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MFM7

Myofibrillar Myopathy Type 8 (MFM8)

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Myofibrillar Myopathy Type 8 (MFM8) (OMIM: #617258) 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).

MFM8 is caused by mutations in the PYROXD1 gene, located on chromosome 12p12.1, which encodes pyridine nucleotide-disulphide oxidoreductase domain-containing protein 1 - a putative redox enzyme thought to protect muscle proteins by maintaining the cell's thiol/redox balance (O'Grady et al., 2016).

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MFM8 was first described by O'Grady and colleagues in 2016, who identified biallelic (recessive) variants in PYROXD1 as the cause of an early-onset myopathy with internalized nuclei and myofibrillar disorganization (O'Grady et al., 2016). The phenotype was later broadened to include an adult-onset limb-girdle-type presentation (Sainio et al., 2019; Lornage et al., 2019).

Unlike most other MFM subtypes, MFM8 is inherited in an autosomal recessive manner, caused by biallelic (homozygous or compound heterozygous) mutations in PYROXD1 (O'Grady et al., 2016). The age of onset is strikingly variable, ranging from infancy and early childhood to adulthood, even within the same condition (O'Grady et al., 2016; Sainio et al., 2019).

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Phenotype highlights:

  1. Slowly progressive muscle weakness, which may be limb-girdle (proximal) or more generalized, with onset ranging from infancy to adulthood (O'Grady et al., 2016; Sainio et al., 2019)
  2. Facial and bulbar involvement in some patients, including weakness of facial muscles and swallowing or speech difficulties (O'Grady et al., 2016; Lornage et al., 2019)
  3. Muscle biopsy shows internalized (central) nuclei and myofibrillar disorganization with the pathological features of myofibrillar myopathy (O'Grady et al., 2016; Lornage et al., 2019)

At the cellular level, PYROXD1 is a redox-regulating enzyme, and loss of its function is thought to impair the cell's protection against oxidative stress and its protein quality-control, leading to myofibrillar disorganization and the structural breakdown characteristic of myofibrillar myopathy (O'Grady et al., 2016).

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Currently, there is no approved disease-modifying therapy for MFM8. Management remains supportive and focuses on monitoring and treating muscular, respiratory, and orthopaedic complications (Selcen, 2011).

Experimental models used to study MFM8 include a zebrafish model in which loss of pyroxd1 reproduces the muscle pathology, supporting the role of PYROXD1 in maintaining myofibrillar integrity (O'Grady et al., 2016).

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Bibliography

  1. Lornage X, Schartner V, Balbueno I, Biancalana V, Willis T, Echaniz-Laguna A, Scheidecker S, Quinlivan R, Fardeau M, Malfatti E, Lannes B, Sewry C, Romero NB, Laporte J, Böhm J. Clinical, histological, and genetic characterization of PYROXD1-related myopathy. Acta Neuropathol Commun. 2019 Aug 27;7(1):138. doi: 10.1186/s40478-019-0781-8. PMID: 31455395.
  2. Majoul MS, Zouari R, Hassine A, Mokni M, Ben Sassi S. Myofibrillar myopathy type 8 mimicking a Limb-Girdle Muscle Dystrophy: the first Tunisian case report. Acta Myol. 2026 Mar;45(1):25-29. doi: 10.36185/2532-1900-2222. PMID: 41954148.
  3. 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, Laporte J, Clarke NF, Bryson-Richardson RJ, Bönnemann CG, Cooper ST, et al. 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. PMID: 27745833.
  4. Sainio MT, Välipakka S, Rinaldi B, Lapatto H, Paetau A, Ojanen S, Brilhante V, Jokela M, Huovinen S, Auranen M, Palmio J, Friant S, Ylikallio E, Udd B, Tyynismaa H. Recessive PYROXD1 mutations cause adult-onset limb-girdle-type muscular dystrophy. J Neurol. 2019 Feb;266(2):353-360. doi: 10.1007/s00415-018-9137-8. PMID: 30515627.
  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.