What differentiates ME/CFS from known primary mitochondrial diseases; could mitochondrial disease cause PEM?

I don't think PEM is common enough to have evolved directly as a protective mechanism but it could work that way in practice. Pain and things caused by the effects of our build up of lactic acid as a result of cellular aerobic respiration failure would be the same as from over exercising and could have evolved so we rest to allow the body to recover.

Fatigue is protective. A least one competitive cyclist has died after taking cocaine to prevent fatigue when his heart just gave out.

I have been ill so long when friends have died who became ill long after me with things like MS. It is very possible that the things which cause us so much trouble actually let us live with ME. The ultimate chronic illness!

 

I just saw these Twitter posts and then remembered this post here too.

(thanks @livinglighter for posting this Twitter post on the other NICE thread):

https://twitter.com/user/status/1379416721312919559


https://twitter.com/user/status/1379303908833693696


@strategist i think you’re right and looking at other conditions could be a pathway to understanding PEM.

(another condition I’ve heard of anecdotally that has caused PEM is channelopathy).

But what do some types of mitochondrial disease and traumatic brain injury (and heart failure?) have in common, that could explain PEM? Or at least PEM-like symptoms? And what links these to ME?

The theory of PEM being a protective mechanism doesn’t fully make sense in this context because people with mitochondrial disease often die young.

 

This post and the next have been copied and following discussion moved from this thread:
Circadian rhythm disruption in [ME/CFS]: Implications for the post-acute sequelae of COVID-19, 2022, McCarthy
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This is not true though.

“Data were compared with those for healthy control subjects and patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome matched for age and gender. Sixty-two per cent of patients with mitochondrial disease reported excessive symptomatic fatigue (Fatigue Impact Scale ≥ 40); whilst 32% reported severe, functionally limiting fatigue symptoms (Fatigue Impact Scale ≥ 80) comparable to perceived fatigue in patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome. Fatigue is common and often severe in patients with mitochondrial disease irrespective of age, gender or genotype.”

https://www.sciencedirect.com/science/article/pii/S0960896615000875

“12. What are the symptoms?
Lack of energy is a common outward symptom of Mitochondrial Disease but inside the body it's much more serious and complex. Mitochondrial Disease may literally cause any symptom, in any organ, with any degree of severity, at any age.”

https://www.thelilyfoundation.org.uk/get-informed/questions-answers/

Ive done a bit of reading about mitochondrial disease which is why I knew about the above. There are several case studies I came across of people who had symptoms such as exercise intolerance, chronic fatigue, post-exertional shortness of breath, headaches & seizures - all of these symptoms can make people feel very unwell - & have been found to have mitochondrial disease. Yes people with ATP problems might have difficulty climbing a stair or lifting an arm, and also have other (sometimes fatal) problems too, but a serious lack of energy & feeling exhausted / tired / fatigued is also a part of their illness.

So it’s not true that having ATP problems doesn’t make you feel unwell. I don’t see why ATP & mitochondrial issues can’t be implicated in ME too, even if it’s not the whole picture.

 

No doubt people with mitochondrial disease will report fatigue but as everyone on this list says, that is not really what ME symptoms are about.

And I think this sort of account is fairly unhelpful. People with any disease can have any symptoms if you keep asking.

I have not looked after people with mitochondrial disease but Murphy, whose work is devoted to it, says that the symptoms of ME do not fit with a failure of mitochondrial function.

You also have to remember that people with mitochondrial disease develop progressive structural damage to tissues like muscle, over and above the ongoing metabolic deficiency, and it would not be surprising if that had an impact. People with ME do not.

 

Genetic mitochondrial disease will be different from acquired disease. A genetic defect will affect all cells so the damage will be severe but acquired disease will not affect every cell in the same way psoriasis does not usually affect every inch of skin or MS destroy every piece of myelin sheath.

If there is a deficit in cellular respiration in ME it is more likely to stop everything working efficiently rather than stop it altogether. From the work that has been done it seems more likely that we have structurally intact mitochondria but something in the serum is preventing them from working properly.

The other thing is that CFS has sown so much confusion there are not many doctors who know how ME affects people. When large numbers of doctors developed longcovid they insisted they did not have anything like ME because they had much more symptoms than just severe fatigue.

Many of us experience not being able to move a limb when we want to. It is a strange sensation, with just a slight shock like using the remote control and the TV not coming on. I think the difference between us and those with mitochondrial disease is that we can move after a short rest.

When I first saw the idea that we need to rely on the emergency production of ATP by anaerobic respiration it gave an explanation for most of my symptoms that I had never had before. It answered questions I had not asked which I was told is a sign of a good hypothesis. No doubt it will need many years and a to of money to work out the exact biochemistry but it is the best direction to look.

 

Actually for mitochondrial disease this is to the case as I understand it. Things are more complicated. But I am not sure how relevant all this is anyway.

 

Does Murphy have a good understanding of ME?

According to a person diagnosed with mito disease and not involved in any way with the ME community those with mito disease can have something resembling PEM.

Maybe PEM will just end up being part of a regulatory response that is seen when there is a physiological problem that requires limiting exertion.

 

Ye I think so. He attended one of the IiME meetings and Jo Cambridge and I had lunch with him and we discussed the symptom issue. He had heard all about PEM all morning and was aware of other features like sensory sensitivities. He was clear that he did not see how these things could be explained by shortage of ATP due to mitochondrial failure.

As I indicated above, people with mitochondrial disease have more than just failure to make ATP. Their tissue deteriorate over years structurally.

And it is always difficult to know how to interpret accounts from people 'diagnosed with mitochondrial disease'. I strongly suspect that a lot of diagnosis of mitochondrial disease is going on that can be questioned.

 

if i hold my arm up briefly it becomes intolerable. whether supine or standing. idk if htat is consisten with m.e. or mito?

i think same occurs using any muscle i try, such as bending foot toward shin while supine, legs and heels fully supported.

[but to make it more complex i have additional issues with the angle which are separate. i have to have legs at a certain elevation [which varies] or it takes too much out of me systemically. also i was told lifting arms up had a clear raynaud's/vascular issue. and also oi.]

 

This might be getting too off-topic now so moderators feel free to move if so. It also might have already been asked/answered somewhere else on the forum.

@strategist @Jonathan Edwards @Mithriel @lunarainbows

I didn't know there was such a thing as mitochondrial disease that is by definition not ME - how is mitochondrial disease diagnosed / ruled out?

[edit: come to think of it - is there anywhere here on S4ME a kind of template list of other things that are usually tested for and ruled out before a diagnosis of ME is made? For example in my situation I think the things that were ruled out (I might have forgotten some) were:
1) Diabetes
2) Cushing's Syndrome
3) Addison's Disease
4) Vitamin D deficiency
5) Anaemia
6) currently active viral infection...
maybe some others but I can't remember them if there were..]

 

7) various Thyroid conditions
8) HIV

Does there also need to be a list of things not commonly tested for that should be considered
1) Mitochondrial disease
2) Lyme’s disease
3) MS
etc

 

Yes, it is a different disease to ME. (PS I know this is off topic, so feel free to move this to a different thread if needed. And sorry that it’s long, I just felt I needed to write some things down).

“Mitochondrial myopathies are a group of neuromuscular diseases caused by damage to the mitochondria—small, energy-producing structures that serve as the cells' "power plants." Nerve cells in the brain and muscles require a great deal of energy, and thus appear to be particularly damaged when mitochondrial dysfunction occurs. Some of the more common mitochondrial myopathies include Kearns-Sayre syndrome, myoclonus epilepsy with ragged-red fibers, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. The symptoms of mitochondrial myopathies include muscle weakness or exercise intolerance, heart failure or rhythm disturbances, dementia, movement disorders, stroke-like episodes, deafness, blindness, droopy eyelids, limited mobility of the eyes, vomiting, and seizures. The prognosis for these disorders ranges in severity from progressive weakness to death.

Most mitochondrial myopathies occur before the age of 20, and often begin with exercise intolerance or muscle weakness. During physical activity, muscles may become easily fatigued or weak. Muscle cramping is rare, but may occur. Nausea, headache, and breathlessness are also associated with these disorders.”

It doesn’t mention fatigue but it is a major symptom as I mentioned before. There are also many other symptoms not mentioned eg respiratory muscle weakness, some people progressively struggle to breathe & need ventilation and some do even die of this.

https://www.ninds.nih.gov/health-information/disorders/mitochondrial-myopathies

It’s difficult to diagnose, and contrary to what was said above in the thread, there most definitely is not “a lot of diagnosis going on”, and nor is it “questioned” by doctors I know. It is actually very difficult to get diagnosed, especially in the U.K. By the time patients are diagnosed here, they are very often very unwell - either having ended up in intensive care & nearly died if not once then several times, have had several stroke like episodes, or are starting to lose their eyesight or hearing (or have already lost it), and losing movement from their eyes. Most people suffer a lot for a long time, and go through several doctors until they happen to find a doctor who recognises the symptoms - because not all doctors (or neurologists) recognise the symptoms or put all the different parts together to arrive at a diagnosis. Some people get “lucky” if they find a good doctor earlier on, or have family members already diagnosed so they get tested too. Or if they have a mitochondrial disease that is already a well-defined one, like MELAS or something, so the symptoms are easier to spot.

Also, to even get diagnosed, you need extensive testing including genetic testing which is physically & emotionally draining, and requires ruling out many other conditions. People are diagnosed through a combo of genetic testing/genome sequencing (blood), mtdna genome testing & respiratory chain enzyme tests (muscle biopsy), lumbar puncture, EMG, other blood tests, MRIs depending on your symptoms etc, if a doctor thinks you have the signs & symptoms. All of this is not something that is exactly done lightly. there are 3 mitochondrial units in the U.K. in London, Newcastle & Oxford.

(I think in the US at least, they don’t really tend to wait as much until organ damage or something really bad has happened, even if it’s a complex case & not easy to diagnose. Maybe this might pick up “milder” cases in the US, but it doesn’t necessarily mean they don’t have the disease as they would’ve still had to have had testing & genetic confirmation surely).

Also, again contrary to what was said above, Pw Mitochondrial disease do feel unwell & do report “crashing” and needing to pace. I’ve seen slides from researchers here in the U.K. which talk about “OT” and “energy management”. They have a specialist physio at the mito service in the U.K. because these patients also have issues with exercise & exertion and need tailored help. There are several examples of patients in the main fb group (U.K., so not exactly easily diagnosed patients) talking about things that sound like post exertional malaise and fatigability - going for a walk but having to rest the next day and the next, doing physio then having severe weakness and pain the next day and being told by the physio they need to build up much more slowly (sound familiar?), doing physio then “never being the same again”, needing to rest every 30 mins, only doing exertion within their limits, others chiming in and agreeing with this), just without ever using the words “post exertional malaise”.

there are lots of different types of mitochondrial disease all with varying symptoms, so there may be some people who don’t feel so fatigued & unwell but just have the organ failure, but there may be others who really do have severe fatigue & symptoms too. Maybe in the past the received wisdom was that it only caused organ failures (& blindness & deafness), not any other symptoms, as those were the only ones known about, but there is a lot more knowledge now.

From what I can see the main and most important difference to ME is because of the organ failures & damage, muscle damage and progressive nature. It’s not the same condition clearly, but there can be some symptom overlap sometimes, although there are also some differences & specific symptoms doctors look for in mitochondrial disease such as the organ involvement.

Sorry for the long post, I wasn’t sure how much to write and am always worried that I am annoying people, or clogging up an ME forum with posts about another condition! but I felt it was important to counter some of the posts here, especially given how difficult it is in reality to get diagnosed & given the symptoms people really do report (& which doctors involved with the patients seem to know about). I think it’s also important that researchers are not put off from research if they think it’s relevant & it’s good to learn from conditions that are better studied rather than dismiss them.

PS I think there’s a list of conditions from the ME association for differential diagnosis, but pretty sure more than 50% of the conditions listed are not routinely tested for, before giving a diagnosis of CFS on the NHS.

 

Thanks so much for taking the time to write all this @lunarainbows! I've read it twice, going to read it a few more times, lots to think about. I really appreciate you writing all of this out so clearly! Really fascinating. Logically it seems to me surely this would have to be excluded to make an ME diagnosis, but I can see from what you're saying about how intensive the testing is that in reality that probably rarely happens.

Also thanks for the tip on the ME Association differential diagnosis page - I found it here - https://meassociation.org.uk/about-what-is-mecfs/diagnosis/

"There are many autoimmune, infective, metabolic and neurological conditions that often have debilitating fatigue as a key clinical feature – sometimes as a presenting feature.

Examples include:

• Non-alcoholic fatty liver disease (Newton et al 2008),
• Primary biliary cirrhosis (Newton et al 2006),
• Scleroderma (Sandusky et al 2009),
• Sjögren’s syndrome (Calabrese et al 1994),
• Systemic lupus erythematosus, hepatitis C and multiple sclerosis (Berger et al 2013; Gaber et al 2014). "

Looks like most of those aren't on that little list that @Peter Trewhitt and I started compiling! Even more to think about..

 

Yes, but that’s not the full list I was thinking of, as I was talking about a list taken from the MEA’s “purple book” (it was first posted on this forum on another thread by another member, I’ve just copied the photo from that post & attached it here), its a long list of conditions. for some of the conditions, the symptoms are quite different to ME, but some of them are closer to ME symptoms. (But I already had quite a few fatiguing diagnoses from that list but was still given an ME/CFS diagnosis, so I don’t think all the conditions here are really treated as differential diagnoses).

 

I don't think Mike Murphy's view would be 'in the past', @lunarainbows. He was picked as a top mitochondrial disease expert by IiME and is currently working in the area at Cambridge.

I do think you need to be careful about what goes on on Facebook groups. Quite a high proportion of members may not actually have a definite mitochondrial disease diagnosis. Some people may in fact have ME.

There is no doubt that people with mitochondrial disease will get fatigued and there will be physios with all sorts of ideas about how to deal with it and there will be people deteriorating who will think physio made them worse. Any of that may be true but any of it may not. As I have said before 'lived experience' is valid as an account of what things feel like but it is not a reliable source of information on what causes what - which is why we have peer reviewed research studies.

 

Thank you @lunarainbows , a very useful account.

 

Luna isn't (mostly) talking about Facebook groups. She has been diagnosed with mitochondrial disease herself by a legitimate doctor. I imagine she is repeating what he told her. And she's talking about academic studies which she read. She made ONE reference to symptoms that someone described in a Facebook group.

It is a common mistake for doctors to assume that patients are talking about things that they've seen on social media, rather than about information that they've acquired from legitimate sources. You are falling into this trap here.

 

No I am not. She mentioned a Facebook group and I commented. My other comments relate to other detailed issues.

I think the conversation has drifted away from the basic point that failure to produce ATP by mitochondria does not plausibly explain ME symptoms when considered in the detailed context.

It is possible that mitochondrial disease may be misdiagnosed as ME but I suspect no more likely than all sorts of other diseases. I think it is important not to think that everyone with ME needs to get tested specifically for mitochondrial disease.

 

My understanding is a differential diagnosis not only has to exist in a patient but has to at least potentially explain the symptoms.

Please note there are potentially four post pathogen syndromes in that list that are not currently counted as ME.

 

Fascinating, don't apologise I don't think you could have got it across any shorter from my perspective and it is important stuff/insight