One-methyl group metabolism in non-ketotic hyperglycinaemia: Mildly elevated cerebrospinal fluid homocysteine levels

Non-ketotic hyperglycinaemia (NKH) is a rare, severe brain disease caused b y deficient glycine cleavage enzyme complex activity resulting in elevated glycine concentrations. Recent experience suggests that factors in addition to glycine kinetics are involved in its pathogenesis. The glycine cleavage reaction through the formation of methylenetetrahydrofolate is an importan t one-methyl group donor. A deficiency in one-methyl group metabolites, in particular of choline, has been hypothesized in NKH. We investigated metabo lites involved in one-methyl group metabolism in plasma and CSF of 8 patien ts with NKH, and monitored the effect of treatment with choline in one pati ent. Plasma and CSF choline and phosphatidylcholine concentrations were nor mal, except for a low plasma choline in the single neonate studied. Choline treatment did not change brain choline content, and was not associated wit h clinical or radiological improvement. Methionine concentrations and, in o ne-patient, S-adenosylmethionine and 5-methyltetrahydrofolate concentration s were normal in CSF. Homocysteine concentrations in CSF, however, were sli ghtly but consistently elevated in all four patients examined, but cysteine , cysteinylglycine and glutathione were normal. Serine is important in the transfer of one-methyl groups from mitochondria to cytosol. Serine concentr ations were normal in plasma and CSF, but dropped to below normal in CSF in three patients on benzoate treatment. These observations add to our unders tanding of the complex metabolic disturbances in NKH.