Cure MFM13
MFM3

Myofibrillar Myopathy Type 3 (MFM3)

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Myofibrillar Myopathy Type 3 (MFM3) (OMIM: #609200) is one of 13 known types of myofibrillar myopathies, a group of genetically heterogeneous disorders characterized by progressive degeneration of muscle fibers (Selcen, 2011; Schröder & Schoser, 2009).

MFM3 is caused by mutations in the MYOT gene, which encodes myotilin, a structural protein located at the Z-disc of skeletal muscle fibers, where it cross-links actin filaments and helps control sarcomere assembly (Salmikangas et al., 2003).

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A note on nomenclature: the family in which the first MYOT mutation was identified had originally been diagnosed with limb-girdle muscular dystrophy type 1A (LGMD1A) (Hauser et al., 2000). It was only once the myofibrillar pathology was recognized that Selcen and Engel (2004) proposed the term "myotilinopathy", and the disorder was later reclassified as MFM3 (Straub et al., 2018). LGMD1A and myotilinopathy are therefore essentially earlier names for what is now called MFM3.

MFM3 is an autosomal dominant disorder, most commonly caused by heterozygous missense mutations clustering in a serine-rich hotspot in exon 2 of MYOT (Hauser et al., 2000; Selcen & Engel, 2004). Beyond point mutations, a recent case report described a MYOT gene duplication causing late-onset myotilinopathy, widening the known mutational spectrum of MFM3 (Spinazzi et al., 2025).

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Disease onset ranges from the fourth to seventh decades of life and is associated with significant clinical variability (Selcen & Engel, 2004).

Phenotype highlights:

  • Progressive skeletal muscle weakness, affecting proximal or distal muscles, with the pattern varying between individuals (Selcen & Engel, 2004; Olive et al., 2005)
  • Peripheral neuropathy and hyporeflexia reported in some patients (Selcen & Engel, 2004)
  • Additional features may include muscle atrophy, dysarthria, and dysphagia (Selcen & Engel, 2004; Olive et al., 2005)
  • Possible respiratory or cardiac involvement, including a reported case of left ventricular noncompaction (Selcen & Engel, 2004; Olive et al., 2005; Finsterer et al., 2020)

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At the cellular level, mutant myotilin disrupts Z-disc architecture and promotes the accumulation of protein aggregates, leading to progressive myofibrillar degeneration (Selcen & Engel, 2004). Muscle biopsies characteristically show myofibrillar disruption and protein aggregates containing myotilin and other Z-disc-associated proteins, with some aggregates showing congophilic, amyloid-like staining (Selcen & Engel, 2004), as well as severe autophagic abnormalities and accumulation of degraded cytosolic material on electron microscopy (Spinazzi et al., 2025).

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Currently, there is no approved disease-modifying therapy for MFM3. Management remains supportive and focuses on monitoring and treating muscular, cardiac, respiratory, and neurological complications. Using this T57I mouse model, an AAV-delivered RNAi (microRNA)-based gene therapy targeting mutant MYOT reduced protein aggregate burden and improved muscle force, providing proof-of-concept for gene-silencing approaches in MFM3 (Liu et al., 2016).

Experimental models used to study MFM3 include transgenic mice expressing the pathogenic myotilin T57I mutation under a skeletal muscle-specific promoter, which recapitulate the hallmark Z-disc streaming, myofibrillar aggregation, and progressive loss of muscle force seen in patients (Garvey et al., 2006).

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Bibliography

  1. Finsterer J, Stöllberger C, Hasun M, Riedhammer K, Wagner M. Multisystem Myotilinopathy, including Myopathy and Left Ventricular Noncompaction, due to the MYOT Variant c.179C>T. Case Rep Cardiol. 2020 May 13;2020:5128069. doi: 10.1155/2020/5128069. PMID: 32509353; PMCID: PMC7244945.
  1. Garvey SM, Miller SE, Claflin DR, Faulkner JA, Hauser MA. Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM. Hum Mol Genet. 2006 Aug 1;15(15):2348-62. doi: 10.1093/hmg/ddl160. PMID: 16801328.
  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. Liu J, Wallace LM, Garwick-Coppens SE, Sloboda DD, Davis CS, Hakim CH, Hauser MA, Brooks SV, Mendell JR, Harper SQ. RNAi-mediated Gene Silencing of Mutant Myotilin Improves Myopathy in LGMD1A Mice. Mol Ther Nucleic Acids. 2014 Apr 29;3(4):e160. doi: 10.1038/mtna.2014.13. PMID: 24781192; PMCID: PMC4013433.
  1. Olivé M, Goldfarb LG, Shatunov A, Fischer D, Ferrer I. Myotilinopathy: refining the clinical and myopathological phenotype. Brain. 2005 Oct;128(Pt 10):2315-26. doi: 10.1093/brain/awh576. PMID: 15947064.
  1. Salmikangas P, van der Ven PF, Lalowski M, Taivainen A, Zhao F, Suila H, Schröder R, Lappalainen P, Fürst DO, Carpén O. Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum Mol Genet. 2003 Jan 15;12(2):189-203. doi: 10.1093/hmg/ddg020. PMID: 12499399.
  1. Schröder R, Schoser B. Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol. 2009 Jul;19(3):483-92. doi: 10.1111/j.1750-3639.2009.00289.x. PMID: 19563540; PMCID: PMC8094720.
  1. Selcen D. Myofibrillar myopathies. Neuromuscul Disord. 2011 Mar;21(3):161-71. doi: 10.1016/j.nmd.2010.12.007. PMID: 21256015.
  1. Selcen D, Engel AG. Mutations in myotilin cause myofibrillar myopathy. Neurology. 2004 Apr 27;62(8):1363-71. doi: 10.1212/01.wnl.0000123576.74801.75. Erratum in: Neurology. 2004 Jul 27;63(2):405. PMID: 15111675.
  1. Spinazzi M, Savarese M, Letournel F, Sagath L, Manero F, Guichet A, Hoischen A, Metay C, Gouju J, Udd B. Myotilin gene duplication causing late-onset myotilinopathy. Eur J Neurol. 2025 Jan;32(1):e70029. doi: 10.1111/ene.70029. PMID: 39757377; PMCID: PMC11702382.
  1. Straub V, Murphy A, Udd B; LGMD workshop study group. 229th ENMC international workshop: Limb girdle muscular dystrophies - Nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017. Neuromuscul Disord. 2018 Aug;28(8):702-710. doi: 10.1016/j.nmd.2018.05.007. PMID: 30055862.