Hypermethioninemia

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/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.

genetic conditions

1. Introduction

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.

2. Frequency

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.

3. Causes

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.

4. Inheritance

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.

5. Other Names for This Condition

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

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 witha novel mutation. J Inherit Metab Dis. 2003;26(8):745-59.
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 ofmethionine metabolism. Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4234-9.
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 youngerbrother of the index patient, and outcomes during therapy. J Inherit Metab Dis.2005;28(6):885-902.
Biochemistry (fifth edition, 2002): Methionine Metabolism
Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. JNutr. 2006 Jun;136(6 Suppl):1636S-1640S. doi: 10.1093/jn/136.6.1636S. Review.
Buist NR, Glenn B, Vugrek O, Wagner C, Stabler S, Allen RH, Pogribny I,Schulze A, Zeisel SH, Barić I, Mudd SH. S-adenosylhomocysteine hydrolasedeficiency in a 26-year-old man. J Inherit Metab Dis. 2006 Aug;29(4):538-45.
Chamberlin ME, Ubagai T, Mudd SH, Thomas J, Pao VY, Nguyen TK, Levy HL, GreeneC, Freehauf C, Chou JY. Methionine adenosyltransferase I/III deficiency: novelmutations and clinical variations. Am J Hum Genet. 2000 Feb;66(2):347-55.
Chou JY. Molecular genetics of hepatic methionine adenosyltransferasedeficiency. Pharmacol Ther. 2000 Jan;85(1):1-9. Review.
Finkelstein JD. Inborn errors of sulfur-containing amino acid metabolism. JNutr. 2006 Jun;136(6 Suppl):1750S-1754S. doi: 10.1093/jn/136.6.1750S. Review.
Harvey Mudd S, Braverman N, Pomper M, Tezcan K, Kronick J, Jayakar P, GargantaC, Ampola MG, Levy HL, McCandless SE, Wiltse H, Stabler SP, Allen RH, Wagner C,Borschel MW. Infantile hypermethioninemia and hyperhomocysteinemia due to highmethionine intake: a diagnostic trap. Mol Genet Metab. 2003 May;79(1):6-16.
Luka Z, Capdevila A, Mato JM, Wagner C. A glycine N-methyltransferase knockoutmouse model for humans with deficiency of this enzyme. Transgenic Res. 2006Jun;15(3):393-7.
Luka Z, Cerone R, Phillips JA 3rd, Mudd HS, Wagner C. Mutations in humanglycine N-methyltransferase give insights into its role in methionine metabolism.Hum Genet. 2002 Jan;110(1):68-74.
Luka Z, Wagner C. Effect of naturally occurring mutations in human glycineN-methyltransferase on activity and conformation. Biochem Biophys Res Commun.2003 Dec 26;312(4):1067-72.
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 persistentisolated hypermethioninaemia. J Inherit Metab Dis. 2001 Aug;24(4):448-64.

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Camila Xu

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Update Date: 23 Dec 2020

Table of Contents

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1. Introduction

2. Frequency

3. Causes

4. Inheritance

5. Other Names for This Condition

References

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1. Introduction

2. Frequency

3. Causes

3.1. The genes associated with Hypermethioninemia

4. Inheritance

5. Other Names for This Condition

References