Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the folate and methionine cycles, encoded by the MTHFR gene. These cycles are involved in the conversion of homocysteine to the amino acid methionine using activated folate, 5-methyltetrahydrofolate (5-MTHF) and vitamin B12.

The normal level of homocysteine in healthy people is determined by adequate dietary intake of methionine, folate and vitamin B12. There are, however, common variants (polymorphisms) of the MTHFR gene in up to 20% of some populations, which cause mild to severe dysfunction in the enzyme, resulting in an elevated blood homocysteine level. Smoking, alcohol intake, the modern urban diet, and sedentary habits are also associated with elevated homocysteine.

Elevated homocysteine is a risk factor for cardiovascular disease, thrombosis, dementia and complications in pregnancy. The mechanisms which promote disease are oxidative stress, inflammation, endothelial injury, smooth muscle cell proliferation, and endoplasmic reticulum stress.^1,2

Hyperhomocysteinemia is normally treated with folate (B9) and other B-vitamins (6,12) ; however, folic acid is less effective than treatment with activated folate.³ Furthermore, it is important to identify the presence of any B12 deficiency first, because treatment with folate can mask this deficiency, and also make folate supplementation ineffective, especially when there is a concurrent enzyme variant (methyl-folate trap).⁴

The term folate covers several different forms of the vitamin including the supplement folic acid used to fortify bread, folinic acid, and activated folate found in the blood and common foods. Folic acid is stable and completely available for absorption, while the bioavailability of natural folate found in foods depends on the degree of cooking, phytates and intestinal health. Good sources of folate are spinach, kale, Brussel sprouts, broccoli, legumes, brown rice, brewer’s yeast, peanuts, oranges and liver.

Folate is not only necessary for amino acid metabolism (histidine, serine, glycine, methionine), and vitamin B12 metabolism, but for cell division (DNA). This means any deficiency can affect tissues with rapidly dividing cells such as blood cells, intestinal cells and the foetus.

A folate deficiency is common in pregnancy and can lead to serious health problems for both the mother and child. It also affects conception and couples undergoing IVF who should use activated folate rather than folic acid if they have this MTHFR variant.⁵

Folate and B12 deficiency have symptoms in common, including fatigue, shortness of breath, palpitations, megaloblastic anaemia, glossitis, cheilosis, forgetfulness, apathy, irritability and mood disorders.

References

1.         Esse R, Barroso M, Tavares de Almeida I, Castro R. The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art. Int J Mol Sci 2019;20.

2.         Moretti R, Caruso P. The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice. Int J Mol Sci 2019;20.

3.         Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica 2014;44:480–8.

4.         Gropper, Smith, Groff. Advanced Nutrition And Human Metabolism. 5th ed. Wadsworth: Cengage Learning; 2009.

5.         Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series. J Assist Reprod Genet 2018;35:1431–5.