Mitochondrial DNA-related mitochondrial myopathy

Mitochondrial DNA-related mitochondrial myopathy is a group of rare neuromuscular disorders caused by pathogenic variants (mutations) in mitochondrial DNA (mtDNA) that primarily affect skeletal muscle function. Because mitochondria are the energy-producing organelles of cells, tissues with high energy demands — particularly skeletal muscle — are most vulnerable. These conditions can result from point mutations, single large-scale deletions, or multiple deletions in mtDNA that impair the mitochondrial respiratory chain (oxidative phosphorylation), leading to deficient cellular energy production. Key clinical features include exercise intolerance, progressive muscle weakness (proximal more than distal), fatigue, and myalgia. Many patients develop progressive external ophthalmoplegia (PEO), characterized by drooping eyelids (ptosis) and limited eye movements. Muscle biopsy typically reveals ragged-red fibers and cytochrome c oxidase (COX)-negative fibers, which are hallmarks of mitochondrial dysfunction. Because mtDNA mutations can affect multiple organ systems, some patients may also experience additional features such as sensorineural hearing loss, cardiac involvement, peripheral neuropathy, or central nervous system manifestations, though the predominant burden falls on skeletal muscle in this disease category. There is currently no curative treatment for mitochondrial DNA-related mitochondrial myopathy. Management is primarily supportive and symptomatic, including physical therapy, aerobic exercise training (which has shown benefit in improving exercise capacity), nutritional supplementation (such as coenzyme Q10, L-carnitine, and B vitamins, though evidence for efficacy is limited), and management of specific complications such as ptosis surgery or cardiac monitoring. Genetic counseling is important given the maternal inheritance pattern. Research into gene therapy and other novel therapeutic approaches is ongoing.

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