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Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome

Jonathan Edwards

"Gibberish"
Messages
5,256
I am not sure that I agree that testing of blood cells is meaningless. If mitochondrial dysfunction is at the root of ME symptoms I do not see how it can be limited to muscle. That would not explain symptoms after mental effort or intolerance of noise and light. If anything my impression is that ME patients do not have symptoms consistent with metabolic problems in muscle. People with mitochondrial myopathies have quite different symptoms.

Muscle is a tissue with constant replenishment of cells and the potential for some cell clones to dominate over others. That allows expression of genetic mitochondrial disease. Nerves and brains have very little cell turnover so I find it very hard to see how a genetic mitochondrial problem could present with mental fatigue or light sensitivity coming on quite quickly in some cases. On the other hand a soluble factor interfering with mitochondrial function body-wide could explain such symptoms.

I tend to agree that one was not expecting any general mitochondrial DNA abnormality to show up. But it would have been just conceivable that such an abnormality provided a susceptibility to some other acquired process involving a soluble circulating factor.
 
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15,786
If mitochondrial dysfunction is at the root of ME symptoms I do not see how it can be limited to muscle.
It wouldn't have to be limited to muscle, or any other single tissue. MELAS features both muscle and CNS involvement, and diabetes is a fairly common symptom as well. Similarly, MIDD is the common clustering of deafness and diabetes - obviously involving two very different types of tissue.

That would not explain symptoms after mental effort or intolerance of noise and light.
It's not something I looked into yet, but the neurological issues in MELAS have a lot to do with lactate (produced by muscles) accumulating in the CSF.

If anything my impression is that ME patients do not have symptoms consistent with metabolic problems in muscle. People with mitochondrial myopathies have quite different symptoms
How so? The symptoms of MELAS are pretty much identical to ME symptoms, with the addition of a few not common in ME - seizures, myoclonus, hemipelgic episodes, diabetes. But there's nothing particularly absolute when it comes to mitochondrial disease symptoms, and there's a decent subset of ME patients which do feature those symptoms.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
It wouldn't have to be limited to muscle, or any other single tissue. MELAS features both muscle and CNS involvement, and diabetes is a fairly common symptom as well. Similarly, MIDD is the common clustering of deafness and diabetes - obviously involving two very different types of tissue.


It's not something I looked into yet, but the neurological issues in MELAS have a lot to do with lactate (produced by muscles) accumulating in the CSF.


How so? The symptoms of MELAS are pretty much identical to ME symptoms, with the addition of a few not common in ME - seizures, myoclonus, hemipelgic episodes, diabetes. But there's nothing particularly absolute when it comes to mitochondrial disease symptoms, and there's a decent subset of ME patients which do feature those symptoms.

You seem to be agreeing with me Valentijn!

I said: If mitochondrial dysfunction is at the root of ME symptoms I do not see how it can be limited to muscle.

MELAS is not limited to muscle. For all I know ME symptoms may be like MELAS. But they are not like the symptoms of a mitochondrial myopathy on its own - which as I understand it is usually due to gradual local dominance of clones carrying faulty mitochondrial DNA
 

Gijs

Senior Member
Messages
690
ME/CFS is not due to mitochondrial myopathy. The mitochondria are not damaged. In the Netherlands some researchers have investigated this by muscle biopsy. I also know that pyruvate has been investigated as well with inconsistent findings. I still believe that ME/CFS is due to autonomic dysfunction.
 
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15,786
MELAS is not limited to muscle. For all I know ME symptoms may be like MELAS. But they are not like the symptoms of a mitochondrial myopathy on its own - which as I understand it is usually due to gradual local dominance of clones carrying faulty mitochondrial DNA
I'm confused. Are you saying that MELAS doesn't involve mitochondrial myopathy?
 

user9876

Senior Member
Messages
4,556
I'm confused. Are you saying that MELAS doesn't involve mitochondrial myopathy?

I think he is arguing that if the symptoms with MELAS are similar to ME then any mutations would need to be more wide spread than just muscles.

What I think is interesting is the idea that mutations would grow quickest in areas where muscle renewal is fastest. So you the brain would be one of the later areas affected with muscles being affected more quickly. Also it is worth wondering about the reverse which is as people go into remission or improve after Rituximab, would the type of remission (or improvement) characteristics be consistent with mitochondrial mutations?
 
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15,786
I think he is arguing that if the symptoms with MELAS are similar to ME then any mutations would need to be more wide spread than just muscles.
But he also said:
I am not sure that I agree that testing of blood cells is meaningless.
Since mitochondrial diseases (including mitochondrial myopathies) typically don't show up in DNA obtained from a blood sample, I can't figure out why he thinks that testing for mitochondrial mutations in the blood is relevant.
 
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15,786
I looked through the data, basically searching for the listed variants on OMIM, which is a large database of disease-causing SNPs.

11 out of 93 CFS patients (12%) had rare mutations which research (mostly multiple case studies) has indicated is causative of a mitochondrial disease. Another 28% had more common mutations which are 2-3x more prevalent in certain mitochondrial diseases, and are likely either a contributing factor or partially linked to a causative factor.

Additionally, samples positive for 3 mutations conclusively known to be causative of mitochondrial disease were re-tested using a different method, not found again, and completely excluded from the result. So it's not clear how many patients had those mutations, nor is the detected amount listed for any of the variants.

There's very little information in the methods or results section, to the point that it probably wouldn't be possible for another team to replicate this experiment. But with in excess of 12% of patients having rare mutations detected in their blood which are implicated in mitochondrial disease, I have to strongly disagree with their conclusion that there's no evidence of mitochondrial mutations in CFS.
 

Rossy191276

Senior Member
Messages
145
Location
Brisbane, Australia
I'm not sure. They have data regarding variants in the supplemental material, but I haven't taken a look. As you say, it doesn't matter much if there isn't, since they aren't using the appropriate methodology to find the mutations.

Hi Valentjin...

You're insight into genetic mitochondrial disease seems awesome...I am wondering why guys like Dr Davis and Dr Naviaux both seem to be saying genetic Mitochondrial disease don't seem to be the problem..Isn't Dr Naviaux a mitochondrial specialist? And surely with Whitney being so sick this would be one of the 1st things Dr Davis would consider and test??

My apologies for my limited understanding but it seems to me this is a crucial theory that should be one of the first to be explored and ruled out first...
 

Rossy191276

Senior Member
Messages
145
Location
Brisbane, Australia
ME/CFS is not due to mitochondrial myopathy. The mitochondria are not damaged. In the Netherlands some researchers have investigated this by muscle biopsy. I also know that pyruvate has been investigated as well with inconsistent findings. I still believe that ME/CFS is due to autonomic dysfunction.

Do you have a link to this study Gijs? Maybe a good idea to post..
 
Messages
15,786
I am wondering why guys like Dr Davis and Dr Naviaux both seem to be saying genetic Mitochondrial disease don't seem to be the problem..Isn't Dr Naviaux a mitochondrial specialist? And surely with Whitney being so sick this would be one of the 1st things Dr Davis would consider and test??
I'm not going to assume that they've tested muscle biopsies for mutations or other abnormalities unless they've explicitly said so somewhere. And in any event, Whitney is a case of 1 person ... I don't believe that genetic mitochondrial disease causes all cases of ME, or even most cases.

But there are ME patients with additional symptoms that are not part of the diagnostic criteria, and generally not considered normal ME symptoms. Some of these symptoms are characteristic of mitochondrial diseases, however, including seizures, hemiplegia, endocrine abnormalities, etc. And those mitochondrial diseases can also feature the same symptoms as ME, including exercise intolerance, OI, abnormal immune reactions, etc.

It's my understanding that thus far Dr Naviaux has been looking at metabolites in the context of mitochondria in ME, rather than the genetics of the mitochondria. And as we've seen in the study discussed in this thread, getting researchers and/or ethic committees to test via biopsies is like pulling teeth :D
 
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15,786
Here's a list of the mutations found in patients in this study which have also been found in research of mitochondrial disease. Due to rarity of the mutations, much of the research is case studies, though it incorporates laboratory confirmation of mitochondrial disease and sometimes laboratory confirmation that the specific mutation results in the mitochondrial dysfunction.

Prevalence in controls is based on disease research into that SNP, or known prevalence from the general population, and is typically derived from a group of 200-1000 people from a limited ethnic background. The study discussed in this thread did not feature controls.

MTNH G12192 (rs3134560) - 0% of controls, 1.1% of patients
MTTG A10044G (rs41362547) - 0% of controls, 1.1% of patients
MTTQ A4336G (rs41456348) - 0.3% of controls, 2.2% of patients
MTRNR1 T961G (rs3888511) - 0% of controls, 2.2% of patients
MTCYB G15257A D171N (rs41518645) - 0.3% of controls, 1.1% of patients
MTND6 T14319C N119D (rs199476110) - 0% of controls, 1.1% of patients
MTND1 A3796G/T T164A/S (rs28357970) - 0.37% of controls, 4.3% of patients
MTND1 T3394C Y30H (rs41460449) - 0.9% of controls, 2.2% of patients

So rare pathogenic mitochondrial mutations which should have a total occurrence of 1.87% of the general population are present at a rate of 15.3% in the patients of this study. If assuming that the three pathogenic mutations removed from the results (all 0% prevalence in controls) were relevant and present in at least 1 patient each, the total rare pathogenic mutations are present at a rate of at least 18.6% in this study. That's a ten-fold increase, which is very remarkable, especially when considering that they largely avoided looking for heteroplasmic mutations.

I'm still ticked off that they removed three of the pathogenic mutations when they didn't show up on re-testing. As heteroplasmic mutations they are rarely found in the blood, so each retest increases the likelihood of a false-negative finding. And there's no reason to think that the initial test was subject to a false-positive result. Basically they're using a testing method which is guaranteed to produce a huge amount of false-negative results, but claiming that false-positives are the problem :confused:
 
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Rossy191276

Senior Member
Messages
145
Location
Brisbane, Australia
Here's a list of the mutations found in patients in this study which have also been found in research of mitochondrial disease. Due to rarity of the mutations, much of the research is case studies, though it incorporates laboratory confirmation of mitochondrial disease and sometimes laboratory confirmation that the specific mutation results in the mitochondrial dysfunction.

Prevalence in controls is based on disease research into that SNP, or known prevalence from the general population, and is typically derived from a group of 200-1000 people from a limited ethnic background. The study discussed in this thread did not feature controls.

MTNH G12192 (rs3134560) - 0% of controls, 1.1% of patients
MTTG A10044G (rs41362547) - 0% of controls, 1.1% of patients
MTTQ A4336G (rs41456348) - 0.3% of controls, 2.2% of patients
MTRNR1 T961G (rs3888511) - 0% of controls, 2.2% of patients
MTCYB G15257A D171N (rs41518645) - 0.3% of controls, 1.1% of patients
MTND6 T14319C N119D (rs199476110) - 0% of controls, 1.1% of patients
MTND1 A3796G/T T164A/S (rs28357970) - 0.37% of controls, 4.3% of patients
MTND1 T3394C Y30H (rs41460449) - 0.9% of controls, 2.2% of patients

So rare pathogenic mitochondrial mutations which should have a total occurrence of 1.87% of the general population are present at a rate of 15.3% in the patients of this study. If assuming that the three pathogenic mutations removed from the results (all 0% prevalence in controls) were relevant and present in at least 1 patient each, the total rare pathogenic mutations are present at a rate of at least 18.6% in this study. That's a ten-fold increase, which is very remarkable, especially when considering that they largely avoided looking for heteroplasmic mutations.

I'm still ticked off that they removed three of the pathogenic mutations when they didn't show up on re-testing. As heteroplasmic mutations they are rarely found in the blood, so each retest increases the likelihood of a false-negative finding. And there's no reason to think that the initial test was subject to a false-positive result. Basically they're using a testing method which is guaranteed to produce a huge amount of false-negative results, but claiming that false-positives are the problem :confused:

So are you saying that because these results have been found with blood testing, which produce lots of false negatives, if the testing had been done on muscle the results would have been even greater...

Seems very relevant- who is the best person to advise of these results?
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
@Valentijn @Kati @Jonathan Edwards

How do we square the results of this study with the acquired mtDNA error found by the Lights in ME/CFS patients?

I can't find the study, but here's a quote from Cort's article:
Using a technique that allowed them to measure both the mutations present at birth and those acquired afterwards, they looked at the mitochondrial DNA of those white blood cells.

(...)

The Light group found at least one mitochondrial mutation not seen in healthy controls in everyone but one of the 40 ME/CFS patients. Plus more than 70% of them had a variant likely to have a high or moderate impact on the production of a key mitochondrial protein; i.e. most had a gene variant likely to cause a serious problem in energy production. The fact that most of the ME/CFS patients had multiple mutations further suggested the mutations were having a real impact.

Significantly, all of the variants were acquired; i.e. none was present at birth – as the result of something in the environment the ME/CFS patients had bumped into. They were scattered throughout the complexes that make up the mitochondrial energy pathway.

About 80% of the ME/CFS patients also had mutations in autoimmune genes (beta adrenergic, acetylcholine and PKA genes), but different genes or gene combinations were found in each patient. All the patients with mitochondrial gene mutations or polymorphisms also had autoimmune gene mutations

https://www.healthrising.org/blog/2...ity-chronic-fatigue-syndrome-alan-light-talk/
 
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