MTHFR - The Motherf**ker Gene

Could you have this common genetic mutation?

Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the body that enables a process called methylation. Some of its functions include:

• DNA repair, cell membrane repair

• Switching genes on and off (although our genetic code is set, lifestyle factors and diet can affect whether they are expressed)

• Activating folates into a usable form

The MTHFR gene provides the instructions for your body to make the enzyme, but when you have a mutation on this gene, your production and functionality of this enzyme is altered. 

There are many different genes that affect MTHFR. DNA strands are made from guanine, adenine, thymine and cytosine. There are currently two main gene mutations for MTHFR that are tested for and heavily researched:

• C677T - cytosine has been changed to thiamine at the 677 position

• A1298C - adenine has been changed to cytosine at the 1298 position

Effects on folate metabolism:

• C677T heterozygous (1 copy): 30-40% loss of function

• C677T homozygous (2 copies): 60-70% loss of function

• A1298C heterozygous: 20% loss of function (may be manageable with diet alone)

• A1298C homozygous: 40% loss of function

• Compound heterozygous (1 copy of C677T & 1 copy of A1298C): 40-50% loss of function

A reduction in folate metabolism can lead to the many outcomes of folate deficiency which can include hormonal and reproductive dysfunction, cognitive and mood disorders, skin disorders, weakness, irritability, apathy, anaemia, gut issues and insomnia.

Signs and Symptoms Include:

🌿 Fatigue 🌿 Infertility or recurrent miscarriage 🌿 Brain fog 🌿 Reduced detoxification capacity (may manifest as intolerance to alcohol, perfumes, caffeine etc or build up of heavy metals in testing) 🌿 Reproductive conditions (extreme period symptoms, endometriosis etc) 🌿 Anaemia despite iron intake 🌿 Acne 🌿 Depression, anxiety 🌿 Headaches, migraines 🌿 Negative reaction to folic acid supplements or processed wheat products 🌿 Skin and respiratory/immune sensitivities

Once we discover an MTHFR mutation, we can focus on increasing the levels of B vitamins and gradually building in good levels of activated B12 and activated folate (ready to use). Dietary changes are needed too to increase the intake of real folate from plant foods and avoid synthetic folic acid that is added to processed wheat products. Folic acid is made in a lab and is NOT the same as folate, though the health and food industries often use folate as an umbrella term.

People with an MTHFR mutation will not be able to process folic acid well and it can build up and become harmful. This is especially important for pregnant women, as folic acid supplements are often pushed during preconception or pregnancy and can cause harm to the mother or baby if the mother has an inability to process it well.

Methylation & MTHFR Issues 

Methylation occurs in all cells of the body except red blood cells. It is simply the chemical bonding of a methyl group to another biological compound. A methyl group is a carbon atom attached to 3 hydrogens.  

The MTHFR enzyme enables this process to occur - the attaching of the methyl group to the other compound. So you need the methyl groups, but you also need the enzyme to attach it. This is why the folate supplement people with this mutation need to take is methylated folate, so it’s already usable.

Methyl groups can be created internally within the Folate Cycle, but when you have issues with folate metabolism due to the MTHFR defect you may not make enough for what you need. Methyl groups can also be obtained via the diet (but you still need enough of the enzyme), and some foods contain activated, methylated forms of folate so they are ready to use. Methyl groups are chemically bonded to thousands of different biological compounds every day to enable the many chemical processes required for life. 

Methylation is particularly important for the functioning of mitochondria, which are the energy-producing parts of cells. This is partly why you can feel very fatigued and foggy when your methylation pathways are not functioning properly.

Methylation is also crucial for foetal development. The DNA of an early embryo progressively undergoes increased methylation leading to organ and tissue formation and development.

Folate vs Folic Acid

Folate is a natural vitamin found in foods like legumes and dark green leafy vegetables (foliage). It is essential for DNA and RNA synthesis, gene expression and stability and cell division and replication, so it is extremely important during times of rapid growth and development such as pregnancy, childhood and adolescence. It also significantly affects rapidly dividing cells, so skin and reproductive issues are common when imbalanced.

Folic acid is a man-made form of folate and is added to most flour products in Australia (only organic flours are free of it) and used in a lot of nutritional supplements. To make folic acid usable, it has to first undergo a number of chemical reactions in the liver and intestines. 

When you have a reduced ability to make the required enzymes for this process, folic acid can build up in the system unutilised, which can put pressure on the liver or make you feel unwell. You can convert a small amount of folic acid when you have an MTHFR issue, but you will benefit much more from eating and supplementing natural forms of folate that are more readily usable by the body, and avoiding high doses of folic acid which can be problematic. 

Food contains the 3 end-stage folates, so while some of the folate you eat still requires some conversion, it is a much simpler process for the body, and some of the folate is already in its completely activated form. If you take in very high amounts of folate from food, your body might not convert all of it into an active form, but any leftover can be recycled into a harmless compound, unlike folic acid which accumulates.

FOLATE (from foliage) is natural and more readily used by the body.

It’s important to eat a lot of green leafy vegetables for ongoing health, or supplement an activated form of folate to prevent deficiency.

FOLIC ACID is synthetic and requires multiple conversions before use.

Most Australian flour products (bread, cakes, biscuits, pastas) have added folic acid, as do many multivitamin supplements, protein powders etc. It’s best to avoid taking in high doses of folic acid, so avoid any supplements with it, and choose organic products wherever possible for grain products as they generally do not have folic acid added.

If you do ingest a lot of folic acid, it can show up on blood tests as high ‘folate’ while you may still experience deficiency symptoms, because it is just accumulating and not being used.

Vitamin B12 and MTHFR 

Vitamin B12 and folate depend upon each other. It is common to have a B12 deficiency if you have any gut issues, take antacids or have a vegan or vegetarian diet. If you have an MTHFR gene mutation and low activated folate, any B12 you do have still might not be utilised well. So, you can be functionally deficient even if you’re actually getting enough in your diet.

Again, this could show up on a blood test as sufficient or high levels of B12 even though the cells may not actually be using it. (It is possible to test for the active forms of folate and B12 to get clear readings on where the levels are at.) In the long term, B12 levels can be supported by getting enough dietary B12 and active folate, but in the meantime, we can supplement with the active form of B12 to make sure those levels are adequate.

B12 deficiency symptoms include:

• Extreme fatigue, weakness, dizziness

• Heart pain

• Anaemia

• Irritability, anxiety, temper outbursts, agitation

• Constipation, food sensitivities, low stomach acid

• Muscle weakness, restlessness

• Chronic inflammation

• Vision disturbances and blurring, numbness, tingling

• Depression, confusion, poor memory, low concentration

• Tongue inflammation

Is This Always Going to Create Health Issues?

Epigenetics is an emerging field of study that shows that genes can be turned on or off. Simply having a particular gene does not always mean you will express the characteristics of that gene, which appears to be the case moreso with genes relating to function rather than physical characteristics. The genetic code ‘loads the gun’ but diet and lifestyle changes ‘pull the trigger’ and set actual signs and symptoms and dysfunction into effect.

Having this genetic mutation does not make you unwell in itself, it just means you can’t get away with certain diet and lifestyle factors to the same degree as some others. Diet, lifestyle and environmental changes can increase the demand for folate, so this can then result in deficiency symptoms if you are not able to keep up with demand. Excessive stress, toxin exposure, poor dietary choices or rapid growth are some factors that may trigger MTHFR symptoms to show up, and if imbalances are prolonged or extreme, this can spiral into chronic health issues that affect multiple biochemical pathways. 

Once the folate and B12 levels are managed, along with any required cofactors and addressing other contributing factors, you may be able to manage an MTHFR mutation through diet and lifestyle practices alone.

Testing

General Blood Tests Signs of B12 and folate issues in standard bloodwork include: low white cell count, low neutrophils, low lymphocytes, elevated mean cell volume, elevated red cell distribution width, elevated homocysteine, elevated creatine kinase, low haemoglobin, elevated GGT liver enzyme, low vitamins A, D, E or K, high or low cholesterol, high or low blood pressure, low thyroid function especially T4.

This can be tested as a baseline before starting nutritional therapy, to monitor progress but also to check for risk signs like high homocysteine which is associated with cardiovascular issues.

Active B12 and Active Folate Testing shows the breakdown of how much folate and B12 you have in an active vs inactive form in the blood.