Glycine N-methyltransferase deficiency: A new patient with a novel mutation
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Summary: 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 µmol/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 β-synthase deficiency by total homocysteine of 9.4–12.1 µmol/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.
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- Glycine N-methyltransferase deficiency: A new patient with a novel mutation
Journal of Inherited Metabolic Disease
Volume 26, Issue 8 , pp 745-759
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- 1. Pediatric Biochemistry/Metabolic Laboratory, Hippocration General Hospital, Thessaloniki, Greece
- 2. Department of Biochemistry, Vanderbilt University, Nashville, TN
- 3. Pediatric Department, Hippocration General Hospital, Thessaloniki, Greece
- 4. Division of Hematology, University of Colorado Health Sciences Center, Denver, CO
- 5. Pathology Department, Hippocration General Hospital, Thessaloniki, Greece
- 6. Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD, USA
- 7. S. Harvey Mudd, NIMH/DIRP/LMB, Building 36, Room 1B-08, 36 Convent Dr 4034, Bethesda, MD, 20892-4034, USA