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Genetics Home Reference: your guide to understanding genetic conditions
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Hypermethioninemia

Reviewed April 2007

What is hypermethioninemia?

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.

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 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.

Read more about galactosemia; homocystinuria; and tyrosinemia.

How common is hypermethioninemia?

Primary hypermethioninemia that is not caused by other disorders or excess methionine intake appears to be rare; only a small number of cases have been reported. The actual incidence is difficult to determine, however, since many individuals with hypermethioninemia have no symptoms.

What genes are related to hypermethioninemia?

Mutations in the AHCY, GNMT, and MAT1A genes cause hypermethioninemia.

Inherited hypermethioninemia that is not associated with other metabolic disorders can be caused by shortages (deficiencies) in the enzymes that break down methionine. These enzymes are produced from the MAT1A, GNMT and AHCY genes. The reactions involved in metabolizing methionine help supply some of the amino acids needed for protein production. These reactions are also involved in transferring methyl groups, consisting of a carbon atom and three hydrogen atoms, from one molecule to another (transmethylation), which is important in many cellular processes.

The MAT1A gene provides instructions for producing the enzyme methionine adenosyltransferase. This enzyme converts methionine into a compound called S-adenosylmethionine, also known as AdoMet or SAMe. The GNMT gene provides instructions for making the enzyme glycine N-methyltransferase. This enzyme starts the next step in the process, converting AdoMet to a compound called S-adenosyl homocysteine, or AdoHcy. The AHCY gene provides instructions for producing the enzyme S-adenosylhomocysteine hydrolase. This enzyme converts the AdoHcy into the compound homocysteine. Homocysteine may be converted back to methionine or into another amino acid, cysteine.

A deficiency of any of these enzymes results in a buildup of methionine in the body, and may cause signs and symptoms related to hypermethioninemia.

Related Gene(s)

Changes in these genes are associated with hypermethioninemia.

  • AHCY
  • GNMT
  • MAT1A

How do people inherit hypermethioninemia?

Hypermethioninemia can have different inheritance patterns. This condition is usually inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Hypermethioninemia is occasionally inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In these cases, an affected person usually has one parent with the condition.

Where can I find information about diagnosis or management of hypermethioninemia?

These resources address the diagnosis or management of hypermethioninemia and may include treatment providers.

  • Gene Tests: Hypermethioninemia with S-Adenosylhomocysteine Hydrolase Deficiency (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/319540)
  • Gene Tests: Isolated Persistent Hypermethioninemia (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/30506)

You might also find information on the diagnosis or management of hypermethioninemia in Educational resources (http://ghr.nlm.nih.gov/condition/hypermethioninemia/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/hypermethioninemia/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook.

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about hypermethioninemia?

You may find the following resources about hypermethioninemia helpful. These materials are written for the general public.

  • MedlinePlus - Health information

    • Health Topic: Metabolic Disorders (http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html)
    • Health Topic: Newborn Screening (http://www.nlm.nih.gov/medlineplus/newbornscreening.html)

  • Educational resources - Information pages

    • Biochemistry (fifth edition, 2002): Methionine Metabolism (http://www.ncbi.nlm.nih.gov/books/NBK22453/?rendertype=figure&id=A3252)
    • Orphanet (http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=88618)
    • Screening, Technology and Research in Genetics (http://www.newbornscreening.info/)
  • Patient support - For patients and families
    Children Living with Inherited Metabolic Diseases (http://www.climb.org.uk/)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

  • Gene Tests - Genetic tests ordered by healthcare professionals

    • Gene Tests: Hypermethioninemia with S-Adenosylhomocysteine Hydrolase Deficiency (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/319540)
    • Gene Tests: Isolated Persistent Hypermethioninemia (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/30506)

  • ACT Sheets - Newborn screening follow up

    • Increased Methionine (http://www.ncbi.nlm.nih.gov/books/NBK55827/bin/Methionine.pdf)
  • ClinicalTrials.gov - Linking patients to medical research (http://clinicaltrials.gov/ct2/results?cond=%22hypermethioninemia%22)
  • PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=(hypermethioninemia%5BTIAB%5D)%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D%20AND%20%22last%203600%20days%22%5Bdp%5D)

  • OMIM - Genetic disorder catalog

    • GLYCINE N-METHYLTRANSFERASE DEFICIENCY (http://omim.org/entry/606664)
    • METHIONINE ADENOSYLTRANSFERASE DEFICIENCY (http://omim.org/entry/250850)
    • S-ADENOSYLHOMOCYSTEINE HYDROLASE (http://omim.org/entry/180960)

What other names do people use for hypermethioninemia?

  • Deficiency of methionine adenosyltransferase
  • glycine N-methyltransferase deficiency
  • GNMT deficiency
  • Hepatic methionine adenosyltransferase deficiency
  • MAT deficiency
  • MET
  • methionine adenosyltransferase deficiency
  • methioninemia
  • S-adenosylhomocysteine hydrolase deficiency

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about hypermethioninemia?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding hypermethioninemia?

acids ; amino acid ; atom ; autosomal ; autosomal dominant ; autosomal recessive ; cell ; compound ; deficiency ; enzyme ; gene ; glycine ; hepatic ; hydrolase ; incidence ; inheritance ; inheritance pattern ; methyl ; methyltransferase ; molecule ; motor ; motor skill ; mutation ; neurological ; newborn screening ; protein ; recessive ; screening ; sign ; symptom

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Augoustides-Savvopoulou P, Luka Z, Karyda S, Stabler SP, Allen RH, Patsiaoura K, Wagner C, Mudd SH. Glycine N -methyltransferase deficiency: a new patient with a novel mutation. J Inherit Metab Dis. 2003;26(8):745-59. (http://www.ncbi.nlm.nih.gov/pubmed/14739680?dopt=Abstract)
  • Barić I, Cuk M, Fumić K, Vugrek O, Allen RH, Glenn B, Maradin M, Pazanin L, Pogribny I, Rados M, Sarnavka V, Schulze A, Stabler S, Wagner C, Zeisel SH, Mudd SH. S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy. J Inherit Metab Dis. 2005;28(6):885-902. (http://www.ncbi.nlm.nih.gov/pubmed/16435181?dopt=Abstract)
  • Baric I, Fumic K, Glenn B, Cuk M, Schulze A, Finkelstein JD, James SJ, Mejaski-Bosnjak V, Pazanin L, Pogribny IP, Rados M, Sarnavka V, Scukanec-Spoljar M, Allen RH, Stabler S, Uzelac L, Vugrek O, Wagner C, Zeisel S, Mudd SH. S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4234-9. Epub 2004 Mar 15. (http://www.ncbi.nlm.nih.gov/pubmed/15024124?dopt=Abstract)
  • Biochemistry (fifth edition, 2002): Methionine Metabolism (http://www.ncbi.nlm.nih.gov/books/NBK22453/?rendertype=figure&id=A3252)
  • Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. J Nutr. 2006 Jun;136(6 Suppl):1636S-1640S. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16702333?dopt=Abstract)
  • Buist NR, Glenn B, Vugrek O, Wagner C, Stabler S, Allen RH, Pogribny I, Schulze A, Zeisel SH, Barić I, Mudd SH. S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man. J Inherit Metab Dis. 2006 Aug;29(4):538-45. Epub 2006 May 30. (http://www.ncbi.nlm.nih.gov/pubmed/16736098?dopt=Abstract)
  • Chamberlin ME, Ubagai T, Mudd SH, Thomas J, Pao VY, Nguyen TK, Levy HL, Greene C, Freehauf C, Chou JY. Methionine adenosyltransferase I/III deficiency: novel mutations and clinical variations. Am J Hum Genet. 2000 Feb;66(2):347-55. (http://www.ncbi.nlm.nih.gov/pubmed/10677294?dopt=Abstract)
  • Chou JY. Molecular genetics of hepatic methionine adenosyltransferase deficiency. Pharmacol Ther. 2000 Jan;85(1):1-9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/10674710?dopt=Abstract)
  • Finkelstein JD. Inborn errors of sulfur-containing amino acid metabolism. J Nutr. 2006 Jun;136(6 Suppl):1750S-1754S. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16702350?dopt=Abstract)
  • Harvey Mudd S, Braverman N, Pomper M, Tezcan K, Kronick J, Jayakar P, Garganta C, Ampola MG, Levy HL, McCandless SE, Wiltse H, Stabler SP, Allen RH, Wagner C, Borschel MW. Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: a diagnostic trap. Mol Genet Metab. 2003 May;79(1):6-16. (http://www.ncbi.nlm.nih.gov/pubmed/12765841?dopt=Abstract)
  • Increased Methionine (http://www.ncbi.nlm.nih.gov/books/NBK55827/bin/Methionine.pdf)
  • Luka Z, Capdevila A, Mato JM, Wagner C. A glycine N-methyltransferase knockout mouse model for humans with deficiency of this enzyme. Transgenic Res. 2006 Jun;15(3):393-7. (http://www.ncbi.nlm.nih.gov/pubmed/16779654?dopt=Abstract)
  • Luka Z, Cerone R, Phillips JA 3rd, Mudd HS, Wagner C. Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism. Hum Genet. 2002 Jan;110(1):68-74. Epub 2001 Dec 7. (http://www.ncbi.nlm.nih.gov/pubmed/11810299?dopt=Abstract)
  • Luka Z, Wagner C. Effect of naturally occurring mutations in human glycine N-methyltransferase on activity and conformation. Biochem Biophys Res Commun. 2003 Dec 26;312(4):1067-72. (http://www.ncbi.nlm.nih.gov/pubmed/14651980?dopt=Abstract)
  • 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. Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia. J Inherit Metab Dis. 2001 Aug;24(4):448-64. (http://www.ncbi.nlm.nih.gov/pubmed/11596649?dopt=Abstract)
  • OMIM: GLYCINE N-METHYLTRANSFERASE DEFICIENCY (http://omim.org/entry/606664)
  • OMIM: METHIONINE ADENOSYLTRANSFERASE DEFICIENCY (http://omim.org/entry/250850)
  • OMIM: S-ADENOSYLHOMOCYSTEINE HYDROLASE (http://omim.org/entry/180960)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: April 2007
Published: February 18, 2013