KETOTIC EPISODES IN GLUTARYL-COA DEHYDROGENASE-DEFICIENCY (GLUTARIC ACIDURIA)

A 7-yr-old boy with glutaryl-CoA dehydrogenase deficiency (glutaric aciduria), presenting periodic episodes of lethargy and ketosis, was studied during two such episodes. The urinary excretions of glutaric and 3-OH-glutaric acids were 3100-7900 and 460-660 fig/mg creatinine, respectively, during these episodes. Urine samples collected before and after the attacks contained 100-5300 and 230-370 μg/mg creatinine of glutaric acid and 3-OH-glutaric acids, respectively. During the episodes, glutaconic acid excretion rose from 14-89 to 93-630 μ /mg creatinine. Adipic acid and suberic acid excretions were increased from 17-100 and 2-13 to 74-224 and 16-32 / μg /mg creatinine, respectively. The excretions of conjugates of propionic, isobutyric, 2-Me-butyric, and isovaleric acids, outside and during the attacks, respectively, were: propionic acid, 7-13 and 5-19 μg /mg creatinine isobutyric acid, 1-7 and 3- 15 μg /mg creatinine; 2-Me-butyric acid, 2-9 and 4-34 / μg /mg creatinine; isovaleric acid, 0-6 and 3-11 μg /mg creatinine. The excretion of total 2-oxo-acids was increased from 0-12 to 29-75 / μg /mg creatinine during the episodes. It is argued that one or more compounds, accumulated as a result of the primary glutaryl- CoA dehydrogenase deficiency, inhibit the oxidation of the branched-chain amino acids and the fatty acids. During excessive catabolism of amino acids and fatty acids this inhibition results in accumulation of metabolites that are excreted in the urine as conjugates and C8C10-dicarboxylic acids, respectively. Short- and medium-chain monocarboxylic acids are known to affect energy metabolism, and it is, therefore, argued that the short-chain monocarboxylic acids, shown to be accumulated in the patient during the ketotic episodes, may have some pathophysiologic significance. Speculation Ketotic episodes with lethargy and severe hypotonia are another feature of glutaric aciduria due to glutaryl-CoA-dehydrogenase deficiency. During such episodes inhibition of the metabolism of branched-chain amino acids and fatty acids, secondary to the inability to metabolize glutaric acid, causes accumulation of branched short-chain monocarboxylic acids and of short- and medium-chain dicarboxylic acids. Straight short- and medium-chain fatty acids influence the mitochondrial energy metabolism, and it is, therefore, speculated that the short-chain monocarboxylic acids, indicated in the present report to be accumulated in the mitochondria of the patient, contribute to the pathophysiology of the ketotic states. © 1979 International Pediatric Research Foundation, Inc.