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

S. H. Mudd, R. Cerone, M. C. Schiaffino, A. R. Fantasia, G. Minniti, U. Caruso, R. Lorini, D. Watkins, N. Matiaszuk, D. S. Rosenblatt, B. Schwahn, R. Rozen, L. LeGros, M. Kotb, A. Capdevila, Z. Luka, J. D. Finkelstein, A. Tangerman, S. P. Stabler, R. H. AllenC. Wagner

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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 β-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 β-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 evaluated whether dietary methionine restriction will be useful in this situation.

Original languageEnglish
Pages (from-to)448-464
Number of pages17
JournalJournal of Inherited Metabolic Disease
Issue number4
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Endocrinology

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