ExtractPropionyl-CoA carboxylase and combined methylmalonyl-CoA (MMA-CoA) racemase and -mutase activities were studied in liver and fibroblasts of two patients with the acute neonatal form of nonketotic hyperglycemia. In all experiments, these enzyme activities studied in tissues of the patients were within the range of healthy control subjects, whereas no propionyl-CoA carboxylase activity was measurable in the fibroblasts of a patient with propionic acidemia. Subcellular fractionation of liver and fibroblasts indicated that the normal amounts of MMA-CoA found after incubation of whole tissue homogenate were formed by propionyl-CoA carboxylase, a mitochondrial enzyme, and not by acetyl-CoA carboxylase, which theoretically could also be involved in the carboxylation of propionyl-CoA.From the above data as well as from clinical and biochemical observations in three patients, it was concluded that there exists a true nonketotic hyperglycinemia which is not related etiologically to the different disorders of the ketotic hyperglycinemia syndrome. True nonketotic hyperglycinemia is not associated with ketoacidosis even after loading with propionate- and MMA precursors. It must be distinguished by exclusion from mild forms of the ketotic hyperglycinemia syndrome which may present clinically as hyperglycinemia without ketosis.SpeculationThe metabolism of propionate, methylmalonate, and branched chain amino acids is normal in true nonketotic hyperglycinemia. Further investigations will have to show whether the observed block in the glycine cleavage reaction to CO2, NH3, and a single-carbon tetrahydrofolate derivative represents the primary enzymatic defect. In view of the four enzymatic steps involved in this complex reaction, it may well be that true nonketotic hyperglycinemia also represents a heterogeneous syndrome. The elevated glycine concentrations in the central nervous system (CNS) may play a significant role in the development of the neurologic symptoms.