Mitochondrial defects involving the Krebs cycle (fumarase deficiency, succinate dehydrogenase deficiency) and abnormal coupling of adenosine dephosphate phosphorylation to oxygen uptake (Luft's diseases) have been described, but the most common mitochondrial myopathies are associated with respiratory chain abnormalities. The clinical presentation in these disorders is heterogeneous. Major manifestations of muscle involvement include infantile hypotonia, weakness, and lactic acidosis; severe exercise intolerance and easy fatigability; and variable fixed weakness, often involving the extraocular muscles. Additionally, infantile or childhood encephalomyopathies have been identified in which CNS (e.g., seizures, ataxia, stroke-like episodes) and muscle symptoms coexist. Clinical syndromes include mitochondrial encephalomyopathy, lactic acidosis and stroke (MELAS), myoclonus epilepsy with ragged red fibers (MERRF), and Kearns-Sayre syndrome, in which ophthalmoplegia, retinal pigmentary degeneration, heart block, and variable CNS features are associated.

Rapid progress has been made in clarifying the molecular basis of these disorders. Deletions of mitochondrial DNA, which codes for some peptide subunits in respiratory chain complexes I, III, IV and V, have been identified in many patients with progressive external ophthalmoplegia, including virtually all patients with Kearns-Sayre syndrome. Mitochondrial DNA point mutations have been identified in patients with MERRF and MELAS. Nuclear genomic defects have been identified on the basis of inheritance pattern or suspected on the basis of selective respiratory chain enzyme defects. Depletion or deficiency of mtDNA has been found to underlie some mitochondrial myopathies.

Unfortunately, progress in treatment of these disorders has lagged and remains largely anecdotal and empirical. In some cases, the metabolic block may be at least partially bypassed. The Krebs cycle intermediate succinate donates electrons to complex II, and in vitro is capable of supporting mitochondrial respiration in the presence of inhibitors of complex I. Thus, succinate, 2 to 6 g per day, may benefit patients with selective or predominantly complex I defects. No side effects have been reported in the small number of patients so treated. In a patient with a selective defect involving complex III of the electron transport chain, exercise intolerance responded to treatment with menadione (vitamin K₃), 20 to 80 mg per day, and ascorbate (vitamin C), 4 to 5 g per day. The therapeutic benefit may relate to the ability of menadione to act as an electron acceptor from complex I of the respiratory chain and for ascorbate to function as an electron donor to complex IV, thus bypassing the site of the metabolic block in complex III. Potential side effects of menadione include hemolysis in persons who are deficient in glucose-6-phosphate dehydrogenase and depression of hepatic function.

Coenzyme Q is a component of the respiratory chain that receives electrons from complex I and II and donates electrons to complex III. Oral supplementation of ubiquinone (CoQ₁₀), 100 to 150 mg per day, has been reported to be of benefit in some patients with Kearns-Sayre syndrome, in some patients with selective complex I defects, and in patients with apparent deficiency of CoQ. Evidence of clinical effectiveness has included improved endurance with reduced levels of blood lactate after standard exercise tests and improved strength of limb or respiratory muscles. In addition to correcting deficiency of the cofactor, Coq may improve mitochondrial function by antioxidant effects. Administration of riboflavin, 100 to 300 mg per day, was associated with improved exercise capacity in a patient with a defect in complex I. The mechanism of benefit is unclear, but flavin mononucleotide and flavin adenine dinucleotide, the physiologically active forms of riboflavin, serve as cofactors in respiratory flavoproteins found in complex I and II of electron transport.

The accumulation of potentially toxic peroxides and related free radicals as a consequence of the block in electron transport is a possible mechanism of muscle injury in respiratory chain defects. Treatment with antioxidants such as vitamin E (tocopherol), 400 to 800 IU per day; ascorbate, 1 to 4 g per day; or ubiquinone may therefore be justified. Glucocorticoids (e.g., prednisone, prednisolone) have been reported to benefit some patients, possibly owing to their capacity to inhibit phospholipases, which mediate lipid peroxidation.

Lactic acidosis present at rest or with minor exercise is a typical feature of respiratory chain defects and is attributable to impaired oxidative metabolism and consequently increased demand of anaerobic glycogenolysis to meet skeletal muscle energy needs. Dichloroacetate, which activates pyruvate dehydrogenase and thus increases entry of pyruvate into mitochondria, has been administered to alleviate lactic acidosis in a variety of clinical settings, including mitochondrial myopathy. Thiamine is a cofactor of pyruvate dehydrogenase and in doses of 200 mg per day has been reported to reduce lactic acidosis in patients with mitochondrial myopathy.

Respiratory chain defects result in secondary blockade of specific steps in beta oxidation. Low muscle carnitine levels have been reported in some patients with electron transport defects, presumably related to the accumulation of these unmetabolized fatty acids. This provides a rationale for treatment with L-carnitine and for institution of a relatively low-fat diet, similar to the management recommended for beta-oxidation defects.

Immunohistochemical differentiation of the invariably fatal form infantile cytochrome oxidase deficiency (mtDNA-encoded subunit II is present) from a benign, reversible form of the disease (subunit II initially is absent) is crucial, to ensure provision of appropriate medical care in the benign condition until reversal of the enzyme defect.