What is an MTHFR mutation

The words MTHFR gene mutation ought not scare you, though they may sound a bit complicated at first. It's easy to understand the basics and what to do about it in practice, and we hope this article will help you to do so.

MTHFR is the abbreviation for an enzyme whose activity is reduced by various gene mutations. There are several types of mutations and depending on which one you have, the activity of the enzyme is reduced to different degrees. These mutations can affect the metabolism of folate (vitamin B9) and its conversion to its active form (methyl folate/5-MTHF) within the body may be slowed down.

As a consequence, an amino acid, homocysteine, may accumulate in the body, as a reduced amount of circulating methyl folate is less efficient in converting it back to methionine. Homocysteine may already be familiar from other articles, along with the fact that high levels of it increase the risk of several chronic diseases. (1) It follows that different MTHFR mutations thus also increase the risk of the same diseases, although this varies considerably from country to country. More on the reasons for this later... (2)

What is the solution?

Many people suggest supplementing with extra methylfolate (5-MTHF) in an attempt to get around the need to produce less methylfolate. This form can already be used by the body without conversion, so it can be used to supplement what it otherwise produces too little of. This is definitely a good idea, especially if a person's folate intake is already low. Folate helps the MTHFR enzyme to function, so that people with better folate intake have lower homocysteine levels even if they have the mutations. (3,4)

The problem is that because this metabolic cycle occurs many times a day, those individuals with the most reduced MTHFR activity need to supplement huge amounts of extra methyl folate to compensate for this enzyme defect alone. For this reason, it is precisely in individuals with MTHFR mutations that methylfolate supplementation is least effective in reducing homocysteine levels. (5)

Thus, methylfolate supplementation is a good idea to improve folate supply and can reduce homocysteine, but at such unfeasibly high doses (several milligrams), no form of folate is safe for long-term use, as excessive folate intake may increase the risk of certain diseases. (6,7) Fortunately, however, there is another strategy that restores enzyme function itself, rather than compensating for reduced enzyme activity by supplementing the end product separately.

Where does riboflavin (vitamin B2) come into the picture?

MTHFR mutations cause a decrease in the activity of the MTHFR enzyme. Why does this decrease occur? Because it makes the enzyme less able to bind to the riboflavin-containing FAD. (8) FAD is short for one of the coenzymes that is produced from riboflavin and is partly responsible for its health effects. MTHFR is therefore a riboflavin-dependent enzyme, and the less riboflavin available, the less functional it becomes.

Is it possible that higher riboflavin intake can compensate for this enzyme defect, saturating the enzyme with FAD and thus, with adequate riboflavin supply, the "dreaded" MTHFR mutations may even be beneficial?

Several researchers have already recognised this link and have tested this hypothesis in their research. Their results provide pretty clear evidence that riboflavin supply is perhaps the most important factor,and one which is poorly understood in the context of MTHFR mutations. 

What research supports this hypothesis?

A 2014 study summarises in some detail the role of riboflavin in MTHFR mutations as described above, and has successfully validated the theory in practice. (8) Their study tested 771 Spanish adults for riboflavin and folate intake, homocysteine levels and whether they had the MTHFR 677CT mutation.

These data showed that people with the MTHFR 677CT mutation had high homocysteine levels only if they had low riboflavin levels. Thus, individuals with a high riboflavin intake did not have elevated homocysteine levels, so that the reduction in MTHFR enzyme function was fully compensated for by higher riboflavin intake.

Moreover, this was independent of the folate intake of the participants, since even those who were otherwise low in folate did not have elevated homocysteine levels, provided that their riboflavin intake was adequate.

In a previous study, supplementation with 1.6 mg of riboflavin per day reduced homocysteine levels by 22% in riboflavin-deficient individuals with the MTHFR 677 TT mutation. (9) (They have the lowest enzyme activity.) This is the average, but even a 40% reduction was measured in certain individuals. The 1.6 mg of riboflavin supplemented is the current officially recommended daily intake, but it is likely that a higher dose would have been more effective. Riboflavin supplementation has no known adverse effects even at much higher doses, and absorption is excellent up to 30 mg. (10)

As mentioned at the beginning of this study, a 25% reduction in homocysteine would reduce the risk of certain cardiovascular diseases, which are the leading causes of death in the world today, by about 15-25%. The above reduction could be achieved by a cheap supplement for this vulnerable group, if they knew about it.

Evolutionary and modern context of riboflavin and MTHFR mutations

Since a significant proportion of the population has one of the MTHFR mutations, it is unlikely that the mutation itself would pose a major health risk, as the carriers would have become extinct long ago. Consider that we humans, as a result of another gene mutation, have become unable to produce vitamin C compared to most animals, partly because we have consumed so much vitamin C-rich food that we no longer need to produce it. It also gave us an evolutionary advantage, because the production of vitamin C also produces a reactive hydrogen peroxide molecule that must then be neutralized, so 'self-produced' vitamin C is worse for our antioxidant system than replacing it from an external source. (11)

It is conceivable that MTHFR mutations may have evolved to enable us to better regulate folate levels, as there can be benefits to both too much and too little, but with adequate riboflavin intake this may be more of an upside: in the past, even those with the mutations consumed enough folate and riboflavin (or vitamin B12, vitamin B6, choline, etc.) so this was not a problem.

However, nowadays, when people eat little riboflavin-rich food and their intake of the other cofactors mentioned is low, MTHFR mutations can cause a lot of problems.

What about the modern diet?

The best sources of riboflavin are foods that people generally don't eat very much: liver and other animal organs, almonds and seaweed. At present, most people get most of their riboflavin from dairy products, but the consumption of dairy products is also declining. What is the origin of the general belief that riboflavin consumption is not a concern and that most people consume enough?

There are several reasons for this, which are beyond the scope of this article, but the two main reasons in brief are that many studies have wrongly identified what were then considered to be adequate levels of riboflavin as in fact already being slightly deficient, and that much of the research comes from the USA, where there is a long history of riboflavin fortification of flour and where people still consume a lot of flour. (12) The riboflavin intake of people in the USA is therefore on average much higher than that of European residents.

As shown in the Spanish study, the riboflavin intake of Europeans, especially young people, is much lower than that of US residents. According to the EGRAC test used in the Spanish study, more than one third of people are not adequately supplied. This is particularly true for people with MTHFR mutations, as they need more riboflavin. (12)

What diseases are affected by MTHFR mutations and does riboflavin help?

A 2002 meta-analysis of the association of MTHFR mutations with the risk of cardiovascular disease also supports our reasoning thus far. (12) In the US, where riboflavin has been added to flour for decades, the presence of the MTHFR TT polymorphism not only did not increase cardiovascular risk, but was found to be protective in 8 of the 11 studies included, whereas in Europe, where it was not, it was a significant risk factor in 18 of the 23 studies included.

The meta-analysis points out that this difference is probably attributed to folate intake, but this is unlikely: only since 1998 has folic acid been added to flour in the US, and most of the studies included were done years ago. And why would dietary folate intake have been higher than in Europe?

Since then there have been several studies on the relationship between MTHFR mutations, riboflavin and cardiovascular disease. Two of these review studies have found that in the case of the mutation mentioned several times (MTHFR TT), riboflavin supplementation alone resulted in a huge reduction in blood pressure of 5-13 millimetres of mercury, without the concomitant use of any antihypertensive drugs. (15,16) This information could prolong the lives of many.

What is also very important, and has been pointed out by the researchers, is that many people in developed countries also have mild riboflavin deficiency, but are unaware of it because they rarely have their levels measured.

A randomized trial in 2020 also showed that riboflavin supplementation not only affects homocysteine, but also normalises levels of substances such as SAM-e, which also play an important role in methylation, and this may be the reason for its antihypertensive effects. (17)

What about other diseases?

Two other links support the above claims.  The first is a 2004 study in which MTHFR mutations and B vitamin intake alone had no significant effect on bone density, but when only the TT mutation was examined, higher riboflavin intake resulted in significantly higher bone density. (18)

The other link is that MTHFR mutations also increase the risk of migraine. (19) Which mutation increases the risk of migraine the most? The TT mutation, mentioned several times, is the one that most decreases the activity of the enzyme and most increases the body's need for riboflavin.

Which micronutrient supplementation has been shown to be highly effective in the treatment of migraine? Yes, also riboflavin, and in high doses, which quickly eliminates the deficiency. (See our separate post on the topic). (20)

Interesting facts

Riboflavin is easily degraded by light, which is why milk is no longer sold in clear bottles. However, it is not significantly reduced by heat treatment, so if you want to preserve the riboflavin content of your food, you can heat-treat it, but keep the exposure to sunlight to a minimum. (21)

Summary and practical recommendations

• The negative effects associated with MTHFR mutations, such as higher homocysteine levels, only occur in individuals with inadequate riboflavin supply.

• With higher riboflavin intake or supplementation of 5-15 mg of riboflavin per day, the MTHFR enzyme can be saturated with FAD and the enzyme can then resume its function. It is safe to supplement this amount of riboflavin without doing a genetic test, the only drawback is that it may cause yellow urine, but it is safe at higher doses. 
• Other substances important for methylation, such as adequate protein intake, vitamins B6, B9, B12, choline, creatine, glycine, should also be taken into account.