Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy

The term myofibrillar myopathies (MFM) refers to uncommon neuromuscular disorders that pathologically are characterized by myofibrillar degeneration and ectopic expression of several proteins. MFM are partly caused by mutations in genes that encode mainly Z-disk-related proteins (desmin, αB-crystallin, myotilin, ZASP, filamin C and BAG3). We reviewed clinical, light and electron microscopy, immunohistochemistry, immunoblotting and genetic findings of 21 patients with MFM (15 unrelated patients and three pairs of brothers) investigated at our neuromuscular center. MFM patients begin to show symptoms at any age, from juvenile to late adult life and present a different distribution of muscle weakness. Cardiac involvement and peripheral neuropathy are common. Typical histological features include focal areas with reduction/ loss of ATPase and oxidative enzyme activity, and amorphous material (eosinophilic on hematoxylin and eosin and dark blue on Engel-Gomori trichrome) in these abnormal fiber areas. Electron microscopy shows disintegration of myofibrils starting from the Z-disk and accumulation of granular and filamentous material among the myofilaments. Immunohistochemical studies demonstrate focal accumulation of desmin, αB-crystallin and myotilin in abnormal muscle fibers while immunoblot analysis does not highlight differences in the expression of these proteins also including ZASP protein. Therefore, unlike immunoblot, immunohistochemistry together with light and electron microscopy is a useful diagnostic tool in MFM. Finally three of our 21 patients have missense mutations in the desmin gene, two brothers carry missense mutations in the gene encoding myotilin, one has a missense mutation in αB-crystallin, and none harbour pathogenic variations in the genes encoding ZASP and BAG3.