Ah! Gotya. Thanks for clarifying.
Ah okay, thanks for clarifying. I think a lot of the pushback comes from myself and several others on the thread interpreting the comment below and others from your posts as you arguing against a unifying mechanism. [Edit: I think everyone here is on board with the idea that rare variants could contribute strongly to someone developing ME/CFS]
See below.
There are going to be more new ME/CFS cases if people get infected far more often than they used to. That’s different from covid having an increased rate of new onset ME/CFS compared to other viral infections.
I don’t understand what you mean «pathway to ME/CFS». Can you clarify?If mitochondrial dysfunction is only one pathway to ME/CFS, you’d expect related findings in just a subset of cases; not seeing it in everyone doesn’t refute the hypothesis. In heterogeneous cohorts, rare events like rhabdomyolysis could be missed (could be underpowered for this group of folks, testing to see the issue could be time-point specific, etc.). I’m not claiming it’s common or even proven; only that its absence at group level doesn’t disprove the hypothesis. I looked hard at rhabdo for a while, and there are case reports of rhabdo in ME/CFS/Long COVID patients - one I recall was an autopsy case from the UK; there were some other mentions on reddit and ME/CFS long hauler sites. So like all of these; they remain to be proven, but IMO anywayremain a plausible, if uncommon, path.
Good question. Reduced ability to generate ATP. If that was the case, we’d have seen it on the day 1 CPETs. Those results are about normal.
I’m not sure I understand what you mean by rare causes of ME/CFS.
Hi Liz, I'm Daniel Missailidis, a postdoc cell biologist who has worked on ME/CFS going on 11 years now. I wrote one of the papers you linked (my PhD training was as a mitochondrial person). We have several different omics datasets and a lot of data from cell lines from people with ME/CFS using various functional assays, particularly mitochondrial ones. This includes a mountain of unpublished data that we are working through. If you are interested in doing anything with omics or functional data from fibroblasts, LCLs or PBMC from people with ME/CFS maybe shoot me an email at D.Missailidis@latrobe.edu.au and we can potentially have a chat with my lab head Sarah Annesley included. We're very open to data sharing and collaboration.
I have thought this for years.
That would definitely be interesting! There have been some twin studies in the past, but I believe those we all before WGS was a more common thing.
I’ve volunteered before but I’m an identical twin with me/cfs, where my brother is healthy. Please contact me if you do this!
Ahh, let me try to clear it up then; I’m not arguing against the idea of a unifying mechanism in a broad conceptual sense. What I’m saying is that I don’t think there’s a single tractable specific mechanism that explains ME/CFS across all patients.
.Definitely interested!
Sorry if I am messing up the links admins! Will try to do better there once I get my head around it
.This is brilliant!!
Yes 100% and we did try to recruit folks in families for exactly that reasonThanks very much for engaging with the forum, @LizWorthey! Great to have you here.
On your above point, would it be worth trying to recruit online people with multiple family members with ME/CFS who have already had their genome sequenced via 23andMe or whatever? Maybe commercial testing isn't good enough, though, or maybe some bias will be introduced in this way. I don't know enough about it.
Or, if better-quality sequencing is needed and no money is easily/rapidly available via grants, how about a crowdfunder? I can see one being very successful, since we wouldn't be talking about hundreds of thousands, presumably, and people are keen on genetics after DecodeME. Speed is of the essence. We all want our lives back (you included!).
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. Happy to chat further.
Thanks for explaining more. I think I get where you're coming from, there's just residual confusion from us understanding the same term to mean different things. For understanding the illness itself I think it comes down to understanding what is the feedback loop driving the chronic disease state. Genes can predispose to falling into that loop, or help keep you in the loop once you get stuck, or modify how that loop presents phenotypically. Around that main point it seems like we may be in agreement, it's just the tricky matter of sorting out how or if any one gene might be involvedAhh, let me try to clear it up then; I’m not arguing against the idea of a unifying mechanism in a broad conceptual sense. What I’m saying is that I don’t think there’s a single tractable specific mechanism that explains ME/CFS across all patients.
What I thought was initially being raised was a single unifying mechanism - everyone has exactly the same underlying defect type of thing. But then the discussion moved to make me think that the suggestion was that there are multiple mechanisms all rolling up to a shared downstream effect; and that I could get behind; though to be clear those very high level mechanisms are often not what you need when you are thinking translationally towards treatments... I’m also new here and this is off our paper, so part of me was trying to strike a balance and not come on too strong
It also seems to align with how e.g. DecodeME describes their findings; they explicitly say ME/CFS “is likely to involve multiple distinct biological processes” - and avoid proposing a single causal mechanism. Their top signals span immune, neuro, and stress pathways, suggesting (depending on how you think on it) that there are either diverse mechanisms converging on a shared "endpoint", or that each are parts of a single unifying process; e.g. something like dysregulated immune signaling in response to physiological stress. A bit of semantics really IMHO. [Edited to be clear that I'm not saying it is immune; just giving this as an example].
Does that help clarify? TLDL I believe there are many mechanisms (how many depends on what you define as a mechanism, but the potential to keep rolling up until you get to a high level "single" unifying mechanism (maybe : ).. ).
Yes, exactly; that’s what I was trying to get at too. It’s hard to meaningfully debate whether there’s a “single unifying mechanism” without first defining what we mean by the term. I suspect as much of the lack of clarity stems from differing interpretations of “mechanism” as it does “unifying”. And of course, that’s a separate issue from the equally important questions re effect sizes, genetics, and inheritance
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I can't remember if DecodeME asked about whether we had rellies with ME/CFS, including rellies in DecodeME itself, which would allow just those people to be WGS'ed?
