CBS / Ammonia / Glutathione

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My First post to this amazing community. Thanks for opportunity to post here.

Here is the mutation summary from 23&Me. (**) are homozygous ones.

DAO / HNMT - Histamine / Allergy / Leaky Gut
FUT2 - Reduced intestinal microbiota
CETP / USF1 / LDL-R Asn464 (rs688) / APOE IVS1+69 - Higher cholesterol (Elevated cholesterol should not be viewed as a primary disease, but rather as a symptom or consequence of hormonal imbalances. In several patients with FHC, we restored cholesterol to normal levels after the patients initiated hormonorestorative therapy) http://www.lifeextension.com/magazine/2006/7/atd/page-01
MAO-A (**) / COMT (**) - Neurotransmitter / Adrenaline / Stress-Hormone / Estrogen-dominance (also hetero on ESR2 - Estrogen Receptor Beta**)
MTHFD1 (**) - Folate metabolism
MTRR - Poor methylation of Vitamin B12
CBS/NOS3 - Sulf(i/a)tes / Ammonia / BH4 / eNOS / Hypertension & ROS
CYP1A2 (**) - Liver Phase 1
GSTP1 (**) - Liver Phase 2 - Glutahione Conjugation
GAD1 (**) - Low GABA / Neurotransmitter
BHMT8 (**) - Core Methylation (Homocysteine -> Methionine)
NR3C1 (**) - HPA Axis / Cortisol / Adrenal Fatigue / Hormone Imbalance / Cholesterol stuff

Combination of up-regulated CBS, down-regulated BHMT8 and NOS3 is really bad. My Homocysteine is 6.9 (on lower end). Here are some of the reasons I believe CBS is expressing -

  1. Hair test: High Sulfur ??
  2. Low B6 (B6 is a Co-factor of CBS enzyme)
  3. OAT: High Orotic Acid in OAT (Marker 60) indicating high ammonia
  4. OAT: Low 2-hydroxybutyric acid (Glutathione Deficiency)
  5. >800 reading in urine sulphate strips whenever I eat broccoli
  6. Cu/Zn balance is screwed up. My hypothesis: because of Moly deficiency caused by CBS+
As everyone here may already know methylations is really a delicate act of balancing all 4-wheels ensuring proper glutathione formation. Having gone through Yasko's books I find it a bit confusing at times. Thus created a short protocol for myself here.

  1. Reduce thiol foods
  2. Take Moly for sulfite + Thorne Pic-Mins (or other good trace minerals without copper and iron)
  3. Take Yasko’s CBS RNA + for ammonia
  4. Keep taking small amount (10%-15% of total calorie intake) of lean meat (It's important to understand that even though meat is high in sulfur, the sulfur is bound in with essential amino acids like methionine. Your body may or may not break apart the amino acid and release the sulfur. The sulfur in vegetables, however, is quickly digested because it's in a thiol form, so you may react to leafy greens and onions more than meat.)
  5. Follow this for 4-6 weeks
  6. Slowly introduce glutathione cofactors along with Moly.
  7. Induce Nrf2 via curcumin or ginger
  8. Take liposomal glutathione
  9. Slowly add liquid hydroxy-cobalamins to tolerance
  10. Measure urine sulphate levels and go to step #1
Regarding Glutathione cofactors designed this formula via GetVitaminLab

L-Serine +100mg
Molybdenum +150mcg
Magnesium (Glycinate) +400mg
Vitamin B6 (Pyridoxal-5′-Phosphate) +10mg (low dose for CBS+)
Vitamin B2 (Riboflavin-5′-Phosphate) +12.5mg
Vitamin B1 (Thiamine HCl) +12.5mg

Even though curcumin / turmeric shifts the pathway to Glutathione formation, I believe curcuin does it magic via activating Nrf2 pathway which is really a low-stress-training for cells. If you activate Nrf2 pathway and you don’t have necessary cofactors present, you essentially will going to face increased oxidative stress.

What you all think about this simplified protocol ?
 

Methyl Head

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Be careful with glycinate as it can aggravate CBS up regulation and kick you into over drive, it's an excitotoxin (along with all glutamates and hydrolyzed anything, maltodextrin etc..) also, with MTRR + BHMT reference heartfixer.com, it's a complicated protocol that would require GABA for excitos, Carnitine and COQ-10 for ATP you'll also need to address homocys being pulled down transulfuration pathway so deplete ammonia and sulfur first then focus on rebuilding glutathione and since you're MTRR you may need to adress B12 with both Methyl and Hydroxy but see what works. Check your COMTs (K/L350A especially) if you're -/- you'll handle methyl donors and need them if you're +/+ then Hydroxy would be the ticket also VDR taq is a another good indicator of how you'll handle methyl donors and what your neurotransmission status is.. The folate metabolism makes it even more complicated because you'll have to balance that issue against poor b12 processing, bad zinc/copper because of CBS and CYP1A2 (I'm ++ for CYP7A1 so I support with fish oil and and very carefully monitor fats furthermore I have faulty zinc protein 8 but I've addressed this with 24-36 mgs zinc gluconate + moly, active B's and manganese for increased enzymes and I'm curious if that will work for you).

Things to add:
High Dose WHOLE FOOD Vitamin C (like emerald's camu camu doesn't aggrevate my CBS and is very clean)
GABA (this is big if you suspect/verify copper zinc imbalance high copper blocks glutamine from converting and can cause Neuron death and some other nasty symptoms)
Zinc Gluconate
Magnesium Citrate (the whole citrate blocking Ceruloplasmin is a myth until you get to uncontrollable shitting levels daily)
Biotin
Niacinamide (No flush)
Hair/Mineral - Yes
Low Sulfur Diet



Arginine/Ornithine (this helps with ammonia in the brain big time but be careful if you respond to arginine just tajke ornithine as it can cause bad symptoms with BH4 deficiency since it won't be broken down to nitric oxide)
Apple Cider Vinegar
Carnitine (helps with ATP and is necessary if you're treating with low animal protein/low sulfur diet)
NADH (great for energy but not crucial)
Good consistent source of potassium (whole food is best, pills are discouraged because potassium nuclears show slower improvement in cell concentration after supplementation and you being MTFH need potassium for sure because once you open those pathways it will gas potassium and cause fatigue, also the crebs cycle needs it and your adrenal balance should improve because of CBS predisposition to store salt, furthermore if you're ACE del16 +/- like me you'll need it because you'll have extremely low cellular concentrations of potassium to begin with)

Stay away from excitiotoxins
common are Gelatin, Hyrdolyzed anything, Caseinate, MSG, processed foods

Add with conditions and/or timing:
Glutamine (depends on homocys though, may be great for you with MTHF and leaky gut on the other hand if you suspect bad copper I wouldn't until you verify and correct levels and your homocysteine at 6.9 makes this a likely no)
Methyl B12 depending on the state of your CBS pathway and urine sulfate, COMT and VDR taq pathway and/or response to mthyl donors if you chose to put the pedal on the floor.
Glutathione (CBS status)
BH4- after you pass through the CBS storm and get below 400 urine sulfate you can consider


This is a fraction of what I'd recommend and it's all about what works for you, happy hunting
 
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Methyl Head

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Also add Vitamin D
Vitamin E Succinate
for BHMT you could add TMG and phosphatidlyserine
BH4 should be the very last thing at about 2.5-5 mg daily (safe up to 200mg clinical for hyperlipidemic and endothelial individuals)
 
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Mary

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Be careful with glycinate as it can aggravate CBS up regulation and kick you into over drive, it's an excitotoxin
Are you sure about this? Can you provide a source? Glycine is an inhibitory neurotransmitter (https://www.ncbi.nlm.nih.gov/pubmed/11396606), and magnesium glycinate is formed by combining magnesium with glycine. Also, glycine helps me sleep.
 

Mary

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Thanks @Methyl Head. BTW, when you reply to someone, it's a good idea to tag them by putting the "@" sign in front of their name as I did with yours here (or like this @Mary), so that they will get an alert that you have responded to them. Or, if you just hit "reply" to their post, it will copy their post into your reply and again they will get an alert that you have responded.

If you're responding to a lengthy post, it's best to highlight the portion(s) you want to respond to, hit "reply" and only the highlighted portions will be automatically copied into your reply, and again, the person you're replying to will get an alert.

Without these alerts, members won't know they have received a reply unless they go into each thread they have posted in, and look for replies, which can be a little cumbersome. :nerd:
 

Mary

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I wrote this with his BHMT 08 in mind as well, as I have it also we are prone to high Glycine and that's from Yasko herself https://dramyyasko.com/wp-content/uploads/2010/06/39-A1-BHMT8.pdf
I don't think we're all prone to high glycine. When I first started taking glycine (for sleep), it hit me like a truck. It helped a lot but I had a very strong detox reaction, such that I had to go to a very low dose. I was very slowly able to increase my dose a little at a time and now I tolerate it with no detox symptoms. It also had the fortuitous effect of almost eliminating my very frequent detox reactions to so many things: apple cider vinegar, cayenne, various amino acids, anything that had "cleansing" properties would cause me to detox. I think the glycine helped my detox pathways. It's used in phase II liver detoxification: https://www.diagnose-me.com/treatment/liver-detoxification-phase-II-support.php
 

Methyl Head

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@Mary Interesting! I saw something similar on heart fixer and figured that it would be different depending on your GB-DMG because it's a known feedback inhibitor so with his low end homocysteine, glycine might not be optimal. did you have high homo-cysteine initially?
 

Mary

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@Mary Interesting! I saw something similar on heart fixer and figured that it would be different depending on your GB-DMG because it's a known feedback inhibitor so with his low end homocysteine, glycine might not be optimal. did you have high homo-cysteine initially?
No, I didn't have high homo-cysteine. It was I think on the low side. I just tried glycine because I was desperate for sleep and read that it could help. To be honest, I don't even read about various SNPs and supplements. I'll read about various supplements - the high points (e.g., excitotoxin or not) - and then just experiment on myself and see what works. I don't have the energy for an in-depth study of all this. I only learned about the role of glycine in phase II liver detoxification after I had such a strong reaction to it initially.

I used to detox a LOT. It was a huge problem for me, and now unless somehow I get a heavy exposure to something (e.g., when I had a new bathroom floor put down), I hardly ever get detox reactions - it's no longer an issue for me. And I had tried Andy Cutler's protocol with no apparent results.
 

Methyl Head

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@Mary I don't think anyone on earth has the energy for an in-depth study on methlylation, there is way too much to know :bang-head:. I suppose Jockers is addressing phase 1 detox but I'm still curious to hear if it has aggravated anyone else/ what his reasoning for this is without any assumptions. I can imagine my reaction with COMT -/- and VDR taq would potentially be different from yours from the psychological side of things. It made me hyper aggressive and aggravated without a clear Herxheimer reaction, it was bad enough for me to find another method and look into it as an option later. I'll look into the reasoning behind this and try to come up with a definitive answer!
 
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Methyl Head

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I used to detox a LOT. It was a huge problem for me, and now unless somehow I get a heavy exposure to something (e.g., when I had a new bathroom floor put down), I hardly ever get detox reactions - it's no longer an issue for me. And I had tried Andy Cutler's protocol with no apparent results.
Cutler worked like a charm for me but I modified what he came up with and turned it into a kind of phase 1 detox then slowly added MthylCbl and phase 2's, I'm in no rush to add sulfur back either... I can't explain how much better I feel on his low thiol list. I'm really suprised to hear that it didn't work for you... out of curiosity, what did?
 

Mary

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Cutler worked like a charm for me but I modified what he came up with and turned it into a kind of phase 1 detox then slowly added MthylCbl and phase 2's, I'm in no rush to add sulfur back either... I can't explain how much better I feel on his low thiol list. I'm really suprised to hear that it didn't work for you... out of curiosity, what did?
I believe it was primarily the glycine (see this post above), as well as inositol and glutamine. By happenchance I started taking them all within close proximity to each other. Each of them caused a detox reaction for me, though the glycine was by far the strongest. I had to go very slowly with the glycine but over a period of several months I was able to increase my dose gradually. The inositol (which I also started for sleep) caused a much milder detox reaction, as did the glutamine, which was part of a branched chain amino acid combo I started around the same time.

After taking these for some 6 months I realized I was no longer detoxing at the drop of a hat. I also had the mercury tri-test by Quicksilver done around this time and it showed that my mercury levels were extremely low, and also that my ability to excrete mercury was very good. I think these three things - the glycine, inositol and glutamine - together helped my detox pathways. I eventually had to stop the glutamine because it started causing insomnia for me, unfortunately.
 

Methyl Head

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@dbose @Mary Interesting! I'd be interested to know what your SNP's are because because Glycine would be an ammonia trap for us and would cause us some pretty nasty symptoms. You may very well be lucky because if you can handle and breakdown glycine in phase 2 then you most likely just had high mercury and don't need to worry about CBS, NOS3, SHMT1 or MTHFR (to a degree perhaps, you could be hetero) at all, as it would be a solid indicator that your body is converting NH3->NH+4 and has the necessary folate for that conversion as well. On the other hand, for me and dbose it would be a huge problem:

1.Because Glycine synthesis requires P-5-P (Active B6) as a cofactor and we can't handle large amounts of b6, (although P-5-P is less of an issue supplemental glycine would increase the need which would kick us into overdrive because of CBS up regulation.)
2. Glycine is an amino acid that can act as an inhibitory neurotransmitter and as we know amino acids require conversion (this conversion is primarily an SHMT1 job but the larger problem is that it's a reversible conversion so it requires breaking down ammonia into ammonium NH3->NH+4 or it needs THF almost immediately )
if we look at:

serine + tetrahydrofolateglycine + N5,N10-Methylene tetrahydrofolate + H2O

we see that it might be OK for us with functional SHMT1 but looking further into the liver equation we now see the problem

CO2 + NH+4 + N5,N10-Methylene tetrahydrofolate + NADH + H+ ⇌ Glycine + tetrahydrofolate + NAD+

So since dbose has the former SNPs mentioned (and is homozygous for MTHFD1 at that, with highly reduced enzyme function) this conversion would be almost impossible and/or happening at an extraordinarily reduced rate causing a serious ammonia trap because he can't metabolize MTFH well to begin with and the neccessary ammonium isn't present because he's NOS3 (so NH3->NH+4 isn't happening he isn't SUOX though so this already bad combo is much worse because there is proper sulfur->sulfate which creates a serious imbalance) meaning that if he took what you took he'd build up glycine and it would cause more ammonia to accumulate because the body would request more NH+4 that it can't produce and would actually block his phase 2 liver pathways as opposed to induce a herxheimer reaction like it did for you. I suggest using Vitamin C with bioflavinoids and Dandelion or Parsley to bypass ;)
 

Mary

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@Methyl Head - you are way beyond me with your chemistry! :confused: Seriously :) But, there are people on this board who could keep up with you and are equipped to discuss all this. I can tell you that in 2010 Nutreval testing showed I had a severe B6 deficiency so I started taking P-5-P which my body liked, a lot. I have a sister who does not have ME/CFS but she had some symptoms of a B6 deficiency which I was aware of because I had been reading up on it, so I got her taking it, and she did well with it also. So I'm sure there's something genetic going on, though I couldn't tell you what. My brain just sort of shuts down when I see equations and diagrams etc. But we are very different - it must be the SNPS!

I guess I am lucky in terms of glycine. But the first time I took it - it was actually gelatin which is high in glycine, which I took for sleep - it left me so spacey I got lost going to my sister's house and had to call her to bring me in so to speak. I was only a few blocks away, I think it was mercury causing the problems. So I may very well not have the various SNPS you talk about above.

re folate: I started taking folate in 2010, and it made a big difference for me. My MCV was high. I responded quickly to the folate, it boosted my energy markedly (I'd already been taking lots of methylcobalamin for years) and then a day or 2 later my potassium tanked badly. Fortunately I had read Freddd's posts about potassium and folate and methylB12, so was able to deal with that, titrating up with a potassium supplement until the severe fatigue induced by low potassium abated. And I've had to take potassium ever since. Actually the fatigue from the folate-induced potassium deficiency was familiar - I'd had it before I even started the folate but never knew what it was. So something is off there - like so many other things! :aghhh:

BTW - you may already know this but ornithine can help with excess ammonia; this study talks about both ornithine and arginine doing that. It also mentions glycine. See https://www.ncbi.nlm.nih.gov/pubmed/3508233

Some insomnia is due to ammonia and ornithine can help with that.
 

Methyl Head

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Arginine/Ornithine (this helps with ammonia in the brain big time but be careful if you respond to arginine just tajke ornithine as it can cause bad symptoms with BH4 deficiency since it won't be broken down to nitric oxide)
Apple Cider Vinegar
Carnitine (helps with ATP and is necessary since you're treating with low animal protein/low sulfur diet)
NADH (great for energy but not crucial)
Good consistent source of potassium (whole food is best, pills are discouraged because potassium nuclears show slower improvement in cell concentration after supplementation and you being MTHF need potassium for sure because activating that detox pathway will gas potassium and cause fatigue/mental slowing, also the crebs cycle needs it and your adrenal balance should improve because of CBS/ACE predisposition to store salt, furthermore if you're ACE del16 like me you'll have extremely low cellular concentrations of potassium to begin with)
 
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Methyl Head

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@Mary - I 100% agree with those suggestions! Anyone with low cellular potassium is likely ACE del16, the fog comes from potassium/sodium imbalance which the brain needs for proper cellular membrane activation and (if you're MAO A that makes ACE much worse because you're extremely bad at breaking down serotonin and aldosterone, causing low/high neurotransmitter cycling, hello methyl groups, I'm ACE del16 +/- of course because it lies on X chromosome, CBS +/+ so i had to go without Methyl groups for a while until I addressed CBS which was absolute torture and then I couldn't break down the resulting neurotransmitters so I got overstimulated... and when I finally added the pieces my potassium tanked while playing ice hockey so I finished the game cramping then I had to crawl out of the rink because I literally couldn't walk and consumed about 7 medium sized bananas when I got home :bang-head::aghhh::rofl:.... what a nightmare... thank god for riboflavin-5! @dbose). I digress, ACE + MAO A combined with high angiogestin and high level potassium dumping and sodium retention would create the level of brain fog you're talking about with elevated anxiety and severely reduced learning and memory retention, depression, mood swings, aggression, OCD and intolerance to methylfolate, so if you struggled with the fatigue feeling initially odds are you have either MAO A or ACE del16 as both would cause that reaction, wouldn't be surprised if your heart rate was abnormal also as arrhythmia would be likely with these plus MCV!

The good news is that you likely just had high mercury because if you had CBS your methyl donors wouldn't have stuck around at all because CBS is like an angry blackhole barreling though space destroying literally everything in its path and a dose of P-5-P >10 mg would only add to toxicity and up regulate CBS even more, so your experimental spirit is right on point! On the other hand, high mercury behaves the same way and is activated by foods/meds higher in thiol groups and it would explain why you might not have responded to Cutler as drastically as I did, did you take co-factors and follow diet? Turmeric is also a sneaky thiol culprit, it's not high in thiol itself but it can help mobilize and raise those thiol groups pretty quickly as it's a catalyzing agent.

Elevated MCV could be the result of a number of different SNP's (MTHFR or MTRR primarily but there a couple others and if you experienced OCD check hephaestin and ceruloplasmin related copper deficiency issues on chromosome 3 because OCD is an has a very odd link with copper related blood disorders but that's very rare and probably not relevant) yours was VERY likely megaloblastic because of your response to folate (deficiency can cause high mean corpuscular volume or megaloblastic aenemia because of induced b12 deficiency) that was likely the result of you taking b12 without folate for a long time which made you both b12 and folate deficient because it exhausted whatever you were getting very quickly and without support I can imagine you were struggling for answers, I DEFINITELY know that feeling :). This doesn't mean you have either SNP though, could be simple deficiency, I've listed a few sources if you're curious to explore!

https://www.omim.org/entry/250940
https://www.snpedia.com/index.php/Yasko_Methylation#NOS3_Gene
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570488/
https://www.ncbi.nlm.nih.gov/pubmed/6313090

Sources for copper issues to cover my bases
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637704/
https://en.wikipedia.org/wiki/Ceruloplasmin
 
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