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Adenosine Mutations Appear to Cause PEM.

Ema

Senior Member
Messages
4,729
Location
Midwest USA
Has anyone tried adenosine monophosphate injections a la the Dr Harvey Sklar protocol?

http://www.legerepharm.com/uploads/CFS_6-1-12_PP.pdf

I'm really interested in adenosine since it seems like it can cause almost all the problems most of experience in ME/CFS.

I originally thought that my adenosine was too high - it was over range on the methylation panel - and not degrading properly into uric acid. My uric acid levels are below range.

When I take inosine (an intermediary), my uric acid levels rise so that part seems to work OK.

I think that my adenosine is not breaking down by adenosine deaminase into inosine possibly due to a genetic defect. When people are homozygous recessive for that gene, they can develop severe combined immune deficiency (ie bubble boy).

I'm wondering if being heterozygous is not simply being a nonsymptomatic carrier as is commonly thought, but actually can produce symptoms.

High adenosine produces fatigue, vasodilation, migraines, orthostatic intolerance, increased neurotransmitters and there are a lot of adenosine receptors in the hypothalamus which might explain why so many of us have endocrine abnormalities.

Adenosine is also displaced by caffeine temporarily which may explain why caffeine helps some of us. It blocks the adenosine which makes us feel more alert.

There is also a relationship with nicotine - but it seems to be the opposite one. Nicotine enhances the circulatory effects of adenosine apparently.

But these two thoughts don't seem to work together - is it high adenosine failing to break down into uric acid? Or just low adenosine in general?

Does anyone know how to find this gene? Is there a place to look up the mutation?

Has anyone ever tried treatment with adenosine or a medication that breaks it down like the asthma med theophylline?

Thanks for your input!

Ema
 
Messages
15,786
Does anyone know how to find this gene? Is there a place to look up the mutation?
I saw something regarding an adenosine gene and immune dysfunction recently on someone's rare results - it might have been your files, but I don't see it in my notes thus far. I'll keep looking, cause I know I saw something in the past couple days!

I'm homozygous for rs4745745 on ADK and another ME/CFS patient is heterozygous for it. Someone else is heterozygous for a missense mutation at rs8187643 on SLC29A2.
 

ukxmrv

Senior Member
Messages
4,413
Location
London
My 23and me results are

rs4745745 AG

rs8187643 --

(and my uric acid levels didn't get high on Imunovir as my NHS GP checked them for me a couple of times)
 
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15,786
@Ema - w00t! I found it, and it was in your results as I thought it might be.

You have a very rare heterozygous version of rs17595410. It's on the USP4 gene, which has an impact on ADORA2A proteins.
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
Thank you, @Valentijn! You were first on my list to find this morning and I was delighted to see that you found this thread...Big help!

So I found the AMPD1 snp rs17602729 last night. It is supposed to be GG; mine is AG.

So I'm trying to figure out what all is involved in this ADA deficiency from a genetic perspective.

So far:
1. AMPD1, rs17602729
2. USP4, ADORA2A, rs17595410

What exactly are these?

I'm homozygous for rs4745745 on ADK and another ME/CFS patient is heterozygous for it. Someone else is heterozygous for a missense mutation at rs8187643 on SLC29A2.

Is there a list anywhere of the genes that are known to code for this adenosine deaminase? It says in the drug monograph for the Adagen replacement adenosine deaminase enzyme that there are 12 genetic mutations associated with severe combined immune deficiency. But it doesn't list them and I don't know where to look for them. Do you?

Ema





 
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15,786
1. AMPD1, rs17602729
2. USP4, ADORA2A, rs17595410

What exactly are these?
rs17602729 is a pathogenic missense mutation on AMPD1, which is "adenosine monophosphate deaminase 1". It's an enzyme which changes adenosine monophosphate into inosine monophosphate. AMPD1 acts in skeletal muscle, wheres AMPD2 is in the liver and AMPD3 is in erthyrocytes.

When there's a deficiency, insufficient energy is generated because you can't get to the ribose usually removed from AMP. It can also cause a reduction in ammonia, which is theorized to cause reduced blood flow and oxygen during exertion. Fatigue, muscle cramping, and pain can result, and it can take days or months to recover. You can read a little bit about your version of it at http://omim.org/entry/102770#0001 . http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222030/ discusses the heterozygous variation, which wasn't quite statistically significant, but might be in a bigger study.

rs17595410 isn't known to be a missense mutation, and it's much rarer so there's no research into it yet. ADORA2A is an adenosine receptor, which "plays an important role in many biological functions, such as cardiac rhythm and circulation, cerebral and renal blood flow, immune function, pain regulation, and sleep. It has been implicated in pathophysiological conditions such as inflammatory diseases and neurodegenerative disorders."
Is there a list anywhere of the genes that are known to code for this adenosine deaminase? It says in the drug monograph for the Adagen replacement adenosine deaminase enzyme that there are 12 genetic mutations associated with severe combined immune deficiency. But it doesn't list them and I don't know where to look for them. Do you?
Searching for "adenosine deaminase" with a "limit" for homo sapiens brings up a good list. ADA, ADAR, ADAR3, ADARB1, ADARB2, ADAT1, ADAT2, ADAT3. There are also a lot of other genes involved in adenosine production, etc.
 
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15,786
@Ema
Other pathogenic mutations on those genes are at:

AMPD1
rs35859650 (A)
i5003567 (T) rs121912682

ADA
rs73598374 (T)
i5002475 (G?) rs387906267
i5002489 (A) rs121908736
i5002480 (A) rs199422328
i5002478 (C) rs267606634
i3002714 (A) rs121908717
i3002715 (T) rs121908714
i5002477 (C) rs267606635
i5002486 (G) rs121908739
i5002488 (T) rs121908737
i5900424 (T) rs121908728
i5002482 (A) rs121908735
i5002476 (T) rs121908722
i5002485 (A) rs121908740
i5002484 (T) rs114025668
i5002479 (A) rs121908729
i5002487 (A) rs121908738
i5002490 (T) rs121908718
i5002492 (C) rs199422327
i5002481 (A or C) rs121908721
i5002491 (A) rs121908715
i5900424 (T) rs121908728

And more to come :p
 
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Ema

Senior Member
Messages
4,729
Location
Midwest USA
So not only am I heterozygous for the AMPD1, I compound this problem by having a faulty adenosine receptor?

So it is at least possible that I am making an inadequate amount of adenosine deaminase and then also am not able to use it efficiently?

This high level of adenosine destroys the immune system in terms of T and B cells which explains low IgG levels and opportunistic infections run amok. And it also explains PEM.
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
@Ema
Other pathogenic mutations on those genes are at:

AMPD1
rs35859650 (A)
i5003567 (T) rs121912682

ADA
rs73598374 (T)
i5002475 (G?) rs387906267
i5002489 (A) rs121908736
i5002480 (A) rs199422328
i5002478 (C) rs267606634
i3002714 (A) rs121908717
i3002715 (T) rs121908714
i5002477 (C) rs267606635
i5002486 (G) rs121908739
i5002488 (T) rs121908737
i5900424 (T) rs121908728
i5002482 (A) rs121908735
i5002476 (T) rs121908722
i5002485 (A) rs121908740
i5002484 (T) rs114025668
i5002479 (A) rs121908729
i5002487 (A) rs121908738
i5002490 (T) rs121908718
i5002492 (C) rs199422327
i5002481 (C) rs121908721
i5002491 (A) rs121908715
i5900424 (T) rs121908728

And more to come :p

Does the letter in parenthesis specify what it should be?

For example, on rs35859650 (A), I'm GG.
 
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15,786
So not only am I heterozygous for the AMPD1, I compound this problem by having a faulty adenosine receptor?
It's hard to guess how your version of USP4 might be affecting you, since there's no research yet. It might be a down-regulation or an up-regulation, or exactly the same.
 

L'engle

moogle
Messages
3,197
Location
Canada
Very interesting. Would this relate to ATP supplementation or is that not recommended. Or would it still do no good if it is the enzyme needed for breaking down adenosine that is faulty. Not to mention the difference between ATP and AMP. Well, complex isn't it?
 
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Ema

Senior Member
Messages
4,729
Location
Midwest USA
Very interesting. Would this relate to ATP supplementation or is that not recommended. Or would it still do no good if it is the enzyme needed for breaking down adenosine that is faulty. Not to mention the difference between ATP and AMP. Well, complex isn't it?
It looks like some people got better from that first link by taking AMP injections...but I don't understand why that would be. Or how reputable that site is, honestly.

I found this warning on another site:

The limited number of human studies involving oral AMP have not indicated any side effects. However, some researchers have expressed concern that supplemental intake of AMP could, in theory, increase levels of adenosine, a substance related to AMP that may interfere with immune function.2Doctors using AMP injections report that too-rapid intravenous administration or inadvertent administration of an intramuscular injection into a vein could cause life-threatening arrhythmias of the heart.3

That seems counterproductive. But I am the first to admit that I don't fully understand how all these things work together. I just think it can't be a coincidence.
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
So maybe people have known about this adenosine deaminase problem for a while. I wonder why we don't hear more about Adagen.

"We learned that the Chairman/CEO of EpiGenesis Pharmaceuticals had discovered that folinic acid is used to treat adenosine depletion. The other thing we came to realize is that we observed immune modulation that appeared to be represented, at least in our patients, by a reduction in some of the CD4 T-cell counts. Please keep in mind that this was an observation and not some double-blinded trial with age and sex matched controls. This information is very intriguing considering that some CFIDS/ME patients go on to develop Idiopathic CD4 Lymphocytopenia (ICL) which has been seen in HIV-negative AIDS patients as reported in the medical literature [1 - 4]. ICL itself has been associated with a deficiency of adenosine deaminase [1]. Technically speaking, adenosine deaminase deficiency causes an increase of dATP, which inhibits S-adenosyl-homocysteine hydrolase, causing an increase in S-adenosylhomocysteine. Both dATP and S-adenosylhomocysteine have toxic affects on lymphocytes, causing them to be functionally defective. The defective function is caused by a depletion of all of the dNTP pools. This causes a breakdown in DNA synthesis and repair of breaks occurring in the DNA. This makes for a very serious disease and that is why the presence of ICL in CFIDS/ME patients causes a severe immunodeficiency where patients become prone to repeated infections. In CFIDS/ME, this is an acquired condition due to the disease progression itself. I should point out that one treatment option for adenosine deaminase deficiency involves the replacement of the enzyme adenosine deaminase itself. The drug used for this is called Adagen by Enzon Pharmaceuticals and it has been used for the treatment of severe combined immunodeficiency disease, known also as SCID, due to adenosine deaminase deficiency."

1. Adenosine deaminase (ADA) deficiency as the unexpected cause of CD4+ T-lympho-
cytopenia in two HIV-negative adult female siblings; Fairbanks LD, Simmonds HA,
Webster AD, Shovlin CL, Hughes JM; Adv Exp Med Biol. 1994;370:471-4
2. Idiopathic CD4+ T-lymphocytopenia--immunodeficiency without evidence of HIV
infection; Ho DD, Cao Y, Zhu T, Farthing C, Wang N, Gu G, Schooley RT, Daar ES;
N Engl J Med. 1993 Feb 11;328(6):380-5
3. Unexplained opportunistic infections and CD4+ T-lymphocytopenia without HIV
infection. An investigation of cases in the United States. The Centers for Disease Control
Idiopathic CD4+ T-lymphocytopenia Task Force; Smith DK, Neal JJ, Holmberg SD;
N Engl J Med. 1993 Feb 11;328(6):373-9
4. Acquired T cell specific deficiency other than acquired immunodeficiency syndrome (AIDS);
Saiki O, Ogawa H, Ikeda T, Masuno T, Tanaka T, Deguchi Y, Endou T, Kishimoto S;
Intern Med. 1992 Jan;31(1):11-6


http://www.ncf-net.org/forum/JustAsk-S07.htm
 
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15,786
I'm confused with rs121908721

Options at 23andme are A or G (I'm GG)

At snpedia I'm seeing the reference allele as C and the risk alleles as G or T
http://snpedia.com/index.php/Special:FormEdit/ClinVar Disease/Severe_combined_immunodeficiency_due_to_ADA_deficiency?redlink=1

But the risk is C in your list @Valentijn. Can you help me make some sense of this one?
It has three known alleles listed, which is probably what's causing the confusion. But "G" should be the normal one. SNPedia might be looking talking about the reverse strand or reading the research backwards. But GG is the normal version. A or C would be the pathogenic versions - interestingly, it looks like either one results in a different pathogenic mutation.
 
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15,786
So does that mean that supplementing ribose directly might be of value?
It's probably worth a try ... there's no guarantee that this gene is causing your problems, since you are heterozygous instead of homozygous. But it's definitely possible that it is contributing a bit. In which case ribose could help, and as far as I know it isn't capable of causing side-effects, etc.
 
Messages
15,786
Very interesting. Would this relate to ATP supplementation or is that not recommended. Or would it still do no good if it is the enzyme needed for breaking down adenosine that is faulty. Not to mention the difference between ATP and AMP. Well, complex isn't it?
The problem isn't with too little AMP, but rather with breaking down AMP into another substance. Hence supplementing ATP and/or AMP is likely to aggravate the problem, not help it.