Acute Neonatal Nonketotic Hyperglycinemia: Normal Propionate and Methylmalonate Metabolism

Abstract

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 mitochondria1 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 M M A 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 CO,, NH,, and a single-carbon tetrahydrofolate derivative represents the primary enzymatic defect.

Effect of Valine on Propionate Metabolism in Control and Hyperglycinemic Fibroblasts and in Rat Liver

“…Consequently, defective or decreased activity of any single enzyme in a series can be overlooked unless the particular enzyme being studied possesses the rate-limiting V,,,, of the series. Additionally, it was not possible for us to demonstrate propionyl-CoA carboxylase activity in livers stored in the frozen state after periods exceeding 1-2 months (22), as did Baumgartner et al (7). The carboxylase instability we noted is consistent with the findings of Giorgio and Whitaker (13).…”

“…Furthermore, the report stated that in nonketotic hyperglycinemia fibroblasts suggests altered propi-oral loading of NKH patients with leucine, isoleucine, valine, onate metabolism in this mutation. Additionally, growth of nonmethionine, and threonine had, no clinical effect on the patient ketotic hyperglycinemia fibroblasts on high concentrations of (7). These data are incompatible with several other reports valine results in greatly increased carboxylase activity.…”

“…and (2) increased propionyl-CoA carboxylase activity in nonkeIn contrast to the report of normal propionate metabolism in nonketotic hyperglycinemia (7,8), evidence derived from studtotic h~~e r g l~c i n e m i c lysates grown On valine-su~~lemented me-ies in our laboratory have shown altered p r o p i o n y~-~o A carboxdia.…”

“…In a more recently published report, the same author hypothesized that the "true nonketotic hyperglycinemic state" is one in which both ~r o~i o n a t e and branched chain amino acid metabolism are norDecreased activity of the propionyl-CoA carboxylase enzyme maiin virro and irt vivo (7). Furthermore, the report stated that in nonketotic hyperglycinemia fibroblasts suggests altered propi-oral loading of NKH patients with leucine, isoleucine, valine, onate metabolism in this mutation.…”

“…Baumgartner et al (7,8) have suggested that in the NKH patient, the enzymes of the propionate pathway are normal. These studies were performed using the substrates propionylCoA and N a H I T O , and measuring I4C label incorporated into methylmalonyl-CoA, succinyl-CoA, and other organic acids.…”