156th ENMC International Workshop: Desmin and protein aggregate myopathies, 9–11 November 2007, Naarden, The Netherlands

Myofibrillar Myopathies: A Clinical and Myopathological Guide

“…The vast majority of MFM patients have an adult onset of their progressive muscle symptoms. Exceptions from this rule are MFM caused by mutations in genes encoding for BAG3, FHL1, plectin and desmin, which may manifest in childhood, adolescence and adulthood (17, 39–41). While MFMs caused by desmin and αB‐crystallin tend to manifest in early and middle adulthood, disease onset beyond the fourth decade of life points toward the diagnosis of myotilin‐, ZASP‐ and filamin C‐related MFMs.…”

“…A broad spectrum of light microscopic changes ranging from mild to severe degenerative muscle alterations has been reported in MFM biopsy specimens. In addition to myopathic features (eg, rounding of muscle fibers, pathological fiber size variation, internally located myonuclei, fiber splitting), subsarcolemmal and/or sarcoplasmic protein aggregates (basophilic or eosinophilic in H&E stains; dark blue or pink in G‐Tri), cytoplasmic bodies, rimmed and non‐rimmed vacuoles, rubbed‐out fibers and core‐like lesions are the classical myopathological findings in MFM (8, 17, 35) (Figure 2). Spheroid bodies, which appear as coiled aggregates arranged in linear packets of greenish material in G‐Tri stains, are highly indicative of myotilinopathy (Figure 3).…”

“…However, pathological protein aggregation is also the characteristic feature in the expanding group of myofibrillar myopathies (MFMs). The paradigm of the latter is a disease caused by mutations in the desmin gene that result in a skeletal myopathy, frequently associated with cardiac abnormalities (17–19, 34, 38). Striated muscles from patients with mutations in the desmin gene characteristically display cytoplasmic accumulation of desmin‐immunoreactive material and myofibrillar alterations (12, 19, 34, 38).…”

“…MFMs are clinically characterized by a progressive course leading to severe disability. To date, no causative or even ameliorating therapies exist for this numerically significant group of hereditary myopathies (17).…”

Extralysosomal Protein Degradation in Myofibrillar Myopathies

“…Intracellular accumulation of altered or misfolded proteins is the basis of many neurodegenerative disorders generically known as protein conformational disorders (8, 15, 16, 55, 67), and is now also considered to play an important pathogenetic role in an expanding group of muscle disorders collectively called protein aggregate myopathies (PAMs) (28, 29). Myofibrillar myopathies (MFMs), representing the largest group of PAMs, are a group of heterogeneous muscle diseases having as a common feature the presence of focal dissolution of the myofibrils, accumulation of the products of myofibrillar degradation and ectopic expression of multiple proteins (14, 44, 64).…”