Glycine N‐methyltransferase deficiency: A novel inborn error causing persistent isolated hypermethioninaemia

Abstract

This paper reports clinical and metabolic studies of two Italian siblings with a novel form of persistent isolated hypermethioninaemia, i.e. abnormally elevated plasma methionine that lasted beyond the first months of life and is not due to cystathionine beta-synthase deficiency, tyrosinaemia I or liver disease. Abnormal elevations of their plasma S-adenosylmethionine (AdoMet) concentrations proved they do not have deficient activity of methionine adenosyltransferase I/III. A variety of studies provided evidence that the elevations of methionine and AdoMet are not caused by defects in the methionine transamination pathway, deficient activity of methionine adenosyltransferase II, a mutation in methylenetetrahydrofolate reductase rendering this activity resistant to inhibition by AdoMet, or deficient activity of guanidinoacetate methyltransferase. Plasma sarcosine (N-methylglycine) is elevated, together with elevated plasma AdoMet in normal subjects following oral methionine loads and in association with increased plasma levels of both methionine and AdoMet in cystathionine beta-synthase-deficient individuals. However, plasma sarcosine is not elevated in these siblings. The latter result provides evidence they are deficient in activity of glycine N-methyltransferase (GNMT). The only clinical abnormalities in these siblings are mild hepatomegaly and chronic elevation of serum transaminases not attributable to conventional causes of liver disease. A possible causative connection between GNMT deficiency and these hepatitis-like manifestations is discussed. Further studies are required to evaluate whether dietary methionine restriction will be useful in this situation.

S -adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism

“…Isolated persistent hypermethioninemia associated with elevated AdoMet may result from a deficiency of glycine N-methyltransferase (GNMT), a defect that has been reported in three children (20,25,26). In these patients, a diagnostically important finding was the absence of N-methylglycine elevation in the face of elevated AdoMet (20). Elevation of both plasma N-methylglycine (sarcosine) and plasma AdoHcy in the present patient provided strong evidence against GNMT deficiency.…”

“…Elevated plasma AdoMet in the present patient demonstrated conclusively that he did not have MAT I͞III deficiency (24). Isolated persistent hypermethioninemia associated with elevated AdoMet may result from a deficiency of glycine N-methyltransferase (GNMT), a defect that has been reported in three children (20,25,26). In these patients, a diagnostically important finding was the absence of N-methylglycine elevation in the face of elevated AdoMet (20).…”

“…The abnormal elevation of AdoMet is plausibly secondary to generalized inhibition by AdoHcy of multiple AdoMet-dependent methyltransferases. The elevations of methionine are explained by down-regulation of the flux from methionine into AdoMet when AdoMet is greatly increased, as was found in the children with deficient activity of GNMT (20,25). The abnormally low plasma phosphatidylcholine and free choline presumably resulted from inhibition by AdoHcy of phosphatidylethanolamine methyltransferase.…”

“…The absence of elevations of plasma tyrosine and urinary succinylacetone together with the clinical presentation ruled out tyrosinemia type 1 as a cause of the hypermethioninemia. The slight to moderate elevations of serum transaminases made it unlikely that hepatocellular disease caused hypermethioninemia of this magnitude (20). The absence of markedly elevated tHcy as well as an elevated plasma cystathionine ruled out cystathionine ␤-synthase deficiency (21,22).…”

Plasma sarcosine does not distinguish early and advanced stages of prostate cancer

“…Specific alterations of sarcosine metabolism exist in folate and in N-methylglycine-transferase deficiency where sarcosine reaches levels as high as 49.3 µmol/l. 13 Jentzmik et al pointed out in their analysis of urine sediments 6 that the sarcosine/creatinine ratios were insensitive to rectal palpation, in contrast with Sreekumar's original findings 1 that observed such sensitivity. That sarcosine correlates with invasion and performs better than PSA to distinguish diagnostic classes in the grey zone of 2 -10 ng/ml PSA 1 also could not be corroborated.…”