Therapeutic Effects of Glycine in Isovaleric Acidemia

Abstract

Extract: The effect of glycine administration on acute leucine loading (125 mg/kg) was tested in a patient with isovaleric acidemia. Serum isovaleric acid at 1 ¾ hr after the leucine loading alone was elevated to 5.60 mg/100 ml and urinary isovalerylglycine excretion was 9.90 mg/mg creatinine/24 hr. When the same amount of leucine was given with glycine (250 mg/kg) serum isovaleric acid was only 0.93 mg/100 ml. Unfortunately, urine was collected for only 12 hr after the leucine-glycine loading. However, the amount of urinary isovalerylglycine was 26.2 mg/mg creatinine in this period. In the following experiments in which a meal containing 80 mg leucine/kg was given, serum isovaleric acid was elevated to 1.14 and 1.01 mg/100 ml at 3 hr and 6 hr after the loading, respectively. How-ever, serum isovaleric acid was only 0.53 and 0.79 mg/100 ml at 3 and 6 hr, respectively, when the identical mean was given with 2 g glycine.

The effect of long term glycine administration (250 mg/kg/24hr) was also tested. It did not prevent two ketotic episodes which were caused by infections. However, the duration of clinical symptoms such as vomiting and a large anion gap in the acute episodes were much shorter with rectal glycine administration. The patient's linear growth and weight gain during glycine administration was much belter than that in the pretreatment period.

Speculation: In isovaleric acidemia, isovaleryl-CoA is not oxidized because of an inborn deficiency of isovaleryl-CoA dehydrogenase activity. The leucine loading tests and clinical response to oral glycine in this patient suggest that exogenously administered glycine enhanced the conjugation of glycine with isovaleryl-CoA, thus preventing accumulation of free isovaleric acid, a toxic substance. With glycine administration, mitochondrial glycine concentration seems to be elevated to a level at which faster reaction velocity of glycine-N-acylation of isovaleryl-CoA is attained. Thus, glycine administration appears to be an effective therapeutic method in the management of acute ketoacidotic episodes in this disease. However, chronic administration failed to prevent ketoacidotic episodes which were induced by infections.