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

This paper reports clinical and metabolic studies of two Italian siblings w ith a novel form of persistent isolated hypermethioninaemia, i.e. abnormall y elevated plasma methionine that lasted beyond the first months of life an d is not due to cystathionine beta -synthase deficiency, tyrosinaemia I or liver disease. Abnormal elevations of their plasma S-adenosylmethionine (Ad oMet) concentrations proved they do not have deficient activity of methioni ne adenosyltransferase I/III. A variety of studies provided evidence that t he elevations of methionine and AdoMet are not caused by defects in the met hionine transamination pathway, deficient activity of methionine adenosyltr ansferase II, a mutation in methylenetetrahydrofolate reductase rendering t his activity resistant to inhibition by AdoMet, or deficient activity of gu anidinoacetate methyltransferase. Plasma sarcosine (N-methylglycine) is ele vated, together with elevated plasma AdoMet in normal subjects following or al methionine loads and in association with increased plasma levels of both methionine and AdoMet in cystathionine beta -synthase-deficient individual s. However, plasma sarcosine is not elevated in these siblings. The latter result provides evidence they are deficient in activity of glycine N-methyl transferase (GNMT). The only clinical abnormalities in these siblings are m ild hepatomegaly and chronic elevation of serum transaminases not attributa ble to conventional causes of liver disease. A possible causative connectio n between GNMT deficiency and these hepatitis-like manifestations is discus sed. Further studies are required to evaluate whether dietary methionine re striction will be useful in this situation.