Cure MFM13
Research
Other MFMs
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Other MFMs

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Myofibrillar Myopathies

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To date, at least thirteen genetically distinct forms of MFM (MFM1–MFM13) have been described (Table 1). These subtypes are caused by mutations in genes encoding proteins that play essential roles in maintaining muscle structure, protein quality control, and cellular stress responses. Despite their genetic diversity, the disease mechanisms often converge on common pathways involving protein misfolding, protein aggregation, impaired autophagy, and disruption of the muscle fiber architecture (Wannarong et al., 2025, Ziemian et al., 2025, Zhou et al., 2026).

Myofibrillar myopathies (MFMs) are a group of rare inherited neuromuscular disorders characterized by progressive muscle weakness and the abnormal accumulation of proteins within muscle fibers. Although the different forms of MFM are caused by mutations in different genes, they share a common pathological hallmark: the breakdown of myofibrils, the structures responsible for muscle contraction, beginning at the Z-disk, followed by the accumulation of protein aggregates within muscle cells. These changes can be observed in muscle biopsies and are a defining feature of the disease group (Schröder et al., 2009, Selcen 2008 and 2011, Fichna et al., 2018, Inoue et al., 2025) 

Individuals with MFM may experience muscle weakness affecting the arms, legs, trunk, or respiratory muscles. Some forms can also involve the heart, leading to cardiomyopathy or cardiac conduction abnormalities. The age of onset, disease severity, and pattern of muscle involvement vary considerably depending on the underlying genetic cause (Schröder et al., 2009, Selcen 2008 and 2011).

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Table 1. Myofibrillar myopathy subtypes
Subtype Gene OMIM Age of Onset First reported Former/alternative names
MFM1 DES #601419 childhood to adulthood Fardeau et al., 1978 desmin-related myofibrillar myopathy or desminopathy
MFM2A CRYAB #608810 childhood to adulthood Vicart et al., 1998 Desmin-related Myopathy ("αB-crystallin chaperone gene causes a desmin-related myopathy"); Alpha-B Crystallin-Related Myopathy; Myopathy, Myofibrillar, with or without Cataract and/or Cardiomyopathy
MFM2B (infantile) CRYAB #613869 infantile-onset Del Bingo et al., 2011 —
MFM3 MYOT #609200 adult-onset Hauser et al., 2000 Myotilinopathy; Limb girdle muscular dystrophy 1A; Spheroid body myopathy
MFM4 LDB3 (ZASP) #609452 adult-onset Selcen et al., 2005 Markesbery-Griggs Distal Myopathy
MFM5 FLNC #609524 — Vorgerd et al., 2005 Filamin C-related filaminopathy
MFM6 BAG3 #612954 child-onset (more often) and adult onset cases Selcen et al., 2009 BAG3-related myofibrillar myopathy
MFM7 KY #617114 early child-onset Hedberg-Oldfors et al., 2016 —
MFM8 PYROXD1 #617258 infancy to adult-onset O'Grady et al., 2016 adult-onset limb-girdle-type muscular dystrophy
MFM9 (early respiratory failure) TTN #603689 young adult to adult-onset Lange et al., 2005 "Hereditary Myopathy with Early Respiratory Failure; (MHERF) Myopathy, Proximal, with Early Respiratory Muscle Involvement; (MPRM) Edstrom myopathy; Myopathy, Distal, with Early Respiratory Failure, Autosomal Dominant"
MFM10 SVIL #619040 infancy, child and adult-onset Hedberg-Oldfors et al., 2020 —
MFM11 UNC45B #619178 child-onset Donkervoort et al., 2020 Myopathy, Congenital, with Eccentric Cores
MFM12 MYL2 #619424 infancy Wetermanet al., 2013 —
MFM13 (rimmed vacuoles) HSPB8 #621078 adult-onset Ghaoui et al., 2013 HSPB8-related Myopathy

Cure MFM13 is dedicated to advancing research and therapeutic development for MFM13, a form of myofibrillar myopathy caused by mutations in the HSPB8 gene. While our primary focus is MFM13, many biological mechanisms are shared across the broader MFM family, including protein aggregation, impaired protein quality control, and progressive muscle degeneration (Zhou et al., 2026).

Studying other forms of MFM can provide valuable insights into common disease pathways, potential biomarkers, and therapeutic strategies that may benefit multiple patient communities. Likewise, advances in MFM13 research may contribute to the understanding and treatment of other myofibrillar myopathies.

The following pages provide an overview of each currently recognized MFM subtype (MFM1–MFM13), including the causative gene, clinical features, inheritance patterns, and key research developments.

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Structural

MFM1 DES MFM3 MYOT MFM4 LDB3 MFM5 FLNC MFM9 TTN MFM10 SVIL MFM12 MYL2

Chaperones

MFM2 CRYAB MFM6 BAG3 MFM11 UNC45B
MFM13 HSPB8

Enzymes

MFM7 KY MFM8 PYROXD1

Bibliography

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  1. Del Bigio MR, Chudley AE, Sarnat HB, Campbell C, Goobie S, Chodirker BN, Selcen D. Infantile muscular dystrophy in Canadian aboriginals is an αB-crystallinopathy. Ann Neurol. 2011 May;69(5):866-71. doi: 10.1002/ana.22331. Epub 2011 Feb 18. PMID: 21337604; PMCID: PMC3085857.
  1. Donkervoort S, Kutzner CE, Hu Y, Lornage X, Rendu J, Stojkovic T, Baets J, Neuhaus SB, Tanboon J, Maroofian R, Bolduc V, Mroczek M, Conijn S, Kuntz NL, Töpf A, Monges S, Lubieniecki F, McCarty RM, Chao KR, Governali S, Böhm J, Boonyapisit K, Malfatti E, Sangruchi T, Horkayne-Szakaly I, Hedberg-Oldfors C, Efthymiou S, Noguchi S, Djeddi S, Iida A, di Rosa G, Fiorillo C, Salpietro V, Darin N, Fauré J, Houlden H, Oldfors A, Nishino I, de Ridder W, Straub V, Pokrzywa W, Laporte J, Foley AR, Romero NB, Ottenheijm C, Hoppe T, Bönnemann CG. Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores. Am J Hum Genet. 2020 Dec 3;107(6):1078-1095. doi: 10.1016/j.ajhg.2020.11.002. Epub 2020 Nov 19. PMID: 33217308; PMCID: PMC7820787.
  1. Fichna JP, Maruszak A, Żekanowski C. Myofibrillar myopathy in the genomic context. J Appl Genet. 2018 Nov;59(4):431-439. doi: 10.1007/s13353-018-0463-4. Epub 2018 Sep 10. PMID: 30203143.
  1. Ghaoui R, Palmio J, Brewer J, Lek M, Needham M, Evilä A, Hackman P, Jonson PH, Penttilä S, Vihola A, Huovinen S, Lindfors M, Davis RL, Waddell L, Kaur S, Yiannikas C, North K, Clarke N, MacArthur DG, Sue CM, Udd B. Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy. Neurology. 2016 Jan 26;86(4):391-8. doi: 10.1212/WNL.0000000000002324. Epub 2015 Dec 30. Erratum in: Neurology. 2016 Mar 15;86(11):1077. doi: 10.1212/WNL.0000000000002556. PMID: 26718575; PMCID: PMC4776089.
  1. Hauser MA, Horrigan SK, Salmikangas P, Torian UM, Viles KD, Dancel R, Tim RW, Taivainen A, Bartoloni L, Gilchrist JM, Stajich JM, Gaskell PC, Gilbert JR, Vance JM, Pericak-Vance MA, Carpen O, Westbrook CA, Speer MC. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet. 2000 Sep 1;9(14):2141-7. doi: 10.1093/hmg/9.14.2141. PMID: 10958653.
  1. Hedberg-Oldfors C, Meyer R, Nolte K, Abdul Rahim Y, Lindberg C, Karason K, Thuestad IJ, Visuttijai K, Geijer M, Begemann M, Kraft F, Lausberg E, Hitpass L, Götzl R, Luna EJ, Lochmüller H, Koschmieder S, Gramlich M, Gess B, Elbracht M, Weis J, Kurth I, Oldfors A, Knopp C. Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles. Brain. 2020 Aug 1;143(8):2406-2420. doi: 10.1093/brain/awaa206. Erratum in: Brain. 2021 Apr 12;144(3):e34. doi: 10.1093/brain/awaa412. PMID: 32779703; PMCID: PMC7447519.
  1. Hedberg-Oldfors, C., Darin, N., Olsson Engman, M., Orfanos, Z., Thomsen, C., van der Ven, P. F., & Oldfors, A. (2016). A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency. European journal of human genetics : EJHG, 24(12), 1771–1777. https://doi.org/10.1038/ejhg.2016.98
  1. Inoue M, Weihl CC. Myofibrillar myopathy: towards a mechanism-based definition as a Z-disk-opathy. Curr Opin Neurol. 2025 Oct 1;38(5):513-523. doi: 10.1097/WCO.0000000000001397. Epub 2025 Jun 9. PMID: 40488240; PMCID: PMC12354002.
  1. Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edström L, Ehler E, Udd B, Gautel M. The kinase domain of titin controls muscle gene expression and protein turnover. Science. 2005 Jun 10;308(5728):1599-603. doi: 10.1126/science.1110463. Epub 2005 Mar 31. PMID: 15802564.
  1. O'Grady GL, Best HA, Sztal TE, Schartner V, Sanjuan-Vazquez M, Donkervoort S, Abath Neto O, Sutton RB, Ilkovski B, Romero NB, Stojkovic T, Dastgir J, Waddell LB, Boland A, Hu Y, Williams C, Ruparelia AA, Maisonobe T, Peduto AJ, Reddel SW, Lek M, Tukiainen T, Cummings BB, Joshi H, Nectoux J, Brammah S, Deleuze JF, Ing VO, Ramm G, Ardicli D, Nowak KJ, Talim B, Topaloglu H, Laing NG, North KN, MacArthur DG, Friant S, Clarke NF, Bryson-Richardson RJ, Bönnemann CG, Laporte J, Cooper ST. Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization. Am J Hum Genet. 2016 Nov 3;99(5):1086-1105. doi: 10.1016/j.ajhg.2016.09.005. Epub 2016 Oct 13. PMID: 27745833; PMCID: PMC5097943.
  1. Schröder, R., & Schoser, B. (2009). Myofibrillar myopathies: a clinical and myopathological guide. Brain pathology (Zurich, Switzerland), 19(3), 483–492. https://doi.org/10.1111/j.1750-3639.2009.00289.x
  1. Selcen D, Engel AG. Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol. 2005 Feb;57(2):269-76. doi: 10.1002/ana.20376. PMID: 15668942.
  1. Selcen D. (2008). Myofibrillar myopathies. Current opinion in neurology, 21(5), 585–589. https://doi.org/10.1097/WCO.0b013e32830a752b
  1. Selcen D, Muntoni F, Burton BK, Pegoraro E, Sewry C, Bite AV, Engel AG. Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol. 2009 Jan;65(1):83-9. doi: 10.1002/ana.21553. PMID: 19085932; PMCID: PMC2639628.
  1. Selcen D. (2011). Myofibrillar myopathies. Neuromuscular disorders : NMD, 21(3), 161–171. https://doi.org/10.1016/j.nmd.2010.12.007
  1. Wannarong T, Milone M, Selcen D, Dyck PJB, Liewluck T. Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes. Neurology. 2025 Nov 25;105(10):e214255. doi: 10.1212/WNL.0000000000214255. Epub 2025 Nov 3. PMID: 41183253.
  1. Zhou W, Marchesi V, McLeod M, Kordala AJ, Szwec S, Mielcarz JA, Poletti A, Tedesco B. Molecular, cellular, and clinical aspects of myofibrillar myopathy caused by HSPB8 frameshift mutations. Biochim Biophys Acta Mol Basis Dis. 2026 Aug;1872(6):168244. doi: 10.1016/j.bbadis.2026.168244. Epub 2026 Apr 6. PMID: 41951012.
  1. Ziemian M, Szmydtka J, Snoch W, Milner S, Wojciechowski S, Dłuszczakowska A, Chojnowski JW, Pallach Z, Żamojda K, Węgrzyn G, Rintz E. Integrative Approaches to Myopathies and Muscular Dystrophies: Molecular Mechanisms, Diagnostics, and Future Therapies. Int J Mol Sci. 2025 Aug 18;26(16):7972. doi: 10.3390/ijms26167972. PMID: 40869293; PMCID: PMC12386774.
  1. Weterman MA, Barth PG, van Spaendonck-Zwarts KY, Aronica E, Poll-The BT, Brouwer OF, van Tintelen JP, Qahar Z, Bradley EJ, de Wissel M, Salviati L, Angelini C, van den Heuvel L, Thomasse YE, Backx AP, Nürnberg G, Nürnberg P, Baas F. Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy. Brain. 2013 Jan;136(Pt 1):282-93. doi: 10.1093/brain/aws293. PMID: 23365102.
  1. Vorgerd, M., van der Ven, P. F., Bruchertseifer, V., Löwe, T., Kley, R. A., Schröder, R., Lochmüller, H., Himmel, M., Koehler, K., Fürst, D. O., & Huebner, A. (2005). A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy. American journal of human genetics, 77(2), 297–304. https://doi.org/10.1086/431959

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