Biomarkers from Plasma Metabolomics of ME/CFS Implicate Redox Imbalance in Disease Symptomatology

[Murph]

@Murph Were you able to find Figure S1 and Figure S2?

Here's S1

Here's s2 (??):

 

[pattismith]

@Murph
@Hip
@wigglethemouse

I think in my case, the low IMP may be a key in my symptoms.

I am doing a trial currently that relieves all my pains and fatigue and muscle weakness:for a few hours with:


-Inosine (adenosine receptor activator)

-Inositol (xanthine oxidase inhibitor) = prevent all the inosine catabolism pathway to produce uric acid

-Caffeine (adenosine receptor inhibitor)

the only side effect is a slight headache and tinnitus, which are minor.

It works only if I take the three of them (I have taken them separately as control).

my hypothesis is an increase of IMP via the salvage pathway (see below)

Table 2. List of metabolites found to be significantly different between controls and patients according to the Wilcoxon rank-sum test.

Nucleotide
Inosine 5’-monophosphate (IMP)

This study is very interesting because Allopurinol is blocking the Xanthine Oxidase, which is supposed to stop the Inosine catabolism into Uric acid (Allopurinol is a drug used to lower blood uric acid in gout patients).


Purine and carnitine metabolism in muscle of patients with Duchenne muscular dystrophy

Abstract
We determined levels of purines, purine metabolites, related enzymes and carnitine in muscle of 8 untreated Duchenne muscular dystrophy (DMD) patients, 12 allopurinol-treated DMD patients and 12 age-matched controls. Muscle of DMD patients was found to be deficient in ATP, ADP, adenylsuccinate, hypoxanthine, guanine and adenylsuccinate synthetase.

In allopurinol-treated DMD patients, mean total adenylate level was only three times less than in controls (versus 14 times less in untreated DMD patients).

Mean inosine monophosphate (IMP), adenine, adenosine, inosine, xanthine, guanine, guanosine and uric acid levels were higher in allopurinol-treated patients than in controls, while mean adenylsuccinate levels were higher than in untreated patients.

Allopurinol also restored acylcarnitine levels to normal and significantly increased free carnitine levels.
These findings strongly support the hypothesis that Duchenne muscular dystrophy involves alterations leading to blockage of the IMP → purine pathway and that allopurinol treatment favours restoration of purine levels by this route.

Furthermore, our results suggest that the observed deficiencies in cell components unrelated to purine metabolism are long-term secondary effects.

There is a salvage pathway that increases IMP from hypoxanthine. This means that blocking Xanthine oxidase (XOR) will block hypoxanthine-uric acid transformation which will probably increase IMP:

​

 

[frozenborderline]

@Murph
@Hip
@wigglethemouse

I think in my case, the low IMP may be a key in my symptoms.

I am doing a trial currently that relieves all my pains and fatigue and muscle weakness:for a few hours with:


-Inosine (adenosine receptor activator)

-Inositol (xanthine oxidase inhibitor) = prevent all the inosine catabolism pathway to produce uric acid

-Caffeine (adenosine receptor inhibitor)

the only side effect is a slight headache and tinnitus, which are minor.

It works only if I take the three of them (I have taken them separately as control).

my hypothesis is an increase of IMP via the salvage pathway (see below)

​

With inositol there’s a lot of studies showing different mixes of isomers being way more effective and potent than myoinositol

 

[S-VV]

3-HB-carnitine is involved in lipid oxidation and peroxidación. It's production is very increased during ketosis.

https://www.ncbi.nlm.nih.gov/m/pubmed/22209095/

 

[wigglethemouse]

I am doing a trial currently that relieves all my pains and fatigue and muscle weakness:for a few hours with:


-Inosine (adenosine receptor activator)

-Inositol (xanthine oxidase inhibitor) = prevent all the inosine catabolism pathway to produce uric acid

-Caffeine (adenosine receptor inhibitor)

FYI - The author of this blog found her and her son needed to take weekends off from Inosine for it to remain effective, i.e. only dosing 5 days a week. They use it as an immune modulator.
Link : http://livewithcfs.blogspot.com/2014/04/imunovir-update-and-inosine.html

 

[wigglethemouse]

I think in my case, the low IMP may be a key in my symptoms.

@pattismith Have you been able to check your AMPD1 gene. (AMP->IMP conversion). Mutations are common.
More info in this post

More info on wikipedia
https://en.wikipedia.org/wiki/AMP_deaminase

 

[pattismith]

@pattismith Have you been able to check your AMPD1 gene. (AMP->IMP conversion). Mutations are common.
More info in this post

More info on wikipedia
https://en.wikipedia.org/wiki/AMP_deaminase

I checked my DNA datas, and found only a mutation on AMPD2 that is not known to cause any disease (frequency allele 11%). I didn't find this SNP to be linked to any problem.

I don't have my full genome done, so I may miss something. The other possibility is an acquired deaminase deficiency (not hereditary), something I want to investigate more.


The lady from the blog takes Inosine alone, and have a lot of allergies.


I don't suffer from allergies, and if I take 1000 mg Inosine/Inositol without caffeine, I fall asleep about one hour later (probably from activation of brain adenosine receptors)….
So our metabolisms may not be exactly similar...

 

[Jenny TipsforME]

The best statistical significance comes from something called Carnitine Palmitoyl Transferase Deficiency II

Does anyone have this come up from genetic results? I have a couple of missense in CPT2 but heterozygous and classified as likely benign but the lab had picked out as a possible cause of episodic weakness
rs1799822 and rs1799821

 

[pattismith]

Does anyone have this come up from genetic results? I have a couple of missense in CPT2 but heterozygous and classified as likely benign but the lab had picked out as a possible cause of episodic weakness
rs1799822 and rs1799821

This study didn't find association between CPT2 gene nor AMPD1 genes and CFS

 

[wigglethemouse]

This study didn't find association between CPT2 gene nor AMPD1 genes and CFS

That was a 17 person study. Alan Light is in the midst of a larger study and early conclusions are that ME/CFS patients have more gene mutations that affect energy production.
Thread : https://forums.phoenixrising.me/ind...te-to-cause-me-cfs-with-alan-light-phd.62439/

In his cohort he found CPT2 to be of interest

 

[pattismith]

That was a 17 person study. Alan Light is in the midst of a larger study and early conclusions are that ME/CFS patients have more gene mutations that affect energy production.
Thread : https://forums.phoenixrising.me/ind...te-to-cause-me-cfs-with-alan-light-phd.62439/

In his cohort he found CPT2 to be of interest
View attachment 30618

Thank you I missed that point, did he find something on the AMPD1 genes?

 

[Jenny TipsforME]

didn't find association between CPT2 gene nor AMPD1 genes and CFS

For all of us there’s a possibility that some symptoms are incorrectly labelled as ME when they’re something else on closer inspection. My muscle problems have felt quite different the last 10 years from the first 10 years of ME, so re this issue I’m more concerned with what’s specifically happening in my body when I’m looking up SNPs. Though I realise that’s not the point of this thread!

I also have an interesting homozygous, loss of function, stop mutation on AMPD1 that I see I’ve previously highlighted in red. There’s conflicting opinion on whether it’s pathogenic for MYOPATHY DUE TO MYOADENYLATE DEAMINASE DEFICIENCY.

At least nine mutations in the AMPD1 gene have been found to cause AMP deaminase deficiency. This condition is characterized by skeletal muscle pain or weakness after exercise or prolonged physical activity (exercise intolerance). Most cases are caused by a mutation that results in a premature stop signal in the instructions for making AMP deaminase (written as Gly12Ter or Q12X). The resulting enzyme is abnormally short and nonfunctional and cannot participate in the purine nucleotide cycle. As a result, the process stalls and energy production in skeletal muscle cells is decreased. Skeletal muscles are particularly sensitive to decreases in energy during periods of exercise or increased activity when energy demands increase. The lack of AMP deaminase as a source of energy production can result in fatigue and muscle weakness or pain in some people with AMP deaminase deficiency.

https://ghr.nlm.nih.gov/gene/AMPD1#conditions

I definitely meet that description, though for me the problem seems progressive and now it’s so little exertion I don’t think most people would describe as exercise,

It gets confusing when there’s several possible genetic explanations for symptoms. Though I read significant muscle weakness is usually caused by AMPD1 in combination with another muscle problem, not on its own.

 

[pattismith]

@Jenny TipsforME

I thought that Inosine intake could rescue the IMP deficiency induced by AMPD failure, via the salvage pathway (from Hypoxanthine).



But this very interesting study about AMPD2 deficiency seems to indicate it doesn't work.

They noticed that treating the mutant cells with adenosine did not replenish the IMP via hypoxanthine as they would have expected, and that it was producing a depletion of guanine nucleotides, which was deleterious, via a negative feedback on de novo purine synthesis.

So the hypothesis I made that Inosine may be helpful via the hypoxanthine salvage pathway is probably wrong.

They tested AICAR and found it to be the best nucleotide to rescue the AMPD2 mutant cells.

Again AICAR, which is also an AMPK activator and a doping agent in sports, is showing an interesting profile for rescuing some altered nucleotide profiles.

 

[wigglethemouse]

I’m more concerned with what’s specifically happening in my body when I’m looking up SNPs

This is where personalised medicine with genetics, metabolomics, and proteomics is so exciting in the coming years. These last few posts are just scratching the surface.

Maureen Hansons data contained 832 matebolites. Metabolon now advertises 1000+ metabolites. Karl Morten at Oxford is measuring 37,000 metabolites. Combine that with genetics and proteomics and just imagine the picture you could get of your body so you can figure out where the blockages were occuring, and see how supplementation is helping or hindering.

It gets confusing when there’s several possible genetic explanations for symptoms. Though I read significant muscle weakness is usually caused by AMPD1 in combination with another muscle problem, not on its own.

I have read a similar thing in papers where they suggest that maybe it is a combination of gene mutations that can cause muscle weakness. Alan Light's early conclusions in his presentation stated that mutations in immune area + mutations in energy area = double to triple risk of getting ME/CFS.

Thank you I missed that point, did he find something on the AMPD1 genes?

He didn't mention this although he did say there were other interesting genes.

 

[voner]

@pattismith, that is a great diagram of the AMP/IMP pathways.

I went down this AMP/IMP wormhole a couple times because I ran my dna results thru Prometheaus ad it flagged A homozygous defect in AMPD1. Here is what the report looked like:
......
rs17602729(T;T)

AMPD1 deficiency homozygous This is found in ~2% of all caucasians. The majority of people with the AMPD gene are asymptomatic, but in response to vigorous exercise, others have symptoms including early fatigue, muscle pain and muscle cramping.
.......
when @Valentijn was participating in these forums, she was collecting a dna database of forum participants and she told me out of the 50 people that she had data for, I was the only one that had this homozygous defect.

When I read about this defect, the symptom description seemed to fit "muscle pain upon exertion", which describes some of my most debilitating symptoms very well, so I explored the possibility that this defect might have something to do with my symptoms pretty aggressively. I actually contacted Dr. Naviaux ( who has some expertise in this area) who told me that he ... and I am paraphrasing from a bad memory .....that he strongly suspected that there was some technical problems with this DNA read? The details escape me now, but he said that in his opinion I should look elsewhere for causation for my symptoms.

I then consulted with a neurologist at an university hospital here in United States that had treated pediatric patients with AMPD1 defects and resulting muscular symptoms. he told me that my symptoms were nothing like the symptoms of the pediatric patients that he had seen years ago.

I don't claim to have an understanding of the details of all this, but I am just offering up my experiences and what I was told... is was a frustrating experience... just another of many.

 

[pattismith]

@voner

This diagram below is even better to sum up the AMPD deficiency.

It would be an important point to discover if the low IMP finding in ME/CFS is reproducible, and to find the cause. AMPD deficiency can also be an acquired one, but I suppose that other causes can produce a low IMP.

 

[pattismith]

interestingly, In the Naviaux study about a suramin trial on the mouse model of autism, they found some abnomalies when compared to control, effectively reversed by suramin, for example:

-low IMP (reversed by suramin)= same that was found in the Levine/Hanson study for CFS/ME
-high Inosine (reversed by suramin)
-low ATP (reversed by suramin)
-high guanosine (reversed by suramin)
-low quinolinic acid (reversed by suramin)
-high nicotinic acid (reversed by suramin)



"Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy"

"Rank Order of metabolites disturbed in the MIA model. Multivariate analysis across the four treatment groups (PIC-Sal=MIA; PIC-Sur=acute suramin treatment; PIC-Sur w/o=5 weeks post-suramin washout; Sal-Sal=Controls). Biochemical pathway assignments are listed on the left. Relative magnitudes of each metabolite disturbance are listed on the right as high (red), intermediate (yellow or light green) and low (dark green). Variable importance in projection (VIP) scores are a multivariate statistic that reflects the impact of each metabolite on the partial least squares discriminant analysis model. VIP scores above 1.5 are significant."