Community symposium on molecular basis of ME/CFS at Stanford Discussion Thread

[MEssias]

Are there any other diseases that cause such a metabolic trap? And are there epidemics caused by metabolic traps?

 

[FMMM1]

Thank you! I thought I was going crazy about how everyone missed the point where Phair said this was not the only metabolic trap. There were other metabolic traps too!This is the only one he shared, for whatever reason. Maybe, this trap is the one Phair has looked at most closely.



There are other traps they are looking at. This is just one. 1 trap for this complex disease is likely too simplistic.

Yea but what are the other traps?

Check out @Murph posts e.g.:
https://forums.phoenixrising.me/ind...-discussion-thread.61590/page-10#post-1002947

On the face of it you need a substrate limited enzyme (i.e.one that functions at lower levels) and a genetic defect on your second enzyme (i.e. one that functions at higher levels).

I think you're likely to be correct about it being too simplistic. However, the high levels of tryptophan are intracellular (difficult to measure) so it may be something you could miss e.g.

• if you only test readily accessible fluids (e.g. blood plasma), or
• if the levels of tryptophan in serum/plasma are not significantly higher/lower than the normal range.

Here's a way to measure intracellular levels of phenylalanine* and guess what they are higher in ME/CFS and tryptophan is likely to be higher as well [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].
*1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
*2) full paper: https://sci-hub.se/10.1039/C8AN01437J.
@Aroa
The measurement of intracellular levels of phenylalanine* is a possible diagnostic test. I've asked European Union (EU) Committee on the Environment, Public Health and Food Safety (ENVI) to lobby for funding to test whether this could be used as a diagnostic test for ME/CFS**. This committee is currently lobbying for funding for research into/diagnostic test for Lyme; the EU has already given a 2 million euro/dollar grant to develop a diagnostic test for Lyme. Feel free to join in i.e. ask your elected representatives for funding for research into/diagnostic test for ME/CFS.

** https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1001161

 

[GodGenghis]

To quote Davis from https://www.omf.ngo/wp-content/uploads/2018/05/Dr-Ron-Davis-MA-Dept-Pub-Health-April-2018.pdf
But we do believe that it is some sort of systemic problem probably with some central control circuit. It’s a matter of trying to find what is that central control circuit that is messed up in some way. We think there is something going on that locks the patients into this and they can’t get out of it. So if we can figure out what that control circuit is then we can figure out our strategy to unlock it. That is our major effort at the moment because that would possibly mean that we don’t need to develop a drug. There may be ways to manipulate that central circuit to get people out of the disease. We have one primary circuit that we are looking at, at the moment; we should figure out whether that is right by the end of the summer.

So ... is it right?

Ron Davis said: "the important thing to point out is that to do all these things, the rate-limiting step on all of this stuff, is having enough funds to hire enough people to do it".

So, for those who want to help, and can help, please consider donating to www.omf.ngo Every little bit helps.

 

[keepontruckin]

I haven't listened to all the information coming out but I did hear that there are some people who think they have other diseases when in fact they are stuck in the metabolic trap. I did not catch the names of those diseases. But should we be getting that information/awareness out to the people they have identified. Who are those people? Should someone spread the word on their forums? More awareness promotes more funding.

When we write to our political representatives seeking funding, we could mention there are other people who have x y and z disease or ailment who really are similar to cfs and ... If there is a higher probability they have a relative trapped in chronic illness they might be more generous.
Maybe this is something that could be done.

 

[charityfundraiser]

Ron Davis said: "the important thing to point out is that to do all these things, the rate-limiting step on all of this stuff, is having enough funds to hire enough people to do it".

So, for those who want to help, and can help, please consider donating to www.omf.ngo Every little bit helps.

Yes, please. I posted two ways, as easy as AmazonSmile but with 10+ times the payout, for everyone to be able to help regardless of how much money you have to spare, here:
https://forums.phoenixrising.me/ind...se-breakthroughs-possible.61655/#post-1003021

 

[Ben H]

Do you think that means that every single one of the 20 severely ill patients had a mutation of IDO2? I wish they would have specified that

Hi @bctjr1993 ,

This was actually on a slide but the camera did not catch it as it went by, fortunately we kindly have an answer from Prof. Phair:


"On average the severely ill patients have 1.7 probably damaging mutations in IDO2.
Every severely ill patient has at least one probably damaging mutation in IDO2.
Two of the most severe are homozygous for a damaging mutation or have three different damaging mutations in IDO2."


B

 

[FMMM1]

Ron Davis said: "the important thing to point out is that to do all these things, the rate-limiting step on all of this stuff, is having enough funds to hire enough people to do it".

So, for those who want to help, and can help, please consider donating to www.omf.ngo Every little bit helps.

Also, try contacting your local elected representative i.e. request more funding. Here's some https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1001161

 

[Aroa]

How would the fact that there are more women with ME correlate with this metabolic trap hypothesis ?

Any ideas ?

 

[FMMM1]

How would the fact that there are more women with ME correlate with this metabolic trap hypothesis ?

Any ideas ?

Women appear to be importing tryptophan into their cells i.e. as an alternative fuel to glucose [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].

Importing tryptophan into your cells would increase your intracellular levels; possibly enough tryptophan to trigger the trap. Guess.

Men didn't show the same pattern of switching to amino acids like tryptophan as a cellular energy source [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].

One of the amino acids women are using as an alternative fuel is phenylalanine; intracellular levels of phenylalanine appear to be higher in people with ME/CFS:
*1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
*2) full paper: https://sci-hub.se/10.1039/C8AN01437J.

*This method appears to be a potential diagnostic test; consider asking your elected representative to lobby for funding for same https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1001161

 

[sb4]

Apparently there was a tryptophan poisoning event in 1989 which caused a disease known as eosinophilia myalgia syndrome (EMS). It has similar symptoms to ME:

Features of the syndrome include intense, debilitating myalgias and marked peripheral eosinophilia. Vasculitis, neuropathy, and pulmonary involvement also may be observed but are not pathognomonic. Death typically ensues from ascending polyneuropathy with resulting paralysis and respiratory arrest. Treatment involves discontinuation of tryptophan ingestion.

 

[JES]

Are there any other diseases that cause such a metabolic trap?

It's the other way around. The metabolic trap causes the disease, assuming that the hypothesis is true. And predisposition to being stuck in the metabolic trap is acquired by a set of mutations in the IDO2 gene. If you watch the presentation of Robert Phair, all of this is explained. It may also be that diseases like MS or Lupus feature similar metabolic problems. We are only beginning to understand metabolomics and genetics with regards to diseases.

And are there epidemics caused by metabolic traps?

I wouldn't use the word epidemic, because epidemic implies a widespread occurence of infectious disease. None of the documented CFS/ME outbreaks can be considered epidemics.

But the metabolic trap hypothesis in theory is compatible with CFS/ME outbreaks. Robert Phair has specifically looked for common mutations in the IDO2 gene. If the IDO2 enzyme is broken in a significant percentage of the population, then an outbreak can start from a trigger. There recently was a measles outbreak in USA because people refuse to vaccinate their kids. Even when it was only a few % of unvaccinated kids, it was enough for it to spread. You also need only a few % of people with genetic predisposition to the metabolic trap and a small CFS/ME outbreak could start among those people.

 

[sb4]

I have decided to increase my glycine intake for unrelated reasons and I was looking up beef gelatins amino acid profile and found it contains pretty much all amino acids except tryptophan. So perhaps taking reasonable doses of gelatin with meals could help decrease the amount of Tryptophan entering the brain.

You may well have to compensate with NAD+ supplementation and 5HTP as lower Tryptophan would probably lead to lower NAD and serotonin/melatonin.

 

[dreamydays]

Is there any way a 5HTP supplement could be converted back to tryptophan?

 

[pamojja]

You may well have to compensate with NAD+ supplementation and 5HTP as lower Tryptophan would probably lead to lower NAD and serotonin/melatonin.

Or maybe supplementing niacin and directly with melatonin. Which I've done with along with gelatin supplementation.

 

[sb4]

Or maybe supplementing niacin and directly with melatonin. Which I've done with along with gelatin supplementation.

Yeah that's probably better but would you get sufficient serotonin? Also getting melatonin in the UK is a real pain.

Did you take gelatin with niacin and melatonin at the same time? Did you feel better with this?

 

[BeautifulDay]

Hi @bctjr1993 ,

This was actually on a slide but the camera did not catch it as it went by, fortunately we kindly have an answer from Prof. Phair:


"On average the severely ill patients have 1.7 probably damaging mutations in IDO2.
Every severely ill patient has at least one probably damaging mutation in IDO2.
Two of the most severe are homozygous for a damaging mutation or have three different damaging mutations in IDO2."


B

Hi Ben,

Forgive me if I'm repeating a question that was already asked. Is there a list of the potentially damaging variants on IDO2 that were found?

I presume that none of the variants that were found were common variants. Since IDO2 has several potentially deleterious variants (using DANN scores of greater than .995 and that are highly conserved among mammalian), that also happen to be fairly common in the population -- I want to make sure people aren't looking at the common one's if they weren't the ones used in the study.

Thanks!

 

[pamojja]

Yeah that's probably better but would you get sufficient serotonin? Also getting melatonin in the UK is a real pain.

Did you take gelatin with niacin and melatonin at the same time? Did you feel better with this?

Absolutely don't have mood or intestinal motility problems, therefore have to assume to be sufficient. Always got melatonin from heathmonthly.co.uk, but see now they don't have it anymore! An other still carrying it is https://swansoneurope.com/search.html?searchIn=0&phrase=melatonin

I take gelatin and high-dose niacin in the morning for other reasons, and melatonin as sleep-aid before bed.

 

[Moof]

Hi Ben,

Forgive me if I'm repeating a question that was already asked. Is there a list of the potentially damaging variants on IDO2 that were found?

I presume that none of the variants that were found were common variants. Since IDO2 has several potentially deleterious variants (using DANN scores of greater than .995 and that are highly conserved among mammalian), that also happen to be fairly common in the population -- I want to make sure people aren't looking at the common one's if they weren't the ones used in the study.

Thanks!

They were common mutations – they had to be, otherwise we wouldn't see outbreaks of ME that affect as many as 20% of the people exposed. One of the potentially damaging mutations occurs in 55% of the severely ill patients, but also in 42% of the [healthy] European population sampled for the 1000 Genomes project. Another one showed up in 17.5% of the severely ill patients, but 23% of the reference population.

 

[BeautifulDay]

They were common mutations – they had to be, otherwise we wouldn't see outbreaks of ME that affect as many as 20% of the people exposed. One of the potentially damaging mutations occurs in 55% of the severely ill patients, but also in 42% of the [healthy] European population sampled for the 1000 Genomes project. Another one showed up in 17.5% of the severely ill patients, but 23% of the reference population.

Thanks Moof! I'll need to study this thread this weekend to catch up on the theory and science behind it.

BTW! Thanks everyone who contributed to this thread and who attended the conference. Great information! Lots to digest.

 

[Ben H]

Hi Ben,

Forgive me if I'm repeating a question that was already asked. Is there a list of the potentially damaging variants on IDO2 that were found?

I presume that none of the variants that were found were common variants. Since IDO2 has several potentially deleterious variants (using DANN scores of greater than .995 and that are highly conserved among mammalian), that also happen to be fairly common in the population -- I want to make sure people aren't looking at the common one's if they weren't the ones used in the study.

Thanks!

Hi @BeautifulDay

Yes there is a list, it is in the Symposium on a slide when Prof. Phair is presenting, will try and dig it up.

Some of the variants were indeed very common, @Moof has explained.

This lends itself to help explaining facets of the outbreaks very well-not forgetting the huge amount of people with mecfs (even if it is a spectrum disease and usual caveats/mis-diagnosis) in general.

Still a hypothesis though atm, albeit a promising one for sure.


B