Ketotic Episodes in Glutaryl-CoA Dehydrogenase Deficiency (Glutaric Aciduria)

Abstract

Summawthe ketoacidosis, a pronounced lactic acidosis and lactic 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 &mg creatinine, respectively, during these episodes. Urine samples collected before and after the attacks contained 100-5300 and 230-370 &mg creatinine of glutaric acid and 3-OH-glutaric acids, respectively. During the episodes, glutaconic acid excretion rose from 14-89 to 93-630 pg/mg creatinine. Adipic acid and suberic acid excretions were increased from 17-100 and 2-13 to 74-224 and 16-32 &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 &mg creatinine isobutyric acid, 1-7 and 3-15 pg/mg creatinine; 2-Me-butyric acid, 2-9 and 4-34 pg/mg creatinine; isovaleric acid, 0-6 and 3-11 pg/mg creatinine. The excretion of total 2-0x0-acids was increased from 0-12 to 29-75 pg/mg creatinine during the episodes. It is argued that one or more compounds, accumulated as a result of the primary glutarylCoA 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 C6-Clodicarboxylic 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. SpeculationKetotic episodes with lethargy and severe hypotonia are another feature of glutaric aciduria due to glutaryl-CoAdehydrogenase 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 mitochondria1 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.Severe ketoacidotic episodes are a well known feature in a number of the organic acidurias. Patients with propionic, isovaleric, and methylmalonic acidurias are often subject to recurrent crises induced by high protein intake or by infections (13,15,21). The clinical and biochemical presentations of these crises resemble one another closely: vomiting and lethargy followed by neurologic symptoms eventually leading to coma, and often to death. Besides is seen in most cases. The ...

Mechanism of Hyperinsulinism in Short-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency Involves Activation of Glutamate Dehydrogenase

“…Urine from hadh Ϫ/Ϫ mice had increased excretion of 3-hydroxyglutarate, which has been reported in affected SCHAD-deficient children, and also of glutaconic acid, which is an unstable metabolite derived from glutaconyl-CoA, an intermediate of glutaryl-CoA reduction. This has not been previously detected in affected children but is seen in some patients with glutaryl-CoA dehydrogenase deficiency (17).…”

Studies on the Effects of Saturated and Unsaturated Short-Chain Monocarboxylic Acids on the Energy Metabolism of Rat Liver Mitochondria

“…The ability of the straight shortchain monocarboxylic acids and of isovaleric acid to produce coma in experimental animals has been shown (2 1,26), and it has been suggested that the coma seen in isovaleric acidemia and Rey's syndrome may be ascribed to these monocarboxylic acids (26,28). Other features of the acute crises of the organic acidurias are lactic acidosis and, in most cases, ketosis (9,13,18,19,24). These biochemical disturbances may be caused by disturbances of the energy metabolism associated with the citric acid cycle.…”

Neurotoxic Effects oftrans-Glutaconic Acid in Rats

“…We cannot at this point establish whether our data have a pathophysiological significance for glutaric aciduria type I. t GA accumulates in urine for excretion [65, 66], and excretion of this acid may become prominent, exceeding that of 3-hydroxyglutaric acid, during episodes of ketosis [4, 67]. Some studies indicated that the diagnostic relevance of t GA is limited [68], since t GA excretion in urine may be inconsistently found.…”