SummaryWe have studied a 17‐year‐old girl with lactic acidosis (3‐18 mEq/liter) and progressive muscle weakness since 9 years of age. Morphological findings in muscle were of a typical ragged red myopathy with multiple collections of bizarre mitochondria, some containing paracrystalline inclusions.The carnitine content of serum and muscle was normal, as were the activities of carnitine palmitoyltransferase, carnitine octanoyltransferase, and carnitine acetyltransferase in the patient's muscle. Measurement of the enzymes of oxidative phosphorylation in both crude muscle homogenates and mitochondrial fractions showed close to normal activities of cytochromecoxidase, succinate dehydrogenase, and ATPase. In contrast, succinate cytochromecreductase activity was greatly reduced in the patient, being 0.035 &mgr;mol/min/g tissue in whole muscle (controls 1.16 ± 0.47 &mgr;mol/min/g tissue) and 8 nmol/min/mg protein in the mitochondria (control, 340 nmol/min/mg protein). Rotenonesensitive NADH‐cytochromecreductase was also undetectable in the patient's mitochondria. Spectral analysis of cytochromes showed decrease of reducible cytochromebto 16% of the control. These results indicate a defect of ubiquinol‐cytochromecreductase or the cytochromebc1segment (complex III) of the electron transport chain. Antibody‐binding studies of the individual components of complex III showed additional deficiencies of core proteins I and II and peptide VI, indicating a more widespread defect of complex III than was evident from spectral analysis and enzyme activity measurements alone.Urine organic acid analysis after fasting and following a medium chain triglyceride load showed unusually high levels of lactate and 3‐hydroxybutyrate, lower than expected levels of acetoacetate and dicarboxylic acids, and the presence of several other metabolites suggesting a disturbed citric acid cycle and redox state. Thus, the defect in this patient may be more widespread than is apparent from the clinical presentation.AbbreviationsCNS, central nervous systemCK, creatine kinaseEMG, electromyogramECG, electrocardiogramMCT, medium chain triglycerideSDS, sodium dodecyl sulfateDCIP, 2,6‐dichloroindophenol