First try at Active Protocol and have questions.

[JasonUT]

MPP Layman's Interpretation: I looked at my previous post with MPP results and I am left scratching my head. The Methylation cycle derivates all look good. SAM, SAH, HS, and Methionine are all in range. The ratio of SAM to SAH is okay. The SAM + SAH does not seem to imply CBS upregulation.

Glutathione (reduced) Deficiency: I have to guess this is caused by low Cysteine. Cysteine is also a pre-cursor to Taurine. Is something getting stuck at Cystathionine or Homosysteine? Homocysteine is at the high end of the range, but still in range. Maybe HS, while still in range, is getting converted a little slow or being pushed to Methionine rather than down the Trans-Sulfuration Pathway? Strangely, Cysteine was in range on the SpectraCell Nutrient Panel. What should I believe? Maybe a trial of NAC supplementation?

B2 Deficiency: Per SpectraCell Micronutrient test and OAT, I am low in B2. B2 is needed to convert B6 to it's active P5P form. And B6 is needed by the Trans-Sulfuration Pathway.

B6 Deficiency: Per SpectraCell Micronutrient test and OAT, I am low in B6. B6 is needed to convert Homocysteine into Cystathionine, and then to Cysteine. Maybe my deficiency in the conversion process is due to low B6?

B9 Deficiency: Per SpectraCell Micronutrient test, OAT, and MPP, I am low in B9. Maybe high dose methylfolate, at 12.6 mg per day, is not the whole answer. Maybe I need to add in some Folinic Acid. My Folinic Acid (WB) in whole blood cells seem to be low per MPP.

Taurine Deficiency: There seems to be some kind of relationship between Taurine, Muscle Cramps, and muscle damage [Source]. It also seems that Taurine can help reduce the sympathetic nervous system response i.e. Fight or Flight response. I found an interesting research article on NCBI here that shows the benefits of Taurine on Chronic Bladder Pain and Pelvic Pain. I was diagnosed with Pelvic Pain Dysfunction on 5/2/2017 and confirmed by Physical Therapist on 5/9/2017, because my Pelvic Muscles are very tight like "guitar strings." My PT described the evil cycle of Pelvic Pain Dysfunction with respect to Sympathetic Nervous System Response. The Sympathetic Nervous System Response feeds the pain and the chronic pain feeds the Sympathetic Nervous System Response. Maybe lifting Taurine can break the evil CPPS cycle?

Cysteine Deficiency: It appears that Cysteine is used for a number of important functions in the body. 1) incorporation into amino acid sequences of proteins, where cysteine promotes protein structure by sulfhydryl bonding; 2) ratelimiting precursor for glutathione synthesis; 3) precursor for taurine (used in bile formation and nerve function); 4) source of sulfate for connective tissue synthesis; 5) source of pyruvate for energy or glucose production; and 6) neurotransmitter [Source]. Symptoms of cysteine deficiency include: apathy, loss of pigmentation in hair, edema, lethargy, liver damage, muscle loss, skin lesions, weakness, fat loss, and slowed growth in children [Source].

This post by Rich VK suggests a temporary Cysteine deficiency as methylation starts-up. I started my Intentional Methyation Protocol on 2/16/2017 and did the MPP blood draw 1 month later on 3/28/2017. Maybe at time of MPP blood draw my methylation cycle was starting-up and robbing the trans-sulfuration pathway of methionine; therefore, lowering cysteine. Will this lift with time? Should I assist the Trans-sulfuration pathway during this time with Taurine, NAC, and/or Glutathione?

When the methylation protocol is begun, the activity of the methionine synthase enzyme in the liver is increased by supplementing B12 and folate forms. This causes more of the homocysteine to be converted to methionine, so less is available to support synthesis of glutathione. One result of this is that the cystine level in the blood goes down, so that less of it is available to the brain.

Yes, ultimately the methylation protocol does increase glutathione. We have documented that with lab testing.

However, the very first thing that happens when B12 and folate are applied together, which is the real essence of this protocol, is that the activity of the methionine synthase enzyme is increased. This enzyme converts homocysteine to methionine. When that starts, there is initially less homocysteine available to enter the transsulfuration pathway, and that ends up lowering the production of cysteine and hence, glutathione.

Over time, the methylation cycle is able to fill by recycling homocysteine to methionine, and then there is more homocysteine available to enter the transsulfuration pathway.

In our clinical study, our first test point after starting the protocol was at three months, and at that point the glutathione level had increased significantly. But at early times, it makes sense that glutathione would initially drop, and that does seem to correspond to the increased excitotoxicity that many people report.

What to do now?

There is a simple diagram in this article which shows Methylation cycle, Trans-Sulfuration Pathway and Cysteine products: Sulfate, Taurine, Glutathione, and metallothionein.

I found an old Methylation Pathways Panel that looks very similar to mine with an interpretation from Rich VK here. He suggests that the CBS pathway is going too slow and may need to supplement with extra B2 and B6. My SpectraCell and OAT both show B2 and B6 deficiencies. I have changed my B-Complex to sublingual and added in some extra B2 FMN sublingual. See post #13 and #16 for my notes on B2 FMN. Maybe adding in the sublingual B-Complex and FMN B2 is why some of my symptoms seem to be improving? I am almost 3 months into this more intentional Methylation Protocol; however, I still feel I'm in the tuning phase trying to find the correct balance of nutrient support. Will Cysteine, Taurine, and Glutathione start lifting soon per Rich VK's 3rd month clinical observations?

Here are quotes from the other thread for FreshVeggies MPP results:

The CBS SNP does not seem to be impacting your methylation cycle. Your SAMe level is normal, and your SAH is high. Your glutathione is depleted. All of this suggests that you have low flow into your transsulfuration pathway, rather than high flow, as the CBS SNPs tend to give a person. My guess is that you are low in vitamin B6 and/or B2, so a B-complex should help you. You may also need some magnesium. I would suggest adding these to the simplified methylation protocol. I would not recommend lowering your protein intake. It is about the only fuel many PWCs can burn, becuase of a partial block early in the Krebs cycle, due to glutathione depletion, which you have. I haven't heard that Yucca causes leaky gut. I wonder if there is a reference for that.

The SNPs only give tendencies. They don't tell you what is actually happening in the person's biochemistry. FV's results on these two panels together are a good example of why I favor running the methylation pathways panel. She does have a heterozygous SNP on one of the CBS genes, but it is clear from her SAMe plus SAH concentrations that her methylation cycle has not been drained. The same appears to be true of yours.

The CBS enzyme requires activated B6 (P5P) for its operation. If B6 (or B2, needed to convert it to P5P) are low, this will inhibit the CBS reaction, and possibly also the CTH reaction (which also needs P5P), which is the other one in the transsulfuration pathway. If these are deficient, there will be low flow through transsulfuration, even if there are CBS SNPs.

It is necessary to have good flow down the transsulfuration pathway to make cysteine. About half the body's cysteine is normally made this way. Cysteine is usually the rate-limiting amino acid for making glutathione. So low flow into transsulfuration is consistent with inability to maintain a normal glutathione level.

Additional Links that may be helpful:
Part 1: The Most Important Blood Test That Is Rarely Ever Run!
Part 2: The Four Pathways of Homocysteine – Are One Or More of Your Pathways Blocked?
Part 3: (Homocysteine) The BHMT Pathway
Part 4: Homocysteine and the Transsulfuration Pathway
N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action - NCBI
Problems? I Have a NAC for That - Psychology Today
Glutathione: We Loves It (NAC and Autism) - Evolutionary Psychiatry
NAC Cysteine - Balancing Brain Chemistry
The Glutathione/Sulfation/Methylation Pathway - Autism Coach

 

[JasonUT]

PR community B-Vitamin repletion brainstorming here.

PR community 3/28/2017 MPP interpretation brainstorming here.

 

[JasonUT]

Pyruvate and me: All of my OATS have shown low Pyruvate. I discussed this a little in post #30 and #31 in relation to B1 deficiency, refeeding syndrome, and oxalates. It appears Pyruvate is produced via Alanine, Cysteine, Glycine, Serine, Threonine, and Tryptophan.

My 3/28/2017 MPP and SpectraCell show deficiencies in Cysteine and Serine. I wounder if repleting Cysteine via methylation/transsuluration pathway support and direct supplementation via NAC would be good for me? Perhaps NAC could help relieve the demands on the other 5 amino acids. I am already supplementing serine via Sunflower Lecithin 15 grams per day and Tryptophan 500 mg at bedtime.

 

[JasonUT]

Methylation Doctor Appointment on 5/18/2017: I saw a new doctor who seems very knowledgeable of the methylation cycle and all associated pathways. He seems to favor Ben Lynch's work.

Overall, he seemed to agree that my methylation cycle and my transsulfuration pathway is being taxed either from low flow or extremely high demand which is sucking up nutrients like crazy. He showed me a separate pathway for Homocysteine other than Methionine path and Transsulfuration pathway. This may explain why I have low Cysteine, Taurine, and Glutathiuone. I wish I would have taken some notes.

Regardless, he wants me to further support my methylation cycle and tanssulfuration pathway with an injection every 72 hours. The injection contains mB12, hB12, calcium folinate (B9), and pyridoxine HCl (B6). At the same time, he wants to dig a little deeper to figure out why my cells are deficient in B1, B2, B3, B6, and B9.

Each 5 mL vial contains 6.25 mg hB12, 6.25 mg mB12, 5 mg calcium folinate (B9), and 6.25 mg pyridoxine HCl (B6). Therefore, each 0.3 ml injection contains 0.38 mg each of hB12, mB12, B6, and 0.3 mg B9.

To start, he wants to run a GPL-TOX panel and GLYPHOSATE test through Great Plains Laboratory. He mentioned something about certain chemicals can block folate receptor sites or something like that. This may explain my 15+ mg daily need for folate.

 

[JasonUT]

Low Catalase and Glutathione causing gray hair: In late 2009 I started having these white patches of hair in my beard. They started small, but moved and morphed in shape. It was the strangest thing, but I have ignored it up to this point. I guess it is called Poliosis. My new methylation doctor commented and said it is caused by hydrogen peroxide in the body. Apparently, there is some school of thought that gray hair may be caused by excess hydorgen peroxide due to a deficiency of catalase enzyme [source].

This research article suggests that both glutathione and catalase play a role in breaking down H2O2 in the body. Both are found in high concentrations in the liver. Is it possible that my white patches in my beard could have been my first sign of glutathione depletion all the way back in 2009?

I found a Selfhacked article here on ways to potentially reduce H2O2.

 

[JasonUT]

Nutritionist Appointment 6/1 Notes:

1. Reviewed Methylation Pathway Panel. Very clear to him that I have a methylation and trans-sulfuration pathway issues.
2. Very interested to see the results of Great Plains GPL-TOX and Glyphosate tests
3. NAC is preferred route, because I need to support all downstream products: taurine, glutathione, other
4. Increase NAC to 3000 mg per day in divided doses. Half-life is about 4 hours. For my treatment, he likes the brands that contain selenium and molybdenum. This may be a life long supplement.
5. Consider nebulized Mucomyst 10 ml BID as an addition to 3000 mg oral NAC
6. Myer's IV may be a bottomless pit, but Glutathione IV could be a good shot-term jumpstart for the body.
7. He feels that I am absorbing nutrients fine via digestion and root-cause is at the cell level. I don't know how he came to this conclusion.
8. Physical therapy for my pelvic floor will likely stir up toxins and viruses.

 

[JasonUT]

MPP Interpretation from HDRI Lab: We got an interpretation from the lab on my Methylation Pathways Panel. Here is the summary.

1. CBS gene defect(s) could have caused self-perpetuating sulfur wasting in urine. This causes sulfur to be exerted in the urine rather than the sulfur being correctly used in the body. This is probably triggered by stress such as an infection. I am homozygous for CBS A360A.
2. They recommended a special sulfur urine test that checks for excessive sulfur compounds. I have been self testing with sulfate urine strips since Sept 2016. My symptoms are high when my urine sulfate levels are high. Does this imply sulfate urine wasting which is causing a shortage in the body?
3. Treatment recommendations: IV glutathione, Kirkman Labs Glutathione Lotion, 100F 20 minute baths with 1.5 cup epsom salt and 0.5 cups baking soda minimum of 4x per week for 4 weeks.
4. Folate deficiency will resolve in time as trans-sulfuration pathway improves.
5. High dose sulfur loading could break the cycle and allow the body to get back into a self-sustaining homeostasis.

This is such a challenging interpretation, because Dr. Google is littered with controversy on the correct interpretation of CBS SNP's. In the end, maybe the CBS SNP doesn't matter. My MPP lab results clearly show a trans-sulfuration deficiency in low cysteine, taurine, and glutathione.

 

[Valentijn]

CBS gene defect(s) could have caused self-perpetuating sulfur wasting in urine. This causes sulfur to be exerted in the urine rather than the sulfur being correctly used in the body. This is probably triggered by stress such as an infection. I am homozygous for CBS A360A.

They're repeating complete nonsense. There are no substantial up-regulations of the CBS gene. A360A isn't capable of doing anything, and it's a synonymous variant which means the different allele still creates exactly the same amino acid in the CBS protein.

And if there were a hypothetical substantial CBS upregulation, it wouldn't cause low levels of glutathione, because the CBS gene feeds into the glutathione formation process. Upregulated CBS would result in more glutathione, not less.

My interpretation is that these people don't know what they're talking about, but probably manage to find an excuse for every customer to spend more money with them.

 

[JasonUT]

@Valentijn

I hear you. It's a confusing mess.

I read the MPP lab's interpretation in a different way. In my mind, they seem to be saying that certain CBS defects may cause the sulfur products to be wasted in urine output rather than being used in the trans-sulfuration pathway; therefore, the trans-sulfuration pathway isn't getting the sulfur products it needs to function causing low glutathione and slow trans-sulfuration. Hence their treatment recommendation of high sulfur loading to overcome the lose in urine wasting.

It seems that Yasko and company seem to suggest a CBS up-regulation should lead to sulfur avoidance. However, the MPP lab is suggesting a CBS de-regulation of a different type and suggesting high sulfur loading as the solution. This caught me by surprise as I haven't heard of sulfur loading before. However, Dr. Google does seem to suggest that increasing sulfur can help increase glutathione.

I am just very unclear on what to expect as I go through sulfur loading treatment. Will this be similar to methylation start-up? Will I start having detox reactions?

 

[Valentijn]

In my mind, they seem to be saying that certain CBS defects may cause the sulfur products to be wasted in urine output rather than being used in the trans-sulfuration pathway ....

This isn't what CBS does though. It converts homocysteine into cystathionine, period. Depending on mutations, it can do this a little faster or varying degrees of slower. It can't cause sulfur to be wasted. Perhaps different genes downstream of CBS can have that effect, but CBS does not.

And even if CBS were capable of doing such a thing, the mutations would have to be capable of having an impact on the enzyme function to be relevant. A360A does not have any impact.

I supplement NAC because it resolves my wired-but-tired problems. It could reasonably be doing this by using up excess glutamate (an excitatory neurotransmitter) to form glutathione. But there's still absolutely no connection between my NAC supplementation and my CBS genetics

 

[JasonUT]

@Valentijn

Interesting discussion. I thought Homocysteine, Cysteine, Cystathionine, Glutathione, and Taurine were all sulfur containing compounds. Could a trans-sulfuration sulfur shortage be created if the important sulfurs are being lost as waste in urine?

Per my MPP, my Homocysteine seems at the higher end of normal. My Cystathionine is low and my cysteine is very low. Could this imply a slow CBS enzyme? If not, what might be the root-cause of the trans-sulfuration pathway deficiencies? What are you thoughts on why this might be happening?

MY MPP Amino Acids in Plasma:
Cystathionine - 0.09 (0.00 - 2.00)
Homocysteine - 1.83 (0.00 - 2.00)
Cysteine - 6.22 (15.00 - 60.00)
Taurine - 55 (60 - 240)
Methionine - 21.40 (14.30 - 28.70)
Glutathione (oxidized) - 0.48 (0.16 - 0.50)
Glutathione (reduced) - 2.7 (3.8 - 5.5)

 

[CCC]

A word of caution here about 100F baths.

I know that's not really very hot (I think - about 38C), but a full bath could be quite exhausting, and some people find that much sulphur to be overwhelming, too.

I can't remember if you're already doing the baths, but if you're not, can I suggest you start with the footbath first, with only a handful of Epsom salts, and see how that goes? That can be enough for many people.

Also, @Valentijn , @JasonUT says he has symptoms correlating with high urine sulfur, so that suggests he has problems somewhere there, even if the genetic thing is not the cause. Is that a fair enough interpretation?

 

[Valentijn]

Could a trans-sulfuration sulfur shortage be created if the important sulfurs are being lost as waste in urine?

Theoretically, sure. But how is that happening? CBS certainly isn't doing it. And sulfur strips are not designed for medical use in human urine, so really aren't a good indication of anything unusual going on. It also wouldn't make sense to have slow cystathionine & cysteine production, but also have excess sulfur being dumped downstream of that process.

Per my MPP, my Homocysteine seems at the higher end of normal. My Cystathionine is low and my cysteine is very low. Could this imply a slow CBS enzyme?

Yes, but it would have nothing to do with A360A. It could have a different genetic cause, or there could be a deficiency of a co-factor, such as vitamin B6.

Also, @Valentijn , @JasonUT says he has symptoms correlating with high urine sulfur, so that suggests he has problems somewhere there, even if the genetic thing is not the cause. Is that a fair enough interpretation?

No, I don't think so. "Symptoms of high urine sulfur" is the sort of vague BS that permeates all sorts of quackery. The symptoms used in such lists tend to be both extensive and common, ensuring pretty much everyone has several.

 

[alicec]

I agree with @Valentjin. That interpretation of your test raises a lot of red flags.

It was Yasko who connected sulfate wasting with CBS function. She claimed that certain CBS SNPs resulted in a huge up-regulation of CBS activity (a complete misreading of a research paper which had nothing to do with the SNPs she was interested in). This meant there was greatly increased flux through the trans-sulfuration pathway which could be detected by increased sulfate in the urine.

Her solution to this was to restrict sulfur (and recommend a whole lot of supplements which she sells).

Given your results it would be difficult to claim that you had increased flux through your trans-sulfuration pathway, but the interpreter of your test still wants to connect CBS activity with sulfate wasting and has come up with a creative explanation which has no basis in reality.

Sulfate wasting certainly exists but it has nothing to do with CBS. It is regulated by transporters in the kidney. It can indeed drain the body's sulfur stores and replacement via topical Epsom salts has been helpful in conditions like autism and endogenous oxalate production where sulfate wasting has been demonstrated.

You could try Epsom salt baths (or skip the bath and apply directly to skin). Many people do find them helpful though it may be because of the action of magnesium. Still if you were wasting sulfate this could be a way of replenishing it.

This won't solve your CBS problem. As I said on another thread, I'd be looking to increasing B6 and addressing oxidative stress.

 

[JasonUT]

@alicec , @Valentijn , @CCC

Thanks for your feedback. As always, the feedback, conversation, and debate always raises good questions and concerns.

I'll try to summarize the facts the best that I can in hopes that it could open up some additional brainstorming:

1. Cysteine, Taurine, and Glutathione are low per my MPP Extended test and are all sulfur containing. This has raised the eyebrows of all my doctors and nutritionist, and provided us with something concrete to work on.
2. Per SpectraCell results, I am clearly deficient in Trans-sulfuration pathway co-factors, B2, B6, and Serine. I plan to complete another SpectraCell Panel in 1 - 2 weeks to see if my revised supplementation plan is making a difference.
3. I have observed that my urine sulfate levels track my symptoms. I have tracked this relationship for 10 months and it is repeatable despite the fact that the sulfate strips were not designed for human urine.

I have talked my doc into ordering a Genova Oxidative Stress Analysis 2.0 (Blood) test. It seems to provide some more oxidative stress markers. I hope this will further shed some light on what is going on. Additionally, I was referred to an Integrative Oncologist who specializes in optimizing oxidation status. He normally only sees Cancer patients undergoing cancer treatment, but I am hoping he will see me.

 

[JasonUT]

Quick Update: I haven't provided an update on my personal health symptoms since May 3 post #37. I was feeling very optimistic about lab findings and treatment progress until June 6. Then I had a notable PEM crash the evening of June 6. It's been 10 days and I still haven't recovered. It's frustrating to say the least. My wife was commenting about how she had been noticing improvements. It's such an incredibly defeating feeling.

Next Steps:
1. July 5 - Environmental Toxic Panel results and appointment with methylation doc
2. July 6 - Nutritionist appointment
3. Complete 2nd SpectraCell Micronutrient, Sulfur Urine test, Oxidative Stress Blood test
4. Reviewing Glutathione IV, Nebulized Glutathione, and Nebulized MucoMyst

 

[CCC]

There are a few things that might help here:
1. Your body might have just run out of something. It can be quite the detective game to work out what that might be.
2. You've accidentally slackened off on something that you needed (e.g. you forget a supplement, notice no immediate effect of dropping it because the decline was gradual). This is our major one at the moment.
3. You did too much and you need to rest. There is a thread on PEM busters here somewhere. I'll post it if I can find it. @Hip might have it book marked.
4. And this is an FYI: Freddd found that taking a glutathione supplement trashed his B12 - but he probably has a rare combination of B12 mutations that mean he can't change any one form of B12 to another - it's unlikely to apply to most people, but it might be relevant in people with severe B12 depletion. Rich suggested it is better all round to increase glutathione 'naturally' by improving B vitamins etc

 

[JasonUT]

@CCC

Thanks for the insight.
1. I should be doing another SpectraCell test this week. Hopefully that will help.
2. Great thought. I switched my 5mg mfolate to 800mcg folinic acid at bedtime on June 2. Maybe that was a bad decision.
3. Yes, it was my little girls birthday and we had family at our house. I'm sure this is part of it.
4. Yeah, I'm nervous about trialing glutathione. My doc wants to use the MPP Extended test and SpectraCell to monitor treatment.

Thanks again for your insight. It's very helpful.

 

[Hip]

There is a thread on PEM busters here somewhere. I'll post it if I can find it. @Hip might have it book marked.

It's here:

List of Supplements Which Reduce PEM (Post-Exertional Malaise) Crashes

 

[CCC]

@CCC

Thanks for the insight.
1. I should be doing another SpectraCell test this week. Hopefully that will help.
2. Great thought. I switched my 5mg mfolate to 800mcg folinic acid at bedtime on June 2. Maybe that was a bad decision.
3. Yes, it was my little girls birthday and we had family at our house. I'm sure this is part of it.
4. Yeah, I'm nervous about trialing glutathione. My doc wants to use the MPP Extended test and SpectraCell to monitor treatment.

Thanks again for your insight. It's very helpful.

I'd go straight back to the 5mg mfolate. Tonight.

Folinic also needs abundant B12 to work well. You might also be one of those people who simply needs straight mfolate.