Clinical Case:
A 15 yr old girl was admitted to the hospital complaining of shortness of breath and of leg
cramps after walking one block. She complained of low tolerance to exercise since age 7, but her
condition worsened when at age 10 muscle weakness developed after exercise. Examination at
the hospital showed that her vital signs were normal. There was mild muscle wasting and some
weakness of all muscle groups. Lab studies showed normal plasma electrolytes except for
bicarbonate which was reduced. When place on a treadmill, her pulse rate increased from 80 to
160 in 3 minutes, and her serum lactate levels increased 4X. Electron microscopy of muscle
tissue revealed abnormal mitochondria, and deposits of glycogen and fat in the muscle cells. She
was treated with a variety of vitamins, biotin, niacin, riboflavin, but none helped her condition.
She was discharged as an outpatient and monitored periodically. At age 17, she had a episode of
lactic acidosis and was readmitted to the hospital. Noninvasive analysis of muscle showed a
creatine phosphate levels were low. Measurement of several mitochondrial enzymes in muscle
showed an absence of cytochrome-c reductase activity. In addition, cytochrome-b was
undetectable. The patient was treated with pharmacologic doses of menadione and ascorbic acid.
Within 24 hrs of treatment, she showed improvement. Over the next year, her improvement was
maintained. Her blood lactate levels remained elevated, although not as high as before treatment.
Resolution:
The patient had a defect in complex III of the ETS, decreasing her ability to synthesize ATP by
oxidative phosphorylation. Since the ETS is defective, she is dependent on glycolysis for her
ATP. The amount of ATP that can be supplied by glycolysis is only about 5% of that derived by
oxidative phosphorylation. The symptoms of weakness, cramps, and lack of tolerance to exercise
can be attributed to decreased ATP synthesis. The low creatine phosphate levels indicates low
ATP supplies. The elevated lactate levels is a result of increased glycolysis. Since NADH
oxidation of the ETS is impaired, NAD+ is regenerated by the NADH-dependent reduction of
pyruvate to lactate. The dissociation of lactic acid to lactate releases H+ which combines with
the bicarbonate. The absence of cytochrome c reductase activity suggested a defect in complex
III which was confirmed by a decrease in cytochrome-b. The rationale for treating this patient
with menadione and ascorbic acid was to provide a shunt for transporting electrons around
complex III. Menadione and ascorbic acid, together, can transfer electrons from CoQ to
cytochrome c. This shunt allows electrons to pass through 2 of the 3 complexes that pump H ions
increasing the patient’s ability to carry out oxidative phosphorylation.
file = clincase1