Your mutations are likely having a large influence on your health. You have some important snp’s, a few not even related to “undermethylation”. Some balance each other out fairly well. However, the deck is stacked against you in regards to b12, and you do have enough going on to slow down the cycle a bit. Keep in mind that just because you have some of these genes does not necessarily mean you are expressing them which is why physiological tests and trial and error with supplementation is so important. There is no great test for functional b12 status though, and considering your mutations and symptoms, I kind of take that as a given in your case.
COMT V158M rs4680 AG +/- Breakdown of dopamine
COMT H62H rs4633 CT +/-
VDR Taq rs731236 AG +/-
MAO-A R297R rs6323 GT +/- Breakdown of serotonin
MTHFR A1298C rs1801131 GG +/+
Downregulations in these enzymes result in slowed breakdown of dopamine and serotonin. Vitamin D Receptor (VDR) Taq directly does not, but vitamin d status influences the creation of dopamine too, which influences methyl tolerance. The body makes these neurotransmitters inactive by attaching methyl groups to them. If you’re not using up methyl groups to do this, its easy to “overmethylate”, which has some rather unpleasant effects. Your deficit of bh4 due to your mthfr 1298 mutation somewhat offsets this, they help offset each really, and I would assume is enough to keep you from overproducing those particular neurotransmitters. Nonetheless, you should stay away from precursors and things like ssri’s. BH4 has other jobs too. A lack of it can impair b12 transport, contribute to pku (phenylalanine intolerance due to impaired ability to process it in the liver) that in lifelong cases usually shows with learning disabilities and a shy or withdrawn personality (though the 1298 mutation is not likely going to cause this directly, it can majorly contribute if other genetic abnormalities are present), and impair creation of nitric oxide. The recommendation is usually to supplement methylfolate actually, but you are probably much better off using up your (possible) limited tolerance of methyl groups taking mb12.
From heartfixer on BH4 and NOS:
In a BH4 dependent reaction, Nitric Oxide Synthase (NOS) converts Arginine in to Nitric Oxide, the molecule that resists plaque formation, vasospasm, and abnormal clotting. If you can make and maintain Nitric Oxide then you will not develop cardiovascular disease. If you have cardiovascular disease and if we can successfully reboot your Nitric Oxide system, than we can stabilize your disease. Every maneuver in drug and non-drug cardiovascular medicine that improves patient symptomatic status and outcome works on this system. Every risk factor (or causative factor for cardiovascular disease) compromises Nitric Oxide generation or maintenance. NOS is also involved in ammonia detoxification, a job that distracts it from its Nitric Oxide generating duties and which uses up BH4. Without adequate levels of BH4 Nitric Oxide Synthase will not convert Arginine in to beneficial Nitric Oxide, but rather in to undesirable free radical species such as superoxide or peroxynitrite.
From Pathways to Recovery:
The BH4 Three-Legged Stool
The added ammonia that is generated due to the enhanced breakdown of methylation cycle intermediates will also burden the adjoining urea cycle, thereby depleting a key intermediate called BH4, which plays a critical role in regulating neurotransmitters and therefore mood. BH4 is needed for serotonin, dopamine, conversion of phenylalanine to tyrosine and language-related function. The A1298C mutation in the MTHFR gene may also impact levels of BH4.
The drawing of a three-legged stool can help you visualize how the body maintains adequate levels of BH4. One leg is for CBS upregulations. The second leg is for MTHFR A1298C, another key SNP on the methylation pathway, which you will learn more about later in this chapter. The third leg is chronic bacteria/ aluminum. Stable BH4 levels require all three legs.
CBS upregulations weaken one leg of the stool by using up BH4 faster than it can be supplied. The NOS mutation can also exacerbate the CBS ammonia problem. In the adjacent urea cycle, inefficient NOS activity can lead to elevated ammonia levels, further draining BH4 limited stores. Reciprocally, CBS upregulations strain the urea cycle, where BH4 is needed to form nitric oxide. The formation of nitric oxide requires two BH4 molecules. With insufficient BH4, the body will instead produce peroxy nitrite (with one BH4 molecule), or super oxide (if no BH4 is available.) These two products can cause oxidative damage. The combination of CBS + and these other SNPs will further weaken this leg of the BH4 stool. MTHFR A1298C mutations (if present) impair the second leg by disrupting the recycling and regeneration of BH4. Chronic bacterial infection (which can lead to aluminum retention) weakens the third leg of the stool, because aluminum inhibits a key enzyme that helps to synthesize BH4. On this program, you will ultimately address all three legs of the BH4 stool by supporting the body to address chronic bacteria/aluminum, supporting the MTHFR A1298C mutation, and addressing CBS/ammonia issues.
Other Interfaces that Impact BH4
Other mutations can also improve (or worsen) our BH4 stool’s sturdiness. While BH4 helps in the formation of neurotransmitters, other factors contribute to neurotransmitter breakdown. Bacterial infections trigger a more rapid breakdown of tryptophan (needed for serotonin). Low levels of BH4 have been associated with hypertension and arteriosclerosis, as well as with more severe parasitic infections. Parasitic infections also deplete B12 levels, impacting methylation cycle function.
Lack of BH4 may result in mast cell degranulation and lead to higher histamine levels, which can produce symptoms such as red ears and other hypersensitivity reactions. Serotonin synthesis as well as ammonia detoxification also require BH4. Elevated ammonia levels can cause flapping and other over-stimulatory behaviors.
Factors that lead to more ammonia, such as high protein diets, generate more ammonia that needs to be detoxified. Each molecule of ammonia requires two molecules of BH4 for ideal detoxification. Excess ammonia in the gut may alter the pH and aggravate imbalances in microbial flora. It’s obvious how these factors interact to impact ammonia detoxification as well as optimal BH4 levels for neurotransmitter synthesis. Keeping the ammonia levels under control is of paramount importance for overall health and wellness, especially for those with an MTHFR A1298C mutation, as any excess ammonia generated can drain stores of BH4. This can affect serotonin levels and to a certain extent cause fluctuations in dopamine (which translates into mood swings). Helping to restore adequate levels of BH4 should also aid in serotonin synthesis, maintaining dopamine levels as well as ammonia detoxification in a more stable manner.
MTR A2756G rs1805087 AG +/-
MTRR A66G rs1801394 GG +/+
ACAT1-02 rs3741049 AG +/-
This is the B12 triple whammy, which is not only a holdup of the methylation cycle but can also result in symptoms of low functional B12, such as neuropathy and myelination problems. MTRR is the enzyme that methylates cobalamin(b12) and you have a homozygous mutation of the gene that is known to have a major downregulatory effect on its performance. This results in less mb12 which slows the methylation cycle. MTR is the enzyme that transfers the methyl group from cobalamin to homocysteine and this mutation is an upregulation. This takes the already too little amount of mb12 you have and uses it up too quickly, leaving you with even less. This is important because mb12 is necessary for other functions in the body. ACAT may also result in a depletion of B12 as well.
You need to supplement with mb12, but theres a problem with that. You are not going to tolerate methyl donors very well because of your COMT/VDR taq status. The recommended procedure in this case is to use hydroxyb12 (a nonactive form of b12 that is a natural form in the body, unlike cyancobalamin) possibly with some adenosylb12 (the active form used by the mithochondria). Ive done some digging around, and found a couple people with hetero comt mutations said they are able to get away with a little bit of mb12. I also think you could get away with more if you were to simultaneously use a methyl sink such as niacin. That idea is an original creation of mine and though not necessarily proven, I have used it myself successfully and see no reason that it shouldnt work, especially if getting mb12 is a priority, as it might be in your case considering your ms like symptoms.
SHMT1 C1420T rs1979277 AG +/-
This enzyme acts in an in-between conversion of dietary folate and the final form of methylfolate that methylates cobalamin and in another reaction takes that in between product and converts it into folinic acid. This mutation is a downregulation that results in less methylfolate and folinic acid. Less methylfolate = slowed methylation. Folinic acid is used in dna construction and a lack of it shows up the most in fast turnover cell needs, particularly the lining of the gut and the immune system. Leaky gut and low immune function result. This is one of the first things to supplement, folinic acid is easy to find and the possiblity of side effects is low, though some people report a “toxic” feeling and increased brain fog.
An ACAT mutation can also result in lowered fat metabolism, lowered energy production, and even mitochondrial dysfunction. Floating (fatty) stools and bumpy skin on your arms and legs called keratosis pilaris (chicken skin) are common symptoms. You were also more likely to have cradle cap.
From Pathways on SHMT and ACAT:
First Priority Mutations
Addressing SHMT and ACAT Mutations
People with the SHMT and/or ACAT mutations sometimes have a greater tendency to experience gut dysbiosis and imbalanced flora. Until the flora are balanced, there’s a risk that the undesirable microbes will retain toxic metals. So, for those with ACAT or SHMT as well as other mutations (such as the MTHFR A1298C) that confer a greater likelihood of retaining aluminum, it is essential, prior to addressing these other mutations, to first stabilize the general gut environment via SHMT and/or ACAT support, by using supplements in the MPA received with your test results.
If both SHMT+ and ACAT + are present, begin with SHMT support first, and once that is in place, layer in ACAT support.
Understanding SHMT Mutations
Based on the research of Dr. Patrick Stover, I’ve concluded that the SHMT mutation often shifts the methylation cycle away from both the long and short routes through the methylation cycle into a side reaction that leads to the production of thymidine (see illustration.)
Supplementing with nucleotides, which are a form of our DNA bases, can help to both support thymidine, while maintaining appropriate methylation cycle activity. In addition, both iron and a form of folate called “5 formyl THF ” help to regulate SHMT activity. That’s why using lactoferrin (which helps to control iron levels) along with low doses of 5 formyl THF (found in the product, ActiFolate) help shift methylation activity back to the short and long routes around the cycle.
Understanding ACAT Mutations
ACAT, (Acetyl-Coenzyme A acetyltransferase) impacts critical pathways and hence functional areas of human biochemistry in several ways, including:
Helping to form cholesterol
Assuring lipid balance and fluidity in the cell membranes, which in turns impacts neurological function
Contributing to energy production via the Krebs cycle and its impact on the mitochondria, which signal cellular activity and supply cellular energy
Mediating the accumulation of oxalates, which, in excess, can contribute to kidney stones and other health problems
ACAT contributes to cholesterol synthesis and membrane lipid balance. Bile acids are first synthesized from cholesterol and next conjugated to taurine. High taurine levels (often seen with ACAT) may reflect a lack of bile acids for conjugation. Since bile salts have been shown to increase ACAT activity, they may help ACAT issues. In addition, policosanol may help with membrane lipid balance and fluidity, which impacts neurological function.
The next portion of the pathway that may be impacted by ACAT is the level of acetyl CoA, which feeds into the top of the TCA cycle (also called the Krebs cycle) at 12:00. Benfotiamine, riboflavin, and pantothenic acid support the reactions between pyruvate and the TCA cycle. In addition, a low dose of alpha lipoic acid (ALA) has been shown to replace acetyl CoA in certain reactions. Either a sprinkle of the ALA supplement or the topical ALA lotion can be used. More is not always better when it comes to support with ALA, although in some cases high dose ALA has been reported to have wonderful effects. ALA use should be based on both genetics and biochemical lab data.
A block at the acetyl CoA point of the Krebs/TCA cycle can also lead to both an accumulation of oxalates and increased levels of methylmalonic acid (MMA). To keep the cycle moving, the oxalates at 11:00 must combine with acetyl CoA coming in at 12:00. Low-dose vitamin K and lactoferrin help with that activity.
Both ACAT and high MMA levels are addressed the same way, with adenosyl B12, other forms of B12, low dose vitamin E succinate, lactoferrin, a sprinkle of actifol (ActiFolate), and nucleotides. MMA may inhibit succinate CoQ reductase, which is vital for electron transport. Vitamin K (menaquinone) and CoQ 10 (ubiquinone) can serve as electron acceptors in these cases.
Since high methionine levels appear to accompany ACAT mutations, SAMe, bile salts, glutathione (GSH,) and CoQ10 all can help to support the conversion of methionine. Curcumin and quercetin help shift the transulfuration pathway toward GSH. Since too much GSH can feed back and inhibit an enzyme that shunts to glutathione, I like to support the overall pathway rather than merely adding GSH.
CBS A360A rs1801181 AG +/-
The cbs mutation is an upregulation. An A360a mutation is considered to be minor, and a heterozygous mutation shouldnt really need much consideration. But, because ammonia depletes bh4 and you are going to need all the bh4 that you can make, if you are not going to directly supplement it (which you would need to be careful with due to comt/mao, im not saying dont, at all, it might benefit you, just sneak up on the doseage if you do) then it might be helpful to lower sulfur intake and/or use yucca root. Excess peroxides will lower BH4 as well. You are likely deficient in gluatathione and the main neutralizer of peroxides in the body is a form of it called glutathione peroxidase. Supplementing selenium will increase glutathione peroxidase and will also boost immune function (this is only recommended if you do not have any acute mercury problems).
Read chapter 8 of Yaskos Pathways to Recovery
I HIGHLY recommend you make an appointment with Dr. Armine, he is one of the few real specialists in the world in this category and is supposed to be very good at dealing with problems like this. I think he could help you alot, way more than most docs/nd’s/whatever.