MTHFR (methylenetetrahydrofolate reductase) - TAWKI

MTHFR (methylenetetrahydrofolate reductase)

Have you noticed your serum Iron is high, your TIBC is high, your % Saturation is optimal or a bit high and Ferritin is low? Perhaps you had high B-12 levels and do not supplement and low folate? (or the opposite). High Heavy metals, or high Estrogen? Do you have a family history of Heart disease, Strokes, Cancer, Dementia, Depression? The MTHFR gene defect may be why.

In 2003, a genetic study called the Human Genome Project was completed. And via that study, they discovered that an important gene towards your health and well-being, called the MTHFR gene, Full name is methylenetetrahydrofolate reductase was defective in a high amount worldwide! Some state more than 60%.

This gene when working correctly helps break down needed metals for use in your body, like iron, or helps break down B12 for use, and other nutrients. It also helps to break down excess metals and toxins, which can be a serious issue when in excess. What this means is, when the MTHFR gene is not working correctly, you might see elevated levels of iron, or B12, or heavy metals…or a family history of heart problems or cancers to name a few, because heavy metals and toxins aren’t being eliminated from the body.

When it’s all working right, the MTHFR gene begins a multi-step chemical breakdown process, aka methylation, which is like this:

The MTHFR gene produces the MTHFR enzyme.

The MTHFR enzyme works with the folate vitamins (B9, folic acid), breaking it down from 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate

5-methyltetrahydrofolate helps convert the amino acid homocysteine down to another essential amino acid, methionine, which is used by your body to make proteins, utilize antioxidants, and to assist your liver to process fats. Methionine helps with depression and even inflammation. It also helps convert estradiol (E2) into estriol (E3)!

Methionine is converted in your liver into SAM-e (s-adenosylmethionine), which is anti-inflammatory, supports your immune system, helps produce then breakdown of your brain chemicals serotonin, dopamine and melatonin, and is involved in the growth, repair and maintenance of your cells.

A proper methylation pathway like the above is will eliminate toxins and heavy metals, which can reduce your risk for cancer, heart disease and other health issues, and put less stress on your adrenals.

Here is what an activated MTHFR mutation can do to you:

It produces a defective MTHFR enzyme of different varieties, it functions less than optimally, it may perform at only 40% of its capacity, or 70% of its capacity. It can mean you won’t break down toxins or heavy metals well when the gene is activated, causing a higher risk for issues like heart problems, cancers, miscarriages, etc. You could find yourself with high iron, copper, lead, mercury, uranium…it varies from person to person.

A way to see what metals might be high is ordering a HTMA test (Hair Tissue Mineral Analysis)

The defective enzyme (especially C677T) doesn’t break down folate vitamins properly (of which folic acid is the precursor to, but we take folate instead), which can cause high homocysteine, which can increase your risk of coronary heart disease (arteriosclerotic vascular disease or venous thrombosis), and related heart and Blood Pressure conditions, as well as increasing your risk for dementia due to lack of Vitamin B’s.

Homocysteine can be poorly converted to glutathione, which is your body’s chief antioxidant and detoxifier. you are then more susceptible to stress and toxin buildup.
Homocysteine can be poorly converted to methionine, and less methionine can raise your risk of arteriosclerosis, fatty liver degenerative disease, anemia (see Wiki), increased inflammation, increased free radical damage… and produce less SAM-e

Less SAM-e can increase depression.

And more broadly, an MTHFR activated mutation 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, Dementia and many other conditions.

You may find yourself with high folate and low B-12 or Low Folate and high B12. Your body will have problems converting inactive forms of folate and B12 to the active forms. What happens is, the inactive folate or B12 will simply build up in your serum, which inhibits the active forms. Low B-12 symptoms can be numbness in fingers, numbness in legs, joint pain, deep depression, paranoia and delusions, memory loss, incontinence, loss of taste and smell, and more. Most serum folate tests are actually measuring folic acid, which needs to be converted to methyl-folate to be used metabolically.

People often notice a family history of heart problems or cancers when this mutation is being passed down.

Two important MTHFR gene mutations with different combinations

The two most problematic MTHFR methylation mutations are called C677T and A1298C. The numbers refer to their location on the MTHFR gene. Genes are passed down by your mother and your father. Most literature states there are a good 40-50 different mutations of this important methylation gene which could be passed down by one, or both or your parents.

There are many combinations of MTHFR methylation mutations:

Homozygous: means you have both copies of either the C677T mutation, or the A1298C mutation, one from each parent.
Heterozygous: means you have one copy of either the C677T mutation, or the A1298C mutation, plus a normal one from the other parent.
Compound Heterozygous: means you have one copy of the C677T mutation from one parent and one copy of the A1298C mutation from the other parent.
Triple heterozygous mutations (more rare): an example would be one C677T, one A1298C, and a P39P or R594Q, for example.

Here are possible combinations:

Normal/Normal for both C677T and A1298C
Heterozygous A1298C / Normal C677T (one parent passed down a single A1298C mutation)
Homozygous A1298C / Normal C677T (both parents passed down the A1298C mutation)
Heterozygous C677T / Normal A1298C (one parent passed down a single C677T mutation)
Homozygous C677T / Normal A1298C (both parents passed down the C677T mutation)
Heterozygous C677T / Homozygous A1298C (one parent passed down the C677T mutation; both passed down the A1298C)
Homozygous C677T / Heterozygous A1298C (both parents passed down the C677T mutation; one passed down the A1298C)
Heterozygous C677T / Heterozygous A1298C (Compound Heterozygous: one parent passed C677T; one passed A1298C)
Homozygous C677T / Homozygous A1298C (Compound Homozygous, meaning you have one C677T, one A1298C)

MTHFR function is reduced – approximately – in this way:

MTHFR A1298C heterozygous (1 copy): 20% reduction in function
MTHFR A1298C homozygous (2 copies): 40% reduction in function
MTHFR C677T heterozygous (1 copy): 30 to 40% reduction in function
MTHFR C677T homozygous (2 copies): 60 to 80% reduction in function
MTHFR A1298 heterozygous and C677T heterozygous (one copy of each): 70% reduction in function

This can be overwhelming at first, it does get easier as you begin to understand.
Dr. Ben Lynch states that being homozygous A1298C or compound heterozygous MTHFR means there is a high chance the mutation is being strongly passed down to your family members. Some have noticed that even simply having one mutation with A1298C can eventually start expressing itself, especially as our bodies age.

Testing

The most definitive way to find out is genetic testing. And a popular self-ordered test comes from 23andme. After the 23andme results come back, you’ll get “raw data” that you won’t be able to read. You would upload that data to any of the following, which in turn will give you a report that is understandable:

LiveWello, which gives a great deal of information to you based on 23and me, plus links to learn more about each gene’s potential problem. Do use the Search bar to see if you have other mutations you hear about.
Genetic Genie, which will look ONLY at your methylation genetics just by reading your 23andMe raw data.
Nutrahacker, though it doesn’t interpret the raw data the way Live Wello does above, Nutrahacker will tell you what supplements may be useful to take, plus more you may want to avoid, due to your mutations. It’s very interesting!
Sterling Hill’s app http://www.mthfrsupport.com/sterlings-app/ or you can contact her and pay for a call to help with interpretation of your genetics.

Ancestry DNA will offer some methylation snps that as of August 30, 2017, 23andMe doesn’t offer anymore. 23andme DOES STILL OFFER the MTHFR C677T and A1298C. You still upload the raw data to the above.

Hair testing will help with heavy metal issues. Direct Labs has a hair test you can order on your own. Though genetic testing above is necessary to know if you have the MTHFR mutation, it’s always interesting to see what heavy metals are not being broken down because of the MTHFR mutation, this also gives you a baseline to refer to later to see if your treatment is working.

Dr. Amy Yasko will test about 30 methylation SNP’s (single nucleotide polymorphisms). You may need a doctor’s prescription. It is considered to be a highly accurate test, this can be more expensive than the more popular 23andme test above.

A vast amount of genetic information can be obtained from www.promethease.com

Another informative test is the NutrEval, which will test your antioxidants, B Vitamins, digestive support, essential fatty acids, and minerals, plus amino acids via a urine collection. This is an extremely expensive test but can be very informative.

There can be other activated, methylation-related gene mutations that are causing you not to break things down and which need attention. It is extremely important to understand, just because you have a gene, it does not mean it is expressing, or is activated. Other blood labs can help you to learn if they are indeed expressing.
After doing 23andme or Ancestry genetic testing and uploading to a website like livewello.com, there are many methyl-related genes you need to look into.

CBS: When doing its job correctly, the CBS gene will convert homocysteine into cystathionine, and this pathway removes sulfur containing amino acids. When it’s not doing its job correctly, you could have an excess of Sulphur, which can cause kidney damage. Experts strongly recommend avoiding processed foods if you have this mutation, since they can have high amounts of Sulphur. This mutation can also cause low serotonin and dopamine and make you sensitive to chemicals. Some people with a CBS mutation can seem to feel wired with the active version of B6 called P5P, so they have to start much lower. On the other hand, one can have an elevated, “up-regulated” CBS pathway, resulting in excess ammonia, urinary sulfates, and lowered breakdown of glutathione.
SUOX: When working correctly, this gene oxidizes sulfite to sulfate. If this gene has a mutation, it can mean you have inadequate levels of molybdenum and can have reactions to foods which are rich in sulfur/sulfites. Much like CBS, you can have too high levels of Sulphur.
MTRR and MTR: An active mutation with MTRR affects your B12 negatively, meaning you have low levels (or high levels with low B-12 symptoms) and could use B12 supplementation. An MTR mutation affects our folate negatively, meaning you have low levels (or high levels with low Folate symptoms). Both B12 and folate are needed for good methylation.
COMT, MOA-A and MOA-B: Mutations here can negatively affect how your body responds to stress, which in turn can negatively affect your methylation. COMT affects the function of dopamine in your brain, and if testing reveals it’s low, L-Tyrosine is a recommended supplement by some doctors.
AHCY – an active mutation in this gene, whether one copy or two, could shut down methylation pathways. It’s L-methionine, an essential amino acid, that is recommended as a supplement to assist your folate to help produce L-glutathione. It is also recommended to take it at bedtime, since it can make some people tired.
VDR BSM, TAQ and FOK – Most people easily maintain a vitamin D25 level between 55 and 75 and they have all done very well taking both D2 and D3 with the exception of two people who happen to have the VDR Bsm variants. Individuals with the VDR Bsm variants do not have to supplement very much if at all with vitamin D. Those who have the Vitamin D Receptor [VDR] Taq [+/+] variants need a lot more vitamin D than the average person. Those with VDR Taq are prone to not making much Dopamine and they are more likely to have some impairment of their immune function. Vitamin D1,25 is required to initiate gene transcription for many of the genes involved in immune function. PICTURE: Vitamin D response elements [VDREs] and D1,25 initiate a cascade of molecular interactions that modulate the transcription of specific genes. BUT…too much Vitamin D1,25 can be toxic and harmful. People with the VDR Bsm variants appear to easily convert vitamin D25 quickly into D1,25. Precisely how or why the VDR Bsm variant does this, I do not know. But in any case people with the VDR Bsm variants do not have to supplement very much if at all with vitamin D. People with the VDR Fok variants are prone to sugar dysregulation, metabolic syndrome and diabetes. The mechanism for this association is also not clearly understood. Lots of detailed information here: http://resqua.com/702188759/what-is-the-significance-of-a-vdr-taq-gene
GPX – if you have an active mutation here, you may be having a problem producing L-glutathione, a needed and powerful antioxidant, and would need supplementation. Glutathione is needed for methylation.

There are others which you will see on your 23andme genetic results.

How to treat it all
You can’t change a defective gene. But you can help it do its job better and minimize problems.

For the MTHFR mutation, it’s strongly recommended to avoid folic acid supplements and in foods (read labels, flours, cereals, even rice have added Folic Acid in the USA!), and instead favor folate in supplementation, especially if you are homozygous MTHFR (having a copy of the same defective gene from each parent). Healthy foods that contain folate should be okay, as would be the active form of folate called methylfolate as a supplement, also called 5-MTHF (5-methyltetrahydrofolate). But we need to start low, such as 400 mcg or less. You don’t want to methylate too fast and cause over-methylation.

It is important that you test via blood any of these B-vitamins before taking them. You will want to know what your levels were at the beginning before treating, so that when you re-test in let’s say, 3 months, whether you will need more or if the amount you are on is adequate. B-12 needs 10-14 days off of it before testing, and the others need 5-7 days off before testing.
B12 might also be high due to an active MTHFR mutation along with an active COMT mutation, so we avoid the synthetic supplemental version of B12 called cyanocobalamin and instead favor the methylcobalamin (methylB12) or adenosylcobalamin (also the active form, but used by your mitochondria), you will need adequate folate supplementation before beginning these. Again, all the latter is simplified and you will need to seek more detailed information from a qualified practitioner or websites and forums on MTHFR.

Another good B-vitamin is the methyl version of B6, called P-5-P, again, it’s important to start low and build in low amounts.
Dr. Ben Lynch feels that “repairing the digestive system and optimizing the flora should be one of the first steps in correcting methylation deficiency”, and that especially includes treating candida because of the toxins it releases, inhibiting proper methylation.
Some experts recommend eating clean, such as Paleo or the GAPS diet.
Avoiding exposure to toxins is important! Look at your household cleaning supplies, for example, or toxic glues you may be using, and more.

**If adding methyl B’s causes you to over-methylate, taking time-released Niacin, 50 mg can slow it down, say some experts. Symptoms of over-methylation can include muscle pain or headaches, fatigue, insomnia, irritability or anxiety. Check your potassium levels before beginning with no tourniquet on your arm (that can falsely elevate your numbers), Potassium can drop in the beginning of adding in Methyl B’s, so if yours is below 4.2, you may want to build that up before beginning.

Minerals play a key role in several enzymatic functions. Vitamin C helps reduce oxidants. Molybdenum (500 mcg) helps break down excess sulfates and sulfites from the CBS and SUOX active mutations.

It is very, very important to avoid high stress and/or quit pushing yourself, as stress can negatively affect your body’s ability to remove toxins.
This website http://www.knowyourgenetics.com/ offers suggestions on how to treat your defects.

Again, all the above is simplified and working with a knowledgeable practitioner will give you the right details.

High Copper/Low zinc
This can be a common finding when you have an MTHFR defect (or other methylation snps)–a high level of copper, which will mean your zinc levels will fall. Zinc is copper’s antagonist. Because the ratio of these two metals is highly important, correcting the problem is crucial, since high copper can be related to hyperactivity, depression, fearful ruminating thoughts, Paranoia, headaches, acne, frequent colds due to lowered immunity, sensitive skin and/or bruising, worsening hypothyroid, adrenal stress and more.
High copper can also make it difficult to raise iron levels or keep those levels where they should be. See our Detox / Copper page for helpful info

Vitamin C is known to help lower high levels of copper via detoxing, but patients report they need to go low and slow to tolerate the detoxing. Zinc is also used the same way–to encourage the lowering of copper, but the same caution with detoxing applies. Lawrence Wilson, MD recommends a nutritional approach to correcting the imbalance: remove IUD’s, avoid high copper foods like chocolate, seeds and avocados, avoid stress and more. Work with your doctor.

MTHFR also affects Estrogen metabolism. Because of this it is a good idea to know your Estrogen levels. We often see high Estrogen and low Progesterone along with high Copper and low Zinc.

What does SNP mean??
As you get to reading about all your genes, you may see the acronym SNP used a lot (sounds like snip). It stands for Single Nucleotide Polymorphism. And SNP is basically another word for a mutation in your gene.

A great quote from Dr Lynch is:

“It’s not what SNP you have. It’s how your biochemistry is working.” Vitamin B12 supports red blood cell formation alongside folate.

When B12 is low, folates get stuck and anemia can occur. By adding B12, folate gets used.

Cell growth and division occur which requires more electrolytes and more phosphatidylcholine.

Being deficient in electrolytes, especially potassium and magnesium, and taking B12, will set you up for failure.”

More to read:

A map of all the possible methylation pathways.
http://www.heartfixer.com/AMRI-Nutrigenomics.htm

Symptoms of methionine deficiency
https://www.livestrong.com/article/495492-methionine-deficiency-symptoms/

List of diseases that have been linked to MTHFR:
http://mthfr.net/mthfr-mutations-and-the-conditions-they-cause/2011/09/07/

Dr. Ben Lynch’s MTHFR website with forums, too.
http://mthfr.net/

National Library of Medicine MTHFR information page
https://ghr.nlm.nih.gov/gene/MTHFR

Informative MTHFR Support website— Also has forum.
https://mthfrsupport.com/

Detailed notes this mother took about MTHFR and methylation from a Dr. Ben Lynch lecture.
http://roosclues.blogspot.com/2012/07/dr-ben-lynch-on-mthfr-genetic-variance.html

Other gene mutations like CBS that need to be addressed before getting too serious with MTHFR
https://mthfrsupport.com/2013/05/other-gene-mutations-that-must-be-addressed-before-starting-an-mthfr-protocol/

FOOTNOTES: