CBS / Ammonia / Glutathione

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Hi Methyl Head, thank you for helping me.

VDR BSM TT: +/+
VDR TAQ GG: +/+
COMT P199P: -/-
COMT V158 AG: +/-
NOS : -/-
CYPA1 and B1: +/-
MTHFR: -/-
GSTM3: +/+
GAD1: +/+
SUOX isn't on the test . Is there another name for it? Is it methylation related?

Well I'm on a diet low in thiols. I still eat small amounts of meat. . I have a hard time with plant based due to adrenal burnout and pre diabetes. I just started IF and I'm planning on eating green juices for lunch and for dinner and ONLY beef broth as far as animal protein. I was vegan for a few weeks and I kept binging on carbs and made my gut worse. I think the broth will be fine. My blood ammonia level is 24.
Btw the first test I quoted you was a nonspecific test. The values above are from 23 and me. But all m MTHFR are negative. And on my spectracell blood test my glutahthione was totally normal.
 

Methyl Head

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@calexis6666 My pleasure! SUOX = Sulfite Oxidase is an enzyme that exists in the mitochondria and is responsible for generating ATP, converting sulfite to sulfate and transferring electrons, it is methylation related and can exacerbate the CBS SNP by increasing the up regulation and releasing even more toxic sulfites into the body. Furthermore, it shunts more homocysteine down the transsulfuration pathway increasing oxidative stress and contributing to already faltering energy production. Your blood ammonia is already in range so the -/- for NOS makes sense. However if your sulfur readings are abnormally high you might have this SNP as well but you'd expect to see extremely low molybdenum if you had it. You are VDR taq +/+ with normal dopamin so I'm guessing your diet and the bioflavinoids you are getting from it are the reason for that. I'm sure you already know your urine sulfate. I'm assuming it wouldn't be high because your on a low thiol diet but it depends on how long you've been doing it, however you might find more answers there.
 

Methyl Head

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And I also know just from symptoms that I have excess glutamate. I may try to take BH4.
BH4 would be a nice addition assuming all is regulated on the transsulfuration pathway and CBS is in check, I'd love to hear about how you feel on it as I've considered taking it myself now that I'm out of the woods detox wise and CBS wise. GABA, NAD+/NADH, CoQ10 and carnitine might be good things for you to try along with vitamin E from annatto because sunflower and soy will likely bother you. If you choose NAD+ go slow, microphagy can feel terrible if you have a lot of bad mtDNA as they'll perform poorly under fission
 
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@calexis6666 My pleasure! SUOX = Sulfite Oxidase is an enzyme that exists in the mitochondria and is responsible for generating ATP, converting sulfite to sulfate and transferring electrons, it is methylation related and can exacerbate the CBS SNP by increasing the up regulation and releasing even more toxic sulfites into the body. Furthermore, it shunts more homocysteine down the transsulfuration pathway increasing oxidative stress and contributing to already faltering energy production. Your blood ammonia is already in range so the -/- for NOS makes sense. However if your sulfur readings are abnormally high you might have this SNP as well but you'd expect to see extremely low molybdenum if you had it. You are VDR taq +/+ with normal dopamin so I'm guessing your diet and the bioflavinoids you are getting from it are the reason for that. I'm sure you already know your urine sulfate. I'm assuming it wouldn't be high because your on a low thiol diet but it depends on how long you've been doing it, however you might find more answers there.
Not sure why SUOX is not in my results.Btw I am SLC +/+ which relates to Pyloria which I have. Anyways, I will get an OAT test to see more what's going on with Sulfur intolerance but my urine strips are way too high. I think it's due to eating sulfur foods when I feel deprived. I am motivated to do better. I will not get better until CBS pathway is cleared. I don't know why but i get headaches when I take GABA. I'll try the NADH. My problem is finding supplements without fillers as I react to them. Would you have a guess why I get a headache even from low amounts of the ionic Molybdenum drops? I do very well with Ornithine though. Ornithine is my savior! What does the VDR +/+ mean? Am I low in vitamin d?
 
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I just read this. Is this correct? Actually VDR +/+ means i'm low in dopamine. But I am less tolerant to methyl groups so this doesn't make sense to me.

"VDR – Bsm/Taq mediates an increase in dopamine production in response to Vitamin D (VDR is an abbreviation for Vitamin D Receptor). The (+/+) form is less active, so you tend to be low in dopamine. Methyl status will be low also, so you will be less sensitive to supplementation with methyl groups.I have (+/+), which read with my normal V158M gene means that I have low vitamin D levels, poor tolerance to toxins and microbes, make less dopamine and need and tolerate more methyl donors."
 
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I just read this. Is this correct? Actually VDR +/+ means i'm low in dopamine. But I am less tolerant to methyl groups so this doesn't make sense to me.
"VDR – Bsm/Taq mediates an increase in dopamine production in response to Vitamin D (VDR is an abbreviation for Vitamin D Receptor). The (+/+) form is less active, so you tend to be low in dopamine. Methyl status will be low also, so you will be less sensitive to supplementation with methyl groups.I have (+/+), which read with my normal V158M gene means that I have low vitamin D levels, poor tolerance to toxins and microbes, make less dopamine and need and tolerate more methyl donors."
 
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Also, I'm trying to figure out if I am an overmethylater or an undermethylater. Despite the genetics.
I have normal levels of copper according to Spectracell blood test but I don't know if blood is the best way to check.
I seem to have symptoms of both under and over methylation.
 
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Also, I'm trying to figure out if I am an overmethylater or an undermethylater. Despite the genetics.
I have normal levels of copper according to Spectracell blood test but I don't know if blood is the best way to check.
I seem to have symptoms of both under and over methylation.
I suspect I am an undermethylator. It fits the best. I guess I'll have my SAME checked.
 
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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 ;)
This is superb @Methyl Head. My 200$/session integrative-GP didn't explain to such a depth. Fantastic. Since then, reading more and more MB books and posts from experts like yourself. Can I send a "thank you" via crypto ?
 
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@Mary - ... 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, ...
Hetero on ACE (rs4343), MAO-A (**) / COMT (**). So Na/K balance is always screwed up !
 
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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)
Thanks @Methyl Head. NOS3 mutation really aggravates CBS up-regulations. So you reckon, L-Ornithine would be fine with CBS/NOS3 ? BTW, I'm a bit hypertensive given SNPs around potassium deficiency / ACE (rs4343) / MAO-A (**) / COMT (**) as discussed earlier. What's your dosage of L-Ornithine ?
 
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@Methyl Head, diet wise what should be our macro split (esp. protein source) when we don't handle sulfur stuff well ?Although I've read sulfur from animal protein (Methionine) is metabolised differently than sulfur from veggies such as Brocolli which is much more damaging for CBS+ folks.

Do you recommend a good amino-acid/protein supplement (like Vital Proteins Collagen Peptides) as I don't want to eat "acidic" meat everyday ?
 
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@Methyl Head, do you reckon Magnesium L-Threonate (as opposed to citrate) can help me especially with my MAO/COMT status.

Even though curcumin is a potent anti-inflammatory and suggested in various other Liver phased detox process, I'm scared to use it because it's a methyl donor. If I take LongVida (Solid Lipid Curcumin Particle; bypasses liver conjugation etc.) along with Magnesium L-Threonate, will it be fine as far as methyl donor is concerned after "calming down" angry CBS ?
 

roller

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@dbose
did you have your findings only from the 23andme.com "Ancestry Kit" for USD99 ?

@Methyl Head @dbose
which would be the next "better" test, perhaps to see those things in more detail, more clearly, more markers (...) ?
 

Methyl Head

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@dbose L- Ornithine- I take 500-1000 daily, usually in the evening as it can have a very calming effect and falls within that period of the circadian rhythm very nicely but you could have other peripheral things going on that change your response so play around and see what works, might be 500 might be 1.5 grams, completely depends on you. Just don't do any arginine as you're likely to have BH4 involvement and peroxynitrates would be the last thing you need roaming around your body.

Protein Magnesium Threonate- This depends entirely on the type of meat you choose, the state of your urine strips, your response to meat in terms of PH, digestion and the inflow/outflow of sulfur to and from the body. Some people may need to completely get rid of meat until their toxicity comes way down (usually > or = 1,300-1,700 on urine sulfate strips) then add it back in later once the transsulfuration pathways burden is clear. At 800 I was able to consume 2-4 oz of meat but I chose dark meat turkey (given your COMT +/+ high tyrosine isn't recommended so maybe dark meat chicken would work) that has less methionine and is generally fattier. Correct, sulfur veggies contain high numbers of Thiol groups and that's the huge difference:

“You’ll find a lot of misleading ‘sulfur’ lists on the web. I’m talking about those compounds that are thiols or that metabolically convert to them, not to the total amount of elemental sulfur in the food. Some forms don’t convert very much and are tolerated at much higher levels than others. E.g. meat is in theory quite sulfurous, but in fact a lot of the sulfur stays in the methionine rather than thiol form so it is a less potent thiol source than an elemental analysis would suggest. Especially if you are taking TMG or choline which helps provide methyl groups so the methionine doesn’t need to get metabolized.” - Andrew Cutler

I'm not endorsing Andrew Cutler's protocol, I'm using this as a template because we may have high mercury as a consequence of our genetics but the root problem is sulfur and ammonia and more specifically high thiol containing (literally called mercaptans because they are also very efficient with capturing mercury) foods that are extremely efficient at accelerating the metabolism of sulfur because they are sulfur analogues of alcohols and a sulfhyrdryl group replaces the oxygen group. This means 2 things: 1. They break down very quickly and we know that CBS as an up regulation is already over functioning so that's why we experience symptoms nwhen we consume them. 2. they're actually more acidic for us (yes inside the body after being deprotonated if we can't metabolism them properly!) so if we have thiolates in high numbers bonded to mercury that would explain a lot of metabolic issues. (Those of you that suspect ANION Gap or Metabolic Acidosis and have severely increased CBS activity (high level toxicity) and correlated end product dysfunction, ATP/mtDNA issues will love what that the next part means).

This means also means that one of the biochemical end products of CBS (AKB NOT AKG!!!! Yasko is wrong here. Please spread this as that's a big thing among those of us that have ME/CFS because it changes the structure and direction of some programs entirely...) used as a very important aspect of mtDNA and ATP production is functioning in a sub-optimal fashion and potentially causing thyroid dysfunction, decreased energy production and chronic illness. AKB is one of the most important aspects of the mitochondrial matrix and krebs cycle so for those of us with Thyroid disfunction and under performing mtDNA related issues here's a potential answer along with IgA and IgE or TPH antibody involvement. (long side bar, this is why I suggested biotin, vitamin E succinate and adenosly/hydroxy b12 in my first post to you a long time ago, people probably thought I was nuts but now you'll see why, and this will answer your magnesium threonate question as well): AKB is the result of the lysis of Cystathione and is one of the degradation products of threonine and the catabolism of the amino acid threonine dehydratase. It's also produced by the degradation of homocysteine and the metabolism of methionine. Here is the conversion from AKB => Succinyl CoA and entry to the Krebs Cycle

AKB, Alpha Keto Acid Dehydrogenase -> Proprionyl CoA, Proprionyl CoA Carboxylase + biotin = (S) Methylmalonyl CoA => (R) Methylmalonly CoA, Methylmalonyl CoA Epemirase -> Methmalonyl CoA Mutase + AdoCbl = Succinyl CoA -> Krebs Cycle. This reaction helps generate functional platforms for new mtDNA and ATP synthesis. So treating any immune disturbances you have while nurturing this will greatly help you improve.


Magnesium Threonate should be just fine but I would take less than the recommended amount if you struggle and keep your magnesium citrate close. Slow moving COMT can keep SAMe around for too long and that can also cause a backup because you're not breaking down and cycling neurotransmitters quickly (thats a really nasty combination). I know I'm intervening in methionine metabolism by taking TMG and Choline (which I need because COMT -/- and VDR taq +/+ is low dopamine and greatest need for methyl donors) but for you, being the opposite, meat would would help in a very small manner of speaking but limit it and you might need to even more because you won't have the donors to block methionine metabolism and your COMT is already slow (Would love to know your VDR taq though, if you're +/+ or +/- that would be a little relief but if you're -/- I'm really sorry). 1-3 oz is OK for now, but mess around with the amount and see what you can tolerate. What you're titrating for is the point where you have enough for AKB, other reactions and nutritional maintenance without the 4-6g of ammonia on top of other metabolic waste left over because that will make things run MUCH slower and add toxicity via the other biochemical phenomena occurring within you. You can push and eventually liberalize your diet a little bit (that's relative to gut health keep in mind) once you drop your sulfur strip readings and your body repairs itself. I didn't add this before because you'd have hated me but NAD+ will induce microphagy if cells are properly supported and that will clear bad mtDNA and help you cycle SAMe potentially but it can make you feel pretty bad, kind of like a detox reaction. I posted small bit about this phenomenon earlier as well.

Turmeric/Curcumin is also very good at raising thiol groups but a little bit will help push your body towards making glutathione instead of taurine so there is that added benefit as well. I wouldn't shy away from using methyl donors just don't take a bath in them. You'll over do it and overdrive yourself quickly, especially with MTHF SNPs. MTHF enzymes are rate limiting for methylation generally so if you put the gas on and go wild with MTHF without the proper enzyme function you could put yourself in hyper drive because you've given yourself what you need but the body has no way of down regulating the over activity.
 
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Methyl Head

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@dbose don't add Vitamin C, I meant to edit this out a long time ago and it skipped my mind but that wouldn't be good for you at all even in the slightest.
 

roller

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reasons for elevated ammonia (and its variations) could be
- genetics (CBS?)
- valproic acid
- benzodiazepines and similar drugs
- infections
- excess ammonia producing bacteria in the gut
- parasites produce ammonia, urea, plus may use hypoxanthin (muscle regeneration)
- (...)

Elevated blood ammonia has also been linked to a surprising variety of functional and metabolic neurological disturbances other than exercise and fatigue, including the development of hepatic coma, convulsions from ammonia toxicity precipitated by high-pressure oxygen breathing, epileptic seizures, and decreased neuronal excitability.
https://www.ncbi.nlm.nih.gov/pubmed/6341752
very good is this from the cleveland clinic http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/hepatic-encephalopathy/

symptoms of HE hepatic encephalities (which is linked to hyperammonia) have quite some overlap with ME CFS.

in the gut, it may suppress anaerobe bacteria (basically bifido/lacto...) and promote the aerobes (entero... ).
could this be a reason for high lactate values? @Avenger

it makes the astrocytes (brain) swelling. dementia.
it toasts muscles.
 
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roller

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helpful with high ammonia:
- abx: rifaximin / neomycin / metronidazole (those are also used for SIBO)
- meds for hyperammonemia: Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate (e.g. Buphenyl).
- lactulose
- l-carnitine (good with l-carnosine)
- citrulline
- L -Ornithine L -aspartate (LOLA). LOLA (Hepa-Merz)
- PROBIOTICS VSL#3
- B1 (Thiamine)
- BIOTIN B7
- ZINC
- BCAA

- toxaprevent (Klinoptilolith-Zeolithe)
- Chlorophyl
- BH4
- Apple Cider Vinegar
- yucca root
- Genistein
- Celery
- molybdenum (only for sulphur issues)
- lactoferrin

avoid:
- high aminoacids.
- tyramine
- octopamine
- probiotics with escheria or staphyl


AMMONIA PROVOKERS: (Limit to essentials for CBS +)
• protein
• B6/P5P
• glutathione
• taurine
• NAC
• LIPID DONORS: (limit for CBS+, NOS+)

Any transdermal creams
• Lipoceutical EDTA and Lipoceutical glutathione
• Higher doses of essential fatty acids (EFAs)
• CoQ10
• Alpha Lipoic Acid (ALA)
• Idebenone

thanks to @Methyl Head for the input.
perhaps those affected can contribute to the list.
 
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