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

I put this post here as I couldn't see a section for Primary Mitochondrial Disease in Missed/Alternative Diagnosis section...

Given the advice that if 3 or more systems are involved that it could possibly be a genetic/primary mitochondrial disease it would seem that anyone that meets ICC/CCC criteria should try to rule out primary mitochondrial disease.

But it seems from Ron Davis's and Naviaux's testing they don't believe there is anything wrong with the mitochondria themselves rather the mitochondrial disfunction is caused by something else

I am wondering peoples opinions on what differentiates ME from known genetic mitochondrial diseases in terms of symptoms...

Given that even though exercise intolerance can be part of mitochondrial disease the fact that GET seems to be prescribed with primary Mitochondrial disease and there is no patient outcry from what I can tell perhaps extreme crashing from exertion in ME is one differentiating point that doesn't occur in genetic MD.

Would you agree or are there others you can think of that are differentiating symptoms/experiences...

 

There are some symptoms pretty common in mitochondrial disease which aren't common in ME, such as diabetes and episodes of hemiparesis.

With a mitochondrial disease like MELAS it's known that lactate accumulation can cause serious problems, so presumably any exercise is undertaken with the primary goal of avoiding increased lactate production. And patients are never being advised to push past their fake symptoms, etc, so any exercise would be a very different therapy than real GET.

There's also no research showing exercise to be helpful, just anecdotal case reports and a hypothesis based on exercise being beneficial for mitochondria in general.

 

Merged thread

Could mitochondrial diseases cause delayed PEM?

Hi,

Sorry I don't know which area of the forum I should post this question in, but I just wanted to ask given the possibility that mitochondrial diseases could be misdiagnosed as ME if anybody knows whether the crashes in functioning in mitochondrial disease can be delayed by a couple of days as they often are in ME or if they always follow immediately after overactvity?
Thank you.

 

It's a good question. I know of one case report where mitochondrial myopathy appears to have been misdiagnosed as CFS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748504/

According to the authors

This patient reported having postexertional malaise

The patient had "a severe deficiency of complexes I and IV and several mtDNA variants" as well as other affected family members.

 

@lunarainbows ?

 

I was diagnosed with probable metabolic myopathy, with an ME-type picture (And mitochondrial myopathy is one type of metabolic myopathy).

So according to the doctors, these kinds of conditions can sometimes look like ME, and present with the symptoms of ME. Including PEM. I have crashes both immediately and for a few days after too. I have PEM & severe ME symptoms.

I tried to find out a bit more, and I came across this post. the person describes her experience on mitochondrial disease forums, where the crashes those patients experience, sound very similar to those experienced by PwME. https://www.s4me.info/threads/13th-...onference-1st-june-2018.532/page-9#post-77665

We don’t really know the mechanism of PEM anyway, so it’s hard to say whether it’s exactly the same underlying mechanism, but it seems very similar at least. I think it could be the case that PEM can be experienced by other conditions as well.

 

Given our current definitions of ME are purely symptom based, if someone who has ME turns out to have a mitochondrial related pathology that surely does not necessarily supersede the previous ME diagnosis. Rather you could argue,

• if it turns out everyone with an operational ME diagnosis has the same mitochondrial condition then ME’s underlying pathology has been elucidated,
• or if it turns out that if not everyone with an ME diagnosis has that mitochondrial disorder then ME as we currently define it can result from more than one pathology.

(Though the former suggestion may be undermined if not every one with the specific mitochondrial condition presents with ME like symptoms.)

Ultimately discovering different pathologies that produce symptoms consistent with an ME diagnosis will help us produce better definitions of the condition, but surely with our current understand discovering a pathology in someone on with ME symptoms of itself is not sufficient to eliminate the previous ME diagnosis.

 

I’ve been thinking more about this the past week or so. I don’t think your first point will turn out to be correct, because I went searching about this topic on this forum. Several are members only threads so I won’t link them here. But there’s been several studies done on PwME who have had muscle biopsies, including a large study looking at their mitochondria (or even other pathologies), and their muscle biopsies have turned out normal. so most PwME won’t have a mito (or metabolic) disorder as it doesn’t seem to be common.

(On second point, would prefer to write more in a members only thread).

 

I remember that the Younger research group (or one of the groups from the USA) reported finding someone with mitochondrial disease in their cohort. Or was it a metabolic disorder? I can't remember the details.

 

One way to better understand PEM (and ultimately ME/CFS) is to find other diseases in which it occurs and where the disease mechanism is better understood.

I suspect that it could be a response by the body to certain kinds of injury or energy deficits. The purpose of PEM would be to stop the person from causing harm to themselves by putting further stress on the injured parts of the body or an already stressed metabolism.

 

This implies, if I am understanding correctly, that PEM is somehow a normal bodily mechanism for self protection, such as normal tiredness is a mechanism to promote sleep or blinking to protect the eyes. We would then presumably expect to see it in a number of different situations unconnected with any individual triggering condition such as ME. This is not a million miles away from the suggestion that ME is an aberrant form of ‘sickness behaviour’ rather than an independent biomedical condition. However do we have any evidence that PEM is a related to a normal protective mechanism as distinct from it being itself a pathological process or the consequence of a pathological process?

The features of delayed onset and the potentially progressive nature or the worsening in PEM over days or even weeks at time, do not for me bring to mind other normal bodily functions.

 

Many of the symptoms of hypoglycemia are caused by the body's attempt to raise blood sugar. This is a normal physiological response to an abnormal state. I think PEM could be something similar, with the symptoms being a combination of those caused by the primary problem and those caused by the physiological response to it.

Various features of PEM like the delay seem more consistent with a response to a problem rather than the problem itself.

I don't think PEM exists in every illness because that's contrary to the evidence. I think it might exist in illnesses that cause specific problems which result in specific responses by the body. Assuming that PEM is one thing and not several different phenomena that are being grouped together.

 

So, throughout most of evolutionary history, this mechanism keeps us alive but slows us up enough so that the wolves get nice fresh meat, instead killing us so the wolves don't have to find and eat rotting meat.

I can see what's in it for the wolves.

I struggle to see any benefit for an individual or tribe.

 

Thinking in historical/evolutionary terms, I suspect in most periods of history or even in a different contemporary culture I would have died relatively early on in the course of my ME, if not already eaten by the wolves, not directly from the ME but from another infection taking advantage the continuous PEM and resultant poor/restricted diet.

 

Died from being left behind because "You look fine, you're just being lazy."

 

It could be, but it could also be just a malfunction that evolution hasn't weeded out yet. If your computer stops working because a single transistor ot trace failed, it isn't because it's trying to protect itself from further damage.

 

Fantasy Evolutionary Biology is a limitless game - there's always something to add in or take away to get a result that fits and it can be quite fun, but we are not talking falsifiable hypotheses.

In this case the starting point seems to be the fairly well researched field of sickness behaviour The concept of sickness behavior: a brief chronological account of four key discoveries

https://zero.sci-hub.se/1754/62fe41ce078c35dc7f6fca309a71f12a/johnson2002.pdf

There's always going to be a challenge for an organism that is operating sub-optimally - does it carry on as usual exposing itself to the threats it effectively deals with when operating optimally, or does it remove itself in expectation that optimal capacity will make a timely return. Obviously this depends on the organism - if you are a perpetually moving Wildebeest dependent on the security of the herd, taking yourself off alone for a few days is unlikely to be a sound strategy. On the other hand if you are a Pangolin, a few days hiding away in your burrow might be the key to survival.

For humans, and possibly other species of Homo, co-operative living means sustained protection - a function of our inordinately long dependent infant-hood - can be afforded to individuals, there are various evolutionary arguments for this behaviour, one candidate is the preservation of memory, where having a varied store of collective knowledge provides a strong evolutionary advantage. There's a remarkable piece of evidence for supported survival of a Neanderthal male: Older Neanderthal survived with a little help from his friends

https://www.sciencedaily.com/releases/2017/10/171023181552.htm

So proposing PEM as a sickness behaviour (note not 'sick role' which is a sociological construct and which is widely misstated from its original conception) isn't unreasonable. However I'm not convinced it is correct. My experience of PEM certainly does in part mirror my experience of a) having a virus, b) having a hang-over, but the differences are notable too i.e rarely any fever, rarely loss of appetite, always greatly increased cognitive problems.

That PEM involves activation of some part(s) of the immune system seems likely but I think that this activation is not directly equivalent to the switching on of the neurological initiators of healthy sickness behaviour, rather there is something else going on which produces an abnormal response which we variously experience as PEM. Although of course we can't currently discount that PEM might serve as an effective sickness behaviour in response to this abnormality !

 

Not actually answering your question, but I vaguely recall something recently (months) where scientists (Oxford?) found that whole genome sequencing found underlying mitochondrial disease [EDIT - apologies just re-read this - the symptoms were very variable and not actually consistent/typical]. So basically the cost effective way to diagnose was whole genome sequencing. I know a family with more than 1 of the children have ME/CFS; I've wondered if those families should routinely be offered whole genome sequencing.

I wonder if Chris Ponting's GWAS study would be capable of testing whether mitochondrial functioning is relevant in ME/CFS?

 

Just seen this thread.

Studies from the NIH showed that people with ME/CFS have diastolic heart failure. Dr Cheney had recently needed a heart transplant after systolic heart failure so he was very interested. He tested his patients and found diastolic heart failure in them too.

He said that in his disease he carried on working his heart normally until it collapsed with the effort but in diastolic failure there was fatigue so people were forced to rest and this protected the heart.

I found the Workwell CPET testing plausible when it first came out because it offers an explanation for delayed PEM where you have no problems then collapse. (It has been 3 days for me for years.) It is a simple mathematical progression.

Consider the anaerobic threshold at day 0 as "normal" but you overdo things so on day 1 the threshold is reduced. Even if you do less you still go over it again and it reduces even more, now resting on day 2 will take you over the threshold lowering the limit even further. Come day 3 you cross from anaerobic at such a low level even a simple action becomes impossible.

 

I feel that PEM is also a "protective mechanism", a pathophysiology that prevents us from dying b/c it stops us in our tracks? My last PEM episode over 4 years ago was so scary that I swore I would never allow myself to overdo again.