Introduction to the MTHFR gene : connecting the dots

A complete guide for real people

Understanding the MTHFR Gene – A Complete Guide for Real People

In the past few years, more and more people have been talking about the MTHFR gene. I remember that 6 years ago, I stumbled across a video of a NYC psychiatrist, Robert McMullen, who talked about this in one of his YouTube videos. This was the first time I came to know this gene. After searching on the web, I quickly understood that it was a major subject for a lot of people. However, it is hard to find reliable and clear and concise informations about.

For many, it still sounds confusing, scientific, or even intimidating. I remember checking websites of biochemistry, my first encounter with the cycle of methylation… It seemed like complex ancient dialect to me, to say the least. This is why I decided to make a little paper about it. In 2024, I watched a video about it (here it is) about somebody who overcame brain fog and chronic fatigue following an MTHFR diagnosis. I really could relate to her story and life history, as I also suffered from crazy brain fog since a long time.

I wrote this guide to explain everything I’ve learned about it, not as a doctor or researcher, but as a person trying to understand my own health better and help others do the same. I want to explain how this gene works, what happens when it doesn’t function well, how it connects to important processes like methylation and detoxification, and most importantly, what you can do about it.

The MTHFR gene is part of our DNA. It gives instructions for making an enzyme that has the same name: methylenetetrahydrofolate reductase. This enzyme plays a crucial role in something called the methylation cycle, a set of chemical reactions that happen all the time in our body and influence many areas of our health.

Methylation is the process of adding something called a methyl group to molecules in the body. A methyl group is a simple structure made of one carbon and three hydrogen atoms, but it has powerful effects. Methylation helps regulate how our genes are expressed, how we detoxify harmful substances, how we repair our DNA, how we produce brain chemicals like dopamine, serotonin, and norepinephrine, and even how we turn food into energy. People can either have too little or too much methylation. Even if the term “under-methylation” or “over-methylation” is debated among the medical community, many biochemist tend to agree on these terms.

When the MTHFR gene is functioning well, the enzyme it makes helps convert a form of folate into its active form, called methylfolate (or 5-MTHF). This is the form that the body uses in the methylation cycle. But when a person has a variation in this gene, sometimes called a mutation (SNPs), the enzyme may not work as well, and methylfolate levels can drop. This slows down the methylation cycle and can lead to a buildup of other compounds in the blood, such as homocysteine. Therefore, a mutation at the MTHFR gene can indirectly be implicated in the patho-genesis of many diseases and health conditions. In those people, even if the blood levels of folates are perfectly normal, deficiencies can exist in some parts of the body. The most important being the brain.

There are two main variations of the MTHFR gene that people usually talk about: C677T and A1298C. These names refer to specific changes in the DNA sequence.

If you have one copy of the C677T variant, you are considered heterozygous. If you have two copies, you are homozygous, and the enzyme produced by the MTHFR gene may function at only 30 to 40 percent of its normal capacity. This variant is especially associated with elevated homocysteine levels, which are a risk factor for heart disease, blood clots, and even neurological issues.

The other common variant is A1298C. It does not usually raise homocysteine levels, but it can still affect neurotransmitter production and detoxification capacity. People with this variant may struggle more with mood issues, anxiety, or sensitivity to chemicals and foods.

Some people have one copy of each variant. This is called compound heterozygous. This combination can still impact methylation and lead to symptoms, especially under stress or with a poor diet.

It is estimated that between 40 and 60 percent of the population carries at least one MTHFR variant. This means it is very common. Having a variant does not mean you are sick, broken, or doomed. It just means your body may need a different kind of support.

The effects of impaired methylation are wide-ranging. Some people may go through life without major issues. Others may experience symptoms that are hard to explain through standard medical testing.

Here are some symptoms and health issues that can be connected to poor methylation or MTHFR mutations:

• Fatigue or low energy that doesn’t go away with rest

• Brain fog, forgetfulness, or trouble concentrating

• Anxiety, depression, or irritability

• Insomnia or difficulty falling asleep

• Sensitivity to chemicals, perfumes, or alcohol

• Frequent headaches or migraines

• Digestive issues, including food sensitivities

• Hormonal imbalances, such as PMS, PCOS, or estrogen dominance

• History of miscarriage or infertility

• Elevated homocysteine levels on blood tests

• Poor stress tolerance or nervous system overactivity

• Joint pain or inflammation without a clear cause

• Poor detox reactions, especially after exposure to drugs or environmental toxins

• A family history of cardiovascular problems, stroke, or mental illness

One of the strongest indicators of methylation issues is high homocysteine. Homocysteine is an amino acid that the body produces as part of the methylation cycle. In a healthy system, homocysteine gets recycled into methionine, which is used to make SAMe, a compound involved in mood regulation, detox, and cellular repair. When methylation is impaired, this recycling slows down, and homocysteine builds up in the blood.

High homocysteine is associated with an increased risk of cardiovascular disease, stroke, neurodegenerative diseases like Alzheimer’s, and complications during pregnancy. It can also affect mental health, increasing the risk of depression, anxiety, and even bipolar disorder in some cases.

Testing your homocysteine levels is a simple blood test that most doctors can order. Ideally, homocysteine should be between 6 and 8 micromoles per liter. Levels above 10 may indicate a need for nutritional support and a closer look at methylation.

The good news is that methylation can often be supported through targeted nutrition. The body needs several key vitamins and minerals to keep this cycle running smoothly. Even if your genes are not ideal, you can often improve function by giving your body the raw materials it needs.

Here are the main nutrients that support MTHFR and methylation:

• Methylfolate (5-MTHF) or Folinic acid : the active form of folate, bypasses the MTHFR enzyme.

  The dosage of folate must be from 1mg to 10mg, depending on the person’s need.

• Vitamin B12 (methylcobalamin or hydroxocobalamin): needed for homocysteine recycling

• Vitamin B6 (P5P form): helps convert homocysteine into cysteine.

  One should be careful to use the active form of B6 (P5P), as some concerns have been raised over B6 toxicity when more than 100 or 200mg are used a day.

• Riboflavin (vitamin B2): supports enzyme function, especially with C677T

• Magnesium: involved in over 300 enzymatic reactions, including methylation.

• Betaine (TMG): helps lower homocysteine through an alternate pathway

• Zinc: important for enzyme function and gene expression

• Choline: supports methylation and liver health

It’s important to choose the right forms of these nutrients. For example, synthetic folic acid is not well metabolized by people with MTHFR variants and may even block folate receptors. Many biochemist agree on the point that folic acid is neither well absorbed nor a good overall choice. People should look for supplements that contain methylfolate instead (or folinic acid). The same goes for B12. Methylcobalamin is the most active form, but some people may do better with hydroxocobalamin, which is gentler. People with some other genetics SNPs (COM-T, for example) will say that they don’t tolerate methylcobalamin and other will say the contrary. All of this is very complex and individualized. One should never forget this.

Start slowly with methylated vitamins. Some people experience side effects when starting methylfolate or methylcobalamin, such as anxiety, insomnia, or overstimulation. This is often due to starting at a dose that is too high or because the body is not ready to detox at that speed. They can feel a bit too “activated” by the vitamins.

Always begin with a low dose, observe how you feel, and increase gradually. I always see people on forum who report “feeling activated” when they take B-vitamins. They tend to be frightened as this effect can cause heart palpitations and a kind of feeling “blah”. But this is linked to a bad reaction to the methyl groups of the B-vitamins. Some people appear to be very sensitive to those little molecules. So one should always proceed with caution and go slow.

However, water soluble vitamins are extremely safe and toxicity is non-existent. In the US, methylfolate has been prescribed under the band name Deplin, which ranges from 7mg to 15mg, which can be considered as a high dose.

Supporting methylation is not just about supplements. Lifestyle matters too. Reducing exposure to toxins, eating nutrient-dense food, staying physically active, sleeping well, and managing stress all support your methylation cycle. If you drink alcohol, consider cutting back or stopping, as alcohol depletes methyl groups and B vitamins. Avoid smoking and processed foods. Drink clean water, ideally filtered, and avoid synthetic fragrances. I would highly advise people with MTHFR gene mutation to join the dedicated Facebook groups about the subject. Some of those people won’t tolerate some foods, or find very relieved of symptoms when they stop those foods. As the subject is pretty complex and individualized, we encourage people to do their own research. There is a website called “MTHFR Australia” that has some great informations about it.

It is also important to recognize that methylation does not exist in isolation. It connects to many other pathways in the body, including those that regulate inflammation, oxidation, neurotransmitter production, and hormone balance. That’s why MTHFR and methylation affect so many systems at once. It’s also why small changes can have a big ripple effect

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Testing for MTHFR can be done through saliva or blood. Some services, like 23andMe or AncestryDNA, can provide raw genetic data that you can analyze using other tools. But even without testing, many people can benefit from supporting methylation through diet and gentle supplementation.

Understanding your genetics is not about fear or labels. It’s about using information to guide your choices. MTHFR is not a disease. It is a variation in how your body handles folate and other nutrients. Once you know how your body works, you can support it in ways that help you feel clearer, more focused, calmer, and more resilient.

You are not broken. You are not defective. You are simply built a little differently, and that is completely okay. The important thing is to learn how your system works and give it what it needs.

Take your time. Go slow. Listen to your body. And never forget that small steps, taken consistently, can lead to big changes.

Even if not considered an important part, I would really advise people to supplement vitamin C and magnesium while dealing with a MTHFR journey. Even if it is not directly implicated in the biochemical process of this gene, one has to adopt a more global approach and aim to support the body. It is very important to give you energy while going through this. The MTHFR journey is really a trial and error kind of path and many people feel lost.

The MTHFR gene issue is not limited to folate. It is linked to homocysteine, detoxification, glutathione. One has to understand the concept of methylation and how modulating it can help to prevent cancer, psychiatric and neurodegenerative diseases.

A lot of people with brain fog, AHDR, depression or even mold toxicity share a common similarity. You guessed it. A mutation at the MTHFR gene. As it impacts glutathione, it also wreck detoxification, which can trigger a lot and a lot of symptoms. If there is a crucial gene check, it would be this one.

Google it, and you will quickly ask yourself :

“Who is this MTHFR*** they are all talking about ???!!!”

Joke aside, it is very important.

Acting on methylation is one of the most powerful somebody can do for his or her health. Here are some complementary documents and sources to help you dig deeper.

Be well,

Complementary documents :

Methylation cycle :

Homocysteine theory of depression :

Sources :

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Castro, R., Rivera, I., Blom, H. J., Jakobs, C., & de Almeida, I. T. (2006). Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: An overview. Journal of Inherited Metabolic Disease, 29(1), 3–20. https://doi.org/10.1007/s10545-006-0106-5

Chen, Z., Karaplis, A. C., Ackerman, S. L., et al. (2001). Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Human Molecular Genetics, 10(5), 433–443. https://doi.org/10.1093/hmg/10.5.433

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Klerk, M., Verhoef, P., Clarke, R., et al. (2002). MTHFR 677C→T polymorphism and risk of coronary heart disease: A meta-analysis. JAMA, 288(16), 2023–2031. https://doi.org/10.1001/jama.288.16.2023

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Olivieri, O., Friso, S., Manzato, F., et al. (2002). Prevalence of methylenetetrahydrofolate reductase C677T mutation in Italian women with unexplained recurrent pregnancy loss. British Journal of Haematology, 119(4), 855–857. https://doi.org/10.1046/j.1365-2141.2002.03921.x

Papakostas, G. I., Petersen, T. J., Mischoulon, D., et al. (2004). Serum folate, vitamin B12, and homocysteine in major depressive disorder: An association with melancholia? Journal of Clinical Psychiatry, 65(4), 519–523. https://doi.org/10.4088/jcp.v65n0411

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Pages and documents about it (full sources)

• www.metametrixinstitute.org/post/2012/09/28/Demystifying-Methylation-Part-Deux.aspx www.neurosciencemyths.com/Methylation.htm

• http://www.nutritional-healing.com.au/content/articles- content.php?heading=Major+Mental+Illness+Biochemical+Subtypes