MTHFR: what is established about the gene variant — and what is not

The short answer: MTHFR is an enzyme in folate metabolism, and a common variant of its gene lowers that enzyme's activity. What is established is that carriers have, on average, somewhat higher homocysteine levels — above all when the folate supply is scarce to begin with. What is not established is that any particular need for a specific form of folate follows from this. Testing is not recommended for the general population. The variant is not a disease but a normal variant, carried in duplicate by about one in ten Europeans.

The reason this topic is so charged lies less in the research than in the selling: a genetic test can be sold, a finding creates pressure to act, and that pressure leads to a more expensive preparation. The evidence does not support this chain at its decisive link.

What the enzyme does

Folate is converted several times in the body before it can do its jobs. Methylenetetrahydrofolate reductase, abbreviated MTHFR, catalyses one of these steps: it converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (5-MTHF) — the form that circulates in the blood and is available for methylation.

Among other things, this form is needed to convert homocysteine into methionine. If the enzyme works more slowly, less 5-MTHF is available, and homocysteine is broken down more slowly. That is why the homocysteine level is the quantity by which the variant is noticed at all.

The two variants

Two single base substitutions appear above all in the literature:

C677T is the better studied of the two. Anyone who has inherited it from both parents (genotype TT) has an enzyme with markedly reduced activity; in cell experiments about a third of the residual activity remains. In Europe the proportion of TT carriers is roughly 10 per cent, with considerable regional differences. Those who carry the variant only once (CT, around 40 per cent) show at most small effects.

A1298C is frequently tested alongside it. Its functional influence is smaller and less clearly documented; on its own it does not lead to elevated homocysteine.

What is established

The connection with homocysteine. TT carriers have, on average, higher homocysteine levels than CC carriers. The effect is real and reproducible.

The dependence on folate status. This is the point that is regularly missing from the sales argument: the difference shows up clearly above all when the folate supply is low. Where the supply is good, it turns out small. The variant therefore describes not so much an increased requirement as a lower tolerance of a scarce supply.

The frequency. A trait carried by one person in ten is a normal variant. This is not a formula for reassurance but a way of placing it: it explains why the variant appears in population studies with such small effect sizes.

What is not established

That folic acid cannot be used with this variant. This is the most common misunderstanding, and it rests on an error of sequence. Synthetic folic acid is first reduced to tetrahydrofolate by a different enzyme, dihydrofolate reductase. MTHFR only comes into play after that — and does so by the same route as folate from food. Reduced MTHFR activity affects both sources equally. The statement "folic acid does not help me, I need the active form" describes a blocking mechanism that does not exist in that way.

That 5-MTHF preparations are superior for carriers. Calcium L-methylfolate is authorised in the EU as a folate source, and the form is unobjectionable. A documented advantage over folic acid for people with the C677T variant — measured against a clinical outcome, not merely a laboratory value — has not been derived from this.

That lowering homocysteine prevents events. Homocysteine can be reliably lowered with folic acid. Large intervention trials were, however, unable to derive from this any corresponding benefit for cardiovascular events. A laboratory value that moves is not yet an outcome that moves.

That testing is useful. Professional bodies advise against routine MTHFR genotyping — among other reasons because the result does not change the recommendation. In both cases it reads: an adequate folate supply.

Why the finding does not change the recommendation

This is the practical core. Suppose a test comes back TT. What follows from that? A good folate supply. Suppose it comes back CC. What follows from that? A good folate supply.

A test whose two results lead to the same action provides no basis for a decision. It provides a number. The intake recommendations — 300 µg folate equivalents for adults, plus 400 µg synthetic folic acid for those trying to conceive — apply irrespective of genotype. How these figures relate to one another is set out in Folic acid daily requirement: 200, 300 or 400 µg?.

Where the variant does deserve attention

Two situations are exceptions, and both belong in medical hands.

The first is severe congenital MTHFR deficiency — a very rare metabolic disease with almost complete loss of enzyme function, which usually shows itself in infancy or childhood. It has nothing in common with the frequent C677T variant but the name.

The second is a markedly elevated homocysteine level, regardless of whether a genotype is known. What matters then is clarifying the cause — and that is more often a deficiency of vitamin B12, B6 or folate than a gene variant. B12 in particular deserves attention here, because a high folate intake can normalise the blood count while the neurological consequences carry on; the details are in Folic acid and vitamin B12.

For whom the question nevertheless suggests itself

The question is asked particularly often by those trying to conceive. Here too the answer is independent of genotype: the recommendation for additional supplementation applies to all women trying to conceive, because the decisive window lies before the pregnancy is established. The genotype does not shift this window. What is specifically recommended in this phase is set out in Folic acid in pregnancy.

What it says on the pack

Folic acid 1,000 µg carries 500 % of the nutrient reference value per tablet. Which compounds are authorised in the EU and how they differ is set out in Folic acid or folate: where the difference lies; further strengths are in the folic acid category.

Food supplements are not a substitute for a balanced and varied diet and a healthy lifestyle. This text is no substitute for medical advice.

For folate, eight claims are authorised in the EU under Regulation (EU) No 432/2012; these five apply irrespective of genotype:

Folate contributes to normal blood formation.

Folate contributes to normal amino acid synthesis.

Folate contributes to normal psychological function.

Folate contributes to the reduction of tiredness and fatigue.

Folate contributes to maternal tissue growth during pregnancy.

Frequently asked questions

I have TT — do I now need the active form? That does not follow. The reduced enzyme activity affects folate from food and folic acid from a preparation equally, because both pass through the same step. 5-MTHF is an authorised and unobjectionable folate source — but a documented advantage specifically with this variant is not thereby demonstrated.

Should I have myself tested? For the general population this is not recommended. The main reason is a practical one: the result does not change the recommendation. Where laboratory values are conspicuous or the medical history points that way, the treating doctor decides.

Does MTHFR explain my tiredness? For folate, the claim "Folate contributes to the reduction of tiredness and fatigue" is authorised — it describes the role of the vitamin, not that of a gene variant. Persistent tiredness has many possible causes and belongs investigated, rather than ascribed to a genotype.

Does a higher dose make sense if the enzyme works more slowly? The upper limit for synthetic folic acid applies unchanged, and it applies to the sum of all preparations and fortified foods. Why this limit exists and what is discussed in the case of a permanently high intake is set out in Folic acid: too much of a good thing.