MTHFR Gene Variants: Diagnosis & Treatment

In the U.S., 1 in 3 people have at least one MTHFR variant, and 1 in 10 have variants in both copies of the MTHFR gene. MTHFR gene variant may lead to low folate and B vitamins levels and higher blood homocysteine levels, which can put people at higher risk for many common health problems.

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Why is the MTHFR Gene Important?

MTHFR is a gene that provides the body with instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme is essential for the methylation of folate, which is vital to reduce the levels of homocysteine in the body. Methylation also helps to optimize many processes in your body, including the production of DNA, metabolism of hormones, and proper detoxification.

What Causes an MTHFR Gene Mutation?

Within our 23 pairs of DNA chromosomes lies the blueprint for producing proteins that determine much of our health and function. Sometimes there are slight variations in the blueprint, where one amino acid gets replaced with another. These are called Single Nucleotide Polymorphisms, or SNPs for short (pronounced like "snip"). One of the most discussed SNPs affects the enzyme Methylenetetrahydrofolate reductase (MTHFR).

Everyone has two MTHFR genes, one inherited from your mother and one from your father. Mutations (variants) can occur in one or both MTHFR genes and are passed down from one or both parents. Having a parent or close relative with an MTHFR gene mutation increases a person's risk of inheriting that variant.

MTHFR Variants

The MTHFR variants are called C677T and A1298C.

C677T

The most common polymorphism affecting MTHFR is C677T which is estimated to affect 20%-40% of white and Hispanic individuals in the U.S. and 1%-2% of U.S. African Americans.

A1298C

A second MTHFR polymorphism is A1298C, with an incidence of 7-12% of North Americans, Europeans, and Australians. Another study in Texas found that A1298C occurred in 27.2% of the Jewish population and 35% of the non-Jewish population.

Health Conditions and MTHFR Mutation

MTHFR is an enzyme critical to the methylation of folate to its active form. This is part of the folate cycle that makes the vitamin bioavailable in the body. The complex reactions also convert homocysteine back into methionine or cysteine, which can then be recycled into the antioxidants Glutathione and help methylate DNA and preserve its integrity. Health conditions can result from lower levels of methyl folate and B12, elevated homocysteine, and reduced detoxification pathways that utilize methylation. These include:

• ‍Cardiovascular diseases such as heart disease or ischemic stroke‍
• Decreased production of methyl folate, the active form of this vitamin
• Risk of Alzheimer's, dementia‍
• Microbleeds and memory problems‍
• Small vessel disease, large vessel atherosclerosis, and resultant ischemic stroke‍
• Cervical artery dissection
• Elevated risk of Parkinson's‍
• Psychiatric disorders such as Schizophrenia‍
• Autism‍
• Reduced fertility in men‍
• Migraines‍
• Pulmonary thromboembolism‍
• Hypersensitivity to mercury‍
• Increased risk of Type 2 Diabetes‍
• Clinical severity of Sickle Cell Disease may be worsened
• Recurrent miscarriages
• More documented problems are possible, so this list is not all-inclusive.
  

*Note:

Since methylation is one of the body's pathways for detoxifying drugs, C677T is involved in methotrexate toxicity, but A1298C is not.

What is Homocysteine?

Homocysteine is an amino acid that is formed by methylation reactions. Homocysteine is normally remethylated to methionine or can be converted to cysteine by the transsulfuration pathway. The enzyme MTHFR aids the conversion of homocysteine to methionine, but in the case of an MTHFR polymorphism, this process may be incomplete, and homocysteine may accumulate due to a shortage of methyl folate or B12.

Folate is part of the "one-carbon pathway" that donates methyl groups (CH3, one carbon) to everything from DNA to detoxification reactions.

The T.T. allele (A.A. from some test providers that look at the other half of the chromosome) reduces the activity of MTHFR by as much as 70%. It can result in significant increases in homocysteine as well as folate deficiencies.

Functional Medicine Labs to Test for MTHFR Complications

• ‍Methylation Panel by Genova Diagnostics. This test panel evaluates the methylation pathway and provides measures of the "input and output" of the pathway and levels of amino acids, vitamins, and minerals critical to methylation.‍
• SpectraCell's Micronutrient Test. This panel measures the levels of nutrients in the serum, and many nutrients are also measured intracellularly. This test provides the micronutrient data from the NutriPro test but without the genetics component since genetics don't change between visits. Evaluation of these nutrients can be used to gauge the function of the methylation and transsulfuration pathways, particularly with homocysteine as an add-on to this panel.
• Some at-home genetic testing kits offer screening for MTHFR as well.

Treatment for MTHFR & Related Health Conditions

Treatment options should be specific to lab work results and symptoms. The goals are often to improve methyl folate levels and methylation pathways and reduce homocysteine levels.

• Methyl folate supplementation can bypass the slow pathway, providing activated folate.
• Folate is present in some foods, with beef or chicken liver having the highest concentration and bioavailability, followed by spinach and other leafy green vegetables.
• Vitamins B6 and B12 are cofactors in methylation, so supplementation should be considered based on lab results and symptoms.
• Riboflavin will also reduce homocysteine levels as it is also a cofactor in methylation. Riboflavin is naturally present in foods but can also be found in supplements and fortified foods. Riboflavin is found mainly in meat and fortified foods but also in some nuts and green vegetables. The highest natural source of riboflavin is beef liver.
• Avoid folic acid, as this version of the vitamin, cannot be fully processed by some people with an MTHFR mutation, leading to hazardous accumulations.
• Betaine, which is trimethylglycine, can help lower homocysteine.  
• Choline can also help to lower homocysteine and improve methylation. The process is like that using betaine because betaine is a choline derivative. The highest natural sources of choline are found in beef liver, chicken liver, and eggs.
• Avoid alcohol as it depletes folic acid, B6, and B12 and inhibits methylation.
• Physical exercise improves methylation in MTHFR individuals, reducing overall cardiovascular risk as a result of the fitness achieved.
• Because methylation is also a detoxification pathway, those with an MTHFR SNP that reduces methylation should avoid dietary sources of mercury, such as large ocean fish. These include tuna, swordfish, and large pelagic fish who bioaccumulate ocean toxins.
  

Summary

Our genetic code is so complex that scientists still make new discoveries yearly. DNA is composed of amino acid pairs, and sometimes a different amino acid is substituted in a pair. This is called a single nucleotide polymorphism or SNP. One of the most studied SNPs is MTHFR, an enzyme that affects the metabolism of folate, B12, and several other critical functions, such as methylation.

Methylation is critical to detoxification, DNA activity, and vitamin metabolism. MTHFR can result in low levels of vitamin B9 (Folate) and elevated levels of homocysteine, increasing the risk of many health conditions. With an appropriate diet, supplements, and lifestyle, it is possible to mitigate these health effects and enjoy a healthy and productive life!