Speculations about the genetics of ME/CFS and DecodeME

[Sean]

I think you need to know when patients are close to it. Knowing that accurately would be a key test to timing different intervention strategies. It's critical.

Definitely important. But...

My experience is that PEM is a permanent feature. It is always there, all that changes is how hard it is cranked up.

It is also a non-linear response, I think, which is part of why it is difficult to learn how to predict and manage.

Even the best management of it is only going to reduce the impact, which is good as far as it goes. An actual cure will require fixing the underlying problem driving PEM.

 

[Kitty]

It is also a non-linear response, I think, which is part of why it is difficult to learn how to predict and manage.

This! I was trying to say something about it when I was waffling about food yesterday, but couldn't muster a string of words that made sense.

 

[MelbME]

Definitely important. But...

My experience is that PEM is a permanent feature. It is always there, all that changes is how hard it is cranked up.

It is also a non-linear response, I think, which is part of why it is difficult to learn how to predict and manage.

Even the best management of it is only going to reduce the impact, which is good as far as it goes. An actual cure will require fixing the underlying problem driving PEM.

There is very little research on it at this stage. What you've described means it's not simple and likely multi-factorial, which I appreciate and is likely true.

Patients currently control exertion of skeletal muscles, some thinking and sensory processes (dark room, reduce noise, etc). But there are internal processes they do have control in over exerting. These are sympathetic drive, immune activation, adrenaline dumping processes (MCAS, POTS), etc. Then there is the fact that energy recovery processes can vary between people.

Even if PEM was a linear process of occurring over a certain level of exertion (not saying it is). It would still appear non-linear because a patient can only control a few factors of exertion.

Agree on the cure or best treatment opportunity being a fixing of PEM.

 

[MelbME]

This isn't really the right place for this, but as I always forget when it is the right moment, here goes!

It's worth bearing in mind that food can have an impact on the likelihood and severity of PEM in some of us. And if research participants need to travel or stay away from home to take part, or will need lunch because it's a full day in clinic, they're likely to vary their eating routines.

It might not even be relevant in the type of work you hope to do, but maybe it's worth adding to the list of questions to ask at the planning stage: do we need to encourage participants to eat their usual food at the usual time, and try to make sure it's feasible for them?

Great point and definitely something to consider. We're really trying to transition as much research to the home as possible because of these types of reasons. Of course CPET or imaging based studies still can't unfortunately.

Very interested in trying to get telehealth and home visits as being more common place for MECFS patients in Australia too. I think this is an important part of improving the care pathway that can be worked on now.

 

[Yann04]

There is very little research on it at this stage. What you've described means it's not simple and likely multi-factorial, which I appreciate and is likely true.

Patients currently control exertion of skeletal muscles, some thinking and sensory processes (dark room, reduce noise, etc). But there are internal processes they do have control in over exerting. These are sympathetic drive, immune activation, adrenaline dumping processes (MCAS, POTS), etc. Then there is the fact that energy recovery processes can vary between people.

Even if PEM was a linear process of occurring over a certain level of exertion (not saying it is). It would still appear non-linear because a patient can only control a few factors of exertion.

Agree on the cure or best treatment opportunity being a fixing of PEM.

Very happy to see you mentioning the “adrenaline dump” or “adrenaline rush” phenomenon a lot of us experience. It’s criminally underreported in the lieterature, I only know of one ME study in english that mentions it, and mostly in passing.

 

[MelbME]

Very happy to see you mentioning the “adrenaline dump” or “adrenaline rush” phenomenon a lot of us experience. It’s criminally underreported in the lieterature, I only know of one ME study in english that mentions it, and mostly in passing.

Well the care model for patients we have built up in our head is about energy preservation and we see pacing and medications to help curtail uncontrollable energy dumps as critical to that.

If you reframe the perspective around energy conservation like we do then it becomes clearer.

Energy drags: controllable exertion (movement, cognitive tasks, sensory input), uncontrollable exertion (infections, adrenaline dumping co-morbidities, overactive immune, sympathetic drive elevated)

Reduced energy provision: reduced blood flow, poor digestion and dietary substrate provision, mitochondrial inefficiency.

From this perspective PEM could simply be dropping below an energy threshold where certain vital organs drastically reduce function which is reversible but has consequence to restarting energy production systemically. Kidneys is a prime target since the gradient of substrate reabsorption needs to be maintained by a certain energy threshold. But liver could certainly also be impacted.

Anyway, this is our broad working idea for some time.

 

[Sean]

But there are internal processes they do have control in over exerting.

I think there is a 'not' missing from that sentence.

Otherwise, yes, there is a lot going on we don't have control over. It doesn't matter how carefully I manage my activity patterns, I still end up being knocked for six at random by unpredictable flare ups.

 

[Kitty]

Very happy to see you mentioning the “adrenaline dump” or “adrenaline rush” phenomenon a lot of us experience.

Energy drags: controllable exertion (movement, cognitive tasks, sensory input), uncontrollable exertion (infections, adrenaline dumping co-morbidities, overactive immune, sympathetic drive elevated)

I've no idea what's actually happening in the body, but for me the adrenaline pump feels like the backup battery kicking in.

I don't get it unless I've overexerted, and one of the problems is the inability to switch it off when the 'emergency' (i.e., trying to complete a mundane task rather than leave it half finished) is over. Nine hours later I can't sleep because the wretched thing is still going.

 

[Trish]

Nine hours later I can't sleep because the wretched thing is still going.

Yes, the 'tired but wired' sleepless night(s) I experience as an early stage of a crash.

 

[MelbME]

I've no idea what's actually happening in the body, but for me the adrenaline pump feels like the backup battery kicking in.

I don't get it unless I've overexerted, and one of the problems is the inability to switch it off when the 'emergency' (i.e., trying to complete a mundane task rather than leave it half finished) is over. Nine hours later I can't sleep because the wretched thing is still going.

Well adrenaline doesn't create energy, it pushes you to use more though it makes substrates of energy (like glucose and fatty acids) more readily available.

 

[Kitty]

Well adrenaline doesn't create energy, it pushes you to use more

That's interesting—though I guess not surprising. It might have a significant role in contributing to PEM, especially as once it starts, it's difficult to switch off.

I don't know to what extent the latter's abnormal, though. I seem to remember it being difficult to settle for a long time after an adrenaline kick before I got ill.

 

[EndME]

Is the term "adrenaline" not simply being used because patients think that is what it may feel like, not because adrenaline actually bares any relevance?

I think at those times it better to avoid medical terminology, even though most of us might know what is being referred to and maybe we should come up with a better and more accurate terminology. I think we should be careful referring to different things as "adrenaline dumps", "energy", "ATP" etc. In particular I wonder if we can maybe uncover more of what might be going on if we drop these kinds of terminologies and go back to the drawing board to describe what one is experiencing in more layman terms.

 

[forestglip]

Isn't there an issue of scientists avoiding even entering the field because of lack of research funds? Where they don't want to devote their life to something where every grant will be rejected?

Quote from an interview with a researcher, Tina Katsaros, in Breakthrough magazine, Autumn 2024:

"Where do you see yourself five years after completing your PhD?
I would love to stay in ME/CFS research, but funding can be challenging to come across – which is why it’s so amazing that there are organisations like ME Research UK that help to fund the research. Ideally, five years after my PhD, I will be doing a post-doc somewhere that allows me to continue ME/CFS research, and, who knows, maybe even a fellowship."