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Severe ME patients have 1.7 broken copies of IDO2

Inara

Senior Member
Messages
455
I have the elevated B6 finding as well. If your alkaline phosphatase (ALP or Alk Phos, aka tissue-nonspecific ALP or TNSALP) tends to run at the bottom of the normal range, like mine does, then it may be due to that.
Yes, that's what I concluded. My ALP is below normal. But why? I have no mutation in the ALPL gene that could reduce it's activity, so I guess there could be something else.

There's apparently a common genetic variation(s) in the ALPL
Do you know which one? Hypophosphatasia was ruled out, and the guys weren't interested in the slightest to look further although they're doing research.

But isn't it interesting to find several people here who have the same?

So the high B6 probably isn't reflecting an inability to use the B6. It's been shown in infants with actual frank hypophosphatasia and extremely elevated B6 levels due to deficient ALP that their tissue levels of B6 are actually pretty normal.
I've seen other publications (I can't now) where tissue B6 was not normal, but low. This seems to be the typical constellation in hypophosphatasia.

I can't even take 5mg of B6.
 

Inara

Senior Member
Messages
455
This post is interesting. Perhaps those of us with low cortisol and low ALP pre-illness due to ALPL gene mutations have a double whammy that prevents utilization of B6 in cells.
I've just wondered if there is a connection between corticosteroid-binding deficiency (or alternatively, low cortisol) and ALP. So thanks! Gives a good starting point for a search.
 

Inara

Senior Member
Messages
455
just quickly glancing at the abstract, it's referring to Intestinal ALP, which is a different isoform of ALP than the Tissue-nonspecific ALP (TNSALP) that I thought was primarily responsible for affecting blood levels of B6. (TNSALP is the isoform that's measured in routine blood labs.)
Are you sure about this? I remember that the common ALP test comprises all the ALP forms, and TNSALP is a special measurement that I encountered when hypophosphatasia was checked. (It's quite possible I misremember though, so just asking.)

Definitely need to look at this in more detail.
I'll be quite interested, because I try to solve this riddle for a while. I even asked a "top endocrinologist" in Germany who had no idea, and it seems we've already come farther with understanding this than him.

I looked further into this and it is known that ACTH stimulates TNSALP at least in the adrenal gland and possibly elsewhere.
Do you maybe have a reference at hand? I'm collecting everything.
 

nandixon

Senior Member
Messages
1,092
Yes, that's what I concluded. My ALP is below normal. But why? I have no mutation in the ALPL gene that could reduce it's activity, so I guess there could be something else.
Did you have the entire ALPL gene sequenced, either specifically or as a result of full genome sequencing, or did you do 23andMe?

Do you know which one? Hypophosphatasia was ruled out, and the guys weren't interested in the slightest to look further although they're doing research.
I was just making a supposition based on how common the elevated B6 (and perhaps the decreased ALP) finding appears to be. But after seeing that @wigglethemouse found that there are a very large number of presently known mutations in the ALPL gene it may be more likely that rather than there being one or two common SNPs there may be many less common ones that might have an effect. (I'm not sure if this gene might have copy number variant issues as well.)

And we're not talking here about SNPs that would actually cause outright hypophosphatasia but rather ones that would cause a relatively mild reduction in the function (or quantity) of the resulting enzyme, similar to the situation with the MTHFR SNPs, for example.

But isn't it interesting to find several people here who have the same?
Yes, assuming the increased B6 is not simply something that would be showing up more often if more of the healthy population were tested.

I've seen other publications (I can't now) where tissue B6 was not normal, but low. This seems to be the typical constellation in hypophosphatasia.
If you have a chance I’d like to see a reference that reports a different result than the one I cited. I'd have thought that if tissue levels of B6 were normal in the most severe forms of congenital hypophosphatasia with defects in ALPL that they'd most likely also be normal in other cases.

Are you sure about this? I remember that the common ALP test comprises all the ALP forms, and TNSALP is a special measurement that I encountered when hypophosphatasia was checked. (It's quite possible I misremember though, so just asking.)
Yes, you're right. I was thinking in the context of hypophosphatasia, where reduced serum ALP and increased B6 is a reflection of reduced TNSALP activity and not of intestinal ALP, for example. But what I said was wrong.

Do you maybe have a reference at hand? I'm collecting everything.
There are several that I haven't looked at more fully, but for example:

The histochemical activity of alkaline phosphatase (Al-Pase), the induction of which is one of the effects of ACTH on the adrenocortical cells...
https://www.ncbi.nlm.nih.gov/pubmed/204155/

These results suggest that ACTH releases alkaline phosphatase by activation of a phospholipase C.
https://www.ncbi.nlm.nih.gov/pubmed/15030184/
 
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Inara

Senior Member
Messages
455
Did you have the entire ALPL gene sequenced, either specifically or as a result of full genome sequencing,
Yes, I had WGS, WES and the gene itself wasn't checked for hypophosphatasia. Nothing of significance.

And we're not talking here about SNPs that would actually cause outright hypophosphatasia but rather ones that would cause a relatively mild reduction in the function (or quantity) of the resulting enzyme, similar to the situation with the MTHFR SNPs, for example.
This was my thought, too, but the variants I have are very common. Is there information somewhere about whether certain SNPs are known to reduce ALP function?

Is the constellation high serum B6/(low tissue B6)/low ALP really so common in general, or just here? I didn't come across many people (online) that have this. But one of them didn't have ME. I don't think it's an ME-specific thing, but maybe it shows that something is going on that might be interesting for ME. Of course, research is needed. I can only speculate.


If you have a chance I’d like to see a reference that reports a different result than the one I cited.
I've finally found it. But I see I misunderstood it then AND remembered incorrectly, duh, so you're right.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC329654/
(Yeah, it's the same you linked... :meh:)
 

Belbyr

Senior Member
Messages
602
Location
Memphis
Got directed to this thread, my B6 from Nancy Klimas is 114.1 (normal range 2.1-21.7)

B12 was also elevated but not nearly as bad 1292 (normal range 200-1100)

*Quest Labs
 

nandixon

Senior Member
Messages
1,092
Got directed to this thread, my B6 from Nancy Klimas is 114.1 (normal range 2.1-21.7)
How much B6 had you been supplementing with, if you had, and if you stopped supplementing prior to the blood draw how long had it been since the last time you took the B6?
 

Belbyr

Senior Member
Messages
602
Location
Memphis
I have a b complex made by pure encapsulations that I took once a day (10mg of B6 is in it). I remember stopping it for a couple days prior to making my trip to Florida to see Klimas. I'm digging through old tests and don't see where anyone checked it before...
 

wigglethemouse

Senior Member
Messages
776
Got directed to this thread, my B6 from Nancy Klimas is 114.1 (normal range 2.1-21.7)
Some folks on this thread with high B6 found their alkaline phosphatase runs at the low end of the range. Be interesting if you could check yours (metabolic panel test)
I have the elevated B6 finding as well. If your alkaline phosphatase (ALP or Alk Phos, aka tissue-nonspecific ALP or TNSALP) tends to run at the bottom of the normal range, like mine does, then it may be due to that.
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
I have chronically LOW B6. My body seeems to suck up every bit I give it. I can't figure out where it is all going. I take 350mg a day.

Seems to be used in heme production, sphingolipid production, methylation, degrading oxalates, etc.

B12 was also elevated but not nearly as bad 1292 (normal range 200-1100)
Er...was this serum B12, which is pretty useless? A methylmalonic acid test is a better measure of B12 status. If you've been supplementing at all, serum will look high, but it may not be reflecting what's in your cells.
 

BeADocToGoTo1

Senior Member
Messages
536
Absorption of B6 is complicated, involving phosphorylation and dephosphorylation, oxidation and reduction, amination and deamination, all primarily taking place in the jejunum and ileum portions of the small intestine. So any type of malabsorption or microbiome dysbiosis can also cause issues.

ALP, vitamins B2, B3, molybdenum, zinc and magnesium are all needed to absorb and utilize vitamin B6.

Low alkaline phosphatase ALP can be a sign of malnutrition, pointing to possible deficiencies in vitamins B and C, zinc and phosphorous.

It might be worthwhile looking into any form of malabsorption and have a close look at your diet quality. My ALP was quite low before fixing microbiome dysbiosis, SIBO, Candida, taking pancreatic enzymes for exocrine pancreatic insufficiency and fixing nutrient deficiencies.

A more technical read on ALP (although most focus is often on too high a level) here:

https://www.ncbi.nlm.nih.gov/books/NBK459201/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838368/
 
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wastwater

Senior Member
Messages
1,271
Location
uk
What’s the relationship between IDO2 and FOX01
Top Transcription factor binding sites by QIAGEN in the IDO2 gene promoter:

  • C/EBPalpha
  • CHOP-10
  • FOXO1
  • FOXO1a
  • GR
  • GR-alpha
  • GR-beta
  • LUN-1
  • NF-kappaB1
  • POU3F2
EBV reduces FOX01 expression
 
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wigglethemouse

Senior Member
Messages
776
What’s the relationship between IDO2 and FOX01
Top Transcription factor binding sites by QIAGEN in the IDO2 gene promoter:
It seems @wastwater got this info from GeneCards
https://www.genecards.org/cgi-bin/carddisp.pl?gene=IDO2

Google brought up this paper showing a relationship between FOXO1 and IDO1 promoter. Maybe you want to read that @wastwater if you are interested in FOXO1 and the IDO pathway.
https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.14026

That paper states IDO1 is more important than IDO2.
Previous studies show that IDO1, IDO2 and trypto-phan 2,3-dioxygenase (TDO) are able to catalyze the degradation of the essential amino acid tryptophan to nicotinamide adenine dinucleotide along the kynurenine pathway; however, TDO is mainly expressed in liver and IDO2 has very low Trp degra-dation activity [1,43–45]. Therefore, IDO1 is the most important rate-limiting enzyme for the kynurenine pathway.

Interestingly they used Melatonin to upregulate IDO1...... as shown in Figure 3
1562039159329.png
 
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godlovesatrier

Senior Member
Messages
2,545
Location
United Kingdom
Does anyone know the specific RSID and mutation combination alele for this gene (IDO2) that I should be looking for in my genetic workup? I've struggled to find the information via google so thanks in advance!
 

bread.

Senior Member
Messages
499
I have a b complex made by pure encapsulations that I took once a day (10mg of B6 is in it). I remember stopping it for a couple days prior to making my trip to Florida to see Klimas. I'm digging through old tests and don't see where anyone checked it before...


Well there you could have part if the reason why you have POTS! B6 induced SFNP. :-/
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
B6 only induces neuropathy at a very high dose, typically over 200mg. Some of us csn tolerate doses up to 500mg a day (not that im recommending it). 10mg us not so high a dose.

Many of us who have POTS are now thought to have autoimmune antibodies, like a1-adrenergic and m4-muscarinic, causing it.
 

bread.

Senior Member
Messages
499
pots is a syndrome, not a disease, it therefor has no one pathological mechanism, the mechanism you mentioned might be a big group.


re b6:

your threshold for toxicity for any given substance is not the same as for another person, there are averages, but they are not tested extensively, that is the first problem, the second problem is that most supplements have much higher dosages of any given substance than they write on their packaging.

(source: Stiftung Warentest Germany, tested over 15 brands, all of them had vastly higher dosages of „substance xy“ than they should have)
 

PracticingAcceptance

Senior Member
Messages
1,858
Does anyone know if they've found the same IDO gene mutations consistently with ME/CFS patients outside that 20-person study?

(Apologies if this question has already been answered, I find it difficult to read technical information.)