Extract: Ketotic hyperglycinemia is a syndrome in which elevated concentrations of glycine occur in body fluids of patients who manifest life-threatening episodes of ketoacidosis very early in life. The disorder originally described under this heading is now known to be more reliably categorized by propionic acidemia than by hyperglycinemia. Studies of the metabolism of glycine and of propionate in this condition have been undertaken. Conversion of glycine-1-14C and of propionate-1-14C to 14CO2 has been studied both in vivo and in vitro. Conversion of glycine-2-14C to serine-3-14C has been studied in vivo. It was found that the conversion of glycine-1-14C to CO2 in vivo was defective in all three of the patients with ketotic hyperglycinemia. At the earliest time points, the specific activities of expired CO2 in control subjects varied from 25 to more than 60 dpm/$mUmole, whereas in patients these values did not exceed 10 and were less than 5 in two patients. Conversion of the second carbon of glycine to the third carbon of serine was normal. The relative specific activity of the third carbon was 20. This value was 2–10 times the values found previously in patients with nonketotic hyperglycinemia where this conversion is defective. Conversion of propionate-1-14C to CO2 was defective both in vivo and in vitro in patients with ketotic hyperglycinemia and with methylmalonic acidemia. In control subjects, specific activities of the CO2 expired following injection of propionate-1-14C approximated 200 dpm/$mUmole at the earliest time points, whereas in VB the comparable specific activity was close to 0. Activity of propionyl-coenzyme A (CoA) carboxylase was absent in the fibroblasts of a patient with ketotic hyperglycinemia. Values of 15—30 dpm/5 mg protein obtained in the patient do not seem to differ significantly from 0, whereas in control subjects the values ranged from 985 to 2655 dpm/5 mg protein. These observations indicate that there are defects in the metabolism of both glycine and propionate in patients with ketotic hyperglycinemia.Speculation: In propionic acidemia with ketotic hyperglycinemia there is a defect in the oxidation of both propionate and glycine in vivo. Propionate carboxylation has been demonstrated to be defective in vitro. The abnormality of propionate metabolism seems to be primary; that of glycine metabolism may be secondary, or both could reflect a defect in synthesis of a common cofactor.
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