Evidence of a genetic background predisposing to complex regional pain syndrome type 1, 2023, Shaikh et al

Genes may be responsible for one complex regional pain case in 3 say researchers.

https://www.physioupdate.co.uk/news...-pain-syndrome-case-in-three-say-researchers/

there is a link at the bottom of this article to the journal paper: https://jmg.bmj.com/content/early/2023/09/15/jmg-2023-109236

 

This looks quite important. There was a confirmatory sample but it would be good to see further confirmation.

CRPS-1 as I understand it is 'spontaneous' in that there is no defined nerve injury beforehand. It can follow soft tissue trauma but need not. If you like it is a 'medically unexplained symptom'. The effects, however, show clear structural pathology. So it is a good example of how unexplained processes can generate major symptomatic problems such as pain.

Finding a range of uncommon gene associations suggests that CRPS-1 may involve some increased neural pathway sensitivity that can get out of control.

 

I asked my good buddy ChatGPT what those genes do:

 

Ion transport, it seems.

 

I don't know much about CRPS. Is this relevant to ME/CFS?

 

Not that I can think of, but it is definitely in the same MUS/"I don't believe in this illness" category that psychosomatic ideology has captured.

Progress is achingly slow, but as more and more conditions falsely categorized as psychosomatic get figured out, it will diminish the validity of the "we don't know the cause = psychological" logical fallacy that the entire construct is made of.

By far the biggest threat to psychosomatic ideology is research. Hence why they always try to stop it. Oh, the irony. It burns. It burns so deep.

 

I don't know if there is much of an overlap/comorbities of those with CRPS having ME/CFS and I guess in a sense we don't know enough about the cohort of either to know if there are similarities

However, as I was reading through this, and having read the recent post that asked people what their gut instinct was on what ME/CFS might turn out to be (and of course other threads on similar lines - which by the way I do think are useful given there might be different types and those who have had this for a long time have been their own guineau pigs and read up a bit so can muse somewhat on their 'sense' of what might fit) it seemed 'of use'. Or might be of interest.

It also made me think of the question of what areas should/might be involved in looking into ME/CFS and where developments that might shed light on parts of what is involved and going wrong might come from ie which areas of specialism have a lot of developing to do and might end up describing parts that currently are little-known but eventually might be relevant for understanding. Or transferrable methodological approaches etc

But really the article struck me most because I think the approach and thinking is very interesting, having read the more summarised version:

and on the journal paper above I found the discussion, as a non-expert in the area, a fascinating introduction to a 'new world' watching someone hypothesise on how the different parts could come together. Particularly from the following paragraphs down fascinating to learn about how different areas can interact and link together (as we think about how complex the picture might be for ME/CFS and the various patterns and symptoms within it):

 

I agree with @bobbler that there are reasons to think this is relevant to thinking about ME, @Hoopoe.

The higher rate of risk genes in men I think is easily explained. If having two X chromosomes (being a woman) is also a risk then women need fewer other genes to tip them into CRPS. For men the other genes are more relevant.

I actually doubt this is to do with autoimmunity or inflammation. The author's musings on mechanisms look a bit guided by fashion. In CRPS-1 the affected part is often reddish but cold. This is not inflammation. It is something we have seen for decades or centuries and never had an explanation for.


So, thinking about why women should have more CRPS-1 and also more ME, without much indication of autoimmunity I started thinking about pain interacting with tissues - which in CRPS is easy for all to see, but unexplained. In ME and fibromyalgia, if that can be usefully defined, there is nothing to see but still a major problem.

I also note that pain can interact with body tissues in anyone, men as well, including me, in remarkable ways. When I had renal colic, which is said to be the worst pain known, my hands became completely drained of blood because of some peculiar pattern of sympathetic nerve activity.

And of course women have Raynaud's much more than men, regardless of any autoimmune problems - constitutional Raynaud's is more common in women.

So what is it that is different about women that might affect interactions between pain and tissues and blood flow? If we forget antibodies, is there anything much different? Do women look different?

Well, yes, very different. The skeleton is a bit different but they mostly look different because in men adipose tissue is collected in the omentum of the gut - beer belly - whereas in women it is distributed evenly around the subcutaneous tissue to produce a more pleasing contour! And presumably this is all about thermoregulation.

In other words women are vastly different in the way peripheral nerves interact with tissue structure, blood flow and metabolism. You will very likely find nothing on blood samples because it is regulation in the body that is different. The cells are the same.
You will probably find nothing specific in any metabolic pathway because the problem is the way the volume knob is being turned and down during the day and night. You still get Radio 1,2,3 or 4.

CRPS may bee of use as a lesson because it shows what can happen if locally the regulatory system goes completely off the scale.

 

Couple of thigs struck me about this:
1) They had a "cohort of well-characterised patients with chronic CRPS-1 (n=34)" and the genes were evident [Note 1]. Highlights the problem in ME/CFS i.e. the population is heterogeneous. Larger GWAS studies, or rather combining studies, have been successfully used as a workaround in dementia.
2) On a lighter note - in the Introduction the authors state "---In 95% of cases, it [CRPS-1] occurs post-traumatically --". The study finds a strong genetic link, despite the small study size, yet the authors don't give up on the old Gods (trauma) - in the Conclusion they state "Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1." OK they've added a new God -- your genes -- maybe the fact that it's published in the BMJ is relevant!


Note 1:
"
Methods Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed.

Results In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher’s p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls.

"Conclusion A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1."