Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci, 2022,Hajdarevic et al

Information on the TPPP variant associated with ME/CFS can be found here : https://www.ncbi.nlm.nih.gov/snp/rs139264145

Nothing interesting stands out. The variant hasn't been cited in any publications (yet seen by the software). It doesn't seem to be a rare variant. Nothing is known about its clinical significance.

It's an intron variant. Introns can affect gene expression but not the structure of the protein. For this reason introns haven't been studied as much as exons which are the part of a gene that describes the structure of the protein.

 

An article that explains what TPPP does

Tubulin polymerization promoting protein 1 (TPPP1)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925458/

 

I might add that together with some other groups I am of the view that tubulin assemblies may well be where all conscious experience of the world occurs. If you like tubulin assemblies are our virtual reality goggles - but for the real world.

I don't think that would mean that a problem with tubulin assembly would produce 'unreal' experiences. I think it more likely that basic homeostatic mechanism are dependent on the tubulin assemblies being serviced and recalibrated regularly (e.g. at night, but also over days, months, years). If that does not happen all sorts of defence mechanisms may be activated - neural, immune or whatever. But since there is actually nothing wrong outside these activations may appear to occur in a vacuum without expected signs of what is triggering them.

 

I might add that if ME relates to a log jam in tubulin servicing via TPPP then it might be good news. There is no evidence for any progressive damage to tubulin assemblies in ME in the way that there is clear evidence in Alzheimer's. I have a strong impression that PWME retain full mental faculties despite brain fog and so on.

So to make an analogy with gas boilers I have recently known: it is not that the heat exchanger has rusted through and leaking water onto the wooden floor (London house), for which there is no solution, but that the water temperature regulator has got clogged and keeps turning the heat off even when it is cold (Suffolk house). Sprucing up the regulator sorts things out nicely.

If there is a gene variant that makes ME more likely it is not in itself enough to cause the problem. Something must have been tripped by some event, which is more difficult to put right with the gene variant. But if we knew what needed putting right it might well be possible to make it less difficult.

 

Thank you very much.

 

Hard to know for sure.

One thing I do know for sure is that having a good night sleep doesn't prevent delayed PEM at all.

 

Sometimes I find delayed PEM, even with rest, can paradoxically get worse over several days following its onset. Often when this happens it is when PEM feels most like a virus or a hangover. It can have a sense that my body thinks there is something it needs to get rid of, rather than a lack of something. Then it may build up to a severe migraine like headache which worsens till I vomit and/or have explosive IBS, when sleep becomes possible and then with rest my PEM begins to subside.

Sometimes PEM feels like a lack of something but other times it feels like a build up of something that should not be there. Could problems relating to a specific protein metabolism result in a shortage of something or an excess or unwanted presence of something or a combination of both?

 

This is what has just been happening to me this last week. :/ It gets worse over several days and sort of peaks until it starts to slowly improve. It feels like a process that cannot be stopped, or like being drugged or poisoned. I feel like you "turn the corner" on it eventually after days of getting worse a bit like a fever when it eventually breaks. I wonder what is going on.

 

my bolding

yes ... there is a delay of 24-36 hrs before between the over exertion and PEM starting. But day 1 of PEM is never the worst, day 2 is worse, day 3 is hell but it usually reaches its zenith on day 3 for me, then the number of very bad days before recovery begins depends on quality of rest im able to get and how major the over exertion was that triggered it.

 

I've shared elsewhere on the forum how anxiety/anger and the resultant significant improvement in all symptoms (assumed to be from adrenaline release) can fool me into thinking i better than i am - and therefore sometimes wrongly believe that the bout of PEM is over leading to further activity instead of rest, leading to worse PEM later.

Just wondering how adrenaline (or some other process/signalling triggered by the sympathetic nervous system response) might affect the tubulin processes.

@Jonathan Edwards is there a way for that to fit in, or to be explained within the tubulin/ TPPP issue we're discussing here (lol sorry dont know what to call it, the details of all this are a bit beyond me!)

 

Hopefully you'll get a better answer than this.

Not sure if you noticed this comment from Jonathan (previous page):
"I think its effects may only be found within cells. So yes, this would explain exactly why the mechanism of me is so hard to observe. Tubulin is a polymerising protein that probably does not occur much in fluid compartments and if it does any changes in the TPPP gene may not affect levels. Tubulin is all about solid phase information, not fluid phase."

However, I think I'd agree with your point "would there be any signals that could be measured. For example, are there particular proteins produced during the process that would change. Or direct effects on the way nerve cells work (something that could be measured (say electomagnetic signal))."

I'm wondering if something else would be changed as a consequence and that could be used as a biomarker.

Also, if this e.g. identifies a sub-group then that group could be looked at in more detail i.e. to identify a biomarker.

 

TPPP sounds like it could have something to do with cadherins. At least this article says that cadherins interact with microtubules.

https://www.ncbi.nlm.nih.gov/books/NBK6079/

Some background information: cadherins and the cell skeleton have come up in other studies before and no one seems to know what to make of that. TPPP seems to roughly fit with this "structural components of cells" theme.

 

There is bound to be a way to fit it in but the question is whether it adds a further 'aha' to the story.
I am a bit preoccupied with other things today but will come back to this. It is only a speculation but it has some theoretical attractions.

 

I've had an interesting experience. I went on holiday with a mobility scooter. The first week, with no responsibilities or energy spent I was feeling relativity well, clear headed. I left the resort once to go to Dubai Mall for 4 hours on a scooter. I forgot there would be thousands of people there! Mentally shattered at the end.

PEM next day. Tracker stable first week to all over the place the second. Hungover. Unable to get up and about even on the scooter. I would drink orange juice and feel worse. I also developed what I think was Polymorphic Light Eruption the second week even though I stayed in the shade for the two weeks.

 

Does anyone think that PEM is more likely to occur in "new" situations? Situations that are not a relaxed routine but where you're learning? They don't have to be stressful in a bad way, they can be pleasant and exciting too.

I am not sure but have the suspicion that being in an new situation makes the brain do extra work which could be a PEM exacerbating factor.

 

Given that the SNP was only found in 2.5% of patients (of the Norwegian cohort), vs 0.5% of controls, at most this is a weak risk factor and we need to be a bit more creative with our hypotheses to explain what might be going wrong rather than saying TPPP function is disrupted due to to this SNP, when in most patients it is not.

 

I don't think anyone was saying that this SNP would account for most ME.
I see it as a bit like C1q deficiency, which accounts for a tiny proportion of cases of lupus but provides a hugely powerful piece of evidence for the importance of complement in the genesis of lupus.

It turns out that there are a number of other ways to get C1q to malfunction in lupus, probably mostly not genetic. There might be lots of other ways to get tubulin assemblage to malfunction - which again may not be genetic. But if thee is a genetic weighting to a variant in TPPP that ought to be telling us something very important.

 

Which is?
(trying to coax you into suggesting some speculative hypotheses)