ABSTRACT
A patient with 3-hydroxy-3-methylglutaric aciduria was diagnosed using gas chromatography mass spectrometry. The patient had severe metabolic acidosis, hypoglycemia and hyperammonemia and excreted abnormal amounts of 3-methylglutaconic, 3-hydroxy-3-methylglutaric, 3-methylglutaric, 3-hydroxyisovaleric and glutaric acids in the urine. 3-Hydroxy-3-methylglutaric acid appeared as two peaks on the chromatogram after trimethylsilylation. One was a tri-trimethylsilyl and the other a di-trimethylsilyl derivative. 3-Methylglutaconic acid appeared as three peaks: cis-, trans- and cyclic cis-isomers. The structure of these derivatives was elucidated by deuterium-labeled trimethylsilyl derivatization. The di-trimethylsilyl derivative of 3-hydroxy-3-methylglutaric acid and the cyclic cis-isomer of 3-methylglutaconic acid do not appear to have been previously described. After treatment with leucine restriction milk, the excretion of leucine catabolites decreased but 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids continued to be excreted at abnormally high levels. It is concluded that these two metabolites are necessary for the chemical diagnosis of HMG-CoA lyase deficiency. This patient is the first case of HMG-CoA lyase deficiency to be reported in Japan.
Subject(s)
Meglutol/metabolism , Oxo-Acid-Lyases/deficiency , Acidosis/genetics , Acidosis/metabolism , Chromatography, Gas , Female , Humans , Hyperglycemia/etiology , Hyperglycemia/metabolism , Hyperglycemia/physiopathology , Infant, Newborn , Leucine Zippers/immunology , Mass Spectrometry , Meglutol/pharmacokinetics , Meglutol/urine , Metabolism, Inborn Errors , Oxo-Acid-Lyases/metabolism , Oxo-Acid-Lyases/urine , Trimethylsilyl Compounds/metabolism , Trimethylsilyl Compounds/pharmacokineticsABSTRACT
3-Hydroxy-3-methylglutaric acid administration to streptozotocin-diabetic rats produced a net decrease of plasma ketone bodies and triglycerides together with a slight decrease of total cholesterol. A nonsignificant enhancement of HDL-cholesterol and a negligible change in HDL-phospholipid was also observed. The effect of 3-hydroxy-3-methylglutarate was dose dependent and was more evident with the compound intraperitoneally injected than orally administered with drinking water. [14C]-3-hydroxy-3-methylglutarate was administered either orally or intraperitoneally both to diabetic and control groups of animals, and a higher radioactivity accumulated in liver and kidneys of diabetic rats compared to the controls. The possible mechanism of action of 3-hydroxy-3-methylglutarate is briefly discussed.
