Cure MFM13
MFM2

Myofibrillar Myopathy Type 2 (MFM2)

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Myofibrillar Myopathy Type 2 (MFM2) (OMIM: 2A #608810 and 2B #613869) is one of 13 known types of myofibrillar myopathies, a group of genetically heterogeneous disorders characterized by progressive degeneration of muscle fibers.

MFM2 was first described in 1998 by Vicart et al., as desmin-related myopathy (Vicart et al., 1998) and is caused by mutations in the CRYAB gene, which encodes αB-crystallin. CRYAB is a small heat shock chaperone protein expressed in skeletal muscle, cardiac muscle, the eye lens, lung, kidney, and nervous system (Thorkelsson et al., 2024, DiMauro et al., 2018). αB-crystallin plays a critical role in maintaining muscle integrity by stabilizing cytoskeletal and sarcomeric proteins and preventing protein misfolding under cellular stress (DiMauro et al., 2018).

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MFM2 can be divided into two subgroups MFM2A (OMIM #608810) with heterozugous mutation and adult onset and more severe MFM2B (OMIM #613869) homozygous with infantile-onset.

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MFM2A (OMIM #608810)

  • Caused by heterozygous mutations in CRYAB
  • Usually adult onset
  • Often due to missense or frameshift mutations that introduce a premature stop codon (Selcen et al., 2003; Vicart et al., 1998)

This form typically leads to slowly progressive myopathy characterized by both proximal and distal muscle weakness, desmin aggregation in skeletal muscle, cardiomyopathy, and cataracts. Because CRYAB also functions in neurons, some patients may also develop peripheral neuropathy. In advanced stages, respiratory failure may occur, which can lead to premature death around the late 50s (Selcen et al., 2003).

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MFM2B (OMIM #613869)

  • Caused by homozygous mutations in CRYA
  • Infantile onset and generally more severe
  • Some cases involve frameshift mutations that result in C-terminal elongation of the
    C-terminal end (Marcos et al., 2020) or truncated protein (Bigio et al., 2011)

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Patients may present early with congenital cataracts, muscle hypotonia, respiratory complications, and feeding difficulties, often requiring respiratory and nutritional support early in life. Despite the severity of physical symptoms, cognitive development is typically preserved.

At the cellular level, αB-crystallin dysfunction impairs protein quality control and chaperone activity, leading to the accumulation of misfolded proteins and disruption of the desmin cytoskeletal network (DiMauro et al., 2018; Selcen et al., 2003). These changes result in myofibrillar disintegration, desmin-positive protein aggregates, Z-disc abnormalities, and progressive degeneration of muscle fibers, which are hallmark pathological features of myofibrillar myopathy (Selcen et al., 2003). Like other MFM subtypes, impaired protein quality-control pathways and defective handling of damaged proteins contribute significantly to disease pathogenesis.

Currently, there is no approved disease-modifying therapy for MFM2. Management remains supportive and focuses on monitoring and treating cardiac, respiratory, ophthalmologic, and neuromuscular complications. Experimental therapeutic approaches aimed at reducing protein aggregation and restoring cellular proteostasis are being explored, although none have yet advanced to clinical application for CRYAB-related myopathy (DiMauro et al., 2018).

Experimental models used to study MFM2 include transgenic mouse models expressing the pathogenic CRYAB p.Arg120Gly (R120G) mutation, which recapitulate key features of the human disease including protein aggregation, skeletal muscle pathology, cardiomyopathy, and cataracts (Wang et al., 2001; Andley et al., 2011). Both transgenic and knock-in R120G mouse models have been instrumental in investigating disease mechanisms and evaluating potential therapeutic strategies targeting protein aggregation and cellular stress responses (Maloyan et al., 2009; Andley et al., 2011). In addition, cell-based models including HEK293 and C2C12 cells expressing mutant αB-crystallin have been used to study protein aggregation, chaperone dysfunction, and interactions with protein quality-control pathways such as BAG3-mediated autophagy (Hishiya et al., 2011).

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Bibliography

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  1. Del Bigio, M. R., Chudley, A. E., Sarnat, H. B., Campbell, C., Goobie, S., Chodirker, B. N., Selcen, D. Infantile muscular dystrophy in Canadian aboriginals is an alpha-B-crystallinopathy. Ann. Neurol. 69: 866-871, 2011
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  1. Selcen, D.; Engel, A.G. Myofibrillar Myopathy Caused by Novel Dominant Negative  alfa B-Crystallin Mutations. Ann. Neurol. 2003 Vicart P, Caron A, Guicheney P, et al. A missense mutation in the alfB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 1998;20:92–95.
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