaux]
21 Service de Neurologie [CHU Limoges]
22 Centre de référence national neuropathies périphériques rares [CHU Limoges]
23 CHU Pitié-Salpêtrière [AP-HP]
24 Laboratoire d'Explorations Fonctionnelles
25 Centre de Référence des Maladies Neuromusculaires Rares de l'Enfant et de l'Adulte Nantes-Angers
26 CHU Limoges
27 MMNP - Maintenance Myélinique et Neuropathies Périphériques
28 CHU Pontchaillou [Rennes]
29 CHU Angers - Centre Hospitalier Universitaire d'Angers
30 CHU Trousseau [Tours]
31 Hôtel-Dieu de Nantes
32 UN - Université de Nantes
33 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]
34 Neuro-Oncologie [Hôpital de la Timone - APHM]
35 IBV - Institut de Biologie Valrose
36 Hôpital Marin
37 Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL]
38 Hôpital d'Instruction des Armées Clermont Tonnerre
39 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière

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 (\textgreater18y) 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

Keywords: Dysphagia; Cataracts; Maternal inheritance; Death rates; Obesity; Cognitive impairment; Myotonic dystrophy; Morbidity

Domains: Life Sciences [q-bio]; Santé publique et épidémiologie; Life Sciences [q-bio]; Genetics; Human genetics

Celine Dogan, Marie de Antonio, Dalil Hamroun, Hugo Varet, Marianne Fabbro, et al.. Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study. PLoS ONE, 2016, 11 (2), pp.e0148264. ⟨10.1371/journal.pone.0148264⟩. ⟨hal-01274908⟩