Once you get the test results, you will most likely wish to move ahead with this program. However, before you begin to implement the suggestions in this chapter, I want to alert you to two things. First, it’s important to implement suggestions in the correct sequence. Second, since detoxification can be very stressful on the body, I always advise people to take sufficient time doing the Step One recommendations before they progress to Step Two. In addition, Step One supports can and should be continued as you move ahead with the program for as long as needed. For some, that will be for quite some time, even lifelong. For others, once the major detoxification has successfully restored function, a gradual step-down in supports, with your practitioner’s guidance, may be possible. However, although the goal of the detox portion of the program is to reduce the current toxic burden, please keep in mind that there is no way to permanently eliminate all future toxic environmental exposures. To maintain health, those with vulnerable genetics may need to support their methylation cycle and some of their organs lifelong.
In Step Two, you will restore methylation function and thus promote detoxification. Since improved methylation prompts the body to excrete accumulated virus, metals, and bacteria, it’s important to understand that the body’s natural process of detoxification differs from the kind of excretion that results from chelation therapy.
To understand the distinction, picture a revolving door (the kind you might see in an office building or hotel.) In our bodies, toxins come in and go out, just as people come and go through the revolving doors. This is an ongoing process throughout our lives, which helps us survive in a toxin-filled world. However, for those with methylation cycle mutations, the revolving door does not work so well. Toxins come in, but they don’t go out easily. Instead, they accumulate.
When you use a chelating agent, it’s like taking some of the accumulated toxins out through a side door of the building—but the revolving door remains impaired. The use of chelation can enhance toxin removal, but it cannot repair the door. As a result, once you stop chelating, the toxins will again build up.
Nutrigenomic tests, on the other hand, reveal how to fix the door—by using nutrition to bypass mutations, and allowing the body’s natural detoxification systems to operate properly. As a result, through this program you may experience an increased level of detoxification, especially if your revolving door has been blocked for a long time. Since detoxification symptoms can be uncomfortable to experience, people often wonder whether they are actually detoxifying or merely responding poorly to a particular supplement. I recommend that you use urine, stool, hair, and blood toxic metal tests to monitor the excretion of these metals. Test results that reveal metal excretion will confirm that you are naturally detoxifying—that, in effect, your revolving door is working again. These same tests will also allow you to track the levels of metal excretion, so that your supplementation can be adjusted.
I recommend that you ensure that essential minerals are balanced before you move ahead to support mutations. Since test results often reveal a drop in essential minerals along with metal excretion, I recommend regularly testing both essential minerals (the Urine Essential Elements or UEE test) and toxic metals (the Urine Toxic Metals or UTM Test). This is especially important when test results show high levels of metal excretion. Taken at the outset, the results of the UEE test will tell you which ones are low and need supplementation.
Track essential elements levels, and keep them in balance. For overall support, use BioNativus liquid minerals along with Cellfood. The dose is two to three drops of each per day.
Mercury excretion can affect the levels of lithium and iodine. You can rebalance iodine with 1/4 to 1⁄2 tablet of the supplement Iodoral (or other natural forms of iodine). For healthy lithium levels, 1/4 lithium oratate is recommended. Frequently, decreases in calcium are seen following lead excretion. Since calcium stimulates excitotoxin activity, I prefer low to normal calcium levels, especially for those with elevated glutamate. For calcium support (if test results show it’s needed), you can utilize herbs with other calming components, such as nettle, chamomile, and chervil. If this does not bring the levels within normal range, use a calcium supplement that also contains magnesium (which prevents excitotoxin activity) and vitamins D and K (which ensure calcium transport within the body.)
Chickweed, nettle, dandelion leaf, and yellow dock are natural sources of boron, which may, like calcium, drop during lead excretion. Chickweed also helps skin rashes. Nettle helps to decrease inflammatory mediators and increase serotonin. Dandelion leaf supports the kidneys. Yellow dock supports regular bowel movements. If boron support is needed, mix small amounts of all of these, or choose one based on its other helpful properties.
For magnesium support, a very absorbable form is magnesium citrate. Aim for higher levels of magnesium so that the calcium/magnesium ratio favors magnesium. High dose zinc can trigger glutamate receptor activity, so only use 40mg (or less) of zinc per day of either zinc picolinate, or Body Bio Zinc. If MAP or OAT test results reveal that all Krebs intermediates are low, you can use a Krebs cycle zinc supplement.
As you’ll learn later in this chapter, healthy molybdenum levels aid in sulfite detoxification.
Selenium is useful in binding to mercury, so use the supplements indicated to assure that you have adequate levels.
Manganese is another key mineral, which is needed to:
Classic signs of chronic manganese deficiency include low cholesterol, elevated alkaline phosphatase levels, and depressed T-cell-mediated immune function (due to thymus issues).
Now with good mineral support in place, let’s assess whether you‘re ready to begin Step Two.
When is the right moment to proceed to Step Two? Here are some signs to look for:
To assure that you are ready to address mutations, consider doing another round of tests, including UAA, MAP (or OAT), CSA and UEE/UTM to see where things stand as compared to the baseline tests, already performed at the beginning of Step One. Make sure to continue the comprehensive supplementation program that was used in Step One. This will ensure that the immune system and other organs are well supported during the elimination process.
For the supplements recommended for methylation cycle support, please keep in mind once again that it’s not necessary to take every supplement in every category. However, for some people, it may eventually be necessary to use them all. Some people may be sensitive to an herb or supplement, making it essential to add supplements slowly, as in Step One, allowing several days to assure that the newly added supplements agree with you or your child before progressing. Yes, it will take a while to introduce them all. Again, this is a marathon, not a sprint!
The suggested dosage on any supplement is 1/2 to one whole capsule or tablet, unless otherwise noted. This is typically below the dosage suggested on the labels of the bottles. Again, my philosophy is to use multiple overlapping supplements with related function, in low doses.
Please check your Methylation Pathway Analysis Report (MPA) for the specific supplement recommendations for each mutation. Based on ongoing research and clinical experience, I will continue to adjust these recommendations. Please check the website periodically for any updates to supplement recommendations.
Moving forward into Step Two, I’ll guide you in implementing the program to bypass methylation cycle mutations. Given the many critical bodily functions tied to the methylation cycle, attaining adequate methylation cycle function will begin the process of viral, bacterial and metal detoxification. In some (but not all) instances, the detox triggered by methylation optimization will be sufficient— and nothing further is needed to promote detoxification. As detoxification proceeds, function is restored. However, in many cases, restoring methylation function does not complete the process of detoxification. That’s why in Step Two, Part Two (in then next chapter), I’ll guide you in the more advanced detox options that follow the methylation supports outlined in this chapter. These options will further promote the release of chronic viral and bacterial infection, which in turn prompts the excretion of toxic metals, as I discussed earlier.
As you’ve learned throughout this book, I regard the entire methylation pathway as “a biomarker” for underlying genetic susceptibility to a number of serious health conditions, including autism. In earlier chapters of the book, you’ve learned the function of this cycle and why I consider it so important. Now we’re going to take a deeper look into this unique cycle and how it works. I encourage you to study and familiarize yourself with the chemical diagrams of the cycle, here in this book and on my website. These diagrams will serve as a map for our discussion. As you come across complex scientific terms, or hear me or others in the chat room speak of specific genes, you can always orient yourself by revisiting these diagrams.
When you look at these illustrations on the page, this cycle appears to be static and flat—but it’s anything but. In fact, it’s always in motion. Different enzymatic reactions are constantly occurring between molecules and chemicals. It’s truly dynamic and alive. I often wish I could develop an animated version of it, and hope one day soon to do this.
Keeping that in mind, all the mutations you’ll read about in your test results appear and are active at specific points in the cycle. I recommend that you familiarize yourself with these various points and their activities, because that will help you understand the process into which we are intervening through this program, and will make the recommendations that much clearer.
As you will note, the diagrams look like a bit like intermeshing gears. Imagine that they are the gears of a series of interlocking water wheels. The wheels always move in a clockwise direction, pouring what they contain into the next phase of the cycle. At various points there are weigh stations, each one manned by an assembly-line worker with a specific job to perform. The worker adds, subtracts, or combines a specific ingredient into the forward flowing stream of water. If any of these workers neglects to add his ingredient, or adds too little or too much, the effects will be felt down line: The process will not result in the anticipated end products, and other workers will have to deal with that. As a result, through the Nutrigenomic test, we are able to figure out which way stations have a problem, and pinpoint what it is. This allows us to compensate in order to assure a good result.
Whenever I use the language of biochemistry, keep in mind that in most cases the scientific term describes a weigh station, what is added or subtracted there, or what effect is produced as the “water” in the water wheels moves forward.
I sometimes also use the metaphor of a clock when discussing the cycle and its movements. When I mention twelve o’clock or five o’clock, know that this is a shorthand to allow you to easily locate the point on the clock—that is, the part of the cycle—being discussed.
I’m a firm believer in the use of the right kind of genetic information as a key ingredient in health care, now and into the future. That means that all who pursue my program are, in a sense, pioneers. Given the kind of medicine with which most Americans grew up, few people are familiar with how to follow an individualized approach to health care—and nothing is more individualized than this kind of genetic analysis and the guide to supplementation that is based on it. As a result, throughout the program you will no doubt have many questions. I try to give you a solid groundwork and answer the most common questions in this book. But the answers to many individual and specific questions can be found by searching through the chat room on my website. And if you don’t find the answer, you can always write in to the chat room and ask your question. One of the experienced parents or I will answer it.
Now, let me orient you to what you will find when your test results arrive. Your Nutrigenomic profile will contain your individualized test results. This profile shows which mutations are present, so that you know which ones you will need to address. The specific supplement recommendations I offer are listed according to mutation.
Your test results contain a Methylation Pathway Analysis Report (MPA), a color-coded chart that shows which mutations—also called SNPs—you or your child has. Please review this as needed and over time, you’ll become more familiar with each of these SNPs. The MPA overviews the supplements congruent for specific SNP results and details why certain supplements are recommended to support deficiencies in the methylation cycle for each SNP. I’ll also explain the rationale for their use in this chapter.
In this part of the program, you will be gradually “layering in” these supplements in a specific sequence. As you familiarize yourself with the SNPs and their areas of function, the rationale for the recommendations will become clearer. Better understanding will in turn support your decision-making process throughout the program. This will help you determine when to add a new supplement, as well as have some familiarity with what its impact might be. All of this will serve you in tracking how well you (or your child) are progressing through the program. When it comes to taking charge of your or your child’s health care, knowledge empowers.
In this chapter I will overview some of the most common and important SNPs. (More detailed information about how different SNPs function in combination with each other can be found in my book, Genetic Bypass.) In combination, the Nutrigenomic test and the MPA report detail the supplementation recommendations for each SNP, taking some of the guesswork out of your journey to health and wellness.
People often ask whether the genetic information found on the test is permanent or a snapshot in time. It’s permanent. While epigenetics—gene expression—which governs whether genes are turned on or off, can change, the genes themselves do not. As you may recall, I explained this earlier in the book with a computer analogy. For this reason, the MPA is a permanent roadmap for today, tomorrow, and twenty years from now. Implementing all of the supplement recommendations based on your MPA is not something to be undertaken on Day One of the program. Accordingly, many of the supplements may not be needed now, but may be later on.
Take some time to familiarize yourself with the underlying rationale for this process. This will help you to choose the supplements needed now, next month, and in the future. Once you are ready to, you can choose your supplements and begin your journey. This program requires a commitment. When you immerse yourself in it, you will better understand it and embrace both the recommendations and the process.
Each mutation or gene/gene variation is designated by a combination of letters and numbers. At first, this may seem like gobbledygook, but over time, these will become more familiar to you, and you will actually begin to understand this new language. If you take a look at the on-line chat room, you may notice that many parents list their child’s SNPs after their own name. This helps all of us understand what they are addressing.
DNA molecules are made from four nitrogen-containing chemicals called bases. These are adenine, thymidine, cytosine, and guanine, commonly referred to by their initials, A, T, C, and G. Each gene has its own sequence of bases, and these letters are used to differentiate one gene from another.
In your Nutrigenomic profile and MPA, you’ll notice that there are two copies of each gene, marked with either a + or a–. One copy comes from each parent. When both copies are identical (either with or without a mutation), the profile will show them as either +/+ or–/–. We then refer to them as “homozygous.” However, when one copy has the mutation (as denoted by a +) and the other does not (as denoted by a–), then we refer to them as “heterozygous.”
The + and—designations indicate whether or not the gene differs from what’s considered “the norm.” A change from the norm is termed as a + sign. No change is designated by a—sign. The parameters of the norm vary from lab to lab, depending in part on the lab’s reference database. The call letter for each SNP indicates the genetic base identified by the lab.
For instance, for the MTHFR gene, we look at a particular SNP designated as C677T. This alphanumeric name reveals that at position 677 in the DNA, the lab regards a change from a C to a T as a mutation. The call letter T and the + designation signify a change from the norm—that is to say, a mutation. If there is no change, then the call letter C and the—designation indicate that this gene follows the norm; in other words, no change, no mutation.
A different lab might denote these letters slightly differently. To assure that the results are consistent and we’re all on the same page, everyone following this program uses the same lab services.
Because different parts of the methylation cycle function in ways that can trigger effects elsewhere in the cycle, it’s important to address mutations in a precise sequence, especially for three critical mutations: SHMT, ACAT, and CBS. I call these the First Priority mutations. If you have SHMT or ACAT, please read about them and address them, if needed, first. And then, if needed, go on to address the CBS mutation. If you only have the CBS mutation, please address that one before proceeding to the second priority mutations later in this chapter. If you don’t have any of the First Priority mutations, skip this section and start with the second priority mutations. (The names of all the mutations will become more familiar to you over time.) As we proceed to discuss each mutation, I’ll orient you to:
Read through the sections on mutations relevant to your or your child’s Nutrigenomic test results and get a sense of what you are dealing with.
However, I want to caution you that this is not a cookbook, where you just take (or give your child) every supplement on every list for which there is a mutation. This is a process that unfolds over time. I recommend that you take baseline tests and then test repeatedly to ascertain your progress. This will guide you in when to introduce supplements or add more in. And, as always work with your health care provider.
In this sequence, you will:
Again, more detail will follow the material on the mutations.
SHMT and/or ACAT mutations: Consider addressing these first if you or your child have any of the following test results: elevated iron on a UEE test, Short Chain Fatty Acid (SCFA) imbalances on a CSA test, suberic, beta hydroxyl methylglutaric acid, or other ketone and fatty acid metabolites imbalances on a MAP or OAT test; or if there are severe gut issues or muscle weakness (which can be related to aluminum retention)
CBS mutations: Unless these are addressed first, adding in other methylation cycle supports can lead to increased levels of ammonia, highly elevated taurine, hydrogen sulfide, and other toxic sulfur byproducts. We address these via the Ammonia Program (see below.)
Address the rest of the methylation cycle imbalances by supporting both the “long way” around the cycle via the MTR/MTRR as well as the “shortcut” through the cycle via the BHMT enzyme.
Prior to beginning Step Two, you may also wish to run an initial, baseline urine amino acid (UAA) a MAP (or OAT) and CSA tests. When looking at these tests in conjunction with the Nutrigenomic test you can refine the supplement choices for you or your child.
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.
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.
ACAT, (Acetyl-Coenzyme A acetyltransferase) impacts critical pathways and hence functional areas of human biochemistry in several ways, including:
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.
In my opinion, CBS mutations significantly add to the challenges of treating autism, making them a first priority for those who have one or both of the two CBS SNPs. Typically, methylation cycle mutations lead to decreased or impaired enzyme function, but the CBS SNPs lead to increased enzyme activity (called “upregulation”). What effects does this produce?
The CBS enzyme is located right between homocysteine and the rest of the transsulfuration pathway, where it acts as a gatekeeper. With this upregulation, the “gate” is always open, sending all of the nutritional support used in this program down a road that does not lead to glutathinone but instead depletes the rest of the cycle. Instead of being directed to produce glutathione, which helps the body to detoxify, our supports head out the open CBS “gate” into the transsulfuration pathway, and may end up as harmful byproducts, such as excess ammonia and sulfites.
Addressing CBS entails the following:
Since there is obviously no point in using supports only to have them drain out via CBS and create ammonia and sulfites, all of these recommendations should be enacted for at least four to six weeks prior to adding in other methylation pathway supports. However, once you have been on the program to address CBS for the above time period, you or your child will have potentially stored sufficient intermediates to manage the problem once you begin other methylation supports. However, it’s very likely you won’t be able to get just the right balance of supplements until you have methylation supports in place. That’s when we get a more complete picture of the interplay between CBS and other mutations. And that’s why I recommend that you undertake concurrent biochemical tests regularly. By doing so, you can fine tune your program. One thing is certain: anyone following the program who has any of the CBS mutations should continue to follow the CBS recommendations long term.
While you are doing the initial phase of the CBS recommendations, you can implement the gut program (see the previous chapter) if you have not already done so in Step One.
This is an overview of the CBS Protocol. For specific recommendations, based on your Nutrigenomic test results, see recommendations by mutation in your MPA report. Before you begin to add in supplements, I recommend that you get an initial baseline UAA, which will help you know where you are in regard to taurine, which is key to bypassing CBS. Begin by using Ammonia RNA (or CBS + RNA) for four to six weeks before adding other methylation cycle support. After four to six weeks of following the CBS Protocol (see below) retest taurine on a UAA. Once it’s at 50% or below you are ready to add in the rest of the methylation cycle support.
Even after you add methylation support, continue to regularly use UAA testing to monitor taurine and ammonia levels to assure that taurine levels remain in the normal range. Since often the taurine will start to climb after methylation cycle support is in place, it’s best to regularly use the UAA tests to track taurine levels so that you can adjust the supplements added to assure that taurine remains in the desired range at 50% or less. Those who are CBS + should run regular UAAs two to three times per year to closely follow taurine levels and support accordingly. If at any time you find that taurine has climbed, increase Ammonia Support RNA or CBS+ RNA until you’ve brought taurine to acceptable levels.
Dosage: 1/4–1/3 dropper or 0.25–0.50mL up to 3x a day with meals as based on taurine levels on a UAA.
The goal is to keep taurine at 50% or lower.
If you or your child is on the specific carbohydrate diet (SCD) or any other high protein diet, remember to lower your protein intake gradually. Drastically reducing protein may trigger rapid detox and/or result in gut imbalances. If the SCD or high protein diet is critical to you or your child’s health, then you may wish to address other aspects of the ammonia protocol first.
Dosage: (sprinkle—1 capsule on high protein meals)
Using a sprinkle or capsule of yucca when eating protein meals is generally helpful, but to determine how much yucca to use, as well as how often to do the charcoal flush, consider testing urinary ammonia levels via a UAA test. And remember to follow the rest of the ammonia protocol—don’t rely on yucca alone to help you address high ammonia.
Dosage: 1 to 2 capsules of charcoal, followed by enough magnesium citrate to produce a bowel movement within 8–12 hours. Once per week or more depending on testing and behaviors.
A charcoal flush soaks up excess ammonia in the body. You may want to do a “trial run” with magnesium citrate the day before to determine how much you need to use to produce a bowel movement within 8–12 hours. You can do the flush on a weekend, as that may be more convenient. Use charcoal flushes if ammonia is high or needs to be kept under control, as indicated on the MPA and/ or biochemical testing.
As you will see on your MPA, there are two different CBS enzymes and therefore different permutations of the basic protocols. Look at your results to see which combination you have and follow the corresponding supplement recommendations below. I recommend that people fine-tune the individual dosage based on test results (from a UAA) that track ammonia and taurine levels, also taking into consideration the number of CBS mutations.
For example, for those who have both copies of CBS C699T, the most severe CBS variation, it’s likely that you need to use the Ammonia Support RNA closer to three times per day. On the other hand, if you had a single CBS A360A, the least severe variation, you may require less of the RNA used only once a day. Biochemical testing done through my office will allow me to determine your optimal dose, but the bottom line is that Ammonia Support RNA should be on board daily with any CBS+, with the amounts adjusted based on ammonia and taurine levels. Do not stop giving it, even once these levels come down. At that point you can determine a maintenance dose that will keep taurine and ammonia in the normal healthy range. Periodic testing will help you make the necessary adjustments.
Since the CBS mutation can lead to elevated levels of taurine and excess sulfur groups, it’s important for those with CBS upregulations to limit their intake of sulfur-containing foods. The intolerance to sulfur may be enhanced or lessened by the specific CBS SNP affected, and will also depend on whether the mutation is homozygous or heterozygous. Excess sulfur, resulting from CBS activity may also trigger chronic stress (the cortisol response), which regulates the pathway mediated by the BHMT enzyme. Normally, sulfur is bound to amino acids (such as homocysteine, methionine, SAMe, SAH, or cysteine), and can’t create systemic havoc. However, with the increased CBS activity produced by this SNP, those sulfur groups are instead released into the system as sulfites.
To avoid that problem, I recommend that if you or your child have CBS upregulations, consult the list of sulfur donors below—and avoid foods and nutrients with high sulfur content. Garlic, an antimicrobial; DMPS, a widely used chelation agent (which helps to remove metals from the body); broccoli; and other common foods and supplemental compounds, like glucosamine sulfate (note the sulfate!) are all sulfur donors. Since those without CBS sometimes need more sulfur donors, you may come across generic recommendations (“eat more broccoli!”) for sulfur-containing foods and supplements, another example of why it’s critical to know your genetics. Once the body is supported nutritionally to address the CBS mutation(s), you will be better able to use sulfur-containing compounds, including glutathione.
What’s more, when it comes to sulfur donors, we don’t want to “throw out the baby with the bath water” because we all need some sulfur. If sulfur is complexed in an herb or vegetable, like broccoli or milk thistle, you will get its other benefits from a low dose. With CBS upregulations (or SUOX which I will discuss later in this chapter) you should avoid MSM, chondroitin sulfate, and magnesium sulfate, at least until this portion of the pathway is in better balance, as determined by UAA testing. But you can use low doses of herbs that contain some sulfur but have other beneficial attributes, such as horsetail grass, spirulina, dandelion leaf, and parsley. In addition, methionine is key to methylation cycle function, and SAMe, which helps to create methionine, contains sulfur, as do taurine and cysteine. All three are sulfur amino acids.
|Coconut milk, juice, and oil||Mustard leaves|
|Epsom Salts baths||Radish|
|Fish||Red hot peppers|
Detoxifying the sulfites produced by CBS activity requires molybdenum, a mineral that performs several biochemical functions.
In addition to processing sulfur, molybdenum helps the body maintain the zinc/ copper ratio and contributes to genetic material. When molybdenum is depleted by excess sulfites resulting from CBS upregulation, this can impact the zinc/ copper ratio.
Manganese is another mineral involved in ammonia detoxification. Excess ammonia can deplete manganese stores. Classic signs of chronic manganese deficiency include low cholesterol, elevated alkaline phosphatase levels, and depressed T-cell-mediated immune function (due to thymus issues). Manganese also contributes to the synthesis of dopamine, a key neurotransmitter that helps to regulate mood. Accordingly, when higher levels of ammonia result from the CBS upregulation, manganese can be recruited to detoxify them, impacting dopamine levels. In addition, the pancreas requires manganese for insulin production. Because of the many functional areas impacted when these two minerals are recruited to rid the body of excess ammonia, I recommend that those with CBS mutations regularly monitor both molybdenum and manganese levels on an essential minerals test—in addition to monitoring both ammonia and taurine levels on a UAA test. If the test results show elevated taurine and ammonia, you and your practitioner can elect to raise the level of ammonia support.
There is one caveat in interpreting test results. While I would expect to see high levels of taurine and ammonia in all those with the CBS mutation, in actuality, sometimes that’s not what the test results always show, especially prior to implementing full methylation cycle supports. So don’t be misled if your baseline results don’t reveal elevated levels of ammonia and/or taurine.
Why will the CBS mutation tend to produce higher levels of taurine? One of the roles of the transsulfuration pathway is to generate both glutathione and taurine. If the cell detects a low level of cysteine, it will favor glutathione synthesis. High levels of cysteine lead to taurine synthesis. With a CBS upregulation, more cysteine is generated, shunting the pathway toward taurine formation. Some animal studies indicate that the CBS C699T represents a forty-fold increase in enzyme activity. The CBS A360A is a less active upregulation. It’s not surprising that in those with the CBS mutation it’s common to see low levels of homocysteine, cysteine, or cystathionine, due to the rapid conversion to taurine.
Taurine is not just a bad guy. It’s calming and helps to prevent seizure activity, so we don’t want taurine levels to drop too low. Until the entire methylation cycle is supplemented properly, it may be impossible to judge the actual taurine level. Once support is in place, if you still see low taurine levels on a UAA test, then you can increase taurine levels by using low-level B complex to stimulate the transsulfuration pathway, and finally, by supplementing directly with taurine, if necessary.
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 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.
Preliminary collaborative research is ongoing with a group of doctors in Japan looking at the use of prescription BH4 to help to compensate for MTHFR A1298C and CBS C699T+ mutations. The initial results are encouraging. Low daily doses of BH4 (1.25 mg) initially appear to stimulate detoxification over the first several weeks of use. After this initial detoxification effect, the BH4 appears to have a very positive impact on language for individuals with CBS C699T+ mutations. It seems it is possible to restore BH4 stores through supplementation.
Because of the complexity of addressing CBS mutations, I recommend that people regularly undertake biochemical tests to assess the current status/success of the Ammonia Program. You can do a urine amino acid test (UAA) test at baseline (prior to beginning the Ammonia Program), and follow up in six to eight weeks. At that point, you should be ready to move ahead with methylation supports. However, if you’re uncertain about that, the test results can help to clarify the decision as to when to move forward with the rest of the program. Once you begin to layer in the second priority supports, you should retest periodically to assure that ammonia and taurine remain at desirable levels. You can adjust if they are not. In the following section, you will see what to look for.
Any of the following values on test results may be indicators for the CBS upregulation. Changes in these values shown by periodic retesting after you begin to layer in methylation support for second priority mutations will also help you track your forward progress with CBS.
In addition to these tests, you can use sulfite and sulfate test strips on a weekly basis to test the conversion of sulfites to sulfates.
As mentioned earlier, CBS C699T and A360A mutations can deplete molybdenum levels, since molybdenum helps to detoxify sulfur, which tends to accumulate with this mutation. Decreased molybdenum will contribute to imbalance in the copper/ zinc ratio. You can confirm via a urine essential elements (UEE) test and supplement accordingly.
On a related note, an enzyme called xanthine oxidase (present in homogenized milk and dairy,) also requires molybdenum for activity. When xanthine oxidase levels become elevated, they deplete molybdenum levels—yet another reason for a casein-free diet. Alternatively, those with CBS mutations should consider consuming only unhomogenized dairy.
Molybdenum, EDTA, carnosine, and zinc can help balance copper/zinc ratios. Chewable zinc tablets with slippery elm also benefit the gut. Dosing begins with 1⁄4 tablet and increases to one tablet per day. The liquid zinc, zinc capsules, or Krebs cycle zinc (once glutamate and GABA levels are balanced) are also an option. Please revisit the section earlier in this chapter on Mineral Support, placing special emphasis on supporting molybdenum and manganese for CBS.
The first printing of The Puzzle of Autism (2004) focused on mutations in the MTHFR gene. Since that time, I have identified other genetic mutations in the methylation pathway that can compromise its function and serve as a predisposing factor for autism. Rather than assessing complete genetic profiles, focusing on key SNPs in vital areas of function led me to note what I call second priority mutations in the COMT, MTR, MTRR, MTHFR, NOS, and SUOX genes, and more recently in the AHCY, BHMT, and PEMT genes. They are second priority for treatment purposes, but not because of their function. Each one plays a crucial role, which I’ll cover in this chapter.
In this section of the book, I’ll guide you in using supports for these genes to:
The goal of this program is to get the interlocking cycles you see below functioning and creating the proper amount of needed bodily biochemicals. To accomplish this, you will use your Nutrigenomic test results and your MPA. This identifies which mutations must be addressed (for you or your child), and with that knowledge, I’ll walk you through how to supplement accordingly. First let’s get familiar with the cycle itself.
By studying this diagram, you can see the three interlocking pathways which, taken together, I call the methylation cycle. First, let’s focus on the pathway at the far right of this diagram. This pathway leads through the methylation cycle from homocysteine to methionine.
The “long way” around this portion of the cycle begins with the forward reaction of the MTHFR enzyme (seen in the middle pathway) and then via the MTR and MTRR enzymes. The “shortcut” goes through the middle of the cycle via the BHMT enzyme, thereby bypassing MTR, MTRR and MTHFR. Using the clock metaphor that I mentioned earlier, the BHMT enzyme uses the biochemicals phosphatidyl serine, phosphatidyl choline, and TMG as substrates to go directly from homocysteine at 6:00 to methionine at 12:00, skipping 7:00 P.M. through 11:00 P.M. This shortcut (also called the “back-door reaction”) generates more norepinephrine relative to dopamine, leading to imbalances that have been implicated in ADD and ADHD behaviors.
Our first goal is to get the methylation cycle moving again. With mutations in these pathways, the pathway becomes dysfunctional, almost as if it has accumulated cobwebs. The easiest and fastest way to get the cycle working again is by supporting the shortcut through the BHMT enzyme.
Next you can go on to support MTR, MTRR, and MTHFR C677T mutations so that the long way around the cycle will function properly. As a result, the body won’t need to rely so heavily on the shortcut. After certain indicators appear in your biochemical tests, you can use the supplement DMG to help slow the shortcut, and instead favor the long way around the methylation cycle. Obviously it is essential to have supported any MTR, MTRR and MTHFR C677T mutations and to run tests to look at pathway function before making this shift. I’ll discuss the testing values that signal the timing of this shift later in this section.
There are advantages to being able to go both via the shortcut and long way around the cycle. That’s why I recommend low-dose supplements for all of the weak points shown by your test results. For example, as you can see in the following illustration, going the long way creates thymidine, a building block for RNA and DNA, which is needed to repair tissues as well as expand T-cell clones in response to infection. By supplementing with specific RNA products I’ve formulated and with nucleotides (the base material for RNA), we make it easier to go the long way around the cycle, even if MTR and MTRR mutations make it harder for these enzymes to generate the necessary RNA and DNA building blocks. In the same way, even in the presence of mutations, 1/4 tablet of Intrinsi B12/Folate and low dose-5 methyl THF (1/4 tablet of Folapro) can supply additional intermediates that would not otherwise be generated sufficiently when there are mutations. Folapro also helps the MTHFR enzyme to create adequate levels of BH4.
Now that you see what we are trying to accomplish, let’s take a specific look at each of the mutations in these pathways.
The COMT enzyme transfers methyl groups which inactivate the neurotransmitter dopamine. With COMT V158M + these enzymes are less active, and thus inactivate dopamine to a lesser extent. The VDR/Taq SNP also impacts overall dopamine levels. That’s why together the VDR/Taq and the COMT V158 status are key indicators of bodily levels of dopamine. The composite of the COMT V158M and the VDR/TAQ status determines the amount of methyl donors a given individual may tolerate.
The norm, VDR /Taq—/has been associated with higher levels of dopamine. VDR /Taq +/ + represents changes in the gene typically resulting in reduced dopamine levels. The combinations and permutations of these four SNP variations cover a wide range of dopamine levels and rates of dopamine breakdown. The supplement recommendations for each composite variation take that into account.
Since COMT +/+ mutations slow the activity of the COMT enzyme, this variant slows dopamine metabolic activity, allowing dopamine levels to build. As a result, these higher levels then feed back and inhibit additional dopamine synthesis. For this reason, individuals who are COMT +/+ seem to have a reduced tolerance for methyl donors.
So what is the best approach to B12 use for those who are COMT +/+ as compared to those who are COMT-/-? According to published work by Dr. James Neubrander, no toxic doses of B12 have been found, and this medical finding is supported by my clinical experience. Parents report back that “the more B12, the better.” In some cases, elevated doses of B12 (50 milligrams and above) have helped to stimulate speech in formerly apraxic children. However, those who are COMT + often cannot tolerate high doses of any methylating agents. For this reason, I tend to focus more on the use of hydroxylcobalamin B12, dibencozide (adenosyl) B12, and cyanocobalamin B12 for those who are COMT +/+ and to use methylcobalamin B12 along with these other forms of B12 for those who are COMT-/-.
Small amounts of the Mood D and the Mood Focus RNAs also can be used to support healthy dopamine levels. Ginkgo has been reported to help to increase dopamine uptake. A very small sprinkle of an extract from Mucuna Pruriens (which contains natural dopamine) can be used by those with lower levels. However, high doses are not suggested. If mood swings occur following use, then go to half the initial dose or discontinue use. In addition, a mushroom extract, (for instance the supplement Mycoceutics), can be used when there’s an increased breakdown of dopamine in conjunction with chronic bacterial issues.
With COMT V158M—and VDR Taq +, the body will better tolerate methyl donors and the MPA supplement recommendations will reflect that.
However, for those with COMT V158M + or VDR Taq – SNPs, it’s best to rotate methyl-containing supplements rather than using them all on a daily basis. Alternatively, those with a lower tolerance for methyl donors can start by using 1⁄2 of each of the recommended supplements if tolerated, and then gradually increasing the dosages over time. You can also support the mitochondria (supplement recommendations are near the end of this chapter) even before methylation cycle support if you desire.
The Fok + status for the VDR (vitamin D receptor) impacts both vitamin D levels, and also has been associated with potential blood sugar issues. Since low vitamin D levels are related to a variety of neurological conditions, recent research suggests that it’s advisable to supplement with at least 1000 IU of supplemental vitamin D daily. In addition, sage and rosemary can help to support vitamin D receptors.
Low blood sugar is related to pancreatic activity which is why with VDR/FOK +, I advise supporting the pancreas. You can use vitamin K, OraPancreas, AyurGymnema, Super Digestive Enzymes, CCK (Resist Fat Apex Lean), and pig duodenum. The essential elements chromium and vanadium also influence blood sugar levels. If their levels drop on an essential minerals test, add them in as supports.
Variations in the VDR Fok marker reflect differences in bone mineral density. Increased bone mineral density can reflect increased calcium absorption, but it’s also been associated with higher blood concentrations of lead.
In addition to blood sugar issues, decreased pancreatic activity is sometimes associated with increased levels of oxalic acid as measured on organic acid tests. Pancreatic supports may help normalize these as well. Avoid the herbs sheep sorrel and turkey rhubarb, which may increase levels of oxalic acid.
When both oxalic acid and triglycerides are elevated, liver support is indicated as well. In addition to OraLiv, OraTriplex, Milk Thistle, and Dandelion Root, you can consider the liver support suggestions in Step One in the previous chapter.
These following genes work together to regenerate and utilize B12 for the critical long way around the methylation pathway, helping to convert homocysteine to methionine: MTR A2756G/MTRR A66G, H595Y, K350A, R415T, S257T, A664A. High levels of homocysteine have been implicated as risk factors in a number of health conditions, including heart disease and Alzheimer’s disease. As for the combined COMT and VDR /Taq status, the MTR and MTRR composite status is also important. Mutations in MTR (the methionine synthase gene) can increase the activity of this gene, leading to a greater need for B12, as the enzyme is using up B12 at a faster rate. The MTRR (methionine synthase reductase gene) helps to recycle B12 for utilization by MTR. Mutations that affect its activity would also suggest a greater need for B12.
If your Nutrigenomic profile shows a mutation in MTR and/or in the MTRR, my recommendations include a focus on B12 support. The level of B12 support will depend on the number and combination of these mutations, so look at your test results to determine all mutations present.
Remember, together and separately, the MTR/MTRR mutations will lower bodily levels of methyl B12, a deficiency that the supplement recommendations can help you to address.
Why is the MTR/MTRR pathway so important? As you recall, there are four pathways through this key portion of the methylation cycle.
Our methylation intermediates (all the biochemicals we need on this pathway) can go one of four ways:
I find that if we limit “traffic” through CBS, SHMT, and BHMT so that we shunt the traffic through MTR/MTRR, we often see increased excretion of metals, especially mercury. Doing this means that we supply all the necessary ingredients for the MTR/MTRR reaction, while balancing the other pathways at a maintenance level. Accordingly, my supplement recommendations for CBS, SHMT, and BHMT will help you limit traffic down those pathways. In this section, we focus on enhancing MTR/MTRR, which entails increasing B12 levels.
However, before supplementing with B12, please first take into account your COMT V158M and VDR/Taq status, which will help to determine whether to focus more heavily on hydroxyl B12 or methyl B12 for support. In my clinical experience, I’ve regularly observed that those with COMT V158M + and VDR Taq – mutations don’t tolerate methyl donors well, including methyl B12. Also adults, regardless of their COMT V158M/VDR Taq status, have more limited tolerance than children for the detox triggered by methyl B12. Despite that, those who are MTR + and MTRR + can and should look at higher-dose B12 support, balancing the ratio of methyl to hydroxyl B12 based on COMT V158M/VDR Taq status. As you gradually proceed to add in B12, you can also take into account your own or your child’s personal tolerance for it. In addition to either methyl or hydroxyl B12, I often suggest the use of low doses of cyano (to support the eyes) and adenosyl B12 with vitamin E succinate, as you will see in the supplement recommendations.
One way to begin B12 support is with one chewable methyl B12 (5mg) or hydroxyl (1 or 2mg) daily, gradually increasing to two, three, or more per day if you can tolerate it. If mood swings occur, then decrease the dose of B12 back down to a more comfortable level. While a new nasal B12 is available, I don’t recommend using that exclusively. I prefer some B12 to be absorbed through the gut with the help of Intrinsic Factor, which is contained in some of the recommended supplements. In addition, the use of oral B12 sprays (available as hydroxyl or methyl,) topical B12 cream, B12 gum and the B12 patch are other means by which to support B12 in the body. I like to see multiple routes and forms of B12 used until I feel that the system has been saturated with B12 (see discussion of cobalt levels below). Literature suggests that oral B12 is as effective as injected B12. However, if preferred, you can consider B12 injections, making sure to use either plain methyl B12 (without any added folinic or NAC) or plain hydroxyl B12 injections. You can use the chewable B12 and the oral B12 spray on the injection “off days.”
If you plan to use injections, start with once per week, and gradually increase to three times per week. Allow your tolerance levels to determine how you can gradually increase the B12. As always work in conjunction with your health care provider.
The MTRR 11 mutation (a call letter other than G, would represent a mutation) appears to be correlated with increased levels of toxic metal excretion. At this point, I suspect that those people who are sometimes categorized by doctors as ”excretors” may in fact carry the MTRR 11 mutation. From what I see clinically, with MTRR 11 mutations, there are often lower overall amino acids on a UAA test. For this reason we look to support with higher levels of the Bowel Inflammatory Pathway Support RNA for those who have an MTRR 11 + status.
In addition to its use of B12, MTR/MTRR also contributes to electron transfer, along with two forms of vitamin B2, or riboflavin, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) as well as NADPH, a form of B3 (NADH and niacinamide). Oxygen inhibits the transfer process. In addition, MTRR acts as an aquacobalamin reductase to aid in the methylmalonyl CoA mutase reaction (MMA reaction).
MTRR is part of the larger family of enzymes known as diflavin oxidoreductases. Another member of this family, cytochrome P450 reductase can substitute for MTRR (Banerjee, JBC July 20, 2001). All in this family of enzymes (which includes MTRR, cytochrome P450 reductase, heme oxygenase, squalene monooxygenase, nitric oxide synthase, and NR1 reductase) share similar structures and domains with other enzymes in this family (Ludwig, Plos biology February 25, 2005).
In test tube reactions, cytochrome P450 reductase has been shown to replace MTRR function.
Indole 3 carbinol (I3C) has been reported to enhance cytochrome p450 levels (LeBlanc, Chem Biol Interact. August 14, 1992.) Indole 3 carbinol may therefore benefit those with MTRR mutations. On the other hand, Alpha lipoic acid (ALA) can reduce cytochrome P450 reductase activity (Dudka, Annals of Nutrition Vol 50, 2006), so only limited ALA support is advised with MTRR mutations. In addition, given the need for NADPH and FAD/FMN for electron transfer, I recommend adding NADH and riboflavin to support MTRR activity, along with adenosyl B12 and low-dose vitamin E succinate to support the MMA reaction.
After following the earlier recommendations in this section to improve B12 levels, you can also go back once more to rebalance glutamate and GABA levels. At this phase, GABA can be added directly. People with COMT V158M–/–usually benefit from ZEN, a supplement product that contains both GABA and theanine, another methyl donor. Other useful supplements at this stage include taurine, pycnogenol, and grape seed extract, all of which are included in the general vitamin. With the exception of taurine (which should not be used in high doses by those with CBS upregulations and/or high taurine) you can raise levels of the above indicated supplements if you notice (or experience) certain behavioral indicators, including difficulties with language, auditory processing, and anxiety levels, particularly anxiety experienced when blood sugar levels are low.
In redressing GABA/glutamate balance, keep in mind that lead inhibits a critical enzyme in the pathway for heme synthesis, resulting in an excess of an intermediate that competes with GABA. In addition, inhibition of this pathway can also cause anemia, as well as the inability to make groups that are needed for B12 synthesis. All of these exacerbate mutations in methionine synthase and methionine synthase reductase.
To address this entails adding B12 along with supplements that address lead toxicity. EDTA capsules or chewing gum, along with weekly EDTA baths or the use of EDTA soap are a gentle way to detoxify lead that are suitable for most people.
Once the methylation cycle is supplemented properly you may begin to see an increased level of detoxification. There may be a “honeymoon” period in which you first see improvement, but this may be followed by a regression in behaviors as the level of creatinine starts to climb. In order to monitor this and to understand changes in behavior resulting in part from this detoxification, it’s advisable to take spot urine samples and run urine toxic metal tests. The urine test results will help you differentiate between a negative reaction to a supplement, the behavioral impact of detoxification, or a mood swing due to dopamine fluxes.
What levels of B12 support are needed? That depends on the individual—and the Urine Essential Elements Test (UEE) can help you to make that determination. Once the cobalt levels found on the UEE are shown as a black line across the test results page, then you have attained the right level of B12 support. You should continue to supplement to maintain that level, while also beginning to introduce additional support to help with oxidized species. Trehalose, spirulina, quercetin, riboflavin, NADH, and ATP are all good for that purpose. On subsequent UEE tests, even as you continue to supplement the same high concentrations of B12, look out for this important indicator: When the cobalt levels drop back to baseline, as you maintain high level B12 support, this is when there are often major increases in excretion. As you can see, it’s important to follow this process with regular UTM/ UEE testing and to work in conjunction with your doctor on the detoxification process.
When it comes to autism recovery, I find this to be a less severe mutation than the other MTHFR mutation, MTHFR A1298C. However, the C677T mutation impacts the body’s ability to convert homocysteine to methionine, leading to increased levels of homocysteine. High homocysteine levels have been associated with heart disease, Alzheimer’s disease, and a range of other inflammatory diseases, including vascular inflammation, and “thick blood,” which can lead to hyper-coagulation and inflammation.
With high homocysteine levels, S adenosyl homocysteine (SAH) accumulates in the body, inhibiting several enzymes in the methylation pathway, including the COMT enzyme discussed earlier in this chapter. While inhibiting COMT can increase dopamine levels for those with COMT V158M -/-, for people with COMT V158M +/+, this very same action can lead to mood swings. SAH also inhibits key enzymes that transfer methyl groups to DNA, RNA and proteins, resulting in the inhibition of DNA methylation.
Appropriate supplementation should help to alleviate these undesirable effects. The C677T mutation serves the forward reaction of the MTHFR enzyme, reducing the ability of the body to make a specific kind of folate called 5 methyl folate. That’s why it’s important to supplement with this specific form of folate and to limit to very low doses any other forms of plain folate or folinic, which compete with 5 methyl folate for transport into the body.
The medical literature is not clear and unified in its understanding of 5 methyl folate, but from my experience one thing is clear: Only 5 methyl folate will bypass the MTHFR mutation. The 5 formyl folate has other advantages, but it will not bypass the mutation. Going from 5 formyl THF to 5 methyl THF requires MTHFR. The product called Folapro is clearly 5 methyl THF. There are products on the market labeled as folinic acid that are 5 formyl THF and others labeled folinic that are 5 methyl THF. Given the confusion, it is safer to use a product based on the chemical formula, rather than to use one based on the name on the label.
As mentioned earlier, a “honeymoon” period often follows putting in methylation supports. For those with a C677T mutation, as well as certain methionine synthase and methionine synthase reductase mutations, this can be one short honeymoon. In some cases, it’s no longer than a single day. In my supplement recommendations, I address some of these mutations in combination because they all occur in a pivotal location in the methylation cycle. As a result, as soon as you begin to supplement properly, you may experience near immediate detoxification as this pathway is rapidly unblocked—just as when a dam is suddenly opened. In order to monitor detoxification, you should run spot urine toxic metal tests (UTM), working in conjunction with your doctor.
If your Nutrigenomic test shows an A1298C mutation in the MTHFR gene, you will be addressing different issues than you would with the C677T mutation. The A1298C mutation has been mapped to the SAMe regulatory region of the gene. Unlike with C677T, a 1298C mutation does not lead to increased levels of homocysteine. Until recently, it appeared that perhaps this mutation was not that serious. However, the scientific literature now suggests that the MTHFR enzyme drives the reverse reaction leading to the formation of BH4, which we discussed earlier in the section on CBS upregulations. Based on what I’ve observed, I believe that the A1289C mutation does indeed impact this reverse reaction, leading to an inability to convert BH2 to BH4, and thus contributing to low BH4 levels. Aluminum also negatively impacts BH4 levels, creating a kind of “double whammy” effect as the mutation impacts the ability to detoxify and limit ammonia, allowing aluminum retention, which then further lowers BH4, worsening the problem.
Both the literature and my personal clinical experience indicate that bacteria can harbor aluminum, which inhibits BH4 synthesis—which is already compromised with MTHFR A1298C mutations. As you progress through the program, if you have this mutation it’s vital to address systemic aluminum, thereby removing a significant impediment to BH4 recycling.
If the Nutrigenomic test reveals that you or your child has this mutation, to understand the importance of BH4, you may want to revisit the discussion of the BH4 three-legged stool earlier in this chapter. While keeping the ammonia levels under control is of paramount importance for everyone, with an MTHFR A1298C mutation it’s particularly important, since excess ammonia drains BH4 levels, already compromised by the conversion problems caused by this mutation.
Low BH4 levels affect dopamine, serotonin, and urea cycle function. Replenishing dopamine stores requires BH4, and as you may recall, dopamine imbalances impact mood. Moreover, the COMT and VDR/Taq status can also add to or detract from maintaining balanced dopamine levels, since these mutations impact dopamine synthesis.
For all of the reasons I mention, with MTHFR A1298C mutations, the focus will be on BH4 support, aluminum excretion, and the gut program, which I introduced at Step One, but will fine tune in Step Two.
With this mutation, imbalances are often seen on a MAP or OAT test, with indicators such as elevated hippuric, imbalances in the benzoic acid ratio, as well as increased non-ideal flora on a CSA. In addition, the early portion of the Krebs cycle may be blocked due to aluminum toxicity. Since aluminum retention is related to chronic bacterial loads, the MTHFR A1298C mutations can limit the body’s ability to address bacterial infection, making it important to focus on the gut program, run regular CSA tests (which indicate bacteria loads), and supplement with supports for chronic bacteria (which you’ll find in the recommended supplement lists). Once first priority mutations, if present, have been addressed, you can begin with Step Two, Part One to add methylation cycle support. There will be further work to do as you move on to Step Two, Part Two, in chapter 7, where we focus more closely on bacterial (and viral) detox with accompanying metal release.
At this stage, first add in methylation support as per the recommendations later in this section. I also recommend that you add mitochondrial support, since aluminum can also impact Krebs cycle activity. Please consult the mitochondrial program in this chapter. Once natural detoxification from these supports has slowed down, you can begin to address bacteria and aluminum with the recommendations on the supplement lists.
In addition, for this mutation, low-dose CCK support (1/8 to 1⁄4 per day of CCK (Resist Fat Apex Lean) along with CCK support RNA) can be helpful, since CCK may help to trigger bacterial detoxification. Over time, you can increase to one tablet per day in divided doses if tolerated. Fine-tuning the gut/microbial program will support bacterial detoxification, sparking aluminum excretion, while balancing the gut flora.
As you can see, I repeatedly recommend using biochemical tests to verify current levels of toxins, as well as biochemicals that need to be raised or maintained and those that need to be lowered. By monitoring toxin and biochemical levels through the following tests, you can assess methylation cycle balance.
Elevated methyl histidine, FIGLU, and uracil reflect imbalance in the entire methylation cycle, while high methylmalonic and low succinic reflect B12 levels. Until the methylation cycle is supplemented properly, it’s harder to accurately measure B12 levels. Moreover, don’t begin to use B12 at appreciable levels until the other mutations in the pathway have full nutritional support. For this reason, methylmalonic and succinic levels may at first appear to be in range, and then shift once you add all other methylation cycle support. If methylmalonic and succinic are in range, yet FIGLU is high, methionine is low, and taurine is elevated, first supplement to bypass mutations and then rerun to test for methylmalonic and succinic levels.
If you have been supporting to bypass mutations and still find that the MMA and succinic are in range while FIGLU remains high, then it’s often helpful to increase plain folate (which can be found at adequate levels in the HHI general vitamin formula.) It can also be helpful to run a CSA, since bacterial issues can elevate the FIGLU.
Folapro, intrinsic B12, nucleotides, and folinic can help to compensate for methylation cycle mutations, opening up the pathway to allow an expansion of T cells for viral elimination. It is for this precise reason that we ask you to WAIT to add these supplements, until the body has had a chance to rebalance in Step One, and then add the immune support necessary in Step Two before beginning a detoxification process.
High levels of methionine sulfoxide may indicate a need for additional ATP. High levels of methionine as well as methionine sulfoxide with sufficient ATP support may suggest decreased MAT enzyme activity and the need to support directly with SAMe, regardless of the COMT and VDR status to bypass MAT (methionine adenosyl transferase) mutations.
At the outset, it’s as if the methylation cycle is inactive and full of cobwebs. If you have mutations in MTR and/or MTRR, then you may need to first support the BHMT pathway to get the methylation cycle moving.
Like the MTR/MTRR route, the BHMT pathway also forms methionine, and activating the BHMT shortcut will bypass mutations in the methionine synthase gene. Since this secondary (or shortcut) pathway uses phosphatidyl serine (PS) and /or TMG as donors, you can add these supplements to drive this reaction. Once the shortcut is activated, you can gradually layer in long route support, including folapro, intrinsi B12/folate, and other forms of B12, as mentioned earlier.
Phosphatidyl serine is available in both plain gel caps and in a chewable form with DMAE (the brand name is Pedi-Active). Since DMAE contains methyl groups, this is a good combination for people who need extra methyl groups based on their COMT and VDR test results.
However, if you can’t tolerate higher levels of methyl donors, or if you experience mood swings, then stop using the Pedi-Active with DMAE.
While DMG works well to support the development of language, it also can inhibit the BHMT reaction. I therefore recommend that people add DMG only after this secondary pathway is properly supplemented with a low dose of TMG, PS/PE/PC, and plain methionine, all of which are contained in the HHI general vitamin, Neurological Health Formula (along with other valuable nutrients.) The recommended dose is one in the morning and one in the afternoon. In general it’s best to wait to add DMG until there’s sufficient B12 to support the long route around the cycle.
The first goal is to keep methylation activity moving via the short cut until you are ready to make the shift to the long route around the cycle. Once the UEE test results show high cobalt excretion visible though a “black line across the page,” you can then add some DMG.
BHMT (betaine homocysteine methyltransferase) is central to the “shortcut” through the methylation cycle, again helping to convert homocysteine to methionine. This activity can be affected by stress and cortisol levels, which impact norepinephrine levels, thereby contributing to ADD/ADHD. However, each of the BHMT genes (BHMT 1, 2, 4, 8) functions somewhat differently, so let’s take a closer look.
Having these three BHMT mutations (1,2, and 4,) +/+ can produce UAA test results similar to that of a CBS mutation—even if you don’t have a CBS upregulation, suggesting that these three BHMT mutations result in higher level intermediates in the transulfuration portion of the pathway. Using Ammonia Support RNA and limiting taurine can help. Adjust your dosages based on urine AA testing. On the other hand, the BHMT 8 mutation often seems to increase MHPG levels relative to dopamine breakdown (HVA), resulting in attention issues. These levels can be tracked on a MAP test. Elevated glycine (indicating emphasis on the shortcut pathway) is common with BHMT 8 +/+. The use of the Attention Support RNA along with NADH, SAMe and DMG (once sufficient B12 is in place) may be helpful for attention issues related to BHMT8 + status. Since this is an open-ended area of clinical discovery, please check into the chat room for updates as my understanding of BHMT is a work in progress.
The MaoA gene codes for the enzyme active in serotonin breakdown. With a Mao A + status, decreased enzyme activity lessens the ability to degrade serotonin. As with COMT V158M +, with Mao A +/+ status, serotonin cycling from high to low levels may result in mood swings or even aggressive behaviors. The Behavior RNA can help with aggression. In addition, as discussed in the section concerning the gut and bacterial issues, chronic infection can deplete tryptophan stores. This can be confirmed via an organic acid test (OAT) and urine amino acid tests (UAA), which indicate high levels of 5 hydroxy indole acetic acid (5HIAA). Obsessive compulsive disorder (OCD) behaviors are also a symptom. Lack of BH4 due to aluminum toxicity, increased levels of ammonia, and/or MTHFR A1298C mutations all impact serotonin levels. The use of frequent low doses of the Mood S RNA and the supplement 5HTP may help balance serotonin, if needed.
As with the ACE deletion (discussed later in this chapter), the Mao A gene is not inherited via standard Mendelian genetics. The Mao A gene “travels” with the X chromosome and is considered a dependent trait. Since the X chromosome in males can only come from the mother, this means that the father’s Mao A status does not contribute to the son’s Mao A status. For females, since one X chromosome comes from each parent, the genetics will tend to reflect both parents with respect to the Mao A SNP.
I rarely see a SUOX + /+ mutation on the Nutrigenomic panel. Imbalances in this enzyme activity can lead to increased amounts of toxic sulfur byproducts, because SUOX helps to detoxify sulfites and turn them into a less toxic form called sulfates. Test results for those with SUOX +/often reveal low levels of manganese, boron, and strontium. A similar pattern may occur in people with very low levels of B12, sometimes creating what I call a “functional SUOX deficiency.” In other words, without actually having the SUOX mutation, people may have other methylation pathway mutations that combine to burden this portion of the cycle and produce a similar effect.
Since the SUOX enzyme uses molybdenum as a cofactor, depletions in molybdenum may result. Decreased molybdenum levels may result from SUOX mutations, CBS activity, or ingestion or use of sulfur-containing compounds. All of these factors can also contribute to food and environmental sensitivities, in part due to the lack of aldehyde oxidase, which I’ll discuss below.
Why are low levels of molybdenum a problem? Molybdenum helps balance the zinc/copper ratio so that copper does not predominate. Excess copper can cause fatigue, depression, insomnia, rashes, and adrenal burnout, among a variety of other symptoms. With SUOX and/or CBS C699T+ mutations, regular UTM and UEE tests are helpful in monitoring essential minerals status. This information helps you track detoxification of heavy metals, while also allowing you the zinc/copper ratio.
Low molybdenum will also tend to decrease xanthine oxidase and aldehyde oxidase activity.
Xanthine oxidase is found in homogenized milk, one reason that dairy intolerances may occur with SUOX +/–status (or with CBS + due to increased burden on the SUOX). Aldehyde oxidase is needed to detoxify aldehydes, including acetaldehyde. Acetaldehyde is a fungal waste product generated by candida. Aldehydes are also found in perfumes, certain foods, and environmental toxins. Food sources of aldehydes include vanilla, cinnamon (including cinnamon flavored toothpaste), cumin, and tarragon. Aldehydes also occur when alcoholic beverages break down.
The urine essential elements test (UEE) will help you track molybdenum levels. You can supplement molybdenum directly or with certain foods.
|Beef kidney||Oat flakes|
|Green leafy vegetables|
Limiting intake of sulfur-based compounds is the simplest way to address the SUOX mutation. It’s important to avoid sulfites in foods because you have a limited ability to convert them. Sulfites may contribute to the extreme acid reflux that people with the SUOX + status sometimes experience. Dried fruits and aged meats are often sources of sulfites. Certain brands of tuna contain sulfites, and salad bars often use sulfites to prevent the lettuce from turning brown.
In some of the cases I’ve seen, people with SUOX +/–status have also complained of severe acid reflux. The reflux did not respond well (or at all) to standard medications for gastroesophageal reflux (GER). These medications target the mechanism that triggers excess acid in the stomach (called histamine 2 blockers). With SUOX, excess sulfites may lead to allergic/asthmatic reactions that have a secondary effect on acid reflux. GER often occurs with asthma. Medical research confirms this association, though it’s not currently known whether asthma causes acid reflux, or vice versa. High sulfites are known triggers for asthma, and certain contributing factors in asthma may lead to excess acid production. Ordinarily, histamine reactions, such as those contributing to asthmatic symptoms, are viewed as allergic responses. However, histamine receptor overactivity is also tied to the excess acid production observed in GERD. According to Pneumological Aspects of Gastroesophageal Reflux (edited by Dal Negro and Allegra):
Gastroesophageal reflux (GER) refers to symptoms and events that result from abnormal regurgitation of gastric contents into the esophagus. Respiratory diseases, in particular bronchial asthma, can be exacerbated by multiple triggers, including GER. The relationship between the occurrence of gastroesophageal disorders and changes in respiratory function has been known for over a century, but the mechanism by which esophageal acid regurgitation can produce respiratory symptoms is still debated. The reasons for these concurrent pathological events are also not fully understood. Determining, for instance, whether reflux itself initiates or exacerbates asthma, or whether asthma or its treatment primarily causes GER is a matter of current investigation.
This work supports the working theory that acid reflux seen in individuals with SUOX mutations or with CBS upregulations may be related to the excess sulfites in their systems. Maintaining adequate levels of molybdenum, limiting sulfur donors, and the use of the Lung Support RNA, Respiratory Support RNA, as well as the Stomach pH Balancing RNA and Stress RNA may help to balance the acid reflux. Quercetin can be used to limit mast cell degranulation for those individuals who are COMT—/–or COMT +/–. In addition, Petadulex (butterbur) may be helpful in balancing allergic/histamine reactions.
Adequate magnesium has been shown to be helpful in addressing asthma and may therefore benefit those with high sulfite levels. In one study of asthmatic children, magnesium given intravenously prevented hospitalization and reversed asthma attack symptoms in the children who were unresponsive to three prior doses of bronchodilators. (Ann Emerg Med. 2000; 36:181–190.). That’s why I advise testing both urine essential element testing (UEE) and urine toxic metal (UTM) on a regular basis.
Acid reflux may also result from both metal toxicity and chronic viral infection. Since Cimetidine (Tagament), an OTC medication for heartburn, has been demonstrated to be effective against herpes virus, it’s possible that chronic viral infection also plays a role in acid reflux.
Finally, high-level B12 has been reported to alleviate sulfite sensitivity. Improvements in asthma have also been reported with high-dose B12 support. Lack of B12 may increase stomach acidity, actually exacerbating acid reflux, which is an indirect way of saying that those with SUOX mutations, with sulfite sensitivity, or with asthma may want to consider high-dose B12 support as described in the sections for MTR and MTRR, even if MTR or MTRR mutation is not present.
The NOS (nitric oxide synthase) enzyme is located in the urea cycle, where it helps with ammonia detoxification. With NOS +/ +, there is reduced enzyme activity, producing an additive effect with CBS upregulations to result in the generation of higher levels of ammonia.
Some research in the medical literature suggests that omega 3 EFAs may limit NOS activity so I recommend using an EFA mixture with omega 3:6:9 only every other day, and alternating it with a different source of omega 3 fatty acids, such as DHA. These essential fatty acids optimize membrane fluidity, and by alternating them, you limit excess omega 3 which can interfere with the NOS enzyme. Since inefficient NOS activity can strain the urea cycle, leading to elevated ammonia levels, this method provides the fats you need without impacting NOS. Those without NOS mutations can consume omega 3’s daily. In addition, consuming a lower protein diet and Stress Foundation RNA (once or twice daily) also helps to support the urea cycle.
I suggest alternating the fatty acids the body needs, because in my clinical experience I’ve noticed that with NOS + there is difficulty processing lipid donors. We all need certain lipids for a variety of bodily functions, so the key here is to use the donors mentioned below in moderation or as recommended in the supplement lists, not to eliminate them altogether.
Deletions of genes affect the activity of the ACE (angiotensin converting enzyme). This causes upregulations in activity of this enzyme leading to a higher rate of conversion of angiotensin I to angiotensin II. High levels of angiotensin II increase the level of aldosterone. In animal studies, high levels of angiotensin II were correlated with increased anxiety and decreases in learning and memory. High levels of aldosterone also tend to increase the activity of AHCY.
Remember, the ACE gene is a deletion of that gene and not a SNP. As such, it may not be inherited in families in the same manner as single-based genetic mutations. While SNPs result from a single base change, a deletion results from the presence (or in some cases, the absence) of a small piece of DNA.
High levels of aldosterone lead to decreased excretion of sodium in the urine and increased excretion of potassium in the urine. This suggests that low sodium and high potassium on a UEE test may reflect aldosterone excess and may indicate ACE upregulations, a helpful indicator for those who have not run a genetic test. In addition, UEE test results can confirm the impact of your supplement program. Elevated excretion of potassium relative to sodium is a strong indicator for the ACE deletion in the absence of appropriate supplementation. After supplementation, urine essential element test results can be used to verify that you have had a positive, balancing effect on potassium and sodium excretion with your supplement program.
In essence, aldosterone is a stress hormone, since it’s released into the bloodstream following stressful situations. Consequently, even in the absence of an ACE upregulation, chronic stress can produce high aldosterone levels, causing sodium retention and increased potassium excretion. However, the potassium is excreted only if the kidneys are functioning properly. With compromised kidney function, potassium may be retained in the body.
While high aldosterone will initially prompt both sodium retention and increased potassium excretion, over time the adrenals become fatigued. As a result, they can no longer release adequate amounts of aldosterone and/or cortisol. At that point, potassium will rise and sodium will fall, resulting in increased retention of potassium. When these sodium and potassium imbalances occur, consider adrenal and kidney support. It’s also helpful to reduce stress, since aldosterone functions as a stress hormone.
ATP can also help balance sodium and potassium levels. Certain toxic minerals, such as thallium, are reported to negatively impact ATP levels. In my clinical experience, it’s often difficult to balance sodium and potassium without adequate ATP support—until sufficient excretion of thallium has occurred.
Support for ACE mutations in this pathway can include Kidney Inflammatory Pathway Support RNA, OraKidney, Ora-Adren 80, Stress and Anxiety Support RNA. BioNativus multiminerals can be used for general mineral support.
Even without specific ACE mutations, many people can benefit from general adrenal and kidney support, which includes OraKidney, Ora-Adren 80, Stress Foundation RNA, Kidney Inflammatory Pathway Support RNA, and ATP support—particularly if test results show high levels of toxic metals (such as thallium.)
On a related note, numerous supplements (and even teas) contain licorice. However, it should be avoided by those with stress, anxiety, and similar imbalances, since licorice inhibits the enzyme 11 beta hydroxysteroid dehydrogenase that break down aldosterone and cortisol, leading to increased aldosterone levels. Licorice can also increase the craving for salt, resulting both in potassium loss and increased water intake. Grapefruit juice also inhibits the activity of this enzyme. If UEE tests reveal imbalances in sodium and potassium excretion, you would be well advised to avoid licorice and grapefruit juice.
Hormones, such as progesterone and estrogen, are also capable of affecting the levels of aldosterone. Progesterone tends to decrease the effects of aldosterone, which would suggest that it may be beneficial for those with the symptoms of elevated aldosterone. These include excess fluid retention or increased excretion of potassium. Conversely, estrogen appears to enhance the level of aldosterone.
PEMT (phosphatidylethanolamine N-methyltransferase) is a gene that bridges the connection between the methylation cycle and estrogen. Research has shown that the PEMT gene is increased by estrogen. In the methylation cycle, PEMT helps to convert phosphatidylethanolamine to phosphatidylcholine. Individuals with the ACAT SNP (discussed earlier in this chapter) show imbalances in ethanolamine levels on biochemical tests, suggesting that there may be a relationship between PEMT polymorphisms and the ACAT mutations. In addition, PEMT is itself affected by methylation cycle mutations as it is a methyltransferase, requiring the adequate presence of methyl groups to function. For this reason, BHMT, MTR, MTRR, COMT, and CBS mutations would have a related and possible cumulative effect on PEMT, because they help to supply the methyl donors needed for PEMT activity. As we begin to look into the role of PEMT, I’m hoping that we will gain further insight about the role of hormones in autism, as well as CFS and other conditions.
This is an important area of inquiry, since there is a predominance of autism in males as compared to females. That supports other indicators that hormones contribute to autism. Looking at PEMT SNPs may offer further understanding of the mechanisms involved. In addition, in most cases females affected by autism have a more severe presentation than males. People with autism tend to have increased seizure activity, and estrogen has a direct effect on seizures.
In addition to addressing specific mutations, there are major areas of the greater methylation cycle that nearly all people need to support, which I’ll discuss in this section of the chapter. Doing so has many benefits: it increases energy levels, and provides a strong foundation for methylation cycle function by assuring that key intermediates are available.
With respect to the gut, as with all aspects of this protocol, there is no “one size fits all” approach. Sometimes it is difficult to know where to start with support, and there is no easy answer. The following is a compilation of suggestions for overall gut health, taking biochemical testing and Nutrigenomics into account. As always, work closely with your physician.
After you get your test results, you can also fine tune organ support for the gut using vitamin C, herbs, Biotene products, xylitol, papaya enzyme, and other supports that you will find in the gut protocol in the previous chapter.
In addition to supporting the overall methylation cycle, B12 levels also impact the gut environment. As you gradually layer in B12 support over time, it will also help to support a healthy gut.
To support both detoxification process and energy, people of all COMT V158M and VDR/Taq types should assure that they can get through the adjacent Krebs cycle (also known as the tricarboxylic or TCA cycle), which is responsible for generating energy via reactions that take place in the mitochondria. Just as with the methylation cycle, we need a whole host of intermediates, which can be accessed via what I call a “mitochondrial support cocktail,” whose ingredients can be customized based on test results. These results will reveal where deficiencies lie so that the support can be added.
As you look at this diagram, you can pinpoint where low levels of key intermediates indicate that you are stuck. For example, if by running a MAP or OAT test, you discover that you’re stuck at 6:00 or 8:00, you can supplement with ATP, NADH, and low dose riboflavin.
Typical ingredients in the cocktail are L-carnitine, CoQ10, idebenone, NADH and a low dose of the Muscle Support RNA. Many of these ingredients contain methyl groups. That means that some people would do well to slowly layer in mitochondrial support and/or to rotate the use of these supplements.
Since decreased mitochondrial energy can lead to fatigue, low muscle tone, muscle weakness, and fine and gross motor issues, certain key supplements contained in this cocktail help both energy production and the detoxification process. Make sure to add them gradually to allow detoxification to occur gradually. A mitochondrial cocktail can be added after you’ve been using methylation support to keep detoxification at a manageable level. Or if there is severe muscle weakness and/or fatigue issues, you can use the mitochondrial support cocktail first.
As you can see from the diagram above, the Krebs cycle connects to our complete methylation cycle via fumarate and aspartate. These two biochemicals are also part of the urea cycle. Low levels of fumarate (resulting from excess ammonia, OTC mutations, or NOS mutations) negatively impact the Krebs cycle. Supplementing directly with L-carnitine fumarate can compensate for low fumarate due to urea cycle issues.
You can also add supports based on organic acid test results of Krebs cycle intermediates, such as:
On the diagram, you will see that the conversion of methylmalonyl Co A to succinyl CoA requires B12. With MTR and MTRR, there are often decreased levels of B12, such that for people with these mutations, supplementing with these intermediates will support the Krebs cycle directly.
Krebs cycle support can also include supplements known as “Krebs cycle intermediates,” (provided they do not include glutamate, aspartate, or their derivatives.) You can test first to determine which supplements to use.
Sometimes, elevated oxalic derivatives combine with high pantothenic and high citric. When this occurs it may indicate that you are not converting pyruvate well, which produces problems entering “the clock.”
Since pyruvate is the link between oxalic and citric, poor conversation of pyruvate can lead to both a buildup of oxalic derivatives and an increase in citric.
Lack of B12 can also have a significant effect on the Krebs cycle. In particular, intermediates in the later part of the cycle (11:00 and 12:00) such as oxalate and fumarate have been reported to increase with a lack of B12. Conversely, intermediates in the beginning of the cycle (1:00, 2:00, 3:00) can build up from excess aluminum in the system. This may be a particular issue for those who are female, have MTHFR A1298C mutations, ACAT mutations and/or chronic bacteria in their systems. I have observed that extreme muscle weakness can be alleviated with aluminum excretion from the body, confirming the theory that aluminum negatively impacts the Krebs cycle. With higher levels of the earlier intermediates, focus on layering in both aluminum support and the mitochondrial cocktail earlier in your program.
Some people have a deficiency in an enzyme called glucose 6 phosphate dehydrogenase (G6PDH) which helps to recycle glutathione, a key detoxification output of the methylation cycle. Both G6PDH and NADH levels can be depleted by high sulfur detoxification and/or a CBS upregulation. It’s also possible that a lower than optimal conversion of pyruvate contributes to G6PDH issues. Since taking NADH will reduce oxidized glutathione, NADH may help to compensate for decreased G6PDH activity.
Sulfur donors can decrease G6PDH activity. Since excess sulfur is more problematic for those with SUOX+ and/or CBS+ mutations, if left unaddressed these mutations can lead to decreased G6PDH activity. Among the varied symptoms of decreased G6PDH activity are the following:
Since red blood cells have a half life of 120 days in the body, it can take several months for the excess sulfur to build and produce a cumulative effect on the G6PDH levels. If you’re using sulfur-based products, watch for signs of sulfur toxicity that manifest over the course of several months, such as broken capillaries, increased bruising, or decreased kidney function. If you experience any of these symptoms, take a break from sulfur-based products. When the G6PDH enzyme does not function well, higher levels of free glucose leading to insulin bursts may result. This sequence increases inflammation. To support decreased levels of G6PDH, in addition to NADH, consider thyroid and adrenal support, alternative sources of five carbon sugars (such as ribose), and The Right C form of vitamin C with ribose .
Glutathione (GST) is vital to detoxification. Even when mutations in the methylation pathway impact the GST enzyme, it still makes sense to support healthy glutathione levels, as GST is a key player in reducing metal accumulation. The transsulfuration pathway generates both glutathione and taurine. The cysteine level will determine which one is produced. Low cysteine levels favor glutathione synthesis. High cysteine levels lead to taurine synthesis. A CBS upregulation (C699T + or A360A +) generates cysteine so high that the pathway is shunted toward taurine formation. Animal models indicate that the CBS C699T represents a forty-fold increase in enzyme activity over the CBS A360A +, which is not as strong of an upregulation. It’s not surprising that, with CBS people, appreciable levels of homocysteine, cysteine, or cystathionine are often lacking, as there is a rapid conversion rate to taurine. In many cases, an amino-acid test result showing very high levels of taurine and ammonia can be the best indicator of CBS upregulation.
While I do not object to adding glutathione, I prefer first getting this portion of the pathway in balance. That’s why prior to introducing glutathione support for CBS people, I recommend first looking at taurine levels on a UAA. Once those levels have come down and the methylation cycle is in better overall balance, the glutathione levels will increase on their own. At that point, consider additional glutathione supplementation to enhance natural glutathione levels.
At the crossroads between the cysteine dioxygenase(CDO) and glutamate cysteine ligase (GCL) reactions, cysteine levels help to favor CDO activity (leading to increased taurine levels) or GCL activity (leading to increased glutathione rather than increased taurine.) With higher glutathione levels, there is often an increased excretion of toxic metals. As result, the interplay of CDO activity and GCL activity is consistent with some observations by Dr. Jill James on glutathione and detox in autism.
Curcumin helps shift the emphasis toward glutathione rather than taurine. Once taurine and ammonia levels are under better control, the use of GSH can directly support glutathione levels as well as help in the early steps of the TCA/Krebs cycle. GSH moves the cycle past citric and isocitric. Since glutathione contains both sulfur and glutamate, more is not necessarily better. Moreover, NADH will help to recycle glutathione. Low dose EDTA also shifts the emphasis from CDO and taurine formation toward GCL and glutathione synthesis.
Recall that glutathione is a sulfur-containing compound and excessive sulfur can decrease glucose 6 phosphate dehydrogenase (G6PDH) levels. Rather than going with the philosophy of the “more glutathione the better,” keep G6PDH in mind and don’t go overboard with the number of sulfur donors. There are many options, including topical glutathione, oral glutathione (an oral lipid based glutathione for enhanced transport), glutathione lozenges, and IV glutathione. Use NADH to recycle glutathione, as recycling issues can result from G6PDH deficiencies. NADH also keeps added glutathione in the reduced form.
To maintain and regenerate healthy glutathione levels, without adding too many sulfur groups, consider using low dose N-acetyl-cysteine (NAC,) vitamin C with rose hips (500mg two to three times per day), vitamin E with mixed tocopherols, and selenium. The HHI Neurological Health Formula general vitamin includes low doses of several sulfur donors such as taurine, broccoli extract, and garlic, which are beneficial.
Curcumin supports an enzyme contributing to glutathione synthesis via the transsulfuration pathway. However, with a COMT V158M + status, curcumin is a double edged sword, since it’s a methyl donor.
The urea cycle detoxifies ammonia, both the ammonia generated by protein breakdown from the foods we eat as well as that generated by CBS upregulations. Several of the genes in the methylation cycle impact urea cycle function because their activity uses up BH4 stores. These include MTHFR A1298C mutations, aluminum due to chronic bacteria, or CBS upregulations and the NOS enzyme. As a result, it’s advisable to support the urea cycle in doing its job.
Another key enzyme in this cycle is OTC (ornithine transcarbamylase).
OTC function can be affected by the status of the methylation pathway. Methylation cycle function controls the ability of this enzyme to turn on and off. For this reason, there is often decreased OTC function prior to comprehensive methylation cycle support.
As you can see, the OTC enzyme “sits” between ornithine and citrulline in the urea cycle. When OTC activity is compromised, UAA tests will often reveal low citrulline yet high ornithine levels. Reduced OTC activity will back up in the urea cycle, producing mid to high levels of arginine and low levels of aspartate. Finally, this cycle also generates fumarate for the Krebs cycle. As mentioned earlier, the urea cycle and the Krebs cycle are linked though aspartate and fumarate. Low citrulline, mid range arginine, mid to high ornithine, very high fumarate, low to very low aspartate, and decreased malic acid as seen on MAP/OAT and UAA test results indicate decreased OTC activity. In these cases, supporting with low doses of citrulline, malic acid, BioThyro and 1⁄4 Krebs cycle intermediates (if aspartate is particularly low) can help. Once the methylation cycle gets into better balance, then the OTC issue will usually resolve. Normalization of the methylation cycle function is seen when test results reveal normal ranges on FIGLU, methylmalonic acid, taurine, and succinic.
Maintaining healthy levels of amino acids is important to make the proteins and enzymes needed for many bodily functions. These can be measured on a UAA test and, if low, can be supplemented. In supplementing amino aids, it’s important to ensure that amino mixtures don’t contain glutamine or glutamate. One good source is the product, Amino Care, available as a tablet or gel cap (the dose is 1⁄2 per day) as well as a topical lotion. Designed to support amino acids without increasing glutamate, this mixture has also been used by cancer patients, since high glutamate can be an issue for cancer, too.
As discussed above, the amino acid citrulline is key to the urea cycle, since it contributes to ammonia detoxification. If measured as low on a UAA test, you can add low-dose citrulline. This is suggested whether the citrulline is low due to reduced OTC function or excessive urea cycle activity as a result of CBS upregulations. In addition, branched-chain amino acids can also be beneficial. The mixture I prefer includes only leucine, isoleucine and valine, with a suggested starting dose of 1⁄2 capsule. Make sure that there is no maple syrup smell in the urine following supplementation, and if there is, discontinue use. BCAA can also help keep glutamate in check. If proline is very low, you can add 1⁄2 capsule or less. LAlanine may be helpful for issues related to DPT. Again, the suggested dose is 1⁄4 to 1⁄2 capsule.
For those with low overall amino acids, the combination of Bowel Inflammatory Pathway Support three times a day with one OraAdrenal seems to improve this issue tremendously. This is very helpful for those with MTRR 11 mutations (for whom low aminos are often an issue) as well as for anyone with low amino acids on UAA tests.
Finally, if histidine, carnosine, and anserine are all low, then it is worth considering histidine support. To be metabolized properly, the histidine requires a functional methylation cycle. The amino acid methionine is supported directly by the HHI general vitamin (Neurological Health Formula.) Additional support for the rest of the methionine/folate cycles will help to support the remainder of the pathway.
Indications of Decreased Urea Cycle/OTC Activity:
Low urea cycle/OTC activity can result from decreased methylation cycle function. If FIGLU is high, methylmalonic is high, succinic is low and methionine is low, this also indicates that methylation cycle support is needed in addition to OTC support.
OAT tests and MAP tests are extremely valuable tools in helping to monitor how well nutritional support is working to bypass mutations in nutritional pathways.
Through balancing the methylation cycle, detoxification will have already begun and may produce sufficient levels of detox to help restore health, balance, and function. So allow that process to run its course. However, to proceed further with detox, you can move ahead with Step Two, Part Two in the next chapter.