Isovaleric Acidemia Presenting with Altered Metabolism of Glycine

Abstract

Pediat. Res. 5: 478-486 (1971) Extract A 7-year-old girl with periodic acidosis, lethargy, and coma beginning during the 1st year of life was studied. Episodes of ketoacidosis usually occurred with minor respiratory or gastrointestinal infections. There was history neither of peculiar body odor nor characteristic smell like that of sweaty feet. Hyperglycinemia, 4.2 mg/100 ml, and hyperglycinuria, 361 mg/liter, were found at times of illness with acidosis. A clinical diagnosis of ketotic hyperglycinemia was made in 1966. Glycine metabolism was therefore investigated in vivo using 14 C-labeled glycine. The oxidation of glycine to respiratory CO2 and formation of serine from glycine were found to be normal. The labeling of urinary hippurate, however, the largest component of the labeled products of glycine in the urine in normal individuals, was virtually zero. An abnormal, labeled product of glycine was found in the urine and identified as isovalerylglycine. As much as 6% of the 14 C-glycine administered was incorporated into urinary isovalerylglycine within 24 hr. Isovalerylglycine in urine was 2880 mg/24 hr, while normal individuals excrete less than 2 mg/24 hr. Isovaleric acid was found in both urine and plasma. Isovaleric acid in the plasma and urine, 2.86 mg/liter and 2.56 mg/day, respectively, was only five to six times larger than that found in normal individuals. Formation and excretion of isovalerylglycine may be a compensatory mechanism for the elimination of toxic amounts of isovaleric acid from the body. Biosynthesis of such huge amounts of isovalerylglycine may alter the overall metabolism of glycine. Isovaleric acidemia may present with hyperglycinemia and hyperglycinuria. Examination of the urine for isovalerylglycine is a convenient method for detecting the syndrome of isovaleric acidemia. SpeculationIsovaleric acidemia, in common with propionic acidemia with ketotic hyperglycinemia and methylmalonic acidemia, produces dramatic episodes of ketoacidosis. It is now clear that, like these conditions, isovaleric acidemia can also produce leukopenia and elevated concentrations of glycine in body fluids. The mechanisms causing these abnormalities are unknown. Elucidation of metabolic interfaces among these conditions could lead to understanding of the pathophysiology involved.

The Oxidation of Glycine and Propionic Acid in Propionic Acidemia with Ketotic Hyperglycinemia

“…A syndrome of propionic acidemia reported by Hommes and colleagues [11] in a patient who died at 5 days of life with metabolic acidosis but without hyperglycinemia probably represents the same disorder. The clinical features of ketotic hyperglycinemia are also found regularly in methylmalonic acidemia [15], and they may be found in isovaleric acidemia [1].…”

“…This hypothesis is favored by the fact that hyperglycinemia also occurs in methylmalonic acidemia and in isovaleric acidemia. However, glycine oxidation in vivo is normal in isovaleric acidemia [1]. The oxidation of glycine-1- 14 C has not been studied in vivo in methylmalonic acidemia.…”

“…C to serine was studied in KH by the isolation of glycine and serine from the blood at intervals during 1 hr following the injection 1 The system contained 25 ml bicarbonate buffer (pH 7.6) and 1 ^Ci sodium propionate-l-14 C (9.78 mCi/mmole). A blank incubation was carried out without cells.…”

“…Weights of the dried residues ranged from 6.7 to 14.3 mg. 2 KH was a patient with ketotic hyperglycinemia, LGwas the patient with methylmalonic acidemia, and DB, JP, and DR were control subjects. 1 The system contained 5 ml bicarbonate buffer, pH 7.5, and 2.5 juCi sodium propionate-l-14 C (5.4 mCi/mmole). Blank incubations were carried out with no cells and with boiled cells, and final values were corrected by the average of these blanks.…”

The Treatment of Isovaleric Acidemia with Glycine Supplement

“…Isovaleric aciduria, first described in 1966 by Tanaka et al (1) was subsequently detected in numerous cases (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). It is an inborn error of metabolism due to a defect of isovaleryl-CoA dehydrogenase (E.C.…”