We 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
cytochrome c oxidase,
succinate dehydrogenase, and
ATPase. In contrast,
succinate cytochrome c reductase activity was greatly reduced in the patient, being 0.035 mumol/min/g tissue in whole muscle (controls 1.16 +/- 0.47 mumol/min/g tissue) and 8 nmol/min/mg
protein in the mitochondria (control, 340 nmol/min/mg
protein). Rotenonesensitive
NADH-cytochrome c reductase was also undetectable in the patient's mitochondria. Spectral analysis of
cytochromes showed decrease of reducible
cytochrome b to 16% of the control. These results indicate a defect of
ubiquinol-cytochrome c reductase or the
cytochrome bc1 segment (
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.(ABSTRACT TRUNCATED AT 250 WORDS)