How do MTHFR Mutations Affect B Vitamin Metabolism?

B vitamin metabolism, which primarily involves the conversion of folate and vitamin B12 into their active forms, is essential for optimal human health. This complex biochemical process is regulated by several enzymes, including the methylenetetrahydrofolate reductase (MTHFR) enzyme.

MTHFR variants are genetic “mutations” that can disrupt the metabolism of folate and other B vitamins, leading to increased levels of homocysteine in the blood. High homocysteine levels have been linked to numerous health issues, including heart disease, stroke, and cognitive decline. Therefore, understanding MTHFR variants and their impact on B vitamin metabolism is crucial for personalized health management and disease prevention.

Before I dive in to the meat of this post, it is worth noting that the MTHFR polymorphisms I discuss here are common. If you carry one of these MTHFR variants, especially two copies, it is worth discussing a homocysteine test with your physician, but don’t stress. MTHFR “mutations,” standing alone, do not cause symptoms, and most sites claiming otherwise have a supplement to sell.

MTHFR variations affect B6, B12 and B9 metabolism only.

There are many different B vitamins, and each one plays an important role in the body. However, not all B vitamins are affected by the MTHFR genes. The common MHTFR variations can affect vitamins B6, B12, and folate, whereas vitamins B1, B2, B3, B5, and B7 are not affected by the MTHFR variations.

B vitamins in a nutshell

1. Thiamine (B1): Helps in the metabolism of carbohydrates, proteins, and fats.
2. Riboflavin (B2): Helps in the production of energy, nerve functioning, and overall cell growth.
3. Niacin (B3): Helps in the production of energy, brain functioning, and skin health.
4. Pantothenic acid (B5): Helps in the production of energy, hormone synthesis, and red blood cell formation.
5. Pyridoxine (B6): Helps in the production of energy, protein metabolism, and nervous system functioning.
6. Biotin (B7): Helps in the metabolism of carbohydrates and fatty acids, and overall skin and hair health.
7. Folate (B9): Helps in the production of DNA, cell growth and replication, and red blood cell formation.
8. Cobalamin (B12): Helps in the production of nerve cells, DNA synthesis, and red blood cell formation.

For more, see: What Each B Vitamin Does

How is folate (B9) metabolism disrupted in a person with MTHFR variations?

The recommended intake of folate is not always met, particularly among women of childbearing age and non-Hispanic Black women. An in-depth analysis indicates that 19% of female adolescents aged 14 to 18 years and 17% of women aged 19 to 30 years do not meet their folic acid intakes. These numbers are even more significant for non-Hispanic black women, with 23% having inadequate total intakes, compared to 13% for non-Hispanic white women.1

As mentioned previously, MTHFR is an enzyme that is involved in the metabolism of folate. MTHFR also helps generate 5-methyltetrahydrofolate (5-MTHF) from 5,10-methylenetetrahydrofolate (5,10-MTHF), which is the active form of folate that is needed for DNA synthesis and methylation reactions.

As I discussed above, the main issue with MTHFR variants and folate is the degradation of the body’s pathway that clears homocysteine.

How is vitamin B6 is affected by MTHFR variants?

Unlike folate, most of us get enough vitamin B6 in our diets.

Based on data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES), vitamin B6 intake is generally adequate among adults, adolescents, and children in the United States. The average figure is approximately 1.5 mg/day for women and 2 mg/day for men.2

Vitamin B6 is a co-factor (helper) in many biochemical reactions. A person with MTHFR variants may experience disruptions in the metabolism of vitamin B6 because of the impaired conversion of pyridoxine (vitamin B6) to its active form pyridoxal 5′-phosphate (PLP).

PLP is central to several processes in the body

PLP is required for many important reactions in the body, including:

•         Amino acid metabolism: PLP is a cofactor for several enzymes involved in the metabolism of amino acids, such as tryptophan, cysteine, and histidine.
•         Homocysteine metabolism: Homocysteine is an amino acid that can be converted to methionine with the help of PLP. If PLP levels are low due to MTHFR variations, homocysteine accumulation may occur, which can increase the risk of cardiovascular disease.
•         Neurotransmitter synthesis: PLP is essential for the synthesis of neurotransmitters such as serotonin, dopamine, and gamma-aminobutyric acid (GABA).
•         Glycogenolysis: PLP is required for the breakdown of glycogen, the storage form of glucose in the liver and muscle tissue.

PLP concentrations tend to be low in people with alcohol dependence; those with obesity; and pregnant people, especially those with preeclampsia or eclampsia. They are also low in people with malabsorption syndromes such as celiac disease, Crohn’s disease, and ulcerative colitis.2

The 2003 – 2004 NHANES analysis demonstrated that 11% of Vitamin B6 supplement users and 24% of individuals in the United States who do not take Vitamin B6 supplements have plasma PLP concentrations below 20 nmol/L. Furthermore, it found low plasma PLP levels among supplement users and non-users alike, more so in women than in men, non-Hispanic blacks than whites, current smokers than never smokers, and those classified as underweight relative to normal weight.2

Teenagers had the lowest concentrations followed by 21–44 year olds with elderly people having levels that were not particularly low even without supplement intake. In light of these findings, it may be necessary to reexamine the current RDAs for adequate Vitamin B6 status in many population groups especially since MTHFR mutations affect B6 metabolism so significantly.

Therefore, disruptions in PLP synthesis in a person with MTHFR variations may lead to issues with amino acid metabolism, homocysteine levels, and neurotransmitter synthesis, as well as glycogenolysis. These disruptions may contribute to (although not solely responsible for) various pathological conditions such as depression, anxiety, cardiovascular disease, and metabolic disorders such as type 2 diabetes.

How is vitamin B12 is affected by MTHFR variants?

Vitamin B12 is an essential nutrient that is needed in the human body for the proper functioning of the nervous system and the production of DNA. It is also needed for the formation of red blood cells and can be found in animal products such as meat, fish, and dairy products.

The 2015-2016 National Health and Nutrition Examination Survey uncovered that those with low socioeconomic status, women, and non-Hispanic Blacks are more likely to have insufficient vitamin B12 intake. Both the United States and United Kingdom have seen 6% of individuals under 60 experiencing Vitamin B12 deficiency, however this number goes up to 20% for those over sixty. Pregnant women may notice a decline in their serum vitamin B12 levels; it is typical for them to return to normal postpartum.3 Several factors are associated with vitamin B12 deficiency including lifestyle, genetic predisposition, and malfunctions in the absorption and transport of vitamin B12 (i.e. presence of MTHFR variations).

MTHFR controls methylation, a process that is an essential for the regulation of gene expression, the processing of neurotransmitters, and the metabolism of certain nutrients, including folate and vitamin B12.

The MTHFR C677T variation has been associated with decreased activity of the enzyme and reduced levels of vitamin B12 in the blood. This occurs because the MTHFR enzyme plays a crucial role in the conversion of homocysteine to methionine. A decrease in MTHFR enzyme activity leads to an increase in homocysteine levels, which can negatively impact the absorption and utilization of vitamin B12 in the body.

MTHFR A1298C variation has also been associated with decreased MTHFR enzyme activity, which can impact the body’s ability to metabolize vitamin B12. However, the impact of this variation on vitamin B12 levels is not as well established as the C677T variation.

Bottom Line

In summary, MTHFR variations can affect the body’s ability to metabolize folate, leading to a deficiency of vitamin B6, among other B vitamins, and can also impact the conversion of homocysteine to methionine. This can have a number of negative health effects, highlighting the importance of identifying and managing MTHFR gene variations.

To compensate for reduced MTHFR activity, individuals with MTHFR variations may need to consume more folate and/or take supplements of 5-MTHF. However, not everyone with MTHFR variations will have the same symptoms or health consequences, as other genetic and environmental factors can also influence folate metabolism. Therefore, it is important for individuals with MTHFR variations to work with a healthcare provider who can help them understand how their genetics may be affecting their health and develop an appropriate treatment plan.