Myofibrillar Myopathy Type 7 (MFM7)

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Myofibrillar Myopathy Type 7 (MFM7) (OMIM: #617114) 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).

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MFM7 is caused by mutations in the KY gene, which encodes kyphoscoliosis peptidase, a transglutaminase-like protein of the muscle Z-disc/costamere. KY interacts with filamin C and other Z-disc proteins and is required for the normal organization and maintenance of the myofibrillar cytoskeleton (Beatham et al., 2004; Hedberg-Oldfors et al., 2016).

MFM7 was first described in 2016, when two groups independently identified biallelic loss-of-function mutations in KY as the cause of a new early-onset neuromuscular disorder: Hedberg-Oldfors et al. reported KY deficiency causing an early-onset disorder with myofibrillar pathology and kyphoscoliosis, and Straussberg et al. reported a congenital myopathy with core targetoid defects caused by a KY mutation (Hedberg-Oldfors et al., 2016; Straussberg et al., 2016).

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Unlike most other MFM subtypes, MFM7 is an autosomal recessive disorder, caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in KY (Hedberg-Oldfors et al., 2016; Straussberg et al., 2016). Disease onset is in early childhood, and it is congenital in some patients (Straussberg et al., 2016).

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Phenotype highlights:

• Early childhood-onset skeletal muscle weakness, affecting both proximal and distal muscles (Hedberg-Oldfors et al., 2016; Straussberg et al., 2016)

• Prominent spinal deformity, including kyphoscoliosis and rigid spine (Hedberg-Oldfors et al., 2016)

• Muscle biopsy shows myofibrillar disorganization with the pathological features of myofibrillar myopathy, including core targetoid defects in some patients (Hedberg-Oldfors et al., 2016; Straussberg et al., 2016)

At the cellular level, loss of kyphoscoliosis peptidase disrupts the normal distribution of filamin C and other Z-disc proteins, leading to myofibrillar disorganization and the hallmark myofibrillar pathology of Z-disc disintegration and myofibrillar breakdown (Beatham et al., 2004; Hedberg-Oldfors et al., 2016).

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Currently, there is no approved disease-modifying therapy for MFM7. Management remains supportive and focuses on monitoring and treating muscular and skeletal complications, including orthopaedic management of the spinal deformity (Selcen, 2011).

Experimental models informing KY biology include the naturally occurring ky-deficient mouse, in which loss of the KY protein causes muscle degeneration and an abnormal distribution of filamin C at the Z-disc, supporting the role of KY in maintaining myofibrillar integrity (Beatham et al., 2004).

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Bibliography

1. Beatham J, Romero R, Townsend SK, Hacker T, van der Ven PF, Blanco G. Filamin C interacts with the muscular dystrophy KY protein and is abnormally distributed in mouse KY deficient muscle fibres. Hum Mol Genet. 2004 Nov 15;13(22):2863-74. doi: 10.1093/hmg/ddh308. PMID: 15385448.

2. Hedberg-Oldfors C, Darin N, Olsson Engman M, Orfanos Z, Thomsen C, van der Ven PF, Oldfors A. A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency. Eur J Hum Genet. 2016 Dec;24(12):1771-1777. doi: 10.1038/ejhg.2016.98. PMID: 27485408.

3. 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.

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

5. Straussberg R, Schottmann G, Sadeh M, Gill E, Seifert F, Halevy A, Qassem K, Rendu J, van der Ven PF, Stenzel W, Schuelke M. Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects. Acta Neuropathol. 2016 Sep;132(3):475-8. doi: 10.1007/s00401-016-1602-9. PMID: 27484770.