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Myofibrillar Myopathy Type 1 (MFM1)

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Myofibrillar Myopathy Type 1 (MFM1) (OMIM: #601419) is one of 13 known types of myofibrillar myopathies, a group of genetically heterogeneous disorders characterized by progressive degeneration of muscle fibers (Muñoz-Mármol et al., 1998, Shelly et al., 2021).

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MFM1 is caused by mutations in the DES gene, which encodes desmin, a key intermediate filament protein responsible for maintaining the structural integrity and alignment of muscle fibers (Clemen et al., 2013). MFM1, also known as desmin-related myofibrillar myopathy or desminopathy, is the most common form of MFM and was first described in a case report by Fardeau et al.1 in 1978 (Xiao et al., 2024, Fardeau et al., 1978).

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The disease is an autosomal dominant disorder, most commonly caused by heterozygous variants, many of which arise de novo (Sugawara et al., 2000; Takegami 2023., Xiao et al., 2024, Castaneda et al., 2026). However, inherited cases have also been reported, including a recent description of familial transmission (Vlaeminck et al., 2025).

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Disease onset ranges from childhood to adulthood and is associated with significant clinical variability (Geng et al., 2024).

Phenotype highlights:

  • Progressive skeletal muscle weakness, often affecting distal muscles or presenting in a limb-girdle distribution (McLaughlin et al., 2013)
  • Early involvement of cardiac muscle, including cardiomyopathy and arrhythmias (Papadopoulos et al., 2023; Goldfarb et al., 2009)
  • Possible respiratory muscle involvement in advanced stages (Goldfarb et al., 2009)

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At the cellular level, desmin dysfunction disrupts the cytoskeletal network, leading to protein aggregation and impaired mechanical stability of muscle cells (Clemen et al., 2013). These changes are often accompanied by Z-disc disruption and accumulation of other proteins, such as αB-crystallin, as well as focal loss of myofibrillar architecture. In more advanced stages, rimmed vacuoles and signs of muscle fiber degeneration may also be observed (Clemen et al., 2013; Goldfarb et al., 2009; Geng et al., 2024).

Currently, there is no approved disease-modifying therapy for MFM1. Management remains supportive and focuses on cardiac and respiratory complications (Goldfarb et al., 2009). Experimental therapeutic strategies, including gene-based approaches, are being explored in the broader field of inherited myopathies, although no gene therapy has yet been established for desmin-related myopathy (Goldfarb et al., 2009). Experimental models used to study MFM1 include human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (Delort et al., 2019; Hovhannisyan et al., 2018; Hovhannisyan et al., 2024), rat neonatal cardiomyocytes (Hovhannisyan et al., 2018), and mouse models such as the R349P desmin knock-in mouse (Holtzhausen et al., 2025).

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  1. Castañeda SL, Amin G, Freiberger MI, Zabalegui F, Renes S, Fernandez A, Rosa AL, Cejas C, Pastor Rueda JM, Waisman A, Ferreiro D, Sevlever G, Miriuka S, Moro LN. Novel in-frame variant in DES (p.Glu353dup) causes myofibrillar myopathy: clinical, in silico and functional studies. J Med Genet. 2026 Mar 20;63(4):216-224. doi: 10.1136/jmg-2025-110852. PMID: 41476018.
  1. Clemen, C. S., Herrmann, H., Strelkov, S. V., & Schröder, R. (2013). Desminopathies: pathology and mechanisms. Acta neuropathologica, 125(1), 47–75. https://doi.org/10.1007/s00401-012-1057-6
  1. Delort F, Segard BD, Hakibilen C, Bourgois-Rocha F, Cabet E, Vicart P, Huang ME, Clary G, Lilienbaum A, Agbulut O, Batonnet-Pichon S. Alterations of redox dynamics and desmin post-translational modifications in skeletal muscle models of desminopathies. Exp Cell Res. 2019 Oct 15;383(2):111539. doi: 10.1016/j.yexcr.2019.111539. Epub 2019 Jul 29. PMID: 31369751.
  1. Fardeau M, Godet-Guillain J, Tome FM, Collin H, Gaudeau S, Boffety C, Vernant P. Une nouvelle affection musculaire familiale, définie par l'accumulation intra-sarco-plasmique d'un matériel granulo-filamentaire dense en microscopie électronique [A new familial muscular disorder demonstrated by the intra-sarcoplasmic accumulation of a granulo-filamentous material which is dense on electron microscopy (author's transl)]. Rev Neurol (Paris). 1978 Jun-Jul;134(6-7):411-25. French. PMID: 570292.
  1. Geng, L., Wang, M., Wang, K., Xu, L., Li, J., Liu, F., & Lu, J. (2024). Desmin-related myopathy manifested by various types of arrhythmias: a case report and literature review.
    The Journal of international medical research, 52(11), 3000605241291741. https://doi.org/ 10.1177/ 03000605241291741
  1. Goldfarb LG, Dalakas MC. Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest. 2009 Jul;119(7):1806-13. doi: 10.1172/JCI38027. Epub 2009 Jul 1. Erratum in: J Clin Invest. 2011 Jan 4;121(1):455. PMID: 19587455; PMCID: PMC2701871.
  1. Holtzhausen, C., Schultheis, D., Berwanger, C., Schuld, J., Schlötzer-Schrehardt, U., Riehl-Nestler, M., Batonnet-Pichon, S., Lilienbaum, A., Mahabir, E., van der Ven, P. F. M., Fürst, D. O., Schröder, R., & Clemen, C. S. (2025). Quantification of Exercise-Induced Sarcomeric Damage in R349P Desmin Knock-In Mice: A New Approach in Myofibrillar Myopathy Research. Neuropathology and applied neurobiology, 51(5), e70038. https://doi.org/10.1111/nan.70038
  1. Hovhannisyan Y, Li Z, Callon D, Suspène R, Batoumeni V, Canette A, Blanc J, Hocini H, Lefebvre C, El-Jahrani N, Kitsara M, L'honoré A, Kordeli E, Fornes P, Concordet JP, Tachdjian G, Rodriguez AM, Vartanian JP, Béhin A, Wahbi K, Joanne P, Agbulut O. Critical contribution of mitochondria in the development of cardiomyopathy linked to desmin mutation. Stem Cell Res Ther. 2024 Jan 2;15(1):10. doi: 10.1186/s13287-023-03619-7. PMID: 38167524; PMCID: PMC10763022.
  1. Hovhannisyan Y,  Kitsara M., Simon A., Kordeli E., Agbulut O., Cardiac cell modelling of myofibrillar myopathy by AAV-mediated transduction of desmin mutations in human iPSC-derived and neonatal rat cardiomyocytes, Archives of Cardiovascular Diseases Supplements, Volume 10, Issue 2, April 2018, Pages 214-215, https://doi.org/10.1016/j.acvdsp.2018.02.086
  1. McLaughlin HM, Kelly MA, Hawley PP, Darras BT, Funke B, Picker J. Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy. BMC Med Genet. 2013 Jul 2;14:68. doi: 10.1186/1471-2350-14-68. PMID: 23815709; PMCID: PMC3711885.
  1. Muñoz-Mármol, A. M., Strasser, G., Isamat, M., Coulombe, P. A., Yang, Y., Roca, X., Vela, E., Mate, J. L., Coll, J., Fernández-Figueras, M. T., Navas-Palacios, J. J., Ariza, A., & Fuchs, E. (1998). A dysfunctional desmin mutation in a patient with severe generalized myopathy. Proceedings of the National Academy of Sciences of the United States of America, 95(19), 11312–11317. https://doi.org/10.1073/pnas.95.19.11312
  1. Papadopoulos C, Malfatti E, Métay C, Keren B, Lejeune E, Buratti J, Xirou S, Chrysanthou-Piterou M, Papadimas GK. Deep Characterization of a Greek Patient with Desmin-Related Myofibrillar Myopathy and Cardiomyopathy. Int J Mol Sci. 2023 Jul 6;24(13):11181. doi: 10.3390/ijms241311181. PMID: 37446359; PMCID: PMC10342265.
  1. Shelly S, Talha N, Pereira NL, Engel AG, Johnson JN, Selcen D. Expanding Spectrum of Desmin-Related Myopathy, Long-term Follow-up, and Cardiac Transplantation. Neurology. 2021 Sep 14;97(11):e1150-e1158. doi: 10.1212/WNL.0000000000012542. Epub 2021 Jul 27. PMID: 34315782.
  1. Sugawara M, Kato K, Komatsu M, Wada C, Kawamura K, Shindo PS, Yoshioka PN, Tanaka K, Watanabe S, Toyoshima I. A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates. Neurology. 2000 Oct 10;55(7):986-90. doi: 10.1212/wnl.55.7.986. PMID: 11061256.
  1. Takegami, N., Mitsutake, A., Mano, T., Shintani-Domoto, Y., Unuma, A., Yamaguchi-Takegami, N., Ishiura, H., Sakuishi, K., Ando, M., Yamauchi, H., Ono, M., Morishita, S., Mitsui, J., Shimizu, J., Tsuji, S., & Toda, T. (2023). The Myocardial Accumulation of Aggregated Desmin Protein in a Case of Desminopathy with a de novo DES p.R406W Mutation. Internal medicine (Tokyo, Japan), 62(19), 2883–2887. https://doi.org/10.2169/internalmedicine.0992-22
  1. Vlaeminck J, Uyttebroeck S, De Schutter E, Cordenier A, Wellekens S, Ströker E, De Rooms K, Helsen C, Hes FJ, Giron P. Case Report: A first case of desmin-related myofibrillar myopathy due to inheritance from a confirmed mosaic asymptomatic carrier. Front Genet. 2025 Jun 18;16:1597851. doi: 10.3389/fgene.2025.1597851. PMID: 40606663; PMCID: PMC12213651.
  1. Xiao, H., Song, L., & Tao, L. (2024). A case report of adolescent myofibrillar myopathy due to a de novo R406W pathogenic variant in desmin with symptoms of "hypertrophic cardiomyopathy". Heliyon, 10(3), e25009. https://doi.org/10.1016/j.heliyon.2024.e25009