VERY LONG-CHAIN ACYL COENZYME-A DEHYDROGENASE-DEFICIENCY PRESENTING WITH EXERCISE-INDUCED MYOGLOBINURIA

A young man presented with recurrent episodes of muscle pain and myogl obinuria after prolonged exercise or fasting. Studies on isolated musc le mitochondria showed slow flux through beta-oxidation and the presen ce of only saturated long-chain acyl coenzyme A (acyl-CoA) esters. The se results strongly suggested a defect in the dehydrogenation of long- chain acyl-CoA esters that we confirmed by measurement of enzyme activ ity in muscle and platelet mitochondrial fractions and fibroblast homo genates. In all tissues studied from the patient, the enzyme activity was approximately 10% of control values with acyl-CoA eaters from C-16 -C22 as substrates. We investigated the intramitochondrial location of the deficient acyl-CoA dehydrogenase by subfractionation of platelet mitochondria and, in contrast to the short-chain and medium-chain enzy mes, which were localized in the soluble fraction, the majority of the acyl-CoA dehydrogenase activity with long-chain substrates was in the membrane fraction. These studies indicate that in humans, the predomi nant enzyme catalyzing the dehydrogenation of long-chain acyl-CoA este rs is membrane-bound and that deficiency of this enzyme is a cause of muscle pain and rhabdomyolysis.