These are my notes for Dr Ben Lynch's presentation about MTHFR and methylation (which can be viewed here). The first 30 minutes of this presentation covered the basics of methylation, and my notes for that part can be found here.
-Disorders related to under-methylation, which therefore can also be associated with MTHFR, include: Autism, MS, Fibromyalgia, Diabetes, Parkinson's, Chronic Fatigue
Syndrome, Alcoholism and other addictive problems, ADHD, Insomnia,
Alzheimer's, Cancer, Allergies, Bipolar, Schizophrenia, Depression,
Anxiety, Neural Tube Defects including Spina Bifida, Cleft Palate,
frequent miscarriages, Infertility, Tongue Tie, Tethered Spinal Cord,
Chiari Malformation, Pulmonary Embolisms, Atherosclerosis, Immune
Deficiency, Chronic Viral Infection, Congenital Heart Defects, Chemical
Sensitivity, Thyroid Dysfunction, Neuropathy, Down's Syndrome, and
mercury poisoning.
-In his list of who to screen for MTHFR variants, in addition to
people based on the list of disorders above, there is also people with
cervical dysplasia, elevated cobalamin, cardiovascular risk, and
newborns and people hoping to conceive.
-MTHFR is very common.
The frequency varies tremendously between different ethnic groups and in
different locations. The two groups with the highest rates appear to
be Mexicans and people from southern Italy. Rates of neural tube
defects tend to correlate to rates of MTHFR (except in the case of
southern Italy).
-Testing looks for the two common variants,
called C667T (what Roo has) and A1298C. There are at least 40 other
variants that are known, but not tested for.
Problems associated with C677T variant, also know as A222V or rs1801133 include-
Cardiovascular function, Homocysteine regulation, DNA regulation, glutathione production, and low methylfolate levels. 1 copy of this variant results in a 40% loss of function of the MTHFR enzyme, 2 copies results in a 70% decrease. Normal is having two Cs at this spot on the gene, not a T.
Problems associated with A1298C variant, also known as E429A or rs1801131 include-
Neurological issues, regulation of neurotransmitters, low BH4 levels, and elevation of nitric oxide. These people may not have deficiencies in methylfolate levels, it appears that this variant may cause issues via production of biopterin. Normal is having two As at this spot, not a C.
Metabolism of Folic Acid and Folate
Folic acid is the non-natural form of this nutrient that is added to fortified foods. It is converted by an enzyme called DHFR into the next form along the pathway (dihydrafolate or DHF), which is a slow process. If folic acid is consumed at a faster rate than the conversion takes place, unmetabolized folic acid builds up in the system which leads to lower levels of NK (natural killer) cells. Dr Lynch suggests that this is the mechanism for why folic acid can lead to cancer, by suppressing NK cells, which are critical in fighting cancerous cells at the very beginning before they become large tumors.
The end product of the chain of transformations is 5-MTHF. This nutrient can be purchased from Thorne and is also available in uncooked leafy greens. Nutrients that are needed to make methylfolate (other than simply eating it straight from leafy greens) are vitamins B2 and B6. These vitamins are necessary cofactors, so even people who do not have a genetic variation and produce a fully functioning enzyme will still be deficient in methylfolate if they do not have adequate B2 and B6.
For 5-MTHF to be used, there needs to be adequate cobalamin levels for the methyl group from the 5-MTHF to go to to make methylB12. Cobalamin levels must be adequate for the 5-MTHF to be used. That is very important as many doctors will address low methylfolate levels without making sure enough cobalamin is present for the 5-MTHF to do anything. Once the methyl group is transferred to the cobalamin to make mB12, it enters the methionine- homocysteine cycle that results in the production of SAM-e which is the body's primary methyl donor. In this way, sufficient methylation capacity is dependent on the functioning of the MTHFR enzyme as well as the list of cofactors (B2, B6, B12, magnesium, etc). Additionally, the SAM-e then is converted to homocysteine, which is then converted to glutathione, which is the body's primary anti-oxidant and a person's glutathione level is largely what determines their susceptibility to metal toxicity (mercury in particular).
The above describes the impact of the C677T variant because it impacts the amount of folate that is converted to methylfolate. The A1298C leads to different issues because it seems to impact the production of BH4 (tetrahydrabiopterin). C677T also affects BH4 levels because methylfolate is needed for the DHFR enzyme to convert BH2 to BH4. Because the mechanism is different, associated symptoms are also different with the 1298 variant. Issues associated with 1298 tend to have more to do with neurological and mental health issues, addictions, chronic pain such as fibromyalgia, and nerve pain. BH4 is needed to convert tyrosine into dopamine, tryptophan into serotonin, and arginine into nitrous oxide and citramine.
Methods for Lowering Homocyteine
One common result of an MTHFR mutation is elevated homocysteine levels. Vitamin B6 supports the conversion of homocysteine to glutathione, which is really important so this is an excellent way to lower it. MethylB12 will convert homocysteine to methionine. Betaine (also called TMG) is very effective at converting homocysteine to methionine as well. TMG is very similar to DMG, and the two are often confused, although for some reason he says that DMG inhibits this conversion while TMG supports it (he also says that giving HCl supplements inhibits the body from producing HCl itself, which is not consistent with mine and many other people's experiences. Giving HCl tends to lead to a person actually making enough on their own). Beets are an excellent food source of betaine. Lastly, riboflavin (B2) also supports the breakdown of excessive homocysteine.
He says not to supplement with glutathione directly because it shuts down the CBS pathway (which is how homocysteine is converted to glutathione). If the CBS enzyme is defeicent, which is also common, then glutathione will already be low (this is very common in kids with autism). Under functioning CBS also results in elevated ammonia, which is problematic for several reasons including that coping with the excess ammonia strains the body's ability to balance neurotransmitters.
A Few Notes About Testing Homocysteine Levels
Most labs do not test properly for homocysteine levels, according to both Dr Lynch and the American Pathology Association. He says home tests are not accurate and should not be used. COnsumption of high methionine foods can give false results on the test. The patient needs to fast for 12 hours prior to having blood drawn. The sample must be put on ice immediately, or the red blood cells need to be spun out right away.
Drugs to Avoid When MTHFR is present
There is a really long list, so I will just list the ones here that I recognize or seem relevant (if you want to see the whole list it's at 1:02 in the presentation). Antacids should be avoided because they deplete B12. Nitrous Oxide inactivates MS (methionine synthase, an important enzyme) and needs to be avoided. This can actually be quite dangerous, even fatal. Oral contraceptives deplete folate. Metformin decreases B12 absorption. Methotrexate and Bactrim reduce the function of important enzymes.
Supplements and Drugs to Address MTHFR
Of the prescription forms of methylfolate, Dr Lynch's favorite is Metanx. He says that Deplin, which ranges from 7.5 mg to 15 mg, is so high that it can cause many problems. He generally does not prefer meds to address MTHFR.
As for supplements, there are many options that are on the market and it is confusing. Choose one that either has an L at the beginning of the name (as in L-methylfolate), a 6S (such as (6s)-5-methylfolate), Quatrefolic, or Metafolin. Avoid forms that begin with an R- (racemic forms, they inhibit absorption of the L-form). Companies are not allowed to put more than 1,000 mcg of L-methylfolate per serving into their products if it is on it's own, or 800 mcg if in a combo formula.
Supps to take to support MTHFR include: L-methylfolate, methylB12 and/or hydroxyB12 (methyl- if the person under methylates, hydroxy- if they over methylate), vitamin E, Krill Oil (better for crossing BBB), Fish Oil, sylimarin (from milk thistle, if oxalate sensitive avoid this), selenium, zinc, glutathione (start low), a strong probiotic (a healthy gut spares the methylation cycle a lot of work), multivitamin with complete B complex and minerals, vitamin D3, vitamin C, electrolytes, magnesium, adaptogens (ashwaghanda is good), potassium.
Protocol to Support MTHFR
The most important thing is to address lifestyle issues to reduce the strain on the body and the methylation pathway. Eat Paleo or GAPS (he recommends people read "The Paleo Solution" by Rob Wolf), reduce toxic exposures, get enough sleep, digestion must be in good shape so that gut is healthy and nutrients can be absorbed, should be having several formed bowel movements per day, try to remove medications that are folic acid antagonists, make sure no folic acid or niacin in supps, test for MTHFR. Specific supps with doses for each MTHFR SNP is at 1:20 in the presentation. Potassium can help reduce side effects from methylcobalamin or methylfolate (due to alkalinizing?). If symptoms are due to over-methylation, give 50 mg of niacin (timed release) to slow down excessive methylation. To avoid pushing methylation too far to cause over-methylation, start low and work up slowly.
