• Mitochondrial myopathies can stem from mutations in either the mitochondrial or nuclear genomes because both encode proteins and RNAs that are critical for mitochondrial function. The variants caused by mitochondrial mutations show maternal inheritance (Chapter 7). Mitochondrial myopathies usually manifest in early adulthood with proximal muscle weakness and sometimes with severe involvement of the ocular musculature (external ophthalmoplegia). There may also be neurologic signs and symptoms, lactic acidosis, endocrinopathy, peripheral neuropathy, and cardiomyopathy. Some mitochondrial diseases are associated with normal muscle morphology, whereas others show aggregates of abnormal mitochondria; the latter impart a blotchy red appearance in special stains—hence the term ragged red fibers. On ultrastructural examination, these correspond to abnormal aggregates of mitochondria with abnormal shape and size, some containing crystalline inclusions.
A diverse group of acquired disorders may manifest with muscle weakness, muscle cramping, or muscle pain. These include inflammatory myopathies, toxic muscle injuries, postinfectious rhabdomyolysis, and muscle infarction in the setting of diabetes. In most instances these are disorders of adults with acute or subacute onsets.
Polymyositis, dermatomyositis, and inclusion body myositis represent the traditional triad of inflammatory myopathies. This triad is a simplified view of complex diseases with variable phenotypes that are not always as well delineated as outlined here. Nevertheless, this approach still helps to outline key principles.
Polymyositis is an autoimmune disorder associated with increased expression of MHC class I molecules on myofibers and predominantly endomysial inflammatory infiltrates containing CD8+ cytotoxic T cells. The autoimmune attack leads to myofiber necrosis and subsequent regeneration (
Fig. 22.6A ). Patients with polymyositis are often successfully treated with corticosteroids or other immunosuppressive agents.
Dermatomyositis is the most common inflammatory myopathy in children, in whom it appears as an isolated entity. In adults, it often manifests as a paraneoplastic disorder. In both contexts, it is believed to have an autoimmune basis. The disease is typically associated with skin manifestations, as implied by the name, and may also have systemic manifestations such as interstitial lung disease. On microscopic examination and ultrastructural studies, it is associated with perivascular mononuclear cell infiltrates with plasma cells, “dropout” of capillaries, the presence of so-called “tubuloreticular inclusions” in endothelial cells, and myofiber damage in a paraseptal or perifascicular pattern (
Fig. 22.6B http://ebooksmedicine.net
Fig. 22.6 Inflammatorymyopathies.(A)Polymyositisischaracterizedbyendomysialinflammatoryinfiltratesandmyofibernecrosis(arrow).(B)Dermatomyositisoftenshowsprominentperifascicularandparaseptalatrophy.(C)Inclusionbodymyositis,showingmyofiberscontainingrimmedvacuoles(arrows).ModifiedGomoritrichromestain.
As with some other autoimmune diseases such as SLE (Chapter 5), type 1 interferon-induced gene products are strongly upregulated in affected muscles. Some patients have autoantibodies that are relatively specific for dermatomyositis; these include antibodies against Mi-2 (a nuclear helicase) and p155 and p140, proteins with uncertain functions.