What the MTHFR?!

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Testing for an MTHFR mutation is a bit of a hot topic in the Functional Medicine community lately. With a fairly simple blood draw or saliva sample, your primary care physician can easily test for the C677T or A1298C mutation. 23andme.com offers testing of a wider span of MTHFR variants, along with many other genetic SNP’s. With such easy access, many people seeking optimal health, or looking to uncover the underlying factors of their disease states, have turned to this genetic testing as a potential answer. Much of the information revolving around the impact of having an MTHFR mutation is considered controversial, and not all of the MTHFR SNP’s have a lot of scientific work behind them just yet. To better understand what the MTHFR gene is, and why it’s important, we must first understand what methylation is, as this the process in the body that is most heavily impacted by a variance of the MTHFR gene.

 What is Methylation?

Methylation is a process in your body wherein a single carbon and three hydrogens, known as a methyl group, are applied to a multitude of critical functions in your body. These include but are not limited to thinking, repairing DNA, turning on and off genes, fighting infections and viruses, and getting rid of environmental toxins. When we extrapolate “getting rid of environmental toxins” to the larger picture of health, what this means is that those with an MTHFR mutation will have some level of impairment when it comes to detoxification. A detoxification impairment leads to high levels of inflammation and nutrient depletion (because your body is frantically trying to detox). High levels of inflammation are being shown to be the root of many diseases that we have not been able to “cure” with conventional medicine. These include, but are not limited to:

Autism

ADHD

Fibromyalgia

Chronic Fatigue Syndrome

Lupus

Multiple Chemical Sensitivity

Hashimoto’s and Hypothyroidism

Graves and Hyperthyroidism

Schizophrenia

Anxiety

Depression

Chronic Viral Infections

Neural Tube Defects /Midline Deficiencies (Spina Bifida, Cleft Palate, Tongue Ties, Penile Adhesions)

Diabetes

Capillary Hermangioma

Frequent Miscarriages

Bipolar Disorder

Methylation pathways in all individuals are impacted by aspects like a highly refined diet of flour and sugar and processed foods, high sugar intake, high additive and preservative intake, high pesticide exposure, high toxin exposure such as mold or heavy metals, and low nutrient intake. Considering that many Americans are exposed to these things and also may have an MTHFR mutation, it’s easy to understand why this is an issue that bares addressing. External toxins, which increase overall toxic load, are also something that will impact the ability of the body to properly methylate. While not a complete list, some of these things are VOC’s (Volatile Organic Chemicals) from paint, air “freshener” plug in scents, perfumes, endocrine disrupters in skincare, flame retardants in your furniture, Lyme disease, vaccinations, smog, fabric softener, fragrance in detergent, triclosan…. So the crux of this is that you can be a person with a variant of the MTHFR gene, and you can be extremely careful about reducing your toxic load, and you can actually be a “better” methylater than someone without a mutation, who is constantly and chronically exposed to toxins.

 

What is an MTHR Mutation?

 THE BASICS

We have two copies of most of the genes we are born with – one from our mother and one from our father. MTHFR mutations are actually quite common, and researchers suspect there are at least 30 different types. C677T and A1298C are the most well-studied and tested MTHFR mutations. This number and letter sequence refers to what is known as a single nucleotide polymorphism or SNP (pronounced “snip”).

There are several ways these genes can be expressed- no mutations present (-/-); One mutated gene or heterozygous (+/-), and 2 copies of a mutated gene or homozygous (+/+). A heterozygous mutation means you have one copy of the mutant allele on the MTHFR gene. A homozygous mutation means you have two copies of the same mutant allele, which is sometimes considered more severe. Heterozygous mutations (+/-) may differ from homozygous mutations (+/+) in associated disease risk since a person with a heterozygous mutation will often still have one fully functioning copy of the gene. There is also compound heterozygous, which is when you have one mutant allele on both the 677 and 1298 base position- this is also implicated in more severe methylataion issues based on the effects of a mutation.

Take C677T for example (also written as C677>T)

While a “normal” MTHFR gene would be C677C (c = cytosine), a mutation/polymorphism has made the gene C677T (t = thymine). Carriers of this T allele produce MTHFR enzymes that are misshapen and thus less efficient, which can potentially lead to issues associated with an MTHFR mutation. Carriers of a homozygous mutation on this gene would look like T677T. The enzyme that is produced from a gene with this mutation is even more misshapen and even less efficient that one produced by a gene with a single mutation. MTHFR is a critical enzyme in the body. It’s required for a metabolic process that repairs DNA, switches genes on and off, and numerous other important functions. Not to be confused with the enzyme, the MTHFR gene provides the instructions for making that MTHFR enzyme. In other words, it “triggers” production of the enzyme. A mutation in the MTHFR gene may therefore affect enzyme function.

The gene can also be written with all letters placed after the numbers. So C677T and A1298C can also be written as 677CT and 1298AC, respectively.

This brief list helps to make more sense of the entire concept.

  • MTHFR C677C = normal MTHFR gene

  • MTHFR C677T = heterozygous mutation (one mutation)

  • MTHFR T677T = homozygous mutation (two mutations)

  • MTHFR A1298A = normal MTHFR gene

  • MTHFR A1298C = heterozygous mutation (one mutation)

  • MTHFR C1298C = homozygous mutation (two mutations)

  • MTHFR C677T + MTHFR A1298C = a compound heterozygous mutation in some combination of C677T + A1298C, C677T + A1298C,  C677T + A1298C, or C677T + A1298C.

It is also important to understand that having a gene with a mutation does not mean that the gene is defective or nonfunctioning, only that it is working with an altered efficiency. Sometimes this means that it is working at a decreased level, but it could also mean that it is functioning at a higher than normal efficiency, or that the gene is lacking regulatory mechanisms normally involved in its expression. Although mutations can occur at any time during our lifetime, it is most likely that we are born with these mutations and will have them throughout our life. These inherited mutations have been passed down to us from previous generations (our parents and grandparents) and may be passed to future generations (our children). This may provide an explanation as to why certain traits or diseases “run in the family”. Although we cannot change our genetic code, we can change how our genes are expressed. Research has revealed that our gene expression is not determined solely by hereditary factors, but it is also influenced by our diet, nutritional status, toxic load and environmental influences or stressors. This phenomenon has been termed “epigenetics”. Researchers in the growing field of epigenetics have demonstrated that certain genes can be over- or under-expressed with certain disease processes. Researchers in this field hope that by understanding of how these genes are regulated and what is influencing them, we may be able to change their expression. Using epigenetic concepts along with a good understanding of the methylation cycle, researchers have begun to make recommendations to optimize genetic expression and help to restore health.

MTHFR is a critical enzyme in the body. It’s required for a metabolic process that repairs DNA, switches genes on and off, and numerous other important functions. Not to be confused with the enzyme, the MTHFR gene provides the instructions for making that MTHFR enzyme. In other words, it “triggers” production of the enzyme. A mutation in the MTHFR gene may therefore affect enzyme function.


MTHFR C677T and A1298C and Homocysteine

One of the biggest concerns for those with an MTHFR mutation is the effect it may have on homocysteine levels in the blood.

Homocysteine is an amino acid linked to a wide range of health problems, and is an independent risk factor for heart disease, stroke and other forms of cardiovascular disease. It is naturally formed in the body, but gets broken down (recycled) by L-methylfolate (active folate). Said another way, a lack of L-methylfolate can lead to an increase in homocysteine. MTHFR mutations directly impact the ability of the body to turn folate into L-methylfolate. Although diet and lifestyle are major influences, your genetics are thought to be responsible for between 45-60% of the variance in plasma (blood) homocysteine levels in normal adults. Of that genetic variance, C677T mutations are thought to account for between 24-53% of all cases.

Research shows that regardless of how much folate you consume, homozygous C677T (T677T) subjects always have significantly lower folate levels than heterozygous C677T. Subsequently, they also have remarkably higher homocysteine concentrations than everyone else; most pronounced when folate intake is low.


Other Health Effects

The process of methylation and the conversion of homocysteine to methionine play an important role in protecting both physical and mental health. Methionine is essential for producing glutathione, the body’s primary antioxidant. The liver also converts methionine into SAM-e, a chemical that helps metabolize brain chemicals dopamine, serotonin, and melatonin. Therefore, it is possible that a defect in the MTHFR gene may promote high levels of homocysteine levels in the blood, negatively affecting mental health and mood.

In the case of an MTHFR mutation, an inability to process folic acid (vitamin B9) can have serious effects. For one, a developing fetus can suffer brain defects like spina bifida or anencephaly if the mother has a severe defect in the gene. Other midline deficiencies such as cleft palates, tongue ties, and penile adhesions are now being linked to mothers with MTHFR mutations. Folate deficiency can also result in lethargy, impaired cognitive function, and mood disorders. Folate deficiency directly impacts glutathione production as well. Glutathione is considered the “master antioxidant” in the body, and when glutathione levels are low, it can lead to symptoms involved in Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, and Fibromyalgia. Low glutathione is also linked to progressive diseases such as ALS, MS, Alzheimer’s, and Parkinson’s.

As mentioned previously, a defect with the MTHFR gene can cause an abnormally high level of homocysteine in the blood. High levels of homocysteine are associated with cardiovascular disease, high blood pressure, glaucoma, ischemic stroke, and atherosclerosis.  Research links migraines and mental disorders (schizophrenia, bipolar disorder, and depression) to inadequate methylation resulting from variances of the MTHFR gene. 98% of those diagnosed with Autism have an MTHFR mutation, and anywhere from 90-94% of those with an ADHD diagnosis have an MTHFR mutation. A defective MTHFR gene producing a defective enzyme and results in an inability to detox heavy metals and toxins, leading to high copper or high mercury levels. High copper levels can result in zinc levels falling, and there is a link between high copper/low zinc and ADHD symptoms. High copper levels can contribute to an inability to raise iron or ferritin levels, and low iron levels are common in children with ADHD. Some research has also examined the effects of the gene defect on influencing the development of certain cancers. The free radical damage and toxic buildup that results from poor methylation, for example, may contribute to certain cancers. Those with hypothyroidism may experience problems associated with a MTHFR defect, mainly because the thyroid produces hormones needed by the MTHFR gene, as well as the high copper/low zinc issue.


MTHFR A1298C

MTHFR A1298C is involved in converting 5-methylfolate (5MTHF) to tetrahydrofolate (THF). Unlike MTHFR C677T, the A1298C mutation does not usually lead to elevated homocysteine levels. Instead, this reaction helps generate BH4. BH4 is important for the detoxification of ammonia. The gene is compromised about 70% in MTHFR A1298C (+/+) individuals, and about 30% in people with a heterozygous (+/-) mutation. BH4 acts as a rate limiting factor for the production of neurotransmitters and catecholamines including serotonin, melatonin, dopamine, norepinephrine, and epinephrine. A MTHFR A1298C + status may cause a decrease in any of these neurotransmitters or catecholamines, potentially leading to anxiety, depression, and other mental illnesses.  A dysfunctional BH4 enzyme may lead to mental/emotional and/or physical symptoms. Mercury, lead, and aluminum may act as a drain on BH4. Impaired detoxification pathways via non-methylation of B12 and folate can lead to heavy metal poisoning if exposed. This includes more minor exposures, such as to the aluminum in vaccines. Individuals with an MTHFR A1298C mutation should be wary of metal implants and amalgam fillings as well.

BH4 is also a cofactor in the production of nitric oxide. A lack of BH4 production can lead to a lack of NO. Some of the things NO does in the body:
• Help memory and behavior by transmitting information between nerve cells in the brain
• Assist the immune system at fighting off bacteria and defending against tumors
• Regulate blood pressure by dilating arteries
• Reduce inflammation
• Improve sleep quality
• Increase your recognition of sense (i.e. smell)
• Increase endurance and strength
• Assist in gastric motility

 

MTHFR C677T

This mutation is mostly associated with reduced enzyme activity, elevated total homocysteine levels and altered distribution of folate. People with a heterozygous mutation experience a 35% decrease of the normal enzyme activity and homozygous individuals a 70% decrease. The reduction of activity of the MTHFR enzyme (which is triggered by the MTHFR gene) has several metabolic cascade effects.

  • Homocysteine is poorly converted to glutathione, which is your body’s chief antioxidant and detoxifier. You are then more susceptible to stress and toxin buildup.

  • Less methionine can raise your risk of arteriosclerosis, fatty liver degenerative disease, anemia, increased inflammation, increased free radical damage, and less SAM-e production.

  • Less SAM-e can lead to depression.

  • An MTHFR defect can increase your risk of a variety of cancers (including breast and prostate cancer), stroke, various heart problems, congenital defects, depression, IBS (irritable bowel syndrome), miscarriages, migraines, chemical sensitivities and many other conditions.

  • Without conversion of B12 and folate to active forms, the inactive forms build up in the body, further inhibiting the active forms that are there. Most serum folate tests are actually measuring folic acid, which needed to be converted to methylfolate to be used metabolically.

Individuals with a homozygous C677T mutation should begin with a low dose of methylated B vitamins, and increase their doses to tolerance. If anxiety or depression onsets or becomes worse, the dose of methylated supplements should be lessened.

MTHFR Mutations Don’t Directly Make You Unwell

But they may cause an exaggerated response to poor diet or lifestyle choices that others can “get away with”. Medication that robs your body of nutrients is another important aspect to consider when looking into how methylation issues may impact you. If you are on medication, do not stop taking it without consulting with your doctor!


Some of the biggest offenders are as follows:

Acid blockers and ant-acids- These drugs deplete the probiotics, or flora, in your gut. A healthy gut flora means not only healthy digestive function (read: nutrient absorption) but also there is a multitude of research on the gut-brain axis and it’s impact on mental health. Reduced probiotics also lead to a reduced ability to produce B12, which is necessary to drive the methylation pathway.

Cholesterol binding drugs- These drugs will deplete your stores of Vitamins A, D, E, and K, all of which are imperative in a healthy inflammatory response. They also reduce one’s ability to absorb folate and cobalamin (B12) from the food you eat. A reduced intake of folate and B12 impedes the methylation process, as mentioned above.

Nitrous Oxide- This is the “laughing gas” you receive at the dentist. It severely depletes your B12- which again, is a necessity for driving the methylation pathway, among other important processes in your body.

Anti-Seizure Drugs- ALWAYS CONSULT WITH YOUR DOCTOR BEFORE STOPPING ANY MEDICATION, especially anti-seizure medication. Many anti-seizure medications deplete your folate levels.

Hormonal Birth Control and Hormone Replacement Therapy- These medications are well known for depleting folate and B12 stores.

Sulfa-containing drugs- These drugs inhibit the methylation pathway by inhibiting the enzyme DHFR, which produces di-hydrofolate, an intermediary in the production of 5-MTHF.

Methotrexate- Often prescribed for Rheumatoid Arthritis, this drug works by antagonizing the absorption and use of of folate. Ironically, many patients with Rheumatoid Arthritis have an MTHFR mutation.

Metformin- This Type II diabetes medication rapidly depletes B12 levels, which again is needed to push the methylation process.

 

This is why dietary and lifestyle considerations are fundamental for certain MTHFR mutations. As the saying goes, “Genes load the gun, environment pulls the trigger.” Reducing your overall toxic load is vital when making sure your methylation pathways are functioning as close to normal as possible. Eating organic produce and organic, pastured and humanely raised meat, and eliminating grains, particularly gluten, will reduce the toxins and inflammation in your body greatly. Farmers markets are a great place to purchase affordable produce that while it may not have a USDA organic seal, is likely grown with even higher standards regarding chemical use. Learning which ingredients to avoid in skincare and laundry detergent will reduce the number of xenobiotics and xenoestrogens you absorb as well. Switching your household cleaners and using an air purifier will reduce toxins in home, as well as cleaning out your indoor air. Be cautious in receiving vaccinations as they place a high toxic burden on the body and can often be the “straw that broke the camels back” in regards to development of health problems. Overall, if you discover that you have an MTHFR mutation, take extra steps to decrease your overall toxic load and take control of your health!

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