Glycine N‐methyltransferase deficiency: A new patient with a novel mutation

Abstract

Summary:We report studies of a Greek boy of gypsy origin that show that he has severe de¢ciency of glycine N-methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine. At age 2 years he was found to have mildly elevated serum liver transaminases that have persisted to his present age of 5 years. At age 4 years, hypermethioninaemia was discovered. Plasma methionine concentrations have ranged from 508 to 1049 mmol/L. Several known causes of hypermethioninaemia were ruled out by studies of plasma metabolites: tyrosinaemia type I by a normal plasma tyrosine and urine succinylacetone; cystathionine b-synthase de¢ciency by total homocysteine of 9.4^12.1 mmol/L; methionine adenosyltransferase I/III de¢ciency by S-adenosylmethionine (AdoMet) levels elevated to 1643^2222 nmol/L; and S-adenosylhomocysteine (AdoHcy) hydrolase de¢ciency by normal AdoHcy levels. A normal plasma N-methylglycine concentration in spite of elevated AdoMet strongly suggested GNMT de¢ciency. Molecular genetic studies identi¢ed a missense mutation in the coding region of the boy's GNMT gene, which, upon expression, retained only barely detectable catalytic activity. The mild hepatitis-like manifestations in this boy are similar to those in the only two previously reported children with GNMT de¢ciency, strengthening the likelihood of a causative association. Although his de¢ciency of GNMT activity may well be more extreme, his metabolic abnormalities are not strikingly greater. Also discussed is the metabolic role of GNMT; several additional metabolite abnormalities found in these patients; and remaining questions about human GNMT de¢ciency, such as the long-term prognosis, whether other individuals with this defect are currently going undetected, and means to search for such persons.

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

“…Loss of heterozygosity within the GNMT gene in the liver tissues of hepatocellular carcinoma patients has been reported, and GNMT alteration appears to be an early event in human hepatocellular carcinoma (11). GNMT is commonly diminished in human hepatoma and hepatoma cell lines (4)(5)(6)(7)(8)(9)(10); hence it is believed to be a susceptibility gene and a potential tumor suppressor for human hepatoma (11). Individuals with mutant GNMT and GNMT knockout mice showed that inactivation…”

A Glycine N-methyltransferase Knockout Mouse Model for Humans with Deficiency of this Enzyme

“…Indeed, the identification of several human individuals with persistent hypermethioninaemia resulted in discovery of natural mutations of GNMT as the reason for those metabolic abnormalities (Mudd et al, 2001;Augoustides-Savvopoulou et al, 2003). Although these individuals have evidence of mild liver disease they appear to be otherwise quite normal aside from their abnormal pattern of methionine metabolites.…”

Glycine N-Methyltransferase Deficiency: A Member of Dysmethylating Liver Disorders?

“…Although his clinical presentation and routine liver tests support the thesis on a benign disorder, his plasma methionine was on three occasions above 1,000 mmol/L, which was estimated as approximate borderline for increased risk of various neurological complications related to hypermethioninemia regardless of the cause (Barić and Fowler 2014;Mudd 2011). Plasma methionine levels above 1,000 mmol/L were observed also in the third reported patient (Augoustides-Savvopoulou et al 2003). Very recent data from patients with methionine adenosyltransferase I/III deficiency (MAT I/III; OMIM 250850; E.C.…”

“…2.1.1.20) is an autosomal recessive inherited disorder of methionine metabolism ( Fig. 1), which has been reported in extenso so far in only three patients from two families (Mudd et al 2001;Augoustides-Savvopoulou et al 2003). In 2015, the fourth patient was described in an abstract (Rakic et al 2015).…”