Myofibrillar Myopathy Type 4 (MFM4)

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Myofibrillar Myopathy Type 4 (MFM4) (OMIM: #609452) 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).

MFM4 is caused by mutations in the LDB3 gene, also known as ZASP, which encodes the Z-band alternatively spliced PDZ-motif-containing protein (ZASP). ZASP is a Z-disc-associated protein that binds α-actinin and helps maintain the structural integrity of the Z-disc in skeletal and cardiac muscle (Faulkner et al., 1999; Selcen & Engel, 2005).

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MFM4 was first described as a distinct genetic entity by Selcen and Engel in 2005, who screened 54 patients with myofibrillar myopathy and identified three heterozygous ZASP (LDB3) missense mutations in 11 of them, establishing ZASP mutation as a novel cause of dominant muscle disease and introducing the term “zaspopathy” (Selcen & Engel, 2005).

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A note on nomenclature: the large multigenerational kindred in which the disorder was later shown to be caused by ZASP had originally been reported by Markesbery and Griggs in 1974 as an autosomal dominant late-onset hereditary distal myopathy, long before the molecular cause was known (Markesbery et al., 1974). In 2007, Griggs and colleagues identified the ZASP A165V mutation in this original family, confirming that the historically described “Markesbery-Griggs distal myopathy” is MFM4 (Griggs et al., 2007). Markesbery-Griggs distal myopathy and zaspopathy are therefore earlier names for what is now called MFM4.

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MFM4 is an autosomal dominant disorder, most commonly caused by heterozygous missense mutations. The recurrent p.A165V variant, located within a motif important for linking ZASP to the Z-disc, is the most frequent cause of the disease (Selcen & Engel, 2005; Griggs et al., 2007).

Disease onset is typically in adulthood, ranging from the fifth to the eighth decade of life, with penetrance essentially complete by age 60 (Selcen & Engel, 2005; Griggs et al., 2007).

Phenotype highlights:

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• Slowly progressive skeletal muscle weakness that is often greater distally than proximally, particularly affecting the lower limbs and causing gait difficulty (Selcen & Engel, 2005; Griggs et al., 2007)

• Cardiac involvement, including cardiomyopathy, reported in a subset of patients (Selcen & Engel, 2005)

• Signs of peripheral neuropathy in some patients (Selcen & Engel, 2005)

• Most patients remain ambulatory into later life, with early involvement of the posterior calf muscles on imaging (Griggs et al., 2007)

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At the cellular level, mutant ZASP disrupts Z-disc architecture and promotes the accumulation of protein aggregates, leading to progressive myofibrillar degeneration. Muscle biopsies show the stereotyped myofibrillar myopathy pathology, with Z-disc disintegration, breakdown of the myofibrils, and abnormal ectopic accumulation of multiple Z-disc-associated proteins (Selcen & Engel, 2005).

Currently, there is no approved disease-modifying therapy for MFM4. Management remains supportive and focuses on monitoring and treating muscular, cardiac, and neurological complications (Selcen, 2011).

Experimental models informing ZASP biology include knockout mouse models of the ZASP orthologue Cypher, in which loss of this PDZ-LIM Z-line protein causes a severe congenital skeletal and cardiac myopathy, supporting the role of ZASP in maintaining Z-disc integrity (Zhou et al., 2001).

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Bibliography

1. Faulkner G, Pallavicini A, Formentin E, Comelli A, Ievolella C, Trevisan S, Bortoletto G, Scannapieco P, Salamon M, Mouly V, Valle G, Lanfranchi G. ZASP: a new Z-band alternatively spliced PDZ-motif protein. J Cell Biol. 1999 Jul 26;146(2):465-75. doi: 10.1083/jcb.146.2.465. PMID: 10427098.

2. Griggs R, Vihola A, Hackman P, Talvinen K, Haravuori H, Faulkner G, Eymard B, Richard I, Selcen D, Engel A, Carpen O, Udd B. Zaspopathy in a large classic late-onset distal myopathy family. Brain. 2007 Jun;130(Pt 6):1477-84. doi: 10.1093/brain/awm006. PMID: 17337483.

3. Markesbery WR, Griggs RC, Leach RP, Lapham LW. Late onset hereditary distal myopathy. Neurology. 1974 Feb;24(2):127-34. doi: 10.1212/wnl.24.2.127. PMID: 4855680.

4. 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.

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

6. Selcen D, Engel AG. Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol. 2005 Feb;57(2):269-76. doi: 10.1002/ana.20376. PMID: 15668942.

7. Zhou Q, Chu PH, Huang C, Cheng CF, Martone ME, Knoll G, Shelton GD, Evans S, Chen J. Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy. J Cell Biol. 2001 Nov 12;155(4):605-12. doi: 10.1083/jcb.200107092. PMID: 11696561.

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