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Glycine N-methyltransferase deficiency

MedGen UID:
338300
Concept ID:
C1847720
Disease or Syndrome
Synonyms: Glycine N-Methyltransferase Deficiency; GNMT Deficiency
SNOMED CT: Hypermethioninemia due to deficiency of glycine N-methyltransferase (763720007); Hypermethioninemia due to GNMT (glycine N-methyltransferase) deficiency (763720007); Glycine N-methyltransferase deficiency (763720007)
 
Gene (location): GNMT (6p21.1)
 
Monarch Initiative: MONDO:0011698
OMIM®: 606664
Orphanet: ORPHA289891

Definition

Hypermethioninemia can occur with other metabolic disorders, such as homocystinuria, tyrosinemia, and galactosemia, which also involve the faulty breakdown of particular molecules. It can also result from liver disease or excessive dietary intake of methionine from consuming large amounts of protein or a methionine-enriched infant formula. The condition is called primary hypermethioninemia when it is not associated with other metabolic disorders or excess methionine in the diet.

People with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit intellectual disability and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage.

Hypermethioninemia is an excess of a particular protein building block (amino acid), called methionine, in the blood. This condition can occur when methionine is not broken down (metabolized) properly in the body. [from MedlinePlus Genetics]

Clinical features

From HPO
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Hypermethioninemia
MedGen UID:
887708
Concept ID:
C4048705
Disease or Syndrome
An increased concentration of methionine in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVGlycine N-methyltransferase deficiency
Follow this link to review classifications for Glycine N-methyltransferase deficiency in Orphanet.

Professional guidelines

PubMed

Keller R, Chrastina P, Pavlíková M, Gouveia S, Ribes A, Kölker S, Blom HJ, Baumgartner MR, Bártl J, Dionisi-Vici C, Gleich F, Morris AA, Kožich V, Huemer M; individual contributors of the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD), Barić I, Ben-Omran T, Blasco-Alonso J, Bueno Delgado MA, Carducci C, Cassanello M, Cerone R, Couce ML, Crushell E, Delgado Pecellin C, Dulin E, Espada M, Ferino G, Fingerhut R, Garcia Jimenez I, Gonzalez Gallego I, González-Irazabal Y, Gramer G, Juan Fita MJ, Karg E, Klein J, Konstantopoulou V, la Marca G, Leão Teles E, Leuzzi V, Lilliu F, Lopez RM, Lund AM, Mayne P, Meavilla S, Moat SJ, Okun JG, Pasquini E, Pedron-Giner CC, Racz GZ, Ruiz Gomez MA, Vilarinho L, Yahyaoui R, Zerjav Tansek M, Zetterström RH, Zeyda M
J Inherit Metab Dis 2019 Jan;42(1):128-139. doi: 10.1002/jimd.12034. PMID: 30740731
Tran C, Bonafé L, Nuoffer JM, Rieger J, Berger MM
Clin Nutr 2018 Aug;37(4):1114-1120. Epub 2017 Jul 25 doi: 10.1016/j.clnu.2017.07.013. PMID: 28779878
Barić I, Staufner C, Augoustides-Savvopoulou P, Chien YH, Dobbelaere D, Grünert SC, Opladen T, Petković Ramadža D, Rakić B, Wedell A, Blom HJ
J Inherit Metab Dis 2017 Jan;40(1):5-20. Epub 2016 Sep 26 doi: 10.1007/s10545-016-9972-7. PMID: 27671891Free PMC Article

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated Methionine +/- Elevated Homocysteine, Homocystinuria (Cystathionine beta-synthase deficiency), 2021

American College of Medical Genetics and Genomics, Algorithm, Elevated Methionine +/- Elevated Homocysteine, 2021

Recent clinical studies

Etiology

Dai X, Liu S, Cheng L, Huang T, Guo H, Wang D, Xia M, Ling W, Xiao Y
Circ Res 2022 May 13;130(10):1565-1582. Epub 2022 Apr 12 doi: 10.1161/CIRCRESAHA.121.320251. PMID: 35410483
Becker PH, Demir Z, Mozer Glassberg Y, Sevin C, Habes D, Imbard A, Mussini C, Rozenfeld Bar Lev M, Davit-Spraul A, Benoist JF, Thérond P, Slama A, Jacquemin E, Gonzales E, Gaignard P
Mol Genet Metab 2021 Jan;132(1):38-43. Epub 2020 Nov 28 doi: 10.1016/j.ymgme.2020.11.007. PMID: 33309011
Kožich V, Stabler S
J Nutr 2020 Oct 1;150(Suppl 1):2506S-2517S. doi: 10.1093/jn/nxaa134. PMID: 33000152
Furujo M, Kinoshita M, Nagao M, Kubo T
Mol Genet Metab 2012 Nov;107(3):253-6. Epub 2012 Aug 11 doi: 10.1016/j.ymgme.2012.08.002. PMID: 22951388
Luka Z, Capdevila A, Mato JM, Wagner C
Transgenic Res 2006 Jun;15(3):393-7. doi: 10.1007/s11248-006-0008-1. PMID: 16779654Free PMC Article

Diagnosis

Becker PH, Demir Z, Mozer Glassberg Y, Sevin C, Habes D, Imbard A, Mussini C, Rozenfeld Bar Lev M, Davit-Spraul A, Benoist JF, Thérond P, Slama A, Jacquemin E, Gonzales E, Gaignard P
Mol Genet Metab 2021 Jan;132(1):38-43. Epub 2020 Nov 28 doi: 10.1016/j.ymgme.2020.11.007. PMID: 33309011
Zhang Z, Wang Y, Ma D, Cheng W, Sun Y, Jiang T
J Pediatr Endocrinol Metab 2020 Jan 28;33(1):47-52. doi: 10.1515/jpem-2019-0285. PMID: 31851615
Keller R, Chrastina P, Pavlíková M, Gouveia S, Ribes A, Kölker S, Blom HJ, Baumgartner MR, Bártl J, Dionisi-Vici C, Gleich F, Morris AA, Kožich V, Huemer M; individual contributors of the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD), Barić I, Ben-Omran T, Blasco-Alonso J, Bueno Delgado MA, Carducci C, Cassanello M, Cerone R, Couce ML, Crushell E, Delgado Pecellin C, Dulin E, Espada M, Ferino G, Fingerhut R, Garcia Jimenez I, Gonzalez Gallego I, González-Irazabal Y, Gramer G, Juan Fita MJ, Karg E, Klein J, Konstantopoulou V, la Marca G, Leão Teles E, Leuzzi V, Lilliu F, Lopez RM, Lund AM, Mayne P, Meavilla S, Moat SJ, Okun JG, Pasquini E, Pedron-Giner CC, Racz GZ, Ruiz Gomez MA, Vilarinho L, Yahyaoui R, Zerjav Tansek M, Zetterström RH, Zeyda M
J Inherit Metab Dis 2019 Jan;42(1):128-139. doi: 10.1002/jimd.12034. PMID: 30740731
Mudd SH
Am J Med Genet C Semin Med Genet 2011 Feb 15;157C(1):3-32. Epub 2011 Feb 9 doi: 10.1002/ajmg.c.30293. PMID: 21308989
Barić I
J Inherit Metab Dis 2009 Aug;32(4):459-71. Epub 2009 Jul 7 doi: 10.1007/s10545-009-1146-4. PMID: 19585268

Therapy

Fernández-Tussy P, Fernández-Ramos D, Lopitz-Otsoa F, Simón J, Barbier-Torres L, Gomez-Santos B, Nuñez-Garcia M, Azkargorta M, Gutiérrez-de Juan V, Serrano-Macia M, Rodríguez-Agudo R, Iruzubieta P, Anguita J, Castro RE, Champagne D, Rincón M, Elortza F, Arslanow A, Krawczyk M, Lammert F, Kirchmeyer M, Behrmann I, Crespo J, Lu SC, Mato JM, Varela-Rey M, Aspichueta P, Delgado TC, Martínez-Chantar ML
Mol Metab 2019 Nov;29:40-54. Epub 2019 Aug 16 doi: 10.1016/j.molmet.2019.08.008. PMID: 31668391Free PMC Article
Martínez-Uña M, Varela-Rey M, Mestre D, Fernández-Ares L, Fresnedo O, Fernandez-Ramos D, Gutiérrez-de Juan V, Martin-Guerrero I, García-Orad A, Luka Z, Wagner C, Lu SC, García-Monzón C, Finnell RH, Aurrekoetxea I, Buqué X, Martínez-Chantar ML, Mato JM, Aspichueta P
J Hepatol 2015 Mar;62(3):673-81. Epub 2014 Oct 18 doi: 10.1016/j.jhep.2014.10.019. PMID: 25457203Free PMC Article
Furujo M, Kinoshita M, Nagao M, Kubo T
Mol Genet Metab 2012 Nov;107(3):253-6. Epub 2012 Aug 11 doi: 10.1016/j.ymgme.2012.08.002. PMID: 22951388
Mudd SH, Brosnan JT, Brosnan ME, Jacobs RL, Stabler SP, Allen RH, Vance DE, Wagner C
Am J Clin Nutr 2007 Jan;85(1):19-25. doi: 10.1093/ajcn/85.1.19. PMID: 17209172
Mudd SH, Cerone R, Schiaffino MC, Fantasia AR, Minniti G, Caruso U, Lorini R, Watkins D, Matiaszuk N, Rosenblatt DS, Schwahn B, Rozen R, LeGros L, Kotb M, Capdevila A, Luka Z, Finkelstein JD, Tangerman A, Stabler SP, Allen RH, Wagner C
J Inherit Metab Dis 2001 Aug;24(4):448-64. doi: 10.1023/a:1010577512912. PMID: 11596649

Prognosis

Hübner V, Hannibal L, Janzen N, Grünert SC, Freisinger P
Genes (Basel) 2022 Jun 27;13(7) doi: 10.3390/genes13071163. PMID: 35885946Free PMC Article
Becker PH, Demir Z, Mozer Glassberg Y, Sevin C, Habes D, Imbard A, Mussini C, Rozenfeld Bar Lev M, Davit-Spraul A, Benoist JF, Thérond P, Slama A, Jacquemin E, Gonzales E, Gaignard P
Mol Genet Metab 2021 Jan;132(1):38-43. Epub 2020 Nov 28 doi: 10.1016/j.ymgme.2020.11.007. PMID: 33309011
Bannick A, Chase S, Miner A, Seeterlin M, Conway RL
Eur J Med Genet 2020 Dec;63(12):104076. Epub 2020 Sep 24 doi: 10.1016/j.ejmg.2020.104076. PMID: 32980525
Martínez-López N, García-Rodríguez JL, Varela-Rey M, Gutiérrez V, Fernández-Ramos D, Beraza N, Aransay AM, Schlangen K, Lozano JJ, Aspichueta P, Luka Z, Wagner C, Evert M, Calvisi DF, Lu SC, Mato JM, Martínez-Chantar ML
Gastroenterology 2012 Sep;143(3):787-798.e13. Epub 2012 Jun 8 doi: 10.1053/j.gastro.2012.05.050. PMID: 22687285Free PMC Article
Augoustides-Savvopoulou P, Luka Z, Karyda S, Stabler SP, Allen RH, Patsiaoura K, Wagner C, Mudd SH
J Inherit Metab Dis 2003;26(8):745-59. doi: 10.1023/B:BOLI.0000009978.17777.33. PMID: 14739680

Clinical prediction guides

de Moraes Meine B, Bona NP, Luduvico KP, de Souza Cardoso J, Spohr L, de Souza AÁ, Spanevello RM, Soares MSP, Stefanello FM
Amino Acids 2020 Dec;52(11-12):1545-1558. Epub 2020 Nov 13 doi: 10.1007/s00726-020-02913-5. PMID: 33184691
Wang W, Yang J, Xue J, Mu W, Zhang X, Wu W, Xu M, Gong Y, Liu Y, Zhang Y, Xie X, Gu W, Bai J, Cram DS
BMC Med Genet 2019 Jan 6;20(1):3. doi: 10.1186/s12881-018-0731-5. PMID: 30612563Free PMC Article
Motzek A, Knežević J, Switzeny OJ, Cooper A, Barić I, Beluzić R, Strauss KA, Puffenberger EG, Mudd SH, Vugrek O, Zechner U
PLoS One 2016;11(3):e0151261. Epub 2016 Mar 14 doi: 10.1371/journal.pone.0151261. PMID: 26974671Free PMC Article
Vázquez-Chantada M, Fernández-Ramos D, Embade N, Martínez-Lopez N, Varela-Rey M, Woodhoo A, Luka Z, Wagner C, Anglim PP, Finnell RH, Caballería J, Laird-Offringa IA, Gorospe M, Lu SC, Mato JM, Martínez-Chantar ML
Gastroenterology 2010 May;138(5):1943-53. Epub 2010 Jan 25 doi: 10.1053/j.gastro.2010.01.032. PMID: 20102719Free PMC Article
Finkelstein JD
J Nutr 2006 Jun;136(6 Suppl):1750S-1754S. doi: 10.1093/jn/136.6.1750S. PMID: 16702350

Supplemental Content

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    Curated

    • ACMG ACT, 2021
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated Methionine +/- Elevated Homocysteine, Homocystinuria (Cystathionine beta-synthase deficiency), 2021
    • ACMG Algorithm, 2021
      American College of Medical Genetics and Genomics, Algorithm, Elevated Methionine +/- Elevated Homocysteine, 2021

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