Methylenetetrahydrofolate reductase deficiency

Methylenetetrahydrofolate reductase deficiency is the most common genetic cause of elevated serum levels of homocysteine (hyperhomocysteinemia). It is caused by genetic defects in MTHFR, which is an important enzyme in the methyl cycle.[1]

Methylenetetrahydrofolate reductase deficiency
Other namesMTHFR

Common variants of MTHFR deficiency are asymptomatic and have only minor effects on disease risk.[2] Severe variants (from nonsense mutations) are vanishingly rare.[3]


The common MTHFR deficiencies are usually asymptomatic, although the 677T variant can cause a mildly increased risk of some diseases.

For individuals homozygous in the 677T variant, there is a mildly elevated risk of thromboembolism (odds ratio 1.2),[4] and stroke (odds ratio 1.26).[5] There is also an elevated risk of neural tube defects among children of individuals with the C677T polymorphism (odds ratio 1.38).[6]

For cardiovascular risk, common MTHFR deficiencies were once thought to be associated but meta-analyses indicate that correlation this was an artifact of publication bias.[clarification needed][7][8]


MTHFR is the rate-limiting enzyme in the methyl cycle, which includes the conversion of homocysteine into methionine. Defects in variants of MTHFR can therefore lead to hyperhomocysteinemia.[9]

There are two common variants of MTHFR deficiency. In the more significant of the two, the individual is homozygous for the 677T polymorphism. This variant in particular is the most common genetic cause of hyperhomocysteinemia.[9] The resulting enzyme is thermolabile and in homozygotes, enzymatic activity is depressed to 35% of its usual level.[10] The second variant is a milder one, caused by a homologous 1298C polymorphism. This leads to 68% of the control values of enzyme activity,[10] and it normally does not lead to low serum folate.[9]


MTHFR deficiency is diagnosed by genetic testing.


In common forms of MTHFR deficiency, elevated plasma homocysteine levels have sometimes been treated with Vitamin B12 and low doses of folic acid.[2] Although this treatment significantly decreases the serum levels of homocysteine, this treatment is not thought to improve health outcomes.[11][12][13]

Due to the ineffectiveness of these treatments, it was no longer considered clinically useful to test for MTHFR in most cases of thrombophilia or recurrent pregnancy loss.[14][15] A more recent evaluation from a case series recommends testing for MTHFR in case of long lasting impaired fertility and repeat miscarriages.[citation needed] Treatment with high doses of folic acid (5 mg/day) are deemed unsuitable for MTHFR isoform carriers, who could alternatively be treated with the metabolically active form, 5-methyltetrahydrofolate.[16] 5-MTHF was shown to induce significantly higher plasma folate concentrations compared to folic acid in homozygous MTHFR mutation carriers in this case series.[citation needed]

A different study corroborates these results and suggests a physiological dose (800 μg) of 5-methyltetrahydrofolate can bypass MTHFR C677T and A1298C isoforms in couples with fertility problems.[16] This treatment with 5-MTHF also avoids un-metabolized folic acid syndrome, which can occur with folic acid intakes of 5 mg per day.[16]


Whether MTHFR deficiency has any effect at all on all-cause mortality is unclear. One Dutch study showed that the MTHFR mutation was more prevalent in younger individuals (36% relative to 30%), and found that elderly men with MTHFR had an elevated mortality rate, attributable to cancer. Among women, however, no difference in life expectancy was seen.[17] More recently, however, a meta-analysis has shown that overall cancer rates are barely increased with an odds ratio of 1.07, which suggests that an impact on mortality from cancer is small or zero.[18]


The prevalence of 677T homozygosity varies with race. 18-21% of Hispanics and Southern Mediterranean populations have this variant, as do 6-14% of North American Whites and <2% of Blacks living outside of Africa. [9]

The prevalence of the 1298C mutation is lower, at 4-12% for most tested populations.[9]

A study in 2000 had identified only 24 cases of severe MTHFR deficiency (from nonsense mutations) across the whole world.[3]

See alsoEdit


  1. ^ Goyette, Philippe; Summer, J. S.; Milos, Renate; others (1994). "Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation". Nat Genet. 7 (2): 195–200. doi:10.1038/ng0694-195. PMID 7920641.
  2. ^ a b Dean L (2012). "Methylenetetrahydrofolate Reductase Deficiency". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520345. Bookshelf ID: NBK66131.
  3. ^ a b Sibani, Sahar; Christensen, Benedicte; O'Ferrall, Erin; Saadi, Irfan; Hiou-Tim, Francois; Rosenblatt, David S.; Rozen, Rima (2000). "Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria". Human Mutation. 15 (3): 280–7. doi:10.1002/(SICI)1098-1004(200003)15:3<280::AID-HUMU9>3.0.CO;2-I. PMID 10679944.
  4. ^ Den Heijer, M.; Lewington, S.; Clarke, R. (2005). "Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies". Journal of Thrombosis and Haemostasis. 3 (2): 292–299. doi:10.1111/j.1538-7836.2005.01141.x. PMID 15670035.
  5. ^ Casas, Juan P.; Bautista, Leonelo E.; Smeeth, Liam; Sharma, Pankaj; Hingorani, Aroon D. (2005). "Homocysteine and stroke: evidence on a causal link from mendelian randomisation". The Lancet. 365 (9455): 224–232. doi:10.1016/S0140-6736(05)70152-5.
  6. ^ Liu, T. C.; Wang, Z. P.; Zhao, Z. T. (2011). Meta analysis on the association between parental 5, 10-methylenetetrahydrofolate reductase C677T polymorphism and the neural tube defects of their offspring.
  7. ^ Clarke, Robert; Bennett, Derrick A.; Parish, Sarah; Verhoef, Petra; Datsch-Klerk, Mariska; Lathrop, Mark; Xu, Peng; Nordestgaard, Barge G.; Holm, Hilma; Hopewell, Jemma C.; others (2012). "Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias". PLoS Med. 9 (2).
  8. ^ Van Meurs, Joyce BJ; Pare, Guillaume; Schwartz, Stephen M.; Hazra, Aditi; Tanaka, Toshiko; Vermeulen, Sita H.; Cotlarciuc, Ioana; Yuan, Xin; Mlarstig, Anders; Bandinelli, Stefania; others (2013). "Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease". The American Journal of Clinical Nutrition. 98 (3): 668–676. doi:10.3945/ajcn.112.044545. PMC 4321227. PMID 23824729.
  9. ^ a b c d e Leclerc, Daniel; Sibani, Sahar; Rozen, Rima (2013). "Molecular biology of methylenetetrahydrofolate reductase (MTHFR) and overview of mutations/polymorphisms". Cite journal requires |journal= (help)
  10. ^ a b Weisberg, Ilan; Tran, Pamela; Christensen, Benedicte; Sibani, Sahar; Rozen, Rima (1998). "A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity". Molecular Genetics and Metabolism. 64 (3): 169–72. doi:10.1006/mgme.1998.2714. PMID 9719624.
  11. ^ Guttormsen, Anne Berit; Ueland, Per Magne; Nesthus, Ingerid; Nyg\a ard, Ottar; Schneede, Jarn; Vollset, Stein Emil; Refsum, Helga (1996). "Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or= 40 micromol/liter). The Hordaland Homocysteine Study". Journal of Clinical Investigation. 98 (9): 2174–2183. doi:10.1172/JCI119024. PMC 507663. PMID 8903338.
  12. ^ Clarke, Robert; Halsey, Jim; Lewington, Sarah; Lonn, Eva; Armitage, Jane; Manson, Joann E.; Banaa, Kaare H.; Spence, J. David; Nyg\a ard, Ottar; Jamison, Rex; others (2010). "Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals". Archives of Internal Medicine. 170 (18): 1622–1631. doi:10.1001/archinternmed.2010.348. PMID 20937919.
  13. ^ Clarke, Robert; Bennett, Derrick; Parish, Sarah; Lewington, Sarah; Skeaff, Murray; Eussen, Simone JPM; Lewerin, Catharina; Stott, David J.; Armitage, Jane; Hankey, Graeme J.; others (2014). "Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals". The American Journal of Clinical Nutrition. 100 (2). doi:10.3945/ajcn.113.076349.
  14. ^ Hickey, Scott E.; Curry, Cynthia J.; Toriello, Helga V. (2013). "ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing". Genetics in Medicine. 15 (2): 153–156. doi:10.1038/gim.2012.165. PMID 23288205.
  15. ^ Traci Pantuso, N. D. "MTHFR Clinical Considerations: A Review". Cite journal requires |journal= (help)
  16. ^ a b c Servy, Edouard J.; Jacquesson-Fournols, Laetitia; Cohen, Marc; Menezo, Yves J. R. (August 2018). "MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series". Journal of Assisted Reproduction and Genetics. 35 (8): 1431–1435. doi:10.1007/s10815-018-1225-2. ISSN 1058-0468. PMC 6086798. PMID 29882091.
  17. ^ Heijmans, Bastiaan T.; Gussekloo, Jacobijn; Kluft, Cornelis; Droog, Simone; Lagaay, A. Margot; Knook, Dick L.; Westendorp, Rudi GJ; Slagboom, Eline P. (1999). "Mortality risk in men is associated with a common mutation in the methylenetetrahydrofolate reductase gene(MTHFR)". European Journal of Human Genetics. 7 (2): 197–204. doi:10.1038/sj.ejhg.5200283. PMID 10196703.
  18. ^ Zacho, Jeppe; Yazdanyar, Shiva; Bojesen, Stig E.; Tybja erg-Hansen, Anne; Nordestgaard, Barge G. (2011). "Hyperhomocysteinemia, methylenetetrahydrofolate reductase c. 677C> T polymorphism and risk of cancer: Cross-sectional and prospective studies and meta-analyses of 75,000 cases and 93,000 controls". International Journal of Cancer. 128 (3): 644–652. doi:10.1002/ijc.25375. PMID 20473868.

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