The signs and symptoms of mitochondrial disorders are varied. Symptoms depend on how an organ is affected by energy deficiency. Muscle function that is compromised will result in muscle fatigue and weakness. Myopathy is common and may show ragged red fibers on a muscle biopsy. Rhabdomyolysis can occur. Brain dysfunction may be expressed as seizures, loss of intellectual function, headache, or signs consistent with stroke. Spastic paraplegia may occur. Ataxia and basal ganglia symptoms are features of some disorders. Vision and eye muscle movement may be compromised, with progressive external ophthalmoplegia being almost diagnostic of an oxidative phosphorylation defect. Cardiomyopathy is frequent, and cardiac rhythm disturbances occur. Liver dysfunction may be expressed as both synthetic deficiencies and liver failure. Diabetes may signal pancreatic involvement. Renal tubular abnormalities and renal failure both occur. Gastrointestinal symptoms include both diarrhea and constipation that are difficult to treat. Alper disease (cerebral degeneration and liver disease) and Leigh disease (subacute necrotizing encephalomyelopathy) show similar brain lesions but in distinctly different areas of the brain. Because the signs and symptoms may involve multiple organs and may seem nonspecific, physicians may not suspect a mitochondrial disorder until significant progression has occurred.
Defects in the mitochondrial respiratory chain may produce lactic acidosis. Given the complexity of the respiratory chain, it is not surprising that the described defects are varied as to cause, intensity, and tissues affected. The metabolism of glucose to carbon dioxide and water, with pyruvate as an intermediate (Fig. 57-2), occurs as part of the energy cycle in many tissues. Interference with mitochondrial oxidative metabolism may result in the accumulation of pyruvate. Because lactate dehydrogenase is ubiquitous, and because the equilibrium catalyzed by this enzyme greatly favors lactate over pyruvate, the accumulation of pyruvate results in lactic acidosis. The most common cause of such lactic acidosis is oxygen deficiency caused by hypoxia or poor perfusion. Lactic acidosis also occurs when specific reactions of pyruvate are impaired. In the liver, pyruvate undergoes carboxylation to form oxaloacetate using the enzyme pyruvate carboxylase; deficiency in this enzyme causes severe lactic acidosis. In many tissues, lactate is catabolized to form acetyl coenzyme A (CoA) by the pyruvate dehydrogenase complex; deficiency in pyruvate dehydrogenase also can cause lactic acidosis. Because these reactions also play a role in gluconeogenesis, hypoglycemia can be a feature of these disorders. These disorders comprise forms of primary lactic acidosis. They frequently present as intractable, lethal acidosis in the first days or weeks of life and are difficult to treat. Some of the enzymes in this pathway can be measured
Figure 57-2 Metabolism of pyruvate and lactate. (1) Alanine aminotransferase, (2) lactate dehydrogenase, (3) pyruvate dehydrogenase, (4) pyruvate carboxylase, (5) Krebs cycle, (6) phosphoenolpyruvate carboxykinase, (7) reverse glycolysis. CoA, Coenzyme A.
and specific diagnosis can be made. This may require white blood cells or tissue biopsy.