Clinical case of management of a patient with Duchenne muscular dystrophy caused by deletion of exons 50–52 of the DMD gene against the background of pathogenetic therapy with viltolarsen

Duchenne muscular dystrophy (DMD) is the most common lumbar-limb muscular dystrophy with an X-linked recessive type of inheritance. It is characterized by a debut at an early age, rapidly progressive atrophy of the striated musculature of the limbs, trunk, heart muscle, which leads to loss of motor skills, severe cardiovascular and respiratory complications.

Currently, a number of new drugs have appeared for the pathogenic therapy of MDD, the effectiveness of which is the most during its early initiation in the ambulatory stage of the disease. One of the new methods of MDD treatment is antisense oligonucleotide therapy. The application of this type of therapy is possible for certain mutations in the DMD gene and is recommended immediately after diagnosis. At the moment, the duration of this method of treatment in the Russian Federation is only a few years.

In our article we discuss a clinical case of the study of a patient suffering from Duchenne muscular dystrophy caused by the deletion of 50–52 exons in the DMD gene, who is on therapy with steroids and Viltolarsen.

A special feature of the case is the late application of Viltolarsen from the age of 9 years. The results of the observation demonstrate a significant effect in stabilization of motor skills, of the functioning of the cardiovascular and respiratory systems, which gives a chance to slow down the course of the disease, improve the quality of life and increase its duration, even taking into account the late initiation of pathogenic therapy.

Contribution:
Kuzenkova L.M. — concept and design of the study, writing the text, editing;
Podkletnova T.V. — concept and design of the study, writing the text, editing;
Uvakina E.V. — concept and design of the study, writing the text, editing;
Popovich S.G. — editing;
Andreenko N.V. — editing;
GlobA O.V. — editing.
All authors approval of the final version of the article, responsibility for the integrity of all parts of the article.

Acknowledgements. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: March 1, 2024
Accepted: March 30, 2024
Published: April 27, 2024

1. Guiraud S., Chen H., Burns D.T., Davies K.E. Advances in genetic therapeutic strategies for Duchenne muscular dystrophy. Exp. Physiol. 2015; 100(12): 1458–67. https://doi.org/10.1113/EP085308

2. Hoffman E.P., Brown R.H. Jr., Kunkel L.M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987; 51(6): 919–28. https://doi.org/10.1016/0092-8674(87)90579-4

3. Stone M.R., O’Neill A., Catino D., Bloch R.J. Specific interaction of the actin-binding domain of dystrophin with intermediate filaments containing keratin 19. Mol. Biol. Cell. 2005; 16(9): 4280–93. https://doi.org/10.1091/mbc.e05-02-0112

4. Gao Q.Q., McNally E.M. The dystrophin complex: structure, function, and implications for therapy. Compr. Physiol. 2015; 5(3): 1223–39. https://doi.org/10.1002/cphy.c140048

5. Kharraz Y., Guerra J., Pessina P., Serrano A.L., Muñoz-Cánoves P. Understanding the process of fibrosis in Duchenne muscular dystrophy. Biomed. Res. Int. 2014; 2014: 965631. https://doi.org/10.1155/2014/965631

6. Ryder S., Leadley R.M., Armstrong N., Westwood M., de Kock S., Butt T., et al. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet. J. Rare Dis. 2017; 12(1): 79. https://doi.org/10.1186/s13023-017-0631-3

7. Duan D., Goemans N., Takeda S., Mercuri E., Aartsma-Rus A. Duchenne muscular dystrophy. Nat. Rev. Dis. Primers. 2021; 7(1): 13. https://doi.org/10.1038/s41572-021-00248-3

8. Hibma J.E., Jayachandran P., Neelakantan S., Harnisch L.O. Disease progression modeling of the North Star Ambulatory Assessment for Duchenne muscular dystrophy. CPT Pharmacometrics Syst. Pharmacol. 2023; 12(3): 375–86. https://doi.org/10.1002/psp4.12921

9. Takeuchi F., Komaki H., Nakamura H., Yonemoto N., Kashiwabara K., Kimura E., et al. Trends in steroid therapy for Duchenne muscular dystrophy in Japan. Muscle Nerve. 2016; 54(4): 673–80. https://doi.org/10.1002/mus.25083

10. Bello L., Gordish-Dressman H., Morgenroth L.P., Henricson E.K., Duong T., Hoffman E.P., et al. Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study. Neurology. 2015; 85(12): 1048–55. https://doi.org/10.1212/WNL.0000000000001950

11. Takeuchi F., Komaki H., Nakamura H., Yonemoto N., Kashiwabara K., Kimura E., et al. Trends in steroid therapy for Duchenne muscular dystrophy in Japan. Muscle Nerve. 2016; 54(4): 673–80. https://doi.org/10.1002/mus.25083

12. Aartsma-Rus A., Straub V., Hemmings R., Haas M., Schlosser-Weber G., Stoyanova-Beninska V., et al. Development of exon skipping therapies for Duchenne muscular dystrophy: a critical review and a perspective on the outstanding issues. Nucleic. Acid. Ther. 2017; 27(5): 251–9. https://doi.org/10.1089/nat.2017.0682

13. Frank D.E., Schnell F.J., Akana C., El-Husayni S.H., Desjardins C.A., Morgan J., et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020; 94(21): e2270–82. https://doi.org/10.1212/WNL.0000000000009233

14. Mercuri E., Muntoni F., Osorio A.N., Tulinius M., Buccella F., Morgenroth L.P., et al. Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study. J. Comp. Eff. Res. 2020; 9(5): 341–60. https://doi.org/10.2217/cer-2019-0171

15. Clemens P.R., Rao V.K., Connolly A.M., Harper A.D., Mah J.K., Smith E.C., et al. Safety, tolerability, and efficacy of viltolarsen in boys with Duchenne muscular dystrophy amenable to exon 53 skipping: a phase 2 randomized clinical trial. JAMA Neurol. 2020; 77(8): 982–91. https://doi.org/10.1001/jamaneurol.2020.1264

16. Frank D.E., Schnell F.J., Akana C., El-Husayni S.H., Desjardins C.A., Morgan J., et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020; 94(21): e2270–82. https://doi.org/10.1212/WNL.0000000000009233

17. Birnkrant D.J., Bushby K., Bann C.M., Apkon S.D., Blackwell A., Brumbaugh D., et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018; 17(3): 251–67. https://doi.org/10.1016/s1474-4422(18)30024-3