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MTHFR Gene Mutation: Variants, Symptoms, and How to Test for It

MTHFR Gene Mutation: Variants, Symptoms, and How to Test for It

The terms MTHFR, methylation, and L-Methylfolate have received a lot of attention in recent years. However, much of the information provided by unqualified sources can be very confusing.

When it comes to understanding MTHFR, it's important to know how to distinguish fact from fiction.

We here at Methyl-Life® are experts on methylation, L-Methylfolate, and health issues caused by MTHFR. We’d like to help you understand the significance of an MTHFR gene mutation— and what it could mean for you— without the scientific jargon. 

What is the MTHFR gene?

MTHFR stands for methylenetetrahydrofolate reductase which is the enzyme produced by the MTHFR gene. 

    The MTHFR gene contains the DNA code to produce the MTHFR enzyme. This enzyme converts the folate you ingest— whether through food or supplements— into the active form of folate, L-5-Methyltetrahydrofolate (or sometimes referred to as 5-MTHF). This is the form that your body needs to use at the cellular level. 

    5-MTHF is important because it’s your body’s most biologically active form of folate. It is the only form naturally found in your bloodstream and is therefore the type of folate used for cellular metabolism and important tasks like:

  • increasing SAMe and therefore serotonin (to improve mood),
  • reducing homocysteine (to support cardiovascular, reproductive and nerve health),
  • boosting glutathione (to enhance detoxification),
  • and supporting cognitive health by crossing the blood-brain barrier.

5-MTHF works alongside vitamin B12 as a methyl group donor, which means it’s involved in a huge range of metabolic and nervous system processes. It’s also vital to numerous metabolic pathways in the body.

The other big job of folate metabolism is converting the amino acid homocysteine into methionine.

However, the MTHFR gene has the potential to mutate. This mutation has been associated with an enormous range of health issues affecting everything from your physiology to your cognitive function.

Also Read: MTHFR Newbies

What is an MTHFR mutation?

Each MTHFR gene SNP (single nucleotide polymorphism) has two copies. You inherit one copy of each SNP from each of your biological parents. 

An MTHFR mutation occurs when one (or more) single nucleotide polymorphisms (SNPs) operate in a ‘varied’ or ‘atypical’ way. It is considered ‘abnormal’ because it negatively affects the regular enzyme production and therefore biochemistry of the body. SNPs refer to a specific position in the genetic material, for example, the MTHFR gene has over 70 different SNPs that deal with folate metabolism. However, only 2 specific MTHFR SNPs are considered ‘well-known’ - mainly because most of the studies have really only been done on these 2 polymorphisms, 677 & 1298, even though many more exist in your body.. 

Abnormal variations of these MTHFR SNPs can be either heterozygous (one variant) or homozygous (two variations). These common variants are passed down from your parents. The more variations you have, the more problems your body will have with methylation.

Note: An MTHFR test result will only show information based on these two ‘well-known’ MTHFR SNPs (677 or 1298), even though other variations may exist on lesser-known SNPs in your body.

A mutation in the MTHFR gene typically results in an insufficient or malfunctioning MTHFR enzyme. The MTHFR gene mutations will affect the enzyme’s ability to function normally because it creates a slightly varied shape (which means certain downstream processes can’t happen correctly). Think of it like a key that’s being generated from a master copy - if it’s even slightly off-shape, then it will not be able to open the door you want. The same is true for an MTHFR variant - because it is making misshapen enzymes, those enzymes can’t properly do all their job functions.  

This impaired function of the MTHFR enzyme leads to significantly low levels of folate and 5-MTHF (active folate in the body). 

A common MTHFR polymorphism in the gene coding for the 5,10-MTHFR gene (C677T) is associated with a decreased activity of the enzyme due to thermolability (destruction or change in response to heat).

You can have either one or two mutations (or variants) on each MTHFR gene SNP or none at all. One MTHFR gene variant is considered heterozygous while two variants would be considered homozygous. For our 2 well-known SNPs, it might look like this (download a more detailed explanation of interpreting test results):

  • SNP - 677
    ○ CC677 - this is considered the typical wild type, which means no variants and normal enzymatic production and function.
    ○ C677T - one variant or heterozygous, which means one part of your SNP’s enzymatic production and function is normal and the other part is not.
    ○ 677TT - two variants or homozygous - this means both parts of your SNP’s enzymatic production and function are NOT normal.
  • SNP - 1298
    ○ AA1298 - this is considered the typical wild type, which means no variants and normal enzymatic production and function.
    ○ A1298C - one variant or heterozygous, which means one part of your SNP’s enzymatic production and function is normal and the other part is not.
    ○ 1298CC - two variants or homozygous - this means both parts of your SNP’s enzymatic production and function are NOT normal.

It’s generally believed that a homozygous mutation is much more likely to contribute to medical conditions than a heterozygous mutation. One study found that family members with a homozygous mutation were morbidly obese, while those with heterozygous mutations were either mildly overweight or had no discernable weight issues.

The Two Well-Known SNPs of MTHFR Gene Variants

Two common MTHFR mutations which have been most studied are:

  • MTHFR C677T / MTHFR 677TT
  • MTHFR A1298C / MTHFR 1298CC

It’s estimated that 30-40% of the United States' population may have a mutation at gene position C677T. Around 25 percent of people of Hispanic descent are homozygous for this variant (677TT), along with 10-15 percent of Caucasians.

Like the C677T mutation, A1298C mutations result in reduced MTHFR activity that is more significant in the homozygous (1298CC) than in the heterozygous (A1298C) or normal states (AA1298). It also doesn't result in a thermolabile protein.

The specific MTHFR variants found on (677 and 1298) result in changes in the DNA (or mutations) that are associated with decreased MTHFR enzyme activity. This means lower levels of L-5-Methylfolate which may in turn lower neurotransmitter levels responsible for mood, like serotonin. It also means high levels of homocysteine may accumulate in the blood, which could increase the risk of premature cardiovascular disease (CVD), the formation of inappropriate blood clots (thrombosis), and stroke.

Approximately 5-14% of the American population is homozygous 677TT, which means they have two copies of the varied gene SNP. There is some ethnic variability in the frequency, with the highest being in those of Mediterranean ancestry and the lowest in African-Americans. 

The C677T & 677TT variants result in a less active form of the MTHFR enzyme, which hinders the body's ability to process folate and homocysteine. 

When a person has both an MTHFR C677T gene mutation (heterozygous) as well as a copy of A1298C, they are said to be compound heterozygous. Many doctors consider this to be a more severe double mutation type. A1298C + C677T results in decreased MTHFR enzyme activity which in turn slows down the homocysteine-to-methionine conversion process. This can lead to an excess buildup of homocysteine in the blood.

The increase in homocysteine is often mild to moderate but will vary from person to person depending upon the amount of MTHFR enzyme activity. Even if someone has two copies of the MTHFR mutation, they may not develop high homocysteine levels since adequate methylfolate intake can "cancel out" the effect of the MTHFR mutation. 

The National Center for Advancing Translational Sciences explains that it's not only important to think about if the variants put you at risk, but how much risk.

Scientists are now learning more about how SNPs may correlate with particular conditions in patients.

It’s worth noting that there are much rarer cases where a triple mutation exists. This would be one SNP resulting in a homozygous variant and the other SNP as a heterozygous variant - see both cases of a triple MTHFR mutation below:

  • 1298CC + C677T
  • 677TT + A1298C

Theoretically there is such a thing as a quadruple mutation, but it is so rare that few survive very long with this kind of mutation status due to the many health complications. It looks like: 1298CC + 677TT

Unfortunately, the College of American Pathologists among others have published recommendations against testing for MTHFR variants since 2001, as they believe it has little impact on homocysteine levels. Many doctors and naturopaths see things quite differently in their clinical practices.

MTHFR Symptoms and Health Conditions

Methylation dysfunction can be linked to a variety of disorders and conditions. Some MTHFR symptoms in adults and children include:

  • Behavioral disorders such as
        Addictive behavior
  • Autoimmune diseases
  •  Allergies
  • Alzheimer’s disease
  • Anemia
  • Anxiety
  • Bipolar disorder
  • Cardiovascular disease such as
        heart attacks
        deep vein thrombosis
        blood clots
        pulmonary fibrosis
  • Chemical sensitivities
  • Chronic fatigue syndrome
  • Depression
  • Dementia
  • Diabetes
  • Environmental and heavy metal toxic build up
  • Fibromyalgia
  • Hair loss
  • Infertility
  • Immune dysfunction
  • Insomnia
  • IBS(Irritable Bowel Syndrome)
  • Migraines
  • Miscarriages
  • Neural tube defects
  • Neuropathy
  • OCD (Obsessive Compulsive Disorder)
  • Schizophrenia
  • Thyroid (dys-) function

Other conditions may include:

  • Cardiovascular issues such as high blood pressure, blood clots, coronary artery disease, and increased risk of heart disease due to reduced folate levels.
  • Thrombophilia, an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels).
  • Colon cancer has been linked to both DNA hypomethylation and DNA ‘breaks’.
  • MTHFR clotting disorder. While the MTHFR mutation is not a clotting disorder in itself, elevated homocysteine levels are. Individuals with MTHFR mutations who have normal homocysteine levels are not at increased risk for clots.
  • Stroke. Research suggests that the TT genotype of the methylenetetrahydrofolate reductase 677TT polymorphic gene is an important determinant for homocysteine levels in Malaysian ischaemic stroke patients.
  • Pregnancy Complications.

Existing data suggests that pregnant women with two MTHFR gene variants (677TT) are twice as likely to have a child with a neural tube defect, though the risk is still low. This guide has an entire section with more information on MTHFR and pregnancy which you can find here.

The MTHFR mutation affects your ability to process specific amino acids and B-vitamins, namely homocysteine and folate.

This means that many conditions associated with these enzymatic imbalances which stem from the MTHFR mutation may develop over time.

MTHFR and Folate Deficiency

As mentioned above, the MTHFR gene contains the DNA code necessary to produce the MTHFR enzyme. This enzyme is required to convert the folate you eat (dihydrofolate) into the form that your body can directly use (methyltetrahydrofolate).  

Symptoms of folate deficiency can include:

  • Fatigue, lethargy
  • Muscle weakness
  • Neurological symptoms such as pins and needles, tingling or burning in the limbs
  • Peripheral neuropathy (i.e. a numbness in the extremities)
  • Psychological issues such as major depression, confusion, poor memory
  • Gastrointestinal issues such as nausea, vomiting, abdominal pain, weight loss, constipation and diarrhea
  • Headache and dizziness, pallor, shortness of breath*

* These are also symptoms of anemia. Anemia is often the first sign of an underlying folate deficiency.

MTHFR and B12 deficiency

Vitamin B12 deficiency is more common in the elderly, vegans and vegetarians. However, even meat-eaters may be unable to absorb sufficient nutrients or have other health issues that interfere with their body’s ability to manufacture the vitamin efficiently, such as those who have MTR and MTRR gene mutations. 

MTHFR mutations impact the body’s ability to use vitamin B12 because it reduces the amount of active folate being produced in the body. B12 requires the active form of folate in order to be absorbed.  

Signs that your body is low or deficient in vitamin B12 can include:

  • Extreme and/or ongoing fatigue
  • Lack of energy
  • Poor appetite
  • Feeling dizzy or faint
  • Headaches
  • Numbness or tingling in the limbs
  • Dermatitis
  • Ringing in the ears
  • Feeling out of breath
  • Confusion or brain fog
  • Anxiety and/or paranoia
  • Pale or yellowed skin
  • Hair loss
  • Parkinson’s symptoms

MTHFR Testing

Most doctors don’t usually test for MTHFR unless they are already testing for high plasma homocysteine levels. The homocysteine blood test may only be taken when a doctor suspects a deficiency in vitamin B12, B6, or folic acid, and/or high homocysteine levels. Some doctors may test for homocysteine levels based on past cardiovascular health issues.

According to the American College of Medical Genetics, MTHFR polymorphism testing is most often ordered by physicians when evaluating a patient for thrombophilia. Knowledgeable fertility and pregnancy doctors (OBGYNs) may check a patient’s MTHFR status if she is having difficulties getting pregnant or having miscarriages.

Fortunately, it is possible to request an MTHFR-specific blood test yourself - just ask your doctor. Be sure to check if your insurance company covers genetic testing though, as some policies do not. 

Alternatively, you can pay out of pocket to get a genetics saliva kit test sent to your house which covers many genetic SNPs, including MTHFR. 23andme is one such company that offers this kind of testing.

So, why test for MTHFR yourself?

A MTHFR test can be a lifesaver. It can provide insight into a huge range of physiological and mental health issues. 

You may want an MTHFR test result if you have high homocysteine levels, or family members with homocysteine-related issues. You should also have an MTHFR test if you have family members dealing with depression, mental health issues, heart disease, or blood vessel disorders. Those who are considering starting a family are also encouraged to get an MTHFR test to check for a variety of reproductive health issues.

Testing options include:

  • Homocysteine blood tests
  • Genetic testing for MTHFR mutations performed in a lab setting through blood test
  • At-home genetic testing for MTHFR mutations (this can be a saliva kit, a cheek swab kit, but can also be a finger prick blood drop test kit as well)

A homocysteine test is designed to:

  • Measure homocysteine (amino acid) levels in blood
  • Identify a deficiency of folate and/or Vitamin B12
  • Screen for the risk of heart attack, stroke, and homocystinuria

The cost of a test ranges from $68-$79, depending on the clinic, and is often covered by insurance. Test results are available within 1-5 days. You will need to fast for at least 10 to 12 hours before the test. You may also have to stop certain medications or supplements as they can influence homocysteine levels and contribute to an inaccurate test result.

An MTHFR test is designed to detect two of the most common mutations on the MTHFR gene. Although it is not routinely ordered, health care providers may request a test as a follow-up to an elevated homocysteine test or after fertility and pregnancy complications such as miscarriages. It may also be ordered if the patient has a risk of cardiac issues or close relatives with known MTHFR genetic mutations. 

The MTHFR test is not offered in every laboratory. Blood samples are usually sent to a reference laboratory for testing.

At-home genetic testing kits for MTHFR include:

  • 23andMe ($200): Saliva test that provides genetic ancestry and additional information. Results take 6-8 weeks.
  • My Home MTHFR ($150): Swab test (from inside of cheeks) detects the mutation. Results take 1-2 weeks.
  • Dr. Amy Yasko’s DNA Nutrigenomic Buccal Swab Test ($495): Detects the MTHFR mutation along with 29 other key health-related SNPs. This pricing also gets you a vast amount of per-SNP ‘nutritional therapy’ information from Dr. Yasko, as well as access to support forums. Dr. Yasko has focused her work on how genetics impact autism. Results take 5-7 weeks.

MTHFR Treatment

An MTHFR mutation doesn’t necessarily mean you will experience all of the associated symptoms or health issues. Medical treatment is usually only required if your homocysteine levels are very high or if you are dealing with depression that is not responding to traditional medication.

Symptoms can depend on which variant of the mutation you have and whether the variations affect both MTHFR genes.

The good news is that knowing you have an MTHFR mutation is an incentive to make appropriate lifestyle changes that maximize your methylation and reduce the risk of symptoms.

Supplementation with methylfolate and other vitamins is a priority. Certain nutrients are crucial to the proper functioning of your body, and taking these nutrients in the form of supplements can make an enormous difference to your overall health.

Supporting your body’s ability to detoxify properly is also important. Impaired methylation can hinder your body’s detoxification pathways, especially in the liver. This means it’s more important than ever to support your natural elimination processes.

Some ways to support your body include:

  • Increase fiber intake to 30-50 grams per day
  • Drink at least 2 liters of pure, filtered water per day (you may even wish to consider an alkalinizing machine)
  • Eat plenty of anti-inflammatory foods such as:
            ○ Brightly colored fruits and vegetables
            ○ High-quality protein
            ○ Healthy fats such as Omega 3s/DHA, MCTs, etc.
  • Avoid or limit all refined sugars
  • Get active by exercising at least five days a week for 30 minutes a day
  • Attend regular sauna treatments and Epsom salt baths
  • Avoid or limit exposure to environmental factors such as:
            ○ pollution,
            ○ molds,
            ○ heavy metals,
            ○ BPAs,
            ○ chemicals found in cleaners, etc. You might consider a good air cleaner for your home.
  • Avoid artificial additives in food
  • Reduce or limit alcohol intake

Monitor your diet and make sure you are eating foods which increase your dietary intake of folate and vitamin b12. Keep in mind that many of the above items to avoid can impair methylation further. 

Supporting a healthy gut can also help you manage your MTHFR symptoms. You can also try to avoid certain foods which cause inflammation (i.e. gluten, dairy and sugar are the big ones that many natural doctors will recommend you avoid or drastically reduce).   

MTHFR and Pregnancy Complications

The MTHFR mutation may be associated with recurrent miscarriages and neural tube defects. Some research suggests that women who have the double 677TT variant are at a higher risk of having a child with a neural tube defect.

It has also been shown that the C677T and A1298C polymorphisms can lead to a folate deficiency, as well as increased levels of plasmatic homocysteine. 

Health risks in pregnancy can include:

  • Anencephaly (in which a baby is born with an underdeveloped brain and an incomplete skull)
  • Neural tube defects, such as spina bifida
  • Birth defects or other human development complications
  • Unexplained, recurrent miscarriages

A 2006 study found that 59 percent of women with a medical history of recurrent miscarriages had multiple homozygous gene mutations, including MTHFR. These complications are associated with blood clotting.

Women are advised to speak with their doctor about testing if they are pregnant and have a known MTHFR mutation or have had:

  • Multiple unexplained miscarriages.
  • A child with a neural tube defect

Doctors may suggest taking blood clotting medications, although there is a lack of evidence to support this. Extra folate as methylfolate (not through folic acid supplementation) or MTHFR prenatal vitamins may also be recommended.

Some reports claim that babies can show physical signs of MTHFR mutations. These are known as “MTHFR midline defects” and include MTHFR stork bites (a common and usually temporary birthmark), and an MTHFR sacral dimple (a small dent in the baby’s lower back). These are not MTHFR variant indicators and do not require medical management. 

MTHFR Diet and Foods to Avoid

Optimizing your body’s methylation processes begins with making changes to your diet and lifestyle. Eating the right foods - and avoiding the “wrong” ones - can help to reduce your risk of symptoms and improve your overall health. 

Increase Dietary Intake of Folate

Dietary folate is the natural, usable form of the vitamin as it occurs in food. Eating folate-rich foods is a good way to improve methylation. 

Women are advised to speak with their doctor about testing if they are pregnant and have a known MTHFR mutation or have had:

  • Dark leafy greens
  • Fruits and fruit juices
  • Nuts
  • Beans
  • Peas
  • Seafood
  • Eggs
  • Dairy products
  • Meat
  • Poultry
  • Grains

It’s worth noting that many dealing with an MTHFR mutation will need to supplement their folate food intake with the active form, methylenetetrahydrofolate or methylfolate for short. Because even if you eat more folate-rich foods, that dihydrofolate form still needs to be converted into methyltetrahydrofolate. Without L-5-Methylfolate, the active folate enzyme, your body cannot properly stimulate important downstream processes like:

  • Boosting SAMe and therefore neurotransmitters like serotonin
  • Reducing homocysteine to support cardiovascular, reproductive, and nerve health
  • Increasing glutathione to enhance detoxification
  • Aiding cognitive balance and brain health

The MTHFR gene has to do this conversion work from the dietary folate form (DHF or dihydrofolate) into the cellular folate form (5-MTHF or methylfolate). And if you have an MTHFR mutation(s), this is where your body needs a real workaround. The easiest way to circumvent these mutations is to simply take the active form of folate via a vitamin supplement. This way you are bypassing the concern altogether that your body is unable to convert folic acid into the necessary folate enzyme.

Increase Dietary Intake of Vitamin B12

As mentioned above, two other common genetic SNPs, MTR and MTRR, may have significant impacts on the conversion and absorption of B12 in the body. 

Because B12 and methylfolate work together on the methylation pathway, you often need both nutrients together in order to circumvent significant health issues. MTHFR mutations may also increase your risk of Vitamin B12 deficiency. 

Food sources of B12 include animal products such as: 

  • Fish
  • Meat
  • Poultry
  • Eggs
  • Milk
  • Other milk products

Unfortunately, the fact that B12 is almost exclusively present in animal-derived foods means that vegans and vegetarians are often low or deficient in this very important nutrient. It’s worth noting that even meat-eaters can be deficient in B12 if they have some of the SNPs listed above (MTHFR, MTR, MTRR).

The best option for vegans and vegetarians is to supplement with a quality vegan-friendly B12 product. Supplementation with a highly bioavailable form of vitamin B12 (consider hydroxocobalamin, adenosylcobalamin or methylcobalamin). 

5,000 mcg is the most effective way to boost and maintain optimal levels of B12, as described below. 

Avoid cyanocobalamin, it requires too many complex conversions before it can be actively used by the body. It is cheap, but fairly ineffective for many.

Support Gut Health

A healthy gut microbiome will optimize your body’s ability to obtain nutrients from food, which in turn will support your overall health and wellbeing. 

Promote the health of your gut bacteria by eating fermented foods such as: 

  • Kimchi
  • Kefir
  • Miso

These contain natural probiotics that aid in digestion.

Eat more healthy fats, especially N-butyrate, a short-chain fatty acid that nourishes the cells which line the gut. N-butyrate occurs naturally in ghee and coconut oil.

Other gut-healing foods include bone broth, flaxseeds, chia seeds, and turmeric.

Finding an effective probiotic can also really help heal the gut.

What Foods and Ingredients Should be Avoided?

Those with MTHFR mutations are advised to avoid foods and supplements containing the synthetic form of folate, folic acid.

Folic acid simply clogs the methylation pipeline in your body that requires the MTHFR gene to generate the methylfolate enzyme. This already happens in a crippled way for those with MTHFR defects). So eating more folic acid is like creating a backup, which can lead to unmetabolized folic acid (UMFA) and other concerning side effects (UMFA has been linked in some studies to cancer).

Folic acid is added to many fortified breads, cereals, pasta, and other grain products. 

Reduce the intake of inflammatory foods such as sugar, gluten, refined grains, trans fats, and processed snacks.

Avoid gluten-containing foods where possible. Those with gluten sensitivity and MTHFR can suffer a double blow as the symptoms of both can amplify one another. Gluten is also a major cause of inflammation in the gut lining. 

Reduce or avoid dairy when you can. It has been suggested that dairy competes with the folate receptor and those with MTHFR may function better without it.

MTHFR Supplementation: B Vitamins and Supporting Nutrients

Knowing the difference between synthetic folic acid and methylfolate is the key to treating MTHFR. 

Synthetic folic is often used in fortified foods or cheap supplements. Doctors may even prescribe it. However, the MTHFR mutation seriously compromises your ability to convert folic acid into a form that your body can use (L-5-MTHF), so it’s important to avoid any supplements or foods that contain folic acid.

The main goal is to optimize methylation in your body. This means:

  • Supplementing with methylfolate, which is the active form of folate and does not require further conversion in your body before it can be absorbed and used. This means it bypasses your MTHFR mutation altogether.
  • Taking the nutrients that support the methylation process such as:
                ○ Magnesium
                ○ Omega 3 / DHA
                ○ NAC (N-acetylcysteine)
                ○ Glutathione
                ○ Vitamin D

Specific B vitamin supplements that are useful in managing MTHFR include:

  • 5-MTHF (active folate or L-methylfolate)
  • Hydroxocobalamin or Methylcobalamin (two active forms of vitamin B12)
  • Pyridoxal 5’-Phosphate (active vitamin B6)

5-MTHF (active folate)

Folate (vitamin B9) is required to produce methyl groups which in turn helps methylation to take place. However, MTHFR can result in an impaired ability to activate folic acid. 

The 5-methylenetetrahydrofolate reductase enzyme is required for the conversion of folic acid into its bioactive form 5-methyltetrahydrofolate (5-MTHF). 

Remember: folate, folic acid, and 5-methyltetrahydrofolate are NOT the same thing AT ALL! 

Many commercial supplements and pharmaceutical prescriptions use folic acid, which is a vastly inferior form of the nutrient that is not directly usable by the body. 

To become metabolically active, folic acid must first be converted to dihydrofolate (DHF) and then tetrahydrofolate (THF), 5,10 methyltetrahydrofolate, then 5 methyltetrahydrofolate (5-MTHF) through a complicated process of enzymatic reduction. As mentioned previously, this process cannot happen if you have an MTHFR genetic mutation that affects the required enzyme. 

5-MTHF is readily absorbed by the body even when metabolic defects are present. Meaning if you take methylfolate directly, it will completely bypass your MTHFR mutation(s). 

Methylcobalamin (active vitamin B12)

Along with methylfolate, B12 is another crucial ingredient in the conversion of homocysteine to methionine. It works alongside the enzymes that use folate to generate and utilize methyl groups.

These methyl groups are produced by a process called the ‘methylation cycle’ which involves various molecules within your body, including S-adenosylmethionine (SAMe), homocysteine, and methionine.

If your diet is not providing adequate B12 - or your body is unable to absorb it properly (which is common for many) - it’s vital that you take a quality B12 supplement to support your body’s needs. Deficiency in vitamin B12 or folate may lead to increased homocysteine levels (which is known to be a risk factor in cardiovascular and other diseases like diabetes, etc.). 

Pyridoxal 5’-Phosphate (active vitamin B6)

Pyridoxal 5'-phosphate (P5P) is also necessary for the recycling of homocysteine. It facilitates the break-down of homocysteine to taurine and cysteine.

P5P is also involved in the body's production of hemoglobin and intrinsic factor. It’s required for the healthy formation of the myelin sheath that surrounds and protects nerve cells.

Note: Pyridoxal-5-Phosphate can build up to toxic levels in some who are supplementing with this nutrient (you guessed it, due to another genetic mutation). These high levels of B6 can result in nasty tight-band headaches for those who take too much of this active nutrient.

So be aware, if you are getting headaches that stop when you stop taking the P-5-P, then consider reducing your dose to an amount where those headaches go away (otherwise you’re getting too much).


L-methylfolate is the most bioactive nutrient form of folate available. This means it is the form of folate that has already been converted, so it can be immediately used by the body’s cells. It’s also the only form of folate which can cross the blood-brain barrier.

Scientific studies have shown that Magnafolate® PRO, which is used in Methyl-Life’s® product line, is even more pure, stable and potent than competing brands Quatrefolic®, Metafolin®, 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 it’s patented Type C crystal molecule type offers superior particle size distribution, stability, dissolution, potency, bioavailability, safety and most importantly, purity.

Unlike folic acid, Magnafolate® is not likely to mask a vitamin B12-deficiency and it is the only form of folate able to cross the blood-brain barrier. Magnafolate® PRO effortlessly works around any MTHFR mutation and can be immediately absorbed and used by the body.

Every serving in Methyl-Life’s® B-Methylated II product contains a moderate dose (3 mg) of free L-Methylfolate as internationally-patented Magnafolate® PRO as well as 3.75 mg of Active B12 (as Methylcobalamin).

Be careful what you buy

if you’re seeing a competing product that shows 3 mg folate DFE on its label, it’s actually got less than half of the total methylfolate per serving when compared to a therapeutic product like, Methyl-Life’s® B-Methylated II (which actually contains ~8 mg folate DFE if compared using that same calculation method).

Don’t be confused by the label and purchase a less potent or less pure product - stick with the highest quality and most pure methylfolate you can buy.

Unmatched stability

Methyl-Life® sent out its 5-year-old products to be tested by a world-renown, folate-specialist lab in Switzerland (along with its top competitor’s products of the same age and dosage levels).
The findings were remarkable - the Methyl-Life® products came back showing they were still fully potent, even after sitting on the shelf for 5 years, and of course, the competitor’s products did not even meet their label’s claims.

Other supplements that can be helpful in managing MTHFR symptoms include:

  • Magnesium
  • Omega 3 / DHA
  • NAC (N-acetylcysteine)
  • Glutathione
  • Vitamin D


Magnesium is an essential mineral your body needs for more than 300 different enzymatic exchanges. It’s also a cofactor for the COMT enzyme, which is required for transferring a methyl group from SAMe to metabolize dopamine, norepinephrine, and epinephrine.

Alongside the B vitamins, magnesium is vital in supporting a healthy mood, cardiovascular and nerve function. Again, be sure to maximize your supplement dollar by getting the most bioavailable magnesium version possible. Consider a magnesium with a liposomal-like delivery mechanism for superior absorption.

Omega 3

This essential fatty acid has scientifically proven benefits for the entire body and mind, particularly mental wellbeing.

It travels easily through the blood-brain barrier to interact with mood-related molecules in the brain, and harbors powerful anti-inflammatory actions that may help relieve depression.

Two omega-3 fatty acids in particular — eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) — are shown to provide the greatest benefits for mood disorders. A 2018 review found that high doses of 1 g/DHA (from fish oil) per day have had significant benefits for depression.

NAC (N-acetylcysteine)

NAC is a precursor for glutathione, which has potent antioxidant and anti-inflammatory properties.

Researchers have described NAC as a neuroprotective nutrient, and recommend a ‘therapeutic cocktail’ of L-5-Methylenetetrahydrofolate, methyl B12, betaine (or TMG), and N-acetylcysteine (NAC) for helping to reduce levels of homocysteine in the body. This, in turn, can reduce the risk of neurodegenerative diseases such as Alzheimer’s.


A powerful antioxidant found in every cell in the body. It’s required for fighting off free radicals, making DNA, supporting immune function, and many more important processes.

It directly neutralizes free radicals, reduces inflammation, and enhances the effect of other antioxidants including vitamin C, E, and lipoic acid.

Glutathione’s sulfur groups aid in heavy metal detoxification by adhering to these toxic compounds and moving them out of the body. Glutathione also protects vitamin B-12 from reacting with toxins and being unable to perform its metabolic tasks.

Another of glutathione’s primary roles is as a precursor for a reaction in the methylation/folate cycle. A lack of active B-12 due to glutathione deficiency can slow down both these cycles. Low glutathione can contribute to the inefficiency of methylation, creating a vicious cycle and further depleting glutathione levels.

MTHFR savvy doctors suggest those dealing with methylation imbalances start first with methylfolate to boost glutathione naturally and then add in more glutathione if it’s still needed.

Many individuals don’t tolerate taking glutathione directly because of the detoxification it kicks off in the body. Many can become fatigued or feel like they’re experiencing flu-like symptoms as a result of excessive detoxification.

Vitamin D

Vitamin D is known for its role in the regulation of gene expression via the vitamin D receptor, a nuclear transcription factor.

Recent research has shown vitamin D is crucial in regulating DNA methylation, and is also involved as a mechanism of modulation of gene expression.

This is your excuse to soak up the sun rays. If you’re in a less than sunny place, like Seattle, make vitamin D3 your preferred form for supplementation.


An MTHFR mutation doesn’t have to mean that you are destined for ill health. Although this mutation has been associated with numerous health conditions and disorders, many of these are preventable and treatable as long as the right advice is followed. As with many symptoms which come from an imbalance in the body, nutrition can be altered to correct those imbalances and therefore treat and alleviate those symptoms.

The first step is to identify your MTHFR mutation through testing. Once confirmed, a MTHFR mutation can be seen as an opportunity to change your diet and lifestyle for the better. This is best done through proper supplementation, the right foods, and appropriate daily routines.

Supplementing your body with methylated vitamins is crucial. Taking a bioactive form of folate (methylfolate) that can be immediately used by your body’s cells is the only way to overcome your inability to convert folic acid.

This form of folate will provide your body with the nutrient required for proper homocysteine conversion, healthy DNA replication and repair, optimal cognitive function, and numerous other fundamental processes.

Choosing the right methylfolate supplement can be tricky. But Methyl-Life® has made it easy for you. We’ve created a comprehensive range of supplements specifically designed for people with MTHFR mutations - plus the information you need to overcome MTHFR-related issues for good. If you’re just getting started, this guide can help you choose the right supplements and options for you.

    Written By,
    - Jamie Hope



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