Alternative titles; symbols
SNOMEDCT: 763720007; ORPHA: 289891; DO: 0111037;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.1 | Glycine N-methyltransferase deficiency | 606664 | Autosomal recessive | 3 | GNMT | 606628 |
A number sign (#) is used with this entry because glycine N-methyltransferase deficiency is caused by homozygous or compound heterozygous mutation in the GNMT gene (606628) on chromosome 6p21.
Mudd et al. (2001) reported 2 Italian sibs, a 4-year-old girl and her 9-year-old brother, with a novel form of persistent isolated hypermethioninemia without cystathionine beta-synthase deficiency (236200), tyrosinemia type I (276700), or liver disease. The children exhibited elevations of plasma S-adenosylmethionine, but plasma sarcosine was normal. These observations suggested deficiency of glycine N-methyltransferase activity. The only clinical abnormalities in these sibs were mild hepatomegaly and chronic elevation of serum transaminases not attributable to conventional causes of liver disease.
Augoustides-Savvopoulou et al. (2003) described an adopted Greek boy of Gypsy origin who presented at 2 years of age because of mild but persistent elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). There was no hepatomegaly. Reevaluation at 4 years of age again showed elevated ALT and AST, whereas other routine laboratory values were normal except for a mild elevation of ferritin. Quantitative plasma amino acid assays showed a marked increase in methionine, and there was increased methionine excretion in the urine. Ultrasound of the liver showed increased echogenicity of periportal spaces only, and needle biopsy at age 5 years showed normal architecture of hepatic parenchyma without significant morphologic changes. Assays of metabolites related to methionine metabolism revealed striking elevation of plasma S-adenosylmethionine with minimal elevation of total plasma homocysteine and normal N-methylglycine, strongly suggestive of GNMT deficiency. The authors noted that this boy was similar to the sibs reported by Mudd et al. (2001) in having mild persistent elevation of serum transaminases without other serious clinical abnormalities; however, Augoustides-Savvopoulou et al. (2003) suggested that additional adverse effects might develop in the future in these young patients.
The transmission pattern of GNMT deficiency in the family reported by Mudd et al. (2001) was consistent with autosomal recessive inheritance.
In the 2 Italian sibs with GNMT deficiency reported by Mudd et al. (2001), Luka et al. (2002) found compound heterozygosity for 2 missense mutations in the GNMT gene (606628.0001-606628.0002). These were the first reported cases of an inborn error affecting the activity of GNMT.
In a 5-year-old Greek boy of Gypsy origin with hypermethioninemia and metabolic studies suggestive of GNMT deficiency, Augoustides-Savvopoulou et al. (2003) screened the GNMT gene and identified homozygosity for a missense mutation (N140S; 606628.0003) that was not found in more than 300 controls.
Liu et al. (2007) found that, at 11 weeks of age, Gnmt -/- mice had increased hepatic S-adenosylmethionine (SAM) concentrations, but no change in S-adenosylhomocysteine (SAH) concentrations, compared with wildtype. Accordingly, Gnmt -/- mice had higher SAM/SAH ratios than wildtype. Gnmt -/- mice also had a modest increase in serum methionine, but not homocysteine. RT-PCR analysis of genes in the 1-carbon metabolism pathway revealed reduced expression of Ahcy (180960), Mthfr (607093), and Ftcd (606806) in Gnmt -/- mice. Assessment of liver/body weight ratios indicated hepatomegaly in Gnmt -/- mice, with earlier onset in females. Histologic analysis demonstrated abnormal glycogen storage in Gnmt -/- liver that was more severe in females. Other organs appeared normal in Gnmt -/- mice. Hematologic analysis showed lower numbers of white blood cells, as well as lower glucose and higher cholesterol levels, in Gnmt -/- mice. RT-PCR analysis of genes involved in glycogen metabolism revealed reduced expression of G6pt (SLC37A4; 602671), Gaa (606800), Pygl (613741), and Pepck (614168) in Gnmt -/- mice. Liu et al. (2007) concluded that the phenotype of Gnmt -/- mice mimics that of patients with GNMT deficiency and also shares several characteristics with GSD1B (232220) patients.
Augoustides-Savvopoulou, P., Luka, Z., Karyda, S., Stabler, S. P., Allen, R. H., Patsiaoura, K., Wagner, C., Mudd, S. H. Glycine N-methyltransferase deficiency: a new patient with a novel mutation. J. Inherit. Metab. Dis. 26: 745-759, 2003. [PubMed: 14739680] [Full Text: https://doi.org/10.1023/B:BOLI.0000009978.17777.33]
Liu, S.-P., Li, Y.-S., Chen, Y.-J., Chiang, E.-P., Li, A. F.-Y., Lee, Y.-H., Tsai, T.-F., Hsiao, M., Huang, S.-F., Chen, Y.-M. A. Glycine N-methyltransferase -/- mice develop chronic hepatitis and glycogen storage disease in the liver. Hepatology 46: 1413-1425, 2007. Note: Erratum: Hepatology 47: 769 only, 2008. [PubMed: 17937387] [Full Text: https://doi.org/10.1002/hep.21863]
Luka, Z., Cerone, R., Phillips, J. A., III, Mudd, S. H., Wagner, C. Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism. Hum. Genet. 110: 68-74, 2002. [PubMed: 11810299] [Full Text: https://doi.org/10.1007/s00439-001-0648-4]
Mudd, S. H., Cerone, R., Schiaffino, M. C., Fantasia, A. R., Minniti, G., Caruso, U., Lorini, R., Watkins, D., Matiaszuk, N., Rosenblatt, D. S., Schwahn, B., Rozen, R., LeGros, L., Kotb, M., Capdevila, A., Luka, Z., Finkelstein, J. D., Tangerman, A., Stabler, S. P., Allen, R. H., Wagner, C. Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia. J. Inherit. Metab. Dis. 24: 448-464, 2001. [PubMed: 11596649] [Full Text: https://doi.org/10.1023/a:1010577512912]