Dystrophinopathies in women

Dystrophinopathies are a spectrum of X-linked muscular disorders associated with pathogenic/likely pathogenic variants in the dystrophin (DMD). Most often, these diseases affect men, while women are typically asymptomatic carriers and do not exhibit clinical symptoms. However, to this day, there has been an increasing number of reported cases of dystrophinopathy manifesting in women. In our study, we present a cohort of 30 women exhibiting clinical symptoms of dystrophinopathy, all of whom carry a heterozygous pathogenic variant in the dystrophin gene. In 20 cases, whole-genome sequencing was performed, ruling out other genetic variants that could account for similar phenotypic manifestations of muscular dystrophy. In three cases, a translocation was suspected based on genomic analysis, and a standard cytogenetic was subsequently conducted. In all other cases, no variants were identified that could explain the phenotype of muscular dystrophy, except for pathogenic variants in the DMD. It discusses the importance of mutation screening in the DMD for women presenting with muscular dystrophy symptoms and investigating carrier status in relatives of patients with Duchenne/ Becker muscular dystrophy.

1. Salari N., Fatahi B., Valipour E. et al. Global prevalence of Duchenne and Becker muscular dystrophy: a systematic review and metaanalysis. J Orthop Surg Res. 2022;17:96. doi: 10.1186/s13018-02202996-8.

2. Vorontsova E.O., Zinina A.V., Shchagina O.A. Myshechnaya distrofiya, svyazannaya s genom DMD, u zhenshchin [Muscular dystrophy associated with the DMD gene in women]. Nervnomyshechnyye bolezni [Neuromuscular Diseases]. 2024;14(3):81-89. (In Russ.) https://doi.org/10.17650/2222-8721-2024-14-3-81-89

3. Gruber D., Lloyd-Puryear M., Armstrong N. et al. Newborn screening for Duchenne muscular dystrophy-early detection and diagnostic algorithm for female carriers of Duchenne muscular dystrophy. Am J Med Genet C Semin Med Genet. 2022;190(2):197-205. doi: 10.1002/ajmg.c.32000.

4. Soltanzadeh P., Friez M.J., Dunn D. et al. Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul Disord. 2010;20(8):499-504. doi: 10.1016/j.nmd.2010.05.010.

5. Heide S., Afenjar A., Edery P. et al. Xp21 deletion in female patients with intellectual disability: Two new cases and a review of the literature. Eur J Med Genet. 2015;58(6-7):341-5. doi: 10.1016/j.ejmg.2015.04.003.

6. Duan D., Goemans N., Takeda S. et al. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. doi: 10.1038/s41572021-00248-3.

7. Demos J., Dreyfus J.C., Schapira F. et al. Biological anomalies in the apparently healthy transmitters of muscular dystrophy. Rev Can Biol. 1962;21:587-97.

8. Hoogerwaard E.M., Bakker E., Ippel P.F. et al. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort study. Lancet. 1999;353(9170):2116-9. doi: 10.1016/s0140-6736(98)10028-4.

9. Schade van Westrum S.M., Hoogerwaard E.M., Dekker L. et al. Cardiac abnormalities in a follow-up study on carriers of Duchenne and Becker muscular dystrophy. Neurology. 2011;77(1):62-6. doi: 10.1212/WNL.0b013e318221ad14.

10. Sarkozy A.., Quinlivan R, Bourke J.P., Ferlini A; ENMC 263rd Workshop Study Group. 263rd ENMC International Workshop: Focus on female carriers of dystrophinopathy: refining recommendations for prevention, diagnosis, surveillance, and treatment. Hoofddorp, The Netherlands, 13-15 May 2022. Neuromuscul Disord. 2023;33(3):274-284. doi: 10.1016/j.nmd.2023.01.003