Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye’s syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate <0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 μmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 Mmole/liter), liver (200-500 nmole/ g), and muscle (500-800 nmole/g); however, treatment with l- carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium- chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA— acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase. The carnitine deficiency in these patients appears to be a secondary consequence of their defect in fatty acid oxidation. It is possible that other patients with “systemic carnitine deficiency,” who fail to respond to carnitine therapy, may also have defects in fatty acid oxidation similar to medium-chain acyl-CoA dehydrogenase deficiency.
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health