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

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 mumol/ 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 mumol/ 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.