Methylenetetrahydrofolate reductase deficiency

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Methylenetetrahydrofolate reductase deficiency
Other namesMTHFR 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]

Contents

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

Symptoms and signs

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

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]

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

Causes

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]

Diagnosis

MTHFR deficiency is diagnosed by genetic testing.[ citation needed ]

Management

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]

Prognosis

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]

Epidemiology

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 also

Related Research Articles

<span class="mw-page-title-main">Folate</span> Vitamin B9; nutrient essential for DNA synthesis

Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.

<span class="mw-page-title-main">Homocysteine</span> Chemical compound

Homocysteine or Hcy: is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the body, homocysteine can be recycled into methionine or converted into cysteine with the aid of vitamin B6, B9, and B12.

<i>S</i>-Adenosyl methionine Chemical compound found in all domains of life with largely unexplored effects

S-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver. More than 40 methyl transfers from SAM are known, to various substrates such as nucleic acids, proteins, lipids and secondary metabolites. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase. SAM was first discovered by Giulio Cantoni in 1952.

<span class="mw-page-title-main">Homocystinuria</span> Disorder of amino acid metabolism

Homocystinuria (HCU) is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected. Symptoms of homocystinuria can also be caused by a deficiency of vitamins B6, B12, or folate.

<span class="mw-page-title-main">Methylenetetrahydrofolate reductase</span> Rate-limiting enzyme in the methyl cycle

Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Natural variation in this gene is common in otherwise healthy people. Although some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer's disease and other forms of dementia, colon cancer, and acute leukemia, findings from small early studies have not been reproduced. Some mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency. Complex I deficiency with recessive spastic paraparesis has also been linked to MTHFR variants. In addition, the aberrant promoter hypermethylation of this gene is associated with male infertility and recurrent spontaneous abortion.

<span class="mw-page-title-main">Methionine synthase</span> Mammalian protein found in Homo sapiens

Methionine synthase (MS, MeSe, MTR) is primarily responsible for the regeneration of methionine from homocysteine in most individuals. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.

<span class="mw-page-title-main">Neural tube defect</span> Group of birth defects of the brain or spinal cord

Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo begin to change shape and form the neural tube. When the neural tube does not close completely, an NTD develops.

<span class="mw-page-title-main">Hyperhomocysteinemia</span> Medical condition

Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of total homocysteine in the blood, conventionally described as above 15 μmol/L.

<span class="mw-page-title-main">Folate deficiency</span> Abnormally low level of folate (vitamin B9) in the body

Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. This may result in megaloblastic anemia in which red blood cells become abnormally large, and folate deficiency anemia is the term given for this medical condition. Signs of folate deficiency are often subtle. Symptoms may include fatigue, heart palpitations, shortness of breath, feeling faint, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. Temporary reversible infertility may occur. Folate deficiency anemia during pregnancy may give rise to the birth of low weight birth premature infants and infants with neural tube defects.

<span class="mw-page-title-main">Cystathionine beta synthase</span> Mammalian protein found in humans

Cystathionine-β-synthase, also known as CBS, is an enzyme (EC 4.2.1.22) that in humans is encoded by the CBS gene. It catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine:

<span class="mw-page-title-main">Levomefolic acid</span> Chemical compound

Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6S)-5-methyltetrahydrofolate, and (6S)-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine. It is also the form found in circulation and transported across membranes into tissues and across the blood–brain barrier. In the cell, L-methylfolate is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). THF is the immediate acceptor of one carbon unit for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine. The un-methylated form, folic acid (vitamin B9), is a synthetic form of folate, and must undergo enzymatic reduction by dihydrofolate reductase (DHFR) to become biologically active.

<span class="mw-page-title-main">MTRR (gene)</span> Protein-coding gene in the species Homo sapiens

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References

  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. S2CID   23877329.
  2. 1 2 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. 1 2 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. S2CID   25475434.
  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): e1001177. doi: 10.1371/journal.pmed.1001177 . PMC   3283559 . PMID   22363213.
  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. 1 2 3 4 5 Leclerc, Daniel; Sibani, Sahar; Rozen, Rima (2013). "Molecular biology of methylenetetrahydrofolate reductase (MTHFR) and overview of mutations/polymorphisms".{{cite journal}}: Cite journal requires |journal= (help)
  10. 1 2 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): 657–666. doi: 10.3945/ajcn.113.076349 . PMC   4095663 . PMID   24965307.
  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}}: Cite journal requires |journal= (help)
  16. 1 2 3 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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