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MTHFR THERMOLABILE POLYMORPHISM

MedGen UID:
343468
Concept ID:
C1856059
Disease or Syndrome
Synonyms: MTHFR deficiency, thermolabile type; MTHFR Thermolabile Variant
 
OMIM®: 236250

Definition

Methylenetetrahydrofolate Reductase (MTHFR) Deficiency is the most common genetic cause of elevated levels of homocysteine in the plasma (hyperhomocysteinemia). The MTHFR enzyme plays an important role in processing amino acids, specifically, the conversion of homocysteine to methionine. Genetic variations in the MTHFR gene can lead to impaired function or inactivation of this enzyme, which results in mildly elevated levels of homocysteine, especially in individuals who are also deficient in folate. In these individuals, a daily supplement of low dose folic acid may reduce and often normalize their homocysteine levels, but this has not been demonstrated to improve health outcomes. A common genetic variant in the MTHFR gene is a 677C>T polymorphism (NM_005957.4:c.665C>T, rs1801133). This variant encodes a thermolabile enzyme that is less active at higher temperatures. Individuals who carry two copies of this variant (“TT homozygous”) tend to have higher homocysteine levels and lower serum folate levels compared to controls. More than 25% of Hispanics and around 10-15% of North America Caucasians are estimated to be homozygous for the “thermolabile” variant (TT genotype). The TT genotype is least common in individuals of African descent (6%). Another common MTHFR variant, 1298A>C (NM_005957.4:c.1286A>C, rs1801131), does not cause increased homocysteine levels in heterozygous or homozygous individuals, but combined heterozygosity of 1298A>C and 677C>T results in an outcome similar to TT homozygous individuals. Until recently, it was thought that MTHFR deficiency, by causing elevated homocysteine levels, led to an increased risk of venous thrombosis, coronary heart disease, and recurrent pregnancy loss. However, more recent analysis has not found an association between elevated homocysteine levels and the risk of venous thrombosis or the risk of coronary heart disease. MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia, recurrent pregnancy loss, or for at-risk family members. Rarely, more severe variants in the MTHFR gene can be a cause of an autosomal recessive inborn error or metabolism where extremely high levels of homocysteine accumulate in the urine and plasma. This can cause developmental delay, eye disorders, thrombosis, and osteoporosis. But more commonly, homocystinuria is caused by variants in a different gene (cystathionine beta-synthase, CBS). [from Medical Genetics Summaries]

Professional guidelines

PubMed

Brockton NT
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Recent clinical studies

Etiology

Vieira MJ, Campos A, do Carmo A, Arruda H, Martins J, Sousa JP
Sci Rep 2019 Dec 12;9(1):18972. doi: 10.1038/s41598-019-55456-5. PMID: 31831825Free PMC Article
Fekih-Mrissa N, Mrad M, Ibrahim H, Akremi I, Sayeh A, Jaidane A, Ouertani H, Zidi B, Gritli N
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Li D, Zhou M, Peng X, Sun H
BMC Ophthalmol 2014 Nov 27;14:147. doi: 10.1186/1471-2415-14-147. PMID: 25428529Free PMC Article
Lok A, Bockting CL, Koeter MW, Snieder H, Assies J, Mocking RJ, Vinkers CH, Kahn RS, Boks MP, Schene AH
Transl Psychiatry 2013 Jul 30;3(7):e288. doi: 10.1038/tp.2013.60. PMID: 23900311Free PMC Article
Lewis SJ, Lawlor DA, Davey Smith G, Araya R, Timpson N, Day IN, Ebrahim S
Mol Psychiatry 2006 Apr;11(4):352-60. doi: 10.1038/sj.mp.4001790. PMID: 16402130

Diagnosis

Vieira MJ, Campos A, do Carmo A, Arruda H, Martins J, Sousa JP
Sci Rep 2019 Dec 12;9(1):18972. doi: 10.1038/s41598-019-55456-5. PMID: 31831825Free PMC Article
Azimova JE, Sergeev AV, Korobeynikova LA, Kondratieva NS, Kokaeva ZG, Shaikhaev GO, Skorobogatykh KV, Fokina NM, Tabeeva GR, Klimov EA
BMC Neurol 2013 Aug 5;13:103. doi: 10.1186/1471-2377-13-103. PMID: 23915182Free PMC Article
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Clin Exp Med 2009 Dec;9(4):327-31. Epub 2009 May 30 doi: 10.1007/s10238-009-0054-0. PMID: 19484352
Lewis SJ, Lawlor DA, Davey Smith G, Araya R, Timpson N, Day IN, Ebrahim S
Mol Psychiatry 2006 Apr;11(4):352-60. doi: 10.1038/sj.mp.4001790. PMID: 16402130
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Therapy

Li D, Zhou M, Peng X, Sun H
BMC Ophthalmol 2014 Nov 27;14:147. doi: 10.1186/1471-2415-14-147. PMID: 25428529Free PMC Article
Lok A, Bockting CL, Koeter MW, Snieder H, Assies J, Mocking RJ, Vinkers CH, Kahn RS, Boks MP, Schene AH
Transl Psychiatry 2013 Jul 30;3(7):e288. doi: 10.1038/tp.2013.60. PMID: 23900311Free PMC Article
Powers HJ
J Nutr 2005 Dec;135(12 Suppl):2960S-2966S. doi: 10.1093/jn/135.12.2960S. PMID: 16317155
Perry IJ
J Hum Hypertens 1999 May;13(5):289-93. doi: 10.1038/sj.jhh.1000803. PMID: 10376845
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Prognosis

Vieira MJ, Campos A, do Carmo A, Arruda H, Martins J, Sousa JP
Sci Rep 2019 Dec 12;9(1):18972. doi: 10.1038/s41598-019-55456-5. PMID: 31831825Free PMC Article
Catalano D, Trovato GM, Ragusa A, Martines GF, Tonzuso A, Pirri C, Buccheri MA, Trovato FM
Eur Rev Med Pharmacol Sci 2014;18(2):151-9. PMID: 24488901
Lok A, Bockting CL, Koeter MW, Snieder H, Assies J, Mocking RJ, Vinkers CH, Kahn RS, Boks MP, Schene AH
Transl Psychiatry 2013 Jul 30;3(7):e288. doi: 10.1038/tp.2013.60. PMID: 23900311Free PMC Article
Alam MA, Husain SA, Narang R, Chauhan SS, Kabra M, Vasisht S
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Perry IJ
J Hum Hypertens 1999 May;13(5):289-93. doi: 10.1038/sj.jhh.1000803. PMID: 10376845

Clinical prediction guides

Vieira MJ, Campos A, do Carmo A, Arruda H, Martins J, Sousa JP
Sci Rep 2019 Dec 12;9(1):18972. doi: 10.1038/s41598-019-55456-5. PMID: 31831825Free PMC Article
Del Gobbo GF, Price EM, Hanna CW, Robinson WP
Clin Epigenetics 2018;10:34. Epub 2018 Mar 13 doi: 10.1186/s13148-018-0468-1. PMID: 29564022Free PMC Article
Azimova JE, Sergeev AV, Korobeynikova LA, Kondratieva NS, Kokaeva ZG, Shaikhaev GO, Skorobogatykh KV, Fokina NM, Tabeeva GR, Klimov EA
BMC Neurol 2013 Aug 5;13:103. doi: 10.1186/1471-2377-13-103. PMID: 23915182Free PMC Article
Lok A, Bockting CL, Koeter MW, Snieder H, Assies J, Mocking RJ, Vinkers CH, Kahn RS, Boks MP, Schene AH
Transl Psychiatry 2013 Jul 30;3(7):e288. doi: 10.1038/tp.2013.60. PMID: 23900311Free PMC Article
Lewis SJ, Lawlor DA, Davey Smith G, Araya R, Timpson N, Day IN, Ebrahim S
Mol Psychiatry 2006 Apr;11(4):352-60. doi: 10.1038/sj.mp.4001790. PMID: 16402130

Recent systematic reviews

Li D, Zhou M, Peng X, Sun H
BMC Ophthalmol 2014 Nov 27;14:147. doi: 10.1186/1471-2415-14-147. PMID: 25428529Free PMC Article
Lewis SJ, Lawlor DA, Davey Smith G, Araya R, Timpson N, Day IN, Ebrahim S
Mol Psychiatry 2006 Apr;11(4):352-60. doi: 10.1038/sj.mp.4001790. PMID: 16402130

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