No abstract

Extractlsovaleric acidemia is an inherited defect of leucine metabolism.The effect of glycine administration on acute leucine loading ( 125 mg/kg) was tested in a patient with isovaleric acidemia. Serum isovaieric acid at I:'/, hr after the leucine loading alone was elevated to 5.60 mg/100 ml and urinary isovalerylglycine excretion was 9.90 mg/mg creatinine124 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 leucinelkg was given, serum isovaleric acid was elevated to 1.14 and 1.01 mg/100 ml a t 3 hr and 6 hr after the loading, respectively. How-erer, serum isovaleric acid was only 0.53 and 0.79 mg/ 100 ml at 3 and 6 hr, respectively, when the identical mean was giten with 2 g glycine.The effect of long term glycine administration (250 mg/kg/24 hr) 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 better than that in the pretreatment period. SpeculationIn 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, mitochondria1 glycine concentration seems to be elevated to a level at which faster reaction velocity of glycine-Nacylation 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.

Summary had started at 3 wk of age. The laboratory studies revealed A 7-week-old infant with methylmalonic acidemia had pancytopenia and hypoplastic bone marrow. The patient responded to large doses of vitamin B12 treatment, and within 3 wk, the blood counts and bone marrow cellularity returned to normal. To understand the mechanism of marrow depression in this infant, we examined the effect of the patient's plasma and methylmalonic acid itself on the in vitro growth of bone marrow-committed stem cells. The patient's plasma obtained before B12 treatment completely inhibited the marrow cell growth, whereas the posttreatment plasma showed no inhibition. Methylmalonic acid when added to the culture dishes in concentrations comparable to those reported in plasma of methylmalonic acidemia patients, inhibited growth of marrow stem cells in a concentrationdependent fashion.On the other hand, 16 to 18 hr incubation of cells in the same concentration of methylmalonic acid did not affect the recovery or viability of the cells. The observations suggest that methylmalonic acid is inhibitory to the proliferation of marrow stem cells. The mechanism of inhibition is yet to be elucidated. SpeculationMMA at a concentration comparable to that reported in patients with methylmalonic acidemia inhibited in vitro growth of marrow hemopoietic cells, but overnight incubation of the cells in MMA at the same concentration did not reduce the number of viable cells determined by the trypan blue dye exclusion test. It appears, therefore, that MMA within the range of concentration tested is not immediately cytotoxic. Its inhibitory action thus seems to require longer cell contact hours than the 16 to 18 hr we used, and it may be directed against rapidly proliferating cell population. The potential mechanisms of inhibition are unknown and more work is needed to understand the interaction of MMA with hemopoietic cells.Leukopenia and thrombopenia are known to occur in the patients with ketotic hyperglycinemias such as methylmalonic (MMA-emia), propionic, or isovaleric acidemia (I 8). but the pathogenesis of the cytopenias is poorly understood. Recently, we had an opportunity to study the hematological aspect of methylmaonic acidemia in an infant with this disorder who presented with b, ne marrow hypoplasia and ketoacidosis. The association of with pancytopenia due to depressed marrow hemoiesis has not been reported. Our studies using recently popularmarrow cell culture technique helped our understandproblems in this patient.