Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes

Myofibrillar myopathy (MFM) is a pathologically defined but genetically heterogeneous myopathy; however, myofibrillar pathology may be absent in some patients with pathogenic variants in MFM-related genes. The natural history of MFM and myopathies associated with MFM-related genes remains poorly characterized.

We retrospectively reviewed patients evaluated at Mayo Clinic (January 1993-March 2024) with either pathologically confirmed MFM or myopathies associated with MFM-related genes. Patients without genetic testing or skeletal muscular manifestations were excluded.

Eighty patients were identified; 56 were genetically characterized (23 with DES, 10 with MYOT, 9 with LDB3, 2 with FLNC, 2 with BAG3, 2 with CRYAB, 1 with FHL1, and 7 others). Myofibrillar pathology was observed in 60 of 65 biopsied patients. The median age at symptom onset was 42.3 years (interquartile range [IQR] 20.2-57.0); 66 presented with muscular onset and 14 with cardiac onset. With a median disease duration of 13.1 years (IQR 8.1-24.0) from symptom onset to last visit, all patients had weakness, commonly distal-predominant (n = 34), followed by proximal-predominant (n = 24) and diffuse (n = 11) weakness. Dysphagia occurred in 16 patients, with 4 requiring feeding tubes. Peripheral neuropathy was found in 21 patients (13 with axonal large fiber neuropathy and 8 with small fiber neuropathy), mostly mild in severity. Gait aids were required in 46 patients (median 10.0 years after onset), and 17 became wheelchair-bound (median 19.0 years after onset). By age 60, 67% and 31% of patients with desminopathy required gait aids and were wheelchair-bound, respectively, compared with 12% and 0% of those with myotilinopathy and 25% and 0% of those with LDB3-related myopathy. Cardiac involvement (n = 31) and respiratory involvement (n = 33) were frequent, manifesting at a median of 7 and 9 years, respectively, after myopathy onset. Seven patients (2 with DES, 1 with ACTA1, 4 genetically uncharacterized) died, mainly due to cardiopulmonary complications. Patients with desminopathy exhibited earlier and higher rates of cardiac involvement (p < 0.001), more frequent respiratory involvement (p = 0.029), earlier gait aid dependence (p = 0.018) despite a similar age at ambulation loss (p = 0.418), lower prevalence of peripheral neuropathy (p = 0.022), and a similar mortality rate (p = 1.000).

MFM and myopathies associated with MFM-related genes are clinically heterogeneous, with desminopathy showing earlier cardiac manifestations and gait aid requirement and more frequent cardiopulmonary involvement. Given the phenotypic variability, genetic diagnosis is crucial for patient management and prognosis.