title: Glycine N -methyltransferase deficiency: a new patient with a novel mutation.
abstract: We report studies of a Greek boy of gypsy origin that show that he has severe deficiency 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 micro mol/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 beta-synthase deficiency by total homocysteine of 9.4-12.1 micro mol/L; methionine adenosyltransferase I/III deficiency by S -adenosylmethionine (AdoMet) levels elevated to 1643-2222 nmol/L; and S -adenosylhomocysteine (AdoHcy) hydrolase deficiency by normal AdoHcy levels. A normal plasma N -methylglycine concentration in spite of elevated AdoMet strongly suggested GNMT deficiency. Molecular genetic studies identified 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 deficiency, strengthening the likelihood of a causative association. Although his deficiency 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 deficiency, such as the long-term prognosis, whether other individuals with this defect are currently going undetected, and means to search for such persons.
authors.affiliation: Pediatric Biochemistry/Metabolic Laboratory, Hippocration General Hospital, Thessaloniki, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Augoustides-Savvopoulou
authors.forename: Z
authors.initials: Z
authors.lastname: Luka
authors.forename: S
authors.initials: S
authors.lastname: Karyda
authors.forename: S P
authors.initials: SP
authors.lastname: Stabler
authors.forename: R H
authors.initials: RH
authors.lastname: Allen
authors.forename: K
authors.initials: K
authors.lastname: Patsiaoura
authors.forename: C
authors.initials: C
authors.lastname: Wagner
authors.forename: S H
authors.initials: SH
authors.lastname: Mudd
mesh_terms: D002675:Child, Preschool; D050938:Glycine N-Methyltransferase; D006801:Humans; D008297:Male; D008715:Methionine / Q000378:metabolism; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics*; D009154:Mutation
chemical_list: D008715:Methionine; D008780:Methyltransferases; C494510:GNMT protein, human; D050938:Glycine N-Methyltransferase