CBS (cystathionine beta synthase) catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine. Dr. Yasko considers addressing CBS mutations as first priority aside from addressing the gut.
This enzyme converts homocysteine to cystathionine. In a separate reaction, cystathionine is then converted to cysteine which in turn goes to taurine or glutathione among other things.
CBS defects are actually upregulations. This means the enzyme works too fast. Therefore, it is common to see low levels of cystathionine and homocysteine since there is a rapid conversion to taurine. This leads to high levels of taurine and ammonia.
The upregulation is caused by one or more SNPs. There are 3 SNPs that can cause upregulation of the CBS enzyme. The worst SNP is called the CBS C699T SNP and Dr. Yasko says this may increase the activity of the CBS enzyme by ten times.
The NOS mutation can exacerbate ammonia issues. Furthermore, addressing CBS can help lower excessive levels of taurine and help detoxify ammonia.
Dr. Yasko recommends that one supports their CBS enzyme for at least 6 weeks before starting methylation supplements. When one tries to take nutrients to support their methylation cycle before addressing the CBS upregulation, all the nutrients basically lead to nowhere. Instead of generating glutathione, the supplements may deplete the rest of the cycle.
Before one starts adding supplements, it may be a good idea to get a baseline Urine Amino Acid (UAA) test from a doctor. This will determine one's Taurine levels. This is outlined in the Dr. Amy Yasko "Autism: Pathways to Recovery" . One should retest their Urine Amino Acid (UAA). Once the UAA is at 50% or below, you can add the methylation supplements. Dr. Amy Yasko believes it is important to regularly use Urine Amino Acid (UAA)testing as taurine should remain at 50% or less. If taurine climbs then you may need to address ammonia.
Yucca Root and Charcoal/Magnesium flushes can help address high ammonia levels.
High doses of L-Ornithine may be effective as well according to medical studies.
The CBS mutation not only leads to excess taurine, but can also lead to excess sulfur groups.
For this reason, it may be a good idea to limit sulfur intake. Excess sulfur intake can trigger a stress response or chronic stress. Sulfur is normally bound to amino acids, but the CBS upregulation can instead release the sulfur groups to sulfites in the body.
There are many things one may need to avoid with a CBS upregulation. Some of the items include garlic, broccoli, eggs, onions, legumes, meat, Epsom salt baths, alpha lipoic acid, glutathione, chelating agents such as DMPS, NAC, Milk Thistle, various other supplements, and much more. Please look to other sources for foods and supplements that are high in sulfur.
Supplementing with molybdenum may help as excess sulfites deplete it.
Manganese is also important in ammonia detoxification.
A low protein diet can help as the body will have less ammonia to detoxify. It's important to measure molybdenum and manganese with a minerals test before supplementing.
BH4 can also become depleted with a CBS upregulation. BH4 helps regulate neurotransmitters and mood. Other mutations, such as MTHFR A1298C, chronic bacterial infections, and aluminum can also lead to low BH4 levels. Lack of BH4 can lead to mast cell degranulation and possibly mast cell activation disorder (MCAD). While difficult to obtain, BH4 supplementation may help in the presence of BH4 deficiency.
Other supplements that may help are Slippery elm bark for the gut. And according to Dr. Yasko, molybdenum, EDTA, carnosine, and zinc may help balance the copper/zinc ratio.
Chronic gut issues lead to higher bacterial loads, thus leading to higher ammonia production as well as leaky gut (reducing nutrient absorption and increased risk for food sensitivity) this area is paramount. You can begin to address the CBS prior to fully addressing gut issues though they should be done in concert. A CBS upregulation substantially drains and floods the urea cycle. This enzyme depletes the precious resource known as BH4 while overloading the urea cycle with its’ faster dumping.
It is paramount to balance any chief defects prior to optimizing the methylation cycle. The CBS enzyme, located at the entrance of the transsulfuration pathway, converts homocysteine to cystathionine. Although the following discussion is somewhat controversial within the research community, my colleagues and I have confirmed (in our own clinical practices) many of Dr. Yasko’s discoveries regarding the CBS upregulation. The increased activity often leads to toxic waste build-up and poor glutathione production in addition to challenges processing sulfur/sulfates. While this may be contingent upon other defects, there may be an elevation in taurine, ammonia, sulfites and hydrogen sulfide. Taurine is an amino acid while the latter three substances are toxic.
Therefore, it is often vital to support this enzyme prior to initiating other methylation treatments. Otherwise, any efforts to support the cycle may only result in increased toxic burden. This may explain the reason some patients cannot tolerate efforts to raise glutathione, particularly since they are sulfur-containing substances, while others derive great benefit without debilitating side effects.
As mentioned, even a partial defect often leads to dumping everything out at 10x the normal rate, hence, the “Hole in the bucket.” This tends to drain the entire pathway of nutrients, homocysteine, and toxins. Once the initial body chemistry and nervous system supports are on board, this is one of the most critical defects to regulate. Nevertheless, since gut bacteria release plenty of ammonia & toxins of their own, it isn’t in your best interest to trap this within the system. The bottom line is that in prematurely addressing the CBS, we could be trapping such waste. The goal is to get basic support on board in order to make detoxification much easier to tolerate. Think of the CBS as an open barn door or a leaky bucket (& please refer to the diagrams I have sent you on this area so that you have a better visual). This means that everything that does & doesn’t belong within the whole pathway are just dumping right on out into the liver & kidneys to be filtered out, much like a hole in the bucket.
This means that as fast as you try to fill your leaky bucket, much of it simply dumps right out. This leads to significant deficiencies within P5P, B6, B-12, minerals, antioxidants, etc. These compounds often drain out, leaving you without critical methylation support to maintain and police the entire system. Moreover, it is often common to see elevated Taurine levels on the amino acid tests. And, since Taurine & Beta alanine share the same amino acid transporter; this level may also be elevated. Even so, when we start supplementing this pathway, it continues to drain out, oftentimes, leading to even higher level of taurine. Nevertheless, low taurine levels should not be supported until proper methylation support is on board. Taurine is a sulfur donor and may trigger more issues. Yet if levels remain low despite methylation support, its’ addition may be very beneficial, particularly for those who suffer from seizures, aggression, anxiety, and/or agitation.
Generally, the transsulfuration pathway (liver pathway) leads to either taurine or glutathione production, though not both. While losing so much toward taurine has its benefits—you often prevent seizures due to its calming qualities—you trade *Glutathione in the process, which is a steep bargain. As your most vital & normally abundant antioxidant, glutathione is required for many processes including immune function and detoxification as well as regulating the function of other antioxidants. In fact, this is the main reason that those with chronic illness suffer from recurrent bacterial, viral, parasitic, & fungal infections as well as cancer, toxic metals, etc. Without glutathione, very little is normally filtered and processed within the system.
Additionally, homocysteine is an indispensable amino acid in the production of SAM and acts as a key precursor for this superstar. Having over 400 known biochemical functions in the body, SAM is the methyl donor or work tag. In the event of a CBS breakdown, Homocysteine quickly escapes, along with other amino acids, vitamins, minerals, toxins, and wastes, both depleting and taxing the system. To make matters worse, everything that dumps out through the CBS often converts into toxic ammonia and sulfites. Unfortunately, this even includes the good supplements and nutrients. This also means that every time you use supplements, diet, and/or medications to support nutritional and methylation deficiencies, you may be inadvertently delivering more & more toxins, thereby adding to your overall toxic burden. This will also extensively raise glutamate levels (as will strep & heavy metals), causing excitotoxicity. As mentioned above, those with the CBS up regulation tend to breakdown homocysteine in order to make cysteine and taurine, rather than glutathione. Moreover, this whole process triggers an enzyme called G6PD, which is instrumental in protecting & cleaning up your red blood cells as well as regulating the blood sugar. This may lead to blood sugar fluctuations throughout the day, from lows to highs, while it further stresses the fight or flight response and glutamate production.
Furthermore, testosterone impacts the CBS defect, actually increasing output. In animal models, they’ve found that a double defect within the CBS C699T can work up to 40x faster, so coupled with higher testosterone levels in males, this may considerably increase nutrient and toxic dumping. With this in mind, it’s important to keep an eye on hormone levels as well as important minerals that help support this enzyme such as the copper/zinc ratios, molybdenum, and manganese.
*GSH is the active form of glutathione that we all require for managing free radicals and filtering toxins. GSSG is the “used” version of glutathione that is oxidized (rusting). The redox ratio of glutathione, known as GSH/GSSG, signifies the levels of new to used glutathione
It is important to remember that in concert, several other SNPs can substantially drive CBS activity up.
*** My suspicion is that the combined MTHFR, CBS, and BHMT defects are taxing the flight or fight system by increasing norepinephrine and cortisol levels. Normally, something would trigger this stress response such as illness, crisis, a busier schedule, supplements, foods, etc., since these further tax the CBS/NOS. Nevertheless, if you have a Sympathetic Dominant nervous system, you will have almost constant activation of the stress response, particularly if not on the appropriate diet and nutritional supports.
Using the simpler terms as discussed in “Your methylation Community,” this passage to the liver is instrumental in detoxifying much of what accumulates from the entire cycle, from the power plant and the rural farming regions to the Communications Facility and SAM’s own manufacturing plant. The shared passageway between the companies (MTR/MTRR) allows the farmers and chain gang (HCY) more direct access to this freeway. Yet it can also be a potential escape route for the prisoners and such getaways could lead to trouble within the system. Even so, if this route is down for roadwork, travel is still possible via the shortcut (BHMT). In fact, due to of all these ties, SAM and the Farmers have a very close working relationship. After all, it’s the supervisor (AHCY) at SAM’s that decides which guys (HCY) in the Chain Gang are ready for release or not.
Despite the good working relationships, there are many issues that could arise and contribute to complications. For instance, a sudden increase in work production on the freeway (CBS) exiting SAM’s could deplete essential supplies for those down the line. Conversely, a bottleneck or roadblock at a key junction of this freeway (SUOX) has potential for even more poisonous waste overwhelming the system. Everything in this pathway is interdependent and has the potential for a domino effect. And, just as a small town relies on the biggest industry for maintaining the economy, the methylation community depends on SAM’s Corp for most of the jobs (methyl groups) necessary for survival. Nonetheless, it’s also crucial that the major thoroughfares and chief junctions run smoothly in order to avoid draining the community or causing rush hour traffic jams and toxic waste spills.
AMMONIA PROVOKERS: (Limit to essentials for CBS +)
• LIPID DONORS: (limit for CBS+, NOS+)
Any transdermal creams
• Lipoceutical EDTA and Lipoceutical glutathione
• Higher doses of essential fatty acids (EFAs)
• Alpha Lipoic Acid (ALA)
Ammonia is simply a combination of nitrogen + hydrogen. It is important to note that nitrogen is formed from the breakdown of protein.
Lipid Donors:(limit for CBS+ & NOS+)
• Any transdermal creams
• Lipoceutical EDTA and Lipoceutical glutathione
• Higher doses of Essential fatty acids (EFAs)
• Alpha lipoic acid (ALA)
• Immune Factors (due to the ALA in the ingredients)
Per Dr. Yasko, aside from having the NOS defect, an EFA mix of omega 3/6/9 is ideal. She recommends two of the DHA (Neuromins) to one of the Omega 3/6/9 mix for a 5:2:1 ratio of omegas. Additionally, she adds one capsule of cod liver oil per day. Recall that fatty acids slow the NOS enzyme down so if there is a defect, these should be utilized in lower doses.
SULFUR DONORS: (Limit if CBS+ yet avoid much more for SUOX +)
• Coconut milk or oil
• N-Acetylcysteine (NAC)
• Magnesium sulfate cream
• Milk thistle (in MTHFR A1298C caps)
• Glucosamine sulfate
• Chondroitin sulfate
• Alpha lipoic acid (ALA)
• Milk thistle
• Epsom salts
“We do need some sulfur in the system. Sulfur that is complexed in an herb is usually okay. Hence, I would not eliminate horsetail grass, spirulina, dandelion leaf, or parsley. Consider that methionine, which we need in the form of plain methionine or SAMe, does in fact contain sulfur and is a sulfur amino acid, as is taurine and cysteine. While many require Methionine supplementation, it is often best to avoid taurine & cysteine. One should only considertaurine if it remains low once methylation has been fully supported. Moreover, while foods/herbs like eggs, garlic, onion, & broccoli are going to be higher in sulfur, using smaller amounts of these give you many positives.” Amy Yasko, PhD.
1). Urine Amino Acid (UAA): Monitor Taurine & Ammonia levels & address—they should be to the left of the report at 50% or less. However, you do need some taurine so the goal is not to eliminate this amino acid. Also, taurine levels may also be low until methylation support is on board.
***Please recall that you will not always see high taurine levels with CBS defects. In many cases, once you initiate methylation support, these levels will rise.
2). Urine Essential Elements (UEE): Monitor Manganese & Molybdenum due to heavy use for ammonia detox
Treatment recommendations for the CBS: This is simply an FYI, please do not start the following supports until you have reviewed this with your practitioner!
It is crucial to address any gut issues before you thoroughly address the CBS defect.
1. Yucca sprinkled on protein to reduce ammonia levels (can also take capsules with meals)
2. Avoid high protein diets such as The South Beach Diet, Atkins, Specific Carbohydrate Diet (SCD), etc.,
as well as high sulfur (please see sulfur list) supplements & foods (glutathione, NAC, SAMe, DMPS, glucosamine, broccoli, etc). This is not to imply that you cannot have any of these foods or supplements in lower doses/portions, it’s simply a caution.
3. CBS/NOS Caps: Start with 1/8 to 1/4 of a capsule once a day and work up to twice daily. The goal is 1⁄2 to 1 cap twice daily for CBS and urea cycle support. Please increase slowly as detox will ensue. This combo supports the CBS, kidneys, NOS, and waste (ammonia) elimination & balance.
4. Spirulina is alkalinizing and assists with ammonia elimination.
5. Molybdenum & Manganese to keep the copper/zinc levels within range & reduce sulfites (monitor
electrolytes and essential elements).
6. Curcumin, a methyl donor, may help shunt toward glutathione production.
AND/OR the CBS RNA listed below. Not everyone requires aggressive CBS or ammonia support.
1. CBS RNA, This needs to be diluted since the detox potential is quite high. You will be slowing the CBS
down which means you’ll actually be keeping the supplements within the system, as well as any existing work tags (methyl groups). This means they will be doing their jobs throughout the pathway and that generally leads to heavy metal, aluminum & other toxin filtering as well as viral, bacteria, & other bug clean up.
2. Ammonia RNA, only if levels are persistently high.
3. Charcoal flush, followed by mag citrate 1-2 x weekly to soak up excess ammonia. (This is not necessary
4. L-carnitine, helps lower ammonia levels
***For those with the CBS defect, avoid magnesium sulfate (Epsom salts), MSM, and Chrondroitin whenever possible. Some sulfur is necessary and even beneficial when taken in at low doses, though generally, may be harmful in higher doses. On the other hand, a bit of garlic, milk thistle, & horsetail are advantageous in smaller doses. It is prudent to choose wisely.
The CBS Upregulation is a complicated subject! The book by Dr. Amy Yasko "Autism: Pathways to Recovery" explains much more detail.
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