Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation, 2025, Birch, Younger et al

[Utsikt]

It is specifically a worsening of the sort of symptoms found in ME/CFS and is not only unexpectedly delayed but unexpectedly prolonged. There is a step change down for an extended period.

I think this is key - if we count all kind of delayed symptom worsening as PEM, you’d have to include e.g. delayed onset muscle soreness - meaning that everyone experiences PEM.

 

[LizWorthey]

I really appreciate you continuing to engaging here. I can definitely see the utility from your perspective and understand how your background leads you there. I guess my experience comes from doing a lot of omics analysis myself and seeing first hand how much overfitting and lack of generalizability can so easily lead people become convinced that noise is real biology.

(Mods feel free to move this discussion back to the original thread to avoid derailing)


I guess that’s the core assumption here—I don’t think the pathogenic variant does actually explain all of their phenotype. When I was looking through each of the heterozygous variants individually, the evidence was very weak for heterozygous variants really ever presenting with the set of symptoms that were listed (which, correct me if I’m wrong, were the symptoms of the homozygous disease not the heterozygous state). Plus I have reason to be skeptical just knowing how thoroughly specific symptoms can get watered down in diagnostic descriptions—flu-like malaise of PEM is not the same as exercise intolerance of some cardiac disorders but they could easily be made to sound the same. [edit: And, like I’ve said previously, it’s possible that you’d frequently find variants to “explain” a phenotype that is already explained by another chronic disease if you looked outside of ME/CFS.]

It doesn’t need to be ignored because it’s rare, it just needs to be held with a lot of skepticism because the way that the analysis is designed will inherently present you with plausible candidates to explain away [edit: part of] someone’s phenotype even though there’s a good chance the variant explains nothing. So there’s no way to differentiate between what’s a variant that reveals real important biology and what’s an expected blip that is just reinforcing confirmation bias.

Given the sheer number of identified genetic disorders, the number of potentially pathogenic variants everyone walks around with, and the number of different symptoms in ME/CFS you could possibly match with a variant, it just seems to me that the odds are substantially more skewed toward irrelevance so you need some reliable way of discerning that before dedicating resources

but I guess the comparable case is lupus—if we went back in time and approached that heterogeneity as evidence against a uniform disease process, you’d just be sending research down endless rabbit holes. Could genetic heterogeneity be important in understanding why someone might be more likely to end up with some symptoms of lupus and not others? Sure. But establishing that definitively would require a massive cohort, because otherwise it’s just likely to give you the same confirmation bias.

The reason to think a unifying disease process is more likely than a scattering of various genetic contributions in ME/CFS is that the core of a chronic disease is a self perpetuating disease mechanism. In autoimmune disease that’s antibody (Jonathan on this forum was part of first hypothesizing and proving that). In hypertension it’s the feedback loop between mechanical damage of blood vessels and cytokines responding to that damage. In all those cases genetics do contribute to the likelihood of falling into a disease state and may well contribute to quirks of how it manifests—but unless it’s a monogenic disease you cannot attribute the maintenance of the disease state to those variants.

[Edit: so the TLDR is that genetic heterogeneity could well be important and explain outliers/subgroups in data, but that is to be expected with any chronic disease mechanism (frankly you expect that heterogeneity even in data from mouse clones raised in the same environment). The genes that contribute to someone’s deviance from other ME/CFS cases are relevant, but ultimately there’s no reason to believe the relevant genes interacting with a larger causative mechanism are the same genes identified due to symptom overlap with monogenic illnesses]

Rare disease geneticist here. Just wanted to say thank you for this work, it is really valuable. It would be super helpful to have a sense of prevalence of individuals who fit ME/CFS criteria who actually have a pathogenic variant for known rare genetic disorders, and only way this is possible is through painstaking variant classification process.

Thank you. I agree; I'm really hoping this careful review is part of the big well supported studies. We are also looking into how to access existing datasets since we have some ways to make the process much more efficient (though still requires that painstaking process at some point). If you know someone who has access to that data would love to collab with them.

 

[LizWorthey]

Have you read our PEM fact sheet? PEM is not just worsening of symptoms.

Love the fact sheet; thanks! I over simplified here, which I shouldn't have. Sorry .

 

[LizWorthey]

I agree with most of this, and we explicitly said we should do exactly what you suggest: validate it, prove it. Chronic diseases are often best approached through unifying biology; overfitting is a real risk in small studies; large cohorts are essential to define shared mechanisms. That said, many large studies fail to replicate or yield robust signals when covariates and population substructure aren’t handled properly. It’s also frustrating when analyses ignore large-effect variants; there are established (though not always perfect) methods to integrate rare, large effects with common, small ones as I'm sure you know .

We just think that as we hunt for those unifying mechanism, we need to recognize that if we choose one, there absolutely can be very heterogeneous yet convergent molecular underpinnings and frequency of the variants shouldn't be a clear-cut threshold.

Take cardiomyopathy. A plausible unifying process is mechano-energetic failure of cardiomyocytes, with many upstream defects converging on it: sarcomere abnormalities, cytoskeleton/desmosome disruption, ion-handling defects, and metabolic or storage disorders. Some patients have a single, large-effect rare variant in one of dozens of genes (e.g. LMNA) sufficient for disease. Others develop cardiomyopathy via acquired factors; alcohol, autoimmune/inflammatory injury, viral infection, nutritional deficiency, often on a background of unrecognized genetic susceptibility. Still others carry moderate-effect variants that require a second hit (e.g. TTN plus anthracyclines), precipitating cardiotoxicity and the same mechano-energetic failure.

With autoimmunity a unifying process might be loss of self-tolerance. Convergent inputs could include impaired central/peripheral tolerance, aberrant antigen presentation, complement/apoptotic-cell–clearance defects, cytokine-signaling imbalance, barrier dysfunction, metabolic/mitochondrial immune rewiring. Some patients harbor single, large-effect variants in monogenic autoimmunity genes sufficient for disease, but sometimes with complex, variable presentations (e.g. FAS). Others develop autoimmunity through complex paths with roles for infections, microbiome shifts, hormonal transitions, or environmental exposures (smoking, silica, drugs), as well as molecular risk factors (e.g. HLA-DRB1, TG, PTPN22). Still others carry moderate-effect variants (CTLA4) that, with a trigger can tip the system into overt autoimmunity and the loss of self-tolerance process.

My point is that rare (and not-so-rare) variants matter. A pathogenic variant shouldn’t be dismissed simply because it’s uncommon or high-effect; doing so risks missing real biology. And totally agree on the need for rigor; I’m arguing against reflexive disregard (not that you are doing that).

 

[jnmaciuch]

I definitely understand that genetic variants are very important for understanding disease, we’re making the same points there.

I guess my concerns all boil down to: this specific individualistic method of pulling out (largely heterozygous) variants by cross-referencing with symptoms of (largely homozygous) genetic disorders seems particularly poised to generate many more red herrings than variants that actually contribute to the things you’re describing. So talking about the virtues of considering individual genetics is a truism that’s kinda beside the point when the issue is that we don’t have reason to trust an individualistic method like this to actually yield that useful information. Without a robust context-specific base of information to define subtypes a priori, incorporating a method like this into studies just sets the stage for making more guesses about pathology to explain away outliers or disappointing results from testing a guess about pathology. Am I making sense there?

[Edited for clarity]

 

[LizWorthey]

I think this is a misunderstanding of PEM. Like a lot of clinical concepts PEM is badly defined and described but I don't think it can be reduced to delayed post-exertional worsening of symptoms. It is specifically a worsening of the sort of symptoms found in ME/CFS and is not only unexpectedly delayed but unexpectedly prolonged. There is a step change down for an extended period.

As you may see from other threads I would not consider dysautonomia, POTS, EDS/HSD (or 'mast cell activation syndrome) as ME/CFS-like diagnoses. They are all dubious concepts based on unproven mechanistic assumptions. They are largely categories used in fringe medicine that I don't think we should get involved in. Fibromyalgia is so vaguely defined that I doubt we have any useful information about whether it can be said to include PEM. A lot of people with ME/CFS would fit fibromyalgia criteria.

I spent my life looking after people with autoimmune disease and I did not come across people with what I regard as ME/CFS PEM. I doubt there is any useful information in this are either because so much of what is written is anecdotal and again from physicians on the fringe. My opinion is also anecdotal but I don't think the literature is reliable on this. A key difference is that for most other illnesses symptom patterns make reasonable sense in terms of what we know about pathology. For ME/CFS they don't really make sense in terms of any pathology we can conceive of - neither metabolic nor inflammatory. Something very different seems to be going on.

I agree that a wide range of genetic defects in different pathways may turn out to be linked to a syndrome like ME/CFS but I don't see that as likely to indicate that the clinical features do not reflect some common causal segment into which different pathways may feed. I don't see it as likely that symptoms arise directly either from ion homeostasis or synaptic signalling or... whatever. The symptomatology of ME/CFS is not generic or vague. It is very specific and very different from any other condition I am aware of, even if that is not very well explained in the literature.

Thanks; definitely defer to you on the criteria and autoimmunity. I used to be a card carrying immunologist; not for a long time though. The last point you make here is exactly the point I'm trying to make (maybe not very well); the higher level pathomechanism/defect can be shared/the same even when the specific defects are varied. Many paths I could see that could end in PEM.

 

[LizWorthey]

I definitely understand that genetic variants are very important for understanding disease, we’re making the same points there.

I guess my concerns all boil down to: this specific individualistic method of pulling out (largely heterozygous) variants by cross-referencing with symptoms of (largely homozygous) genetic disorders seems particularly poised to generate many more red herrings than variants that actually contribute to the things you’re describing. So talking about the virtues of considering individual genetics is a truism that’s kinda beside the point when the issue is that we don’t have reason to trust an individualistic method like this to actually yield that useful information. Without a robust context-specific base of information to define subtypes a priori, incorporating a method like this into studies just sets the stage for making more guesses about pathology to explain away outliers or disappointing results from testing a guess about pathology. Am I making sense there?

[Edited for clarity]

Yes agreed; and yes I do think you are making sense and we are saying a lot of the same thing.

I'd respectfully say that this: "pulling out (largely heterozygous) variants by cross-referencing with symptoms of (largely homozygous) genetic disorders" isn't actually what we stated. We have 4 participants with heterozygous variant with increased disease risk/symptoms/aberrant results published as requiring only one heterozygous variant, 6 cases with heterozygous variants causal for mendelian disease published as requiring only one heterozygous variant, but homozygous/compound heterozygous versions of the disease also seen, and 7 cases with heterozygous variants published indicating that mendelian disease requires homozygous/compound het variants, but where heterozygous effects aberrant results or symptoms have been documented. Now we do have multiple family members in there as noted and discussed so that is a bias. And I'm not saying these variants are even the only thing contributing genetic or otherwise.

But my point is that we can take those large datasets and pull out the rare large effect variants and analyse/interpret them n-of-1 AND do the case-control studies. Often others talk like these are competing approaches.. Do both. : ). And set up the case-control explicitly looking for both rare large effect and common cumulative effect variation.

Would be interested, truly, on folks thoughts on this patient: a history of "crashes" and day/week long impact on mental and physical capabilities following pediatric and young adult common 1980s viral infections; childhood and adult periodic exercise intolerance; myalgias, muscle cramps, TMJ during times of notable stress, bouts of gastrointestinal complaints lasting weeks since teenage years; consistent hyperlipidemia since 20s despite a healthy lifestyle including years with v. low animal fats and v. low red meat; acute fatty liver of pregnancy with hemolysis and elevated liver enzymes and hepatic steatosis - a pregnancy that they never really got back to health baseline from; fibromyalgia, PEM, ADHD, chronic fatigue, brain fog, muscle weakness, night blindness and light sensitivity, rapid 6 month loss of vision acuity, hematuria/nose bleeds/hemoptysis, sleep hypopnea, increased severity of infections/length of infections/number of infections, migraines, and palpitations following severe (not hospitalised) Covid infection in early 2020, with Long COVID/ME/CFS diagnosis. What of these symptoms might you see as being associated with the presence of the most common pathogenic variant in the mitochondrial trifunctional protein HADHA associated with fatty acid oxidation defects (of note with the baby also having the same variant)? Any thoughts would be great as this is the type of thing we see in some of our participants and teasing it out isn't always easy or clear.

 

[jnmaciuch]

We have 4 participants with heterozygous variant with increased disease risk/symptoms/aberrant results published as requiring only one heterozygous variant, 6 cases with heterozygous variants causal for mendelian disease published as requiring only one heterozygous variant, but homozygous/compound heterozygous versions of the disease also seen, and 7 cases with heterozygous variants published indicating that mendelian disease requires homozygous/compound het variants, but where heterozygous effects aberrant results or symptoms have been documented.

I think your table might have a problem with every reference number being for the wrong paper. I wanted to go through and read your references to see what I was missing since the majority of my searching found that heterozygous individuals for those identified genes did not have strong evidence of having the same symptoms of homozygous disease outside of one or two case studies specifically noted as being unusual.

 

[jnmaciuch]

But my point is that we can take those large datasets and pull out the rare large effect variants and analyse/interpret them n-of-1 AND do the case-control studies. Often others talk like these are competing approaches.. Do both. : ). And set up the case-control explicitly looking for both rare large effect and common cumulative effect variation.

I suppose this point will have to wait for confirmation of what exactly the evidence is that the heterozygous mutations do present with those laundry lists of symptoms, since mostly what I was finding was that the homozygous state might look something like ME/CFS but the heterozygous state largely tends to just present with something like increased risk of bone fracture (like SLC12A3, which was called "definitive pathogenic" in your table). Because unless those claims are very well established, this n-of-1 approach doesn't add useful information

The symptoms listed for many of these disorders sound like they deviate quite a bit from ME/CFS descriptions even considering its heterogeneity (jaundice and splenomegaly?). If these descriptions truly describe the phenotypes of each of those participants to a T, it's not so much proving that ME/CFS is an issue of lots of different genetic issues converging to the same phenotype as being a worry of this specific cohort not being well adjudicated

 

[LizWorthey]

I suppose this point will have to wait for confirmation of what exactly the evidence is that the heterozygous mutations do present with those laundry lists of symptoms, since mostly what I was finding was that the homozygous state might look something like ME/CFS but the heterozygous state largely tends to just present with something like increased risk of bone fracture (like SLC12A3, which was called "definitive pathogenic" in your table). Because unless those claims are very well established, this n-of-1 approach doesn't add useful information

The symptoms listed for many of these disorders sound like they deviate quite a bit from ME/CFS descriptions even considering its heterogeneity (jaundice and splenomegaly?). If these descriptions truly describe the phenotypes of each of those participants to a T, it's not so much proving that ME/CFS is an issue of lots of different genetic issues converging to the same phenotype as being a worry of this specific cohort not being well adjudicated

Sorry think you are conflating the two items I wrote; probably because they were in the same response from me, I think. The "laundry list of symptoms" was from a single patient with ME/CFS/Long COVID with a pathogenic Mito variant not Gitelmans and/or the other findings. Any thoughts on the role given that variant and those symptoms is what I'd really love to get peoples opinion on. Not for the paper per se, but in general . Any thoughts there would be fab.

And we will have to respectfully disagree. N-of-1 is a critical, but not the only critical step I think.

Can you comment more on "specific cohort not being well adjudicated". The adjudication is discussed. It's small sampling, but it's a good cohort.

 

[LizWorthey]

I think your table might have a problem with every reference number being for the wrong paper. I wanted to go through and read your references to see what I was missing since the majority of my searching found that heterozygous individuals for those identified genes did not have strong evidence of having the same symptoms of homozygous disease outside of one or two case studies specifically noted as being unusual.

There was renumbering of refs in the edit phase; not sure if that is captured in the pre-print. I will check (should have already, but have been sick).

 

[jnmaciuch]

Sorry think you are conflating the two items I wrote; probably because they were in the same response from me, I think.

No, sorry for not being clear, I was talking about the symptoms attributed to the variants in your table

And we will have to respectfully disagree. N-of-1 is a critical, but not the only critical step I think.

I think the core of the disagreement is the level of uncertainty that the identified variants from an n-of-1 analysis actually explain any of the symptoms identified when the participant does not have the specific genotype well-documented to present with those symptoms. It seems like you feel very confident in the variants and the listed symptoms, but I am even less so after trying to look into the references. I am seeing several instances where the given genotype is not expected to show up with the symptoms listed for that variant.

My worry is that n-of-1 are very likely to turn up is random variants that may have no impact whatsoever on the persons actual symptoms despite seeming like they couldnt relevant. If there is a way to get much more grounded support for the relevance of variants found in this way I’d be happy to see that data

Can you comment more on "specific cohort not being well adjudicated". The adjudication is discussed. It's small sampling, but it's a good cohort.

As I think someone else may have said earlier, if there is another feasible explanation for all a person’s symptoms then the ME/CFS diagnosis is not appropriate to give. In which case their appearance in your cohort is a case of actual misdiagnosis, not evidence that ME/CFS is a convergent disease presentation from lots of different genetic abnormalities.

Any thoughts on the role given that variant and those symptoms is what I'd really love to get peoples opinion on.

I think the whole point is that you can’t know the direct contribution of a variant unless there is a specific treatment for that genetic disease you could administer. What I’m getting from looking up heterozygous mutations for HADHA is a small number of case studies noting even in the title that having those symptoms while heterozygous is atypical (and unlike that participant are all for compound heterozygosity).

So for a case like you present, the possible impact of that variant will always be just a guess. It could be a guess that’s good enough to inform clinical practice and try to help symptom management. But if you’re trying to move from that guess to something like trying to explain an apparent subgroup in a small study for a biomarker or explain a non-responder in a trial I would not consider that information to be robust enough to draw any sort of conclusions.

 

[Jonathan Edwards]

With autoimmunity a unifying process might be loss of self-tolerance.

I think autoimmunity (my life work!) may be a slightly misleading analogy. ME/CFS has a very dist9nct clinical presentation. Autoimmunity does not. It is a category for a wide range of parallel but in many cases causally unrelated errors of B cell regulation that all involve production of abnormal Ig populations. That shows up with the different MC risk inputs and other things. RA and coeliac probably have little in common. The lupus cluster diseases do overlap but each different pathway has a different clinical presentation.

 

[Jonathan Edwards]

the higher level pathomechanism/defect can be shared/the same even when the specific defects are varied. Many paths I could see that could end in PEM.

I think we are agreed that rare gene variants could be key to unpicking ME/CFS, just as homozygous C1q deficiency gives us the key to lupus. And I agree that upstream pathways to PEM may vary quite a lot but they somehow have to feed in to a common step. If that step is muscle weakness it is quite easy to see how ion control and inflammation could both be upstream but the unique time course of ME/CFS clinical features makes me think that such a wide range of options is unlikely.

We have had a lot of discussion on the forum about the time course of PEM and possible mechanisms. I think we can discount inflammation because it isn't there. I think we can probably discount a simple failure to generate ATP. Ion imbalance also has not shown up and would be hard to explain with the time course. Genetic variants affecting these things could confer risk maybe but I am sceptical about the argument that people with ME/CFS have major differences in key pathways such that different treatments will help different people. 'Precision medicine' is one of the current fashions but I have yet to see much come out of it.

What DecodeME has shown for me is that the statistical approach on big numbers is very powerful but the hard bit is interpreting the genes you think you have found. Without the statistical linkage the interpretation problem remains. In a way I think the most useful thing would be to find a gene variant that causes ME/CFS that we were totally not expecting. But that is a Catch22 because there are any number of gene variants in all of us that look irrelevant. It seems we do need some statistics but maybe a more focused analysis on an enriched population such as very early onset cases. But it is not my field and I am looking on with great interest.

 

[LizWorthey]

I think autoimmunity (my life work!) may be a slightly misleading analogy. ME/CFS has a very dist9nct clinical presentation. Autoimmunity does not. It is a category for a wide range of parallel but in many cases causally unrelated errors of B cell regulation that all involve production of abnormal Ig populations. That shows up with the different MC risk inputs and other things. RA and coeliac probably have little in common. The lupus cluster diseases do overlap but each different pathway has a different clinical presentation.

Ahh yes; I was using that term because it was the one mentioned before by another poster in a response to this thread - so I ran with it . I don't see that comment now so it might have been edited or I'd have double checked it. Did not mean to imply that I thought it was one entity.. Ta!

 

[LizWorthey]

I think we are agreed that rare gene variants could be key to unpicking ME/CFS, just as homozygous C1q deficiency gives us the key to lupus. And I agree that upstream pathways to PEM may vary quite a lot but they somehow have to feed in to a common step. If that step is muscle weakness it is quite easy to see how ion control and inflammation could both be upstream but the unique time course of ME/CFS clinical features makes me think that such a wide range of options is unlikely.

We have had a lot of discussion on the forum about the time course of PEM and possible mechanisms. I think we can discount inflammation because it isn't there. I think we can probably discount a simple failure to generate ATP. Ion imbalance also has not shown up and would be hard to explain with the time course. Genetic variants affecting these things could confer risk maybe but I am sceptical about the argument that people with ME/CFS have major differences in key pathways such that different treatments will help different people. 'Precision medicine' is one of the current fashions but I have yet to see much come out of it.

What DecodeME has shown for me is that the statistical approach on big numbers is very powerful but the hard bit is interpreting the genes you think you have found. Without the statistical linkage the interpretation problem remains. In a way I think the most useful thing would be to find a gene variant that causes ME/CFS that we were totally not expecting. But that is a Catch22 because there are any number of gene variants in all of us that look irrelevant. It seems we do need some statistics but maybe a more focused analysis on an enriched population such as very early onset cases. But it is not my field and I am looking on with great interest.

Yes totally on the same page here, which is nice to see. I know many are quite rightfully less than enamoured with genetics and "precision medicine". Though I would say that precision medicine or as I often call it "human genetics" has been a tremendous boon in the rare disease side of things. I do ponder rhabdomyolysis as a connection. Maybe not everything of course. It is biology and disease after al.

 

[LizWorthey]

No, sorry for not being clear, I was talking about the symptoms attributed to the variants in your table


I think the core of the disagreement is the level of uncertainty that the identified variants from an n-of-1 analysis actually explain any of the symptoms identified when the participant does not have the specific genotype well-documented to present with those symptoms. It seems like you feel very confident in the variants and the listed symptoms, but I am even less so after trying to look into the references. I am seeing several instances where the given genotype is not expected to show up with the symptoms listed for that variant.

My worry is that n-of-1 are very likely to turn up is random variants that may have no impact whatsoever on the persons actual symptoms despite seeming like they couldnt relevant. If there is a way to get much more grounded support for the relevance of variants found in this way I’d be happy to see that data


As I think someone else may have said earlier, if there is another feasible explanation for all a person’s symptoms then the ME/CFS diagnosis is not appropriate to give. In which case their appearance in your cohort is a case of actual misdiagnosis, not evidence that ME/CFS is a convergent disease presentation from lots of different genetic abnormalities.


I think the whole point is that you can’t know the direct contribution of a variant unless there is a specific treatment for that genetic disease you could administer. What I’m getting from looking up heterozygous mutations for HADHA is a small number of case studies noting even in the title that having those symptoms while heterozygous is atypical (and unlike that participant are all for compound heterozygosity).

So for a case like you present, the possible impact of that variant will always be just a guess. It could be a guess that’s good enough to inform clinical practice and try to help symptom management. But if you’re trying to move from that guess to something like trying to explain an apparent subgroup in a small study for a biomarker or explain a non-responder in a trial I would not consider that information to be robust enough to draw any sort of conclusions.

Ahh ok - gotcha. In the cohort during the screening other reasons for the symptoms were excluded - the ones people think about. Of course that would never touch on e.g. rare variant type things as these people and their doctors would have no knowledge of that in advance.

We may need to say - excellent chat - and I truly mean that - and then, as you note, do more work, think harder, work together, and try to untangle it all. TBH I'm writing so much because I had a steroid shot today for flu and it gave me insomnia . I promise I'm not a keyboard warrior normally .

The impact of a mitochondrial trifunctional protein variant isn’t unknown or guessed at though; it’s very well studied and classically presents with exercise intolerance and early fatigability. That’s not the same as PEM, but most reported patients are pediatric; so I have asked myself whether a baby or child would ever get a PEM diagnosis; I don’t know. Would love experts thoughts here.

The reason for putting this out there is to have the dialogue with experts - thinking more about hypotheses testing. For trifunctional protein, that hypothesis is that a single variant can contribute to disease.

This was carefully thought about: when both copies are altered you can see a pediatric-lethal disorder that doesn’t resemble ME/CFS (lethargy, hypoglycemia, hypotonia, liver and heart problems, coma, sudden death); when both are altered but with different variants, you can see later-onset, often milder disease with fewer catastrophic features but with exercise intolerance/early fatigability, chronic fatigue, weakness, peripheral neuropathy, and late-onset cardiomyopathy.

When only one copy is altered, physiologic changes; and in some case reports, symptoms, have been seen; these may well reflect an unrecognized “second hit,” but heterozygous mouse models also show liver long-chain fatty-acid abnormalities, oxidative-stress differences versus wild type, and other downstream effects.

Triggers for acute episodes are well known to include illness, infection, strenuous exercise, prolonged fasting, and stress.

And there are precedents in these same pathways: disorders with early-onset recessive forms and later-onset, milder dominant forms that were only recognized much later because everyone was looking for the catastrophic childhood phenotype. It's seen in other mitochondrial diseases too; LHON-Plus.

One item I have had in my mind is to ask mitochondrial geneticists if they would ever consider testing for PEM in those patient's records or adding that term; or it wouldn't seem important to them to do so. If anyone knows the answer; that would be great to know.

Anyway. I will sign off; really love the discussions. Sorry I'm writing so much. My brain is firing .

 

[hotblack]

Anyway. I will sign off; really love the discussions. Sorry I'm writing so much.

Only just catching up with these posts but please don’t apologise. It’s great to have another researcher here discussing their work and wider aspects of ME/CFS. The more the better!

 

[Ferry]

I think we can discount inflammation because it isn't there.

This is a bit off topic, but my throat has never been the same since I had glandular fever. Exertion makes it sore. When I am not in PEM, my GP described my throat as looking "slightly inflammed". During severe PEM he has described it as looking very inflammed and recommended I take antibiotics. (I asked him to do a swab and the results were negative.)

I am thus not certain there is no inflammation in ME/CFS, but I may be misunderstanding your general point. I know there isn't encephalomyelitis.

 

[Jonathan Edwards]

I am thus not certain there is no inflammation in ME/CFS, but I may be misunderstanding your general point. I know there isn't encephalomyelitis.

Lymphoid tissues are tricky. Throat 'inflammation' is probably often mostly activity in the lymphoid ring around the pharynx. Lymphoid tissue is normally full of white blood cells and when activated is not really 'inflamed' (you do not see neutrophils coming for instance), although similar cytokines may be operating as in inflammation.

So , yes, this points to a process that at least shares some features with inflammation, but I think we can be reasonably sure that there is no inflammation in tissues like muscle and brain.