Myofibrillar myopathies

MFMs typically present with progressive skeletal muscle weakness, frequently distal-predominant, accompanied by cardiomyopathy, respiratory involvement, and peripheral neuropathy. In a tertiary-referral cohort of 80 patients, weakness was distal-predominant in 34, proximal-predominant in 24, and diffuse in 11; dysphagia occurred in 16, and peripheral neuropathy (predominantly axonal large-fibre, less commonly small-fibre) in 21. Cardiac and respiratory involvement were frequent, manifesting at a median of 7 and 9 years after myopathy onset, respectively. Symptom onset is predominantly in adulthood, with a median age at onset of 42.3 years (IQR 20.2-57.0); rare childhood- and juvenile-onset forms are documented, including DNAJB6-related juvenile myopathy. Histopathologically, the diagnostic substrate is intracytoplasmic accumulation of degraded contractile and chaperone proteins; recent genetic discoveries have broadened the causative gene
spectrum beyond Z-disk components, supporting a mechanism-based redefinition of MFM as a Z‑disk-opathy.

Myofibrillar myopathies are ultra-rare disorders in Europe, with an estimated prevalence of less than 1 case per 100,000 population; however, precise epidemiological data are lacking because of genetic heterogeneity, variable clinical presentation, and historical underdiagnosis.

A large number of genes have been associated with MFMs. The genetic forms can be grouped into Z‑disk structural proteinopathies and chaperone-assisted/ protein-homeostasis MFMs. In tertiary-referral cohorts, desminopathy (DES, distal/proximal weakness with prominent cardiomyopathy) is most frequently reported. Z-disk structural proteinopathy forms include myotilinopathy (MYOT, late-onset distal-predominant weakness) and ZASPopathy (LDB3, adult-onset distal myopathy with cardiac involvement). Chaperone-assisted forms include BAG3-related myopathy (BAG3, severe early-onset with cardiomyopathy and neuropathy) and alpha-B crystallinopathy (CRYAB, late-onset weakness with cataracts and cardiomyopathy).

The genetic conditions associated with MFMs follow heterogeneous inheritance patterns. Autosomal dominant transmission predominates among the Z-disk structural proteinopathies, while autosomal recessive and X-linked forms are described for individual entities; chaperone dysfunction is a recurrent pathogenic theme across the spectrum. De novo variants are documented for several genes.

• Where MFM is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Wannarong T, Milone M, Selcen D, Dyck PJB, Liewluck T. Natural history and phenotypic spectrum of myofibrillar myopathies and myopathies associated with MFM-related genes. Neurology. 2025;105(10). PMID: .
• Inoue M, Weihl CC. Myofibrillar myopathy: towards a mechanism-based definition as a Z-disk-opathy. Curr Opin Neurol. 2025;38(5):513-523. PMID: .
• Juntas Morales R, Perrin A, Solé G, Lacourt D, Pegeot H, Walther-Louvier U, et al. An integrated clinical-biological approach to identify interindividual variability and atypical phenotype-genotype correlations in myopathies: experience on a cohort of 156 families. Genes (Basel). 2021;12(8):1199. PMID: .