Does an MTHFR Mutation Increase the Risk of a Stroke?

Around 30-40 percent of the global population is affected by some form of mutation on the gene that produces the enzyme Methylenetetrahydrofolate reductase (MTHFR). Depending on the variant, the MTHFR mutation affects the body’s ability to carry out processes related to methylation.  

MTHFR is required for metabolizing the amino acid homocysteine, a type of amino acid produced naturally in the body. High blood levels of homocysteine signal a breakdown in the metabolism process of this amino acid, which can have serious biochemical and life consequences. 

Accumulation of homocysteine can cause irritation and inflammation of the blood vessels, increase the risk of atherosclerosis (hardening of the arteries), heart attack and/or stroke, and venous thrombosis (blood clots in the veins). 

This article will discuss the factors associated with different MTHFR mutations and how they may increase the risk of a stroke. We will also discuss the signs to be aware of and steps you can take to reduce the risk of stroke or other cardiovascular events. 

Homocysteine is a type of sulfur-containing amino acid produced by the demethylation of methionine; an amino acid derived primarily from animal protein. 

The body manages homocysteine levels by converting homocysteine into other products via the methionine-homocysteine pathway. This process requires cofactors folate, B6, and B12. 

Slight deficiencies of these vitamins can lead to an accumulation in homocysteine levels. These deficiencies may occur due to poor diet and/or genetic polymorphisms in the key enzymes of homocysteine metabolism. 

Hyperhomocysteinemia is a major risk factor in cardiovascular diseases, including cerebral stroke. Excess homocysteine damages endothelial cells and can lead to abnormal clotting, increasing the risk of stroke, especially among those with high blood pressure. Patients with coronary heart disease (CHD) are shown to have significantly higher mean homocysteine levels than healthy people. 

The MTHFR enzyme is a key enzyme in the folate and homocysteine metabolism, which means homocysteine levels are largely affected by MTHFR polymorphisms and folate status. MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-Me-THF, which provides the methyl group for the remethylation of homocysteine to methionine, during which tetrahydrofolate (THF) is formed. Vitamin B6 and B12 act as cofactors in the re-methylation process, along with several other enzymes. Homocysteine levels increase as vitamin B concentrations decrease.

Folate insufficiency decreases the ability to re-methylate homocysteine, leading to an increased homocysteine level. Homocysteine levels may also rise when B12 is deficient, as B12 is an essential cofactor in the re-methylation cycle.

The MTHFR 677TT genotype (a double mutation), in particular, is known to decrease the availability of folate for methylation. A meta-analysis of 72 studies involving 12,390 cases and 16,274 controls revealed that an MTHFR C677T mutation increased the risk of ischemic stroke by around 32% compared to controls. 

Similarly, the MTHFR A1298C polymorphism was shown in a meta-analysis of 40 articles, including 5,725 cases, to increase susceptibility to ischemic stroke in adults.

A stroke occurs when a blood vessel that delivers oxygen to the brain either ruptures causing a bleed (hemorrhagic) or is blocked by a clot (ischemic). Brain cells served by this particular blood vessel shut down due to lack of oxygen, resulting in loss of function to the part of the body controlled by these brain cells. 

Early warning signs of a stroke include sudden weakness, numbness and signs of paralysis, difficulty speaking, distorted vision, dizziness, difficulty walking, severe headache, possible nausea or vomiting. Stroke symptoms usually affect only one side of the body, resulting in loss of function of one arm or leg.

Numerous studies have shown that homocysteine levels may be modified by providing the nutritional cofactors required for methylation and the proper functioning of the methionine cycle. This can help to reduce the risk of stroke. 

Methylfolate is key to reducing homocysteine levels, especially when combined with vitamins B12 and B6. 

An analysis of 12 trials including 1,114 subjects found that folic acid supplementation resulted in a decrease in serum homocysteine levels, with an overall reduction of 25% decrease in homocysteine. Combined vitamin B12 supplementation produced a modest additional 7% reduction in homocysteine levels.

Similarly, a 2019 systematic review of intake of vitamin B6, folate, and vitamin B12 and the risk of coronary heart disease found that a higher intake of folate and vitamin B6 was associated with a lower risk of coronary heart disease in the general population.

Also worth noting is a study involving 12,000 Indian soldiers working in a high-altitude environment, which showed that daily supplementation with folate, vitamin B6, and vitamin B12 reduced thrombotic events over a period of 2 years.

The above studies have shown that the effects of an MTHFR variant on homocysteine can be modified by improving the concentration of folate in the body. However, this should not be confused with folic acid. 

Folic acid is not recommended for those with MTHFR polymorphisms. It is not the bioequivalent of natural dietary folates and cannot cross the blood-brain barrier. It has no coenzyme activity and must be reduced to tetrahydrofolate form (the metabolically active form) before being used by the body. Folic acid has not been shown to lower homocysteine directly and may cause renal toxicity. 

Methylfolate (L-5-methyl-THF) is considered superior to folic acid as it doesn’t mask the hematological symptoms of vitamin B12 deficiency, and it is less likely to interact with drugs that inhibit dihydrofolate reductase (the enzyme that converts dihydrofolate to tetrahydrofolate).

Most importantly, methylfolate can bypass folate insufficiency due to MTHFR deficiency. Unlike folic acid, it can enter the folate cycle directly without the need for further enzymatic modification.

Methylfolate supplements are readily available over-the-counter and online, often labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate. 

One brand specifically recommended for people with a heightened need for bioavailable folate is Methyl-Life®. The Methyl-Life® product range is made with the internationally-patented Magnafolate® PRO, clinically tested as the world’s purest methylfolate and the most active form of folate in plasma circulation. Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly in the body. 

The Methyl-Life® range includes methylfolate dosages from 2.5mg to 15mg, Active B12, and Methylated Multivitamins.