Myofibrillar Myopathy Type 5 (MFM5)

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Myofibrillar Myopathy Type 5 (MFM5) (OMIM: #609524) 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).

MFM5 is caused by mutations in the FLNC gene, which encodes filamin C, the muscle-specific filamin isoform. Filamin C cross-links actin filaments and localizes to the Z-disc and sarcolemma, where it interacts with myotilin and other Z-disc proteins and is essential for the structural integrity and repair of the myofibril (van der Ven et al., 2000; Fürst et al., 2013).

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MFM5 was first described by Vorgerd and colleagues in 2005, who identified a heterozygous mutation in the dimerization domain of filamin C (the rod-domain nonsense mutation p.W2710X) in a large German family, defining a novel form of autosomal dominant myofibrillar myopathy (Vorgerd et al., 2005). The disorder is also referred to as a filaminopathy.

A note on nomenclature: FLNC mutations produce more than one muscle-disease phenotype. In addition to the aggregate-positive myofibrillar myopathy caused by rod-domain mutations (MFM5), FLNC haploinsufficiency and other variant classes cause a distal myopathy and, in some families, a cardiomyopathy; the term filaminopathy is used broadly for FLNC-related muscle disease (Guergueltcheva et al., 2011; Fürst et al., 2013; Kley et al., 2021).

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MFM5 is an autosomal dominant disorder, most commonly caused by heterozygous mutations in FLNC. Disease onset is typically in adulthood, usually between the fourth and sixth decades of life (Vorgerd et al., 2005; Kley et al., 2021).

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Phenotype highlights:

• Slowly progressive skeletal muscle weakness, usually beginning proximally in the lower limbs and later becoming more generalized (Vorgerd et al., 2005; Kley et al., 2021)

• Cardiac involvement, including cardiomyopathy, and respiratory muscle weakness in a subset of patients (Vorgerd et al., 2005; Kley et al., 2021)

• Muscle biopsy shows the characteristic myofibrillar pathology with filamin C-positive protein aggregates (Vorgerd et al., 2005; Fürst et al., 2013)

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At the cellular level, mutant filamin C misfolds and forms protein aggregates, disrupting Z-disc architecture and impairing autophagic clearance of damaged proteins. These changes produce the hallmark myofibrillar pathology of Z-disc disintegration, myofibrillar breakdown, and ectopic accumulation of multiple Z-disc-associated proteins (Fürst et al., 2013; Ruparelia et al., 2016).

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Currently, there is no approved disease-modifying therapy for MFM5. Management remains supportive and focuses on monitoring and treating muscular, cardiac, and respiratory complications (Selcen, 2011).

Experimental models used to study MFM5 include a zebrafish model expressing the pathogenic filamin C p.W2710X mutation, which reproduces protein aggregation and demonstrates that the disease results from impaired autophagy and filamin C insufficiency (Ruparelia et al., 2016).

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Bibliography

1. Fürst DO, Goldfarb LG, Kley RA, Vorgerd M, Olivé M, van der Ven PF. Filamin C-related myopathies: pathology and mechanisms. Acta Neuropathol. 2013 Jan;125(1):33-46. doi: 10.1007/s00401-012-1054-9. PMID: 23109048.

2. Guergueltcheva V, Peeters K, Baets J, Ceuterick-de Groote C, Martin JJ, Suls A, De Vriendt E, Mihaylova V, Chamova T, Almeida-Souza L, Ydens E, Tzekov C, Hadjidekov G, Gospodinova M, Storm K, Reyniers E, Bichev S, van der Ven PF, Fürst DO, Mitev V, Lochmüller H, Timmerman V, Tournev I, De Jonghe P, Jordanova A. Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency. Neurology. 2011 Dec 13;77(24):2105-14. doi: 10.1212/WNL.0b013e31823dc51e. PMID: 22131542.

3. Kley RA, Leber Y, Schrank B, Zhuge H, Orfanos Z, Kostan J, Onipe A, Sellung D, Güttsches AK, Eggers B, Jacobsen F, Kress W, Marcus K, Djinovic-Carugo K, van der Ven PFM, Fürst DO, Vorgerd M. FLNC-Associated Myofibrillar Myopathy: New Clinical, Functional, and Proteomic Data. Neurol Genet. 2021 Jun;7(3):e590. doi: 10.1212/NXG.0000000000000590. PMID: 34235269.

4. Ruparelia AA, Oorschot V, Ramm G, Bryson-Richardson RJ. FLNC myofibrillar myopathy results from impaired autophagy and protein insufficiency. Hum Mol Genet. 2016 Jun 1;25(11):2131-2142. doi: 10.1093/hmg/ddw080. PMID: 26969713.

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. van der Ven PF, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S, Hayess K, Pacholsky D, Taivainen A, Schröder R, Carpén O, Fürst DO. Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin. J Cell Biol. 2000 Oct 16;151(2):235-48. doi: 10.1083/jcb.151.2.235. PMID: 11038172.

8. Vorgerd M, van der Ven PF, Bruchertseifer V, Löwe T, Kley RA, Schröder R, Lochmüller H, Himmel M, Koehler K, Fürst DO, Huebner A. A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy. Am J Hum Genet. 2005 Aug;77(2):297-304. doi: 10.1086/431959. PMID: 15929027.

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