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Do MTHFR Mutations Cause Folic Acid Build Up? | Methyl-Life

Do MTHFR Mutations Cause Folic Acid Build Up? 

An MTHFR genetic mutation impairs the body’s ability to break down folic acid, which may lead to a buildup of folic acid in the body. Excess folic acid can contribute to a range of health issues, including cognitive decline, mood and behavioral disorders, and potentially even increase the growth rate of cancer cells.

At least 40% of people around the world have some form of MTHFR genetic mutation, and yet most of them don’t know it.

MTHFR (methylenetetrahydrofolate reductase) is the enzyme produced by the MTHFR gene. It’s required for metabolizing folate and breaking down the amino acid homocysteine.

Those with an MTHFR polymorphism cannot properly convert folic acid into a usable form. Studies suggest that this poor metabolism may cause folic acid to accumulate in high concentrations. This is referred to as unmetabolized folic acid (UMFA) syndrome.

Knowing how this genotype could impact your health is crucial, as we will explain below.

Why Folic Acid Matters to the MTHFR Gene?

When you eat foods or take supplements containing folic acid, the MTHFR enzyme converts it to the active form of folate, known as methyl-folate. Methyl-folate is crucial for the methylation process, which is required for many important bodily functions. It’s involved the production of DNA, metabolism of various hormones, healthy detoxification, the formation of healthy cells—especially red blood cells—and much more.


However, when folic acid cannot be converted to its usable form, methylation cannot happen. Worse still, the presence of an MTHFR SNP means the unmetabolized synthetic folic acid accumulates and can actually become hazardous.


A folate deficiency is not the same as a folic acid deficiency. Folic acid is a synthetic form of folate, while folate is the form that your body needs to use in circulation. Only the active form 5-methyl-THF can participate in the gene activation and DNA repair that the body needs, as well as supporting rapid cell growth, regulation and division during pregnancy. Moreover, a folic acid deficiency is impossible because it is folate that your body needs and uses, not folic acid.

Also Read: Is There a Connection Between MTHFR and Eczema?

Can Folic Acid Build Up Worsen the Symptoms of MTHFR?

A buildup of unmetabolized folic acid (UMFA) in the blood may lead to a range of health concerns. It may also worsen the symptoms of an MTHFR mutation.


Studies in mice have shown that high doses of folic acid can cause some patients to develop a “pseudo MTHFR” syndrome, in which elevated unmetabolized folic acid leads to higher levels of homocysteine.


High blood concentrations of folic acid may decrease the toxicity of natural killer cells.


Researchers also suggest that taking high amounts of folic acid may reduce MTHFR protein and activity levels, leading to an MTHFR enzyme deficiency. This deficiency results in hepatocyte degeneration, in which liver cells cannot function properly. This may have serious clinical implications for people taking high-dose folic acid supplements, especially if they have an MTHFR mutation.


Excess folic acid supplements may also mask megaloblastic anemia, which can mean that the cause (of the vitamin B12 deficiency) is missed.


Other research has linked high intake of folic acid supplements to age-related mental decline, particularly in people with low vitamin B12 levels.  By contrast, the use of methylfolate (naturally-derived folate) alongside B12 maybe used for treating and slowing Alzheimer’s disease-related cognitive decline.


Most concerning is new research that suggests excess unmetabolized folic acid may cause cancerous cells to grow or spread. Animal studies have shown that excess folic acid may promote the progression of precancerous and cancer cells.

Will Variants of the MTHFR Mutation Respond Differently to Folic Acid?

Will Variants of the MTHFR Mutation Respond Differently to Folic Acid?

Over one-third of the world’s population is estimated to be carriers of MTHFR SNPs, and more than 20% are thought to be affected by symptoms. Different variants may have slightly different responses to folic acid. 


It’s thought that around 60% of the US population are intermediate metabolizers of folate or heterozygous for the genetic polymorphism of the MTHFR enzyme (meaning they have one mutation out of two possible on a Single Nucleotide Polymorphism [SNP]), while up to 25%+ of certain populations are homozygous for these genetic variations (meaning they have two mutations out of two possible on a SNP).


Two well-known and studied variants of the MTHFR gene that can occur on the SNP are C677T and A1298C. Each of these variations may respond slightly differently to folic acid supplementation.

C677T variant

It’s estimated that 30-40%  of the US population may have a mutation at gene position C677T. The Hispanic and Caucasian population have the highest prevalence (48% and 45%respectively), while African Americans are much lower (24%).  In southern Italy, the frequency of 677TT and1298CC homozygous mutations are 25% and 12.5% respectively (these are considered double mutations and have a much greater impact on the body).

The C677T results in a 35% reduction in activity for heterozygotes (C/T or those with single mutations) and a 70% reduction in activity for homozygotes (T/T or those with double mutations).

People with the MTHFR 677TT genotype who take folic acid are shown to have an average amount of folate in their blood that is only about 16% lower than people with the MTHFR CC677 genotype.


Some studies have shown a connection between as light increase in autism risk and the C677T variation. The findings of the meta-analysis suggest that the C677T polymorphism is significantly associated with autism disorders in every genotype.


This variant is present in 7-12% of North American, European, and Australian populations; it is less common in Hispanics(4%–5%) and Asians (1%–4%). Being homozygous for 1298CC results in 60% of normal MTHFR enzyme function. Compound heterozygous (one abnormal MTHFR C677T gene and one abnormal MTHFRA1298C gene) also results in decreased enzyme function and can have adverse effects on the body according to some doctors.

Folic Acid Supplementation with MTHFR

To become usable, folic acid must go through a complicated process of enzymatic reduction. First, it is converted to dihydrofolate (DHF), then tetrahydrofolate (THF), then 5,10 THF, and finally 5-MTHF. As mentioned previously, this process cannot happen properly if you have the MTHFR genetic mutation.


Those with some form of MTHFR gene mutation are not advised to take folic acid due to the risk of folic acid buildup. Excess unmetabolized folic acid can lead to toxicity, which in turn may lead to the binding (or blocking) of the (natural) 5 MTHF receptors and transporters by the folic acid.


Dihydrofolate (the co-enzymatic form of folate through which folic acid enters one-carbon metabolism) has been shown to inhibit MTHFR, causing high concentrations of folic acid to inhibit the formation of bioactive folate.


Women with an MTHFR polymorphism have up to 75% reduction in the capacity to form active folate. Liver DHFR activity is slow and weak, reducing the ability of synthetic folic acid to enter the folic acid cycle.


Accumulated unmetabolized folic acid can lead to many issues including a higher risk of complications during pregnancy. Some research suggests UMFA may increase the risk of immune dysfunction due to the dysregulation of natural killer cells. A study investigating high folic acid treatment in patients with and without MTHFR mutation showed that excess folic acid, even with functioning MTHFR, could have detrimental effects on cells.


Studies investigating the effect of folic acid supplementation on depression response have had mixed results, as have studies investigating the effect of taking folic acid as an adjunct to an antidepressant. Some results have shown an improvement in depression, and some show no clinical benefit.


Most researchers have recommended that those with MTHFR variations must take only the active form of folate, 5-MTHF. This form will bypass the defective gene and provide the body with the bioactive enzyme that it needs, as well as reducing homocysteine levels. High homocysteine levels can cause negative health complications.

Folate Supplementation with MTHFR

5-MethylTHF (also known as (6S)-5-methylTHF) is the predominant micronutrient form of folate that circulates in plasma and is required for numerous biological processes.

Unlike folic acid, 5-MTHF (or L-methylfolate)can cross the blood-brain barrier and does not mask pernicious anemia or vitamin B12 deficiency. It is readily available for transport and metabolism and can be safely taken in high doses. 5-MTHF is a better alternative because it’s a natural form of folate directly available for gastrointestinal absorption. Supplementation has been shown to effectively improve folate biomarkers in young women in early pregnancy, which can prevent neural tube defects.

In a recent double-blind, randomized, placebo-controlled trial of 144 women of childbearing age, researchers demonstrated that supplementation with L-methylfolate was more effective than folic acid at increasing red blood cell folate concentrations. They recommended prenatal vitamins include 5-methyl-THF rather than folic acid, as it would be “universally beneficial”.

L-methylfolate is not recognized as an antidepressant or antipsychotic medication. Although, L-methylfolate may enhance the effects of antidepressant medications.


Synthetic folic acid poses a range of problems to the body due to the complicated process by which it is metabolized. This is especially problematic for those with an MTHFR mutation because they lack the gene efficiency required to break down folic acid into the active enzyme form of folate needed by the body’s cells and receptors. This can lead to unmetabolized folic acid accumulating in the bloodstream, and potentially causing serious health issues.

Although the severity of symptoms can depend on which variant of the MTHFR mutation you have, the risks of folic acid build up are best avoided completely by taking methylated folate.

Naturally-occurring 5-MTHF is readily absorbed by the body even when metabolic defects are present. This means that taking L-methylfolate can effectively bypass a genetic mutation you might have.

The most biologically active folate supplements are those that include:

● (6S)-5-methyltetrahydrofolate or (6S)-5-MTHF

● (6S)-5-methyl-tetrahydrofolic acid, calcium salt or L-methylfolate

● (6S)-5-methyltetrahydrofolic acid, monosodium salt or L-methylfolate

These are the active crystalline forms of the naturally-occurring predominant form of folate. This type of water-soluble B-vitamin plays a key role in central metabolic pathways, including in cell division and repair.

Methyl-Life® products contain the purest and most bioactive nutrient form of folate available, Magnafolate® PRO. This is the form of folate that has already been converted, so it can cross the blood-brain barrier and be immediately used by the body’s cells.

A great option for prenatal health is Methyl-Life®’s L-Methylfolate B-Methylated-II, which contains L-methylfolate (3mg) and Methylcobalamin (3.75 mg).

Studies have shown that Magnafolate® PRO is even more pure, stable and potent than competing brands Quatrefolic® and Extrafolate®. This is because Magnafolate® is built on a calcium crystalline molecule structure just like the pharmaceutical brand of L-methylfolate. This Calcium Salt L-5-Methyltetrahydrofolate with C-effective crystal form offers superior particle size distribution, stability, dissolution, potency, bioavailability and safety. A unique and patented sonification technology is used to micronize the nutrient which results in less machine parts touching the material, and therefore 3x the purity of other leading brands.

Supplementing with a quality methylfolate is the most effective way to optimize your body’s methylation processes and avoid the risk of folic acid buildup.

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