Myofibrillar Myopathy Type 6 (MFM6)

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Myofibrillar Myopathy Type 6 (MFM6) (OMIM: #612954) 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).

MFM6 is caused by mutations in the BAG3 gene, which encodes BCL2-associated athanogene 3, a co-chaperone protein. BAG3 works with heat-shock proteins (including HSP70 and the small heat shock protein HSPB8) to mediate chaperone-assisted selective autophagy, a protein quality-control pathway that removes mechanically damaged proteins from the Z-disc and is essential for maintaining muscle under contractile stress (Arndt et al., 2010; Selcen et al., 2009).

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MFM6 was first described by Selcen and colleagues in 2009, who identified a recurrent heterozygous BAG3 mutation (p.P209L) as the cause of a severe dominant childhood muscular dystrophy with myofibrillar pathology (Selcen et al., 2009). The inheritance pattern and phenotypic features of BAG3-related MFM were further defined by Odgerel et al. (2010). The disorder is also known as BAG3-related myofibrillar myopathy.

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MFM6 is an autosomal dominant disorder, most commonly caused by the recurrent heterozygous p.P209L mutation, many cases of which arise de novo (Selcen et al., 2009; Odgerel et al., 2010). Disease onset is usually in childhood, although the phenotype and age of presentation can vary (Selcen et al., 2009; Konersman et al., 2015).

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Phenotype highlights:

• Early-onset, rapidly progressive skeletal muscle weakness, often more severe than in other MFM subtypes (Selcen et al., 2009; Odgerel et al., 2010)

• Prominent and often early cardiomyopathy, which may be the presenting feature (Selcen et al., 2009; Konersman et al., 2015)

• Respiratory insufficiency and rigid spine in many patients (Selcen et al., 2009)

• Peripheral (axonal) neuropathy, and cardiac conduction abnormalities including long QT syndrome, reported in some patients (Odgerel et al., 2010; Kostera-Pruszczyk et al., 2015)

At the cellular level, mutant BAG3 impairs chaperone-assisted selective autophagy, so mechanically damaged Z-disc proteins are no longer efficiently cleared. This leads to protein aggregation and the hallmark myofibrillar pathology of Z-disc disintegration, myofibrillar breakdown, and ectopic accumulation of multiple Z-disc-associated proteins (Arndt et al., 2010; Selcen et al., 2009).

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Currently, there is no approved disease-modifying therapy for MFM6. Management remains supportive and focuses on monitoring and treating cardiac, respiratory, and neuromuscular complications; because of the early and severe cardiomyopathy and the risk of cardiac conduction abnormalities, cardiac surveillance is particularly important (Selcen et al., 2009; Kostera-Pruszczyk et al., 2015). Experimental therapeutic strategies for the myofibrillar myopathies, including approaches aimed at restoring protein quality control and autophagy, are being explored across the broader group of inherited myopathies and muscular dystrophies (Ziemian et al., 2025).

Experimental work has shown that BAG3 mediates chaperone-assisted selective autophagy and that loss of this pathway causes progressive muscle degeneration, providing a mechanistic basis for BAG3-related myopathy (Arndt et al., 2010).

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Bibliography

1. Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol. 2010 Jan 26;20(2):143-8. doi: 10.1016/j.cub.2009.11.022. PMID: 20060297.

2. Konersman CG, Bordini BJ, Scharer G, Lawlor MW, Zangwill S, Southern JF, Amos L, Geddes GC, Kliegman R, Collins MP. BAG3 myofibrillar myopathy presenting with cardiomyopathy. Neuromuscul Disord. 2015 May;25(5):418-22. doi: 10.1016/j.nmd.2015.01.009. PMID: 25728519.

3. Kostera-Pruszczyk A, Suszek M, Płoski R, Franaszczyk M, Potulska-Chromik A, Pruszczyk P, Sadurska E, Karolczak J, Kamińska AM, Rędowicz MJ. BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome. J Muscle Res Cell Motil. 2015 Dec;36(6):423-32. doi: 10.1007/s10974-015-9431-3. PMID: 26545904.

4. Odgerel Z, Sarkozy A, Lee HS, McKenna C, Rankin J, Straub V, Lochmüller H, Paola F, D'Amico A, Bertini E, Bushby K, Goldfarb LG. Inheritance patterns and phenotypic features of myofibrillar myopathy associated with a BAG3 mutation. Neuromuscul Disord. 2010 Jul;20(7):438-42. doi: 10.1016/j.nmd.2010.05.004. PMID: 20605452.

5. 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.

6. Selcen D. Myofibrillar myopathies. Neuromuscul Disord. 2011 Mar;21(3):161-71. doi: 10.1016/j.nmd.2010.12.007. PMID: 21256014.

7. 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.

8. 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.

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