Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from CFS/ME, 2019, Cabanas et al

Electrolytes, unite!

 

They could well be on to something but they need to do more than just testing 12 patients before declaring, based on the use of a "gold standard" test, that the results apply to all with ME. Just because the test is gold standard doesn't mean that they used it on gold standard patients, and even if the patients could be representative of all, 12 patients is still just too small a number.

 

Two sentences, one from the article, one from the study itself, for me stood out:

"..Genetic variations in TRP ion channels have been previously reported by NCNED in immune cells from CFS/ME patients..."
and
"...Numerous and significant anomalies including genetic, proteomic, and functional anomalies in TRPM3 ion channels have been reported in CFS/ME patients suggesting perturbations in Ca2 signalling in NK cells from CFS/ME patients..."

So like many channelopathies, these are genetic, if I understand correctly. We would be born with them. Does that mean that the two-trigger scenario would apply? These genetic anomalies go unnoticed, or do not levy any noticeable impact, until something like a virus or other infection triggers a cascade of events that unleashes the channelopathy?

Channelopathies often go unnoticed until later in life. But NK channelopathies pose many questions. We are constantly invaded by bacteria and viruses, pretty much from birth to death. Why does it take so long to get us to the point of no return?

Also, would this - because it's NK cells - mean ME/CFS is an immune dysfunction after all, or would it now fall under the channelopathy umbrella? I think, too, there is such a thing as acquired channelopathies. How do these investigators know these are endogenous physiologies (this may be an extremely ignorant question)?

Six is a small sample size, yes. But for six to have a channelopathy identified is not insignificant. We cannot extrapolate from that, but six channelopathies is kind of weird - I don't think there are a lot out there in general.

 

$2.2m late last year from Stafford Fox, I think @Trish is referring to: https://app.secure.griffith.edu.au/...-bolster-efforts-of-griffith-cfs-researchers/

We won’t find out until at least mid 2020 about the grants, according to NHMRC: https://meaustralia.net/2019/05/19/research-council-expects-to-fund-me-and-cfs-projects-in-2020/

 

Nothing wrong with small sample size and work out what is what. Big sample size would throw in too many differences; where as this gives a good base to then test against. More focus and I would like to see how this all changes with PEM, lactic acid and the metabolic trap. Everyone focuses on the medication but if we understood the mechanics of the switch we could avoid it?

 

I agree, there is nothing wrong with a small sample size - as long as it's a starting point. As noted above, finding the same issue in 6 out 6 patients suggests that this could be important, but we don't know in how many of the wider patient population. Obviously it would seem to be important to those six, but I would want to see further analysis to see if it is repeated in a larger population before drugs are tested, as potentially all they may be doing is is looking for something to help those six patients.

My concern is the lack of caution. In my opinion, they are making statements that go far beyond the evidence they have gathered so far, and they have history of doing this. Fluge and Mella waited until they had tested Rituximab on more than 152 patients in total before stating whether or not it worked, as frustrating as it is I would prefer this level of caution in all of our researchers.

 

I get your point and would agree, however when funding is not easy to come by and you are fighting CBT and GET I may just forgive them... a little.

So what would be your next step? I don't see they would get funding for a bigger group without trying a drug? Trying a drug and seeing the result may give them more information?

 

Well, my step would be seeing if their initial results held up in a larger group. Why do you think they wouldn't they get funding for a bigger group? If they have money to test drugs, surely they must have money that could be used to validate, or not, their results?

 

Thoughts @Jonathan Edwards? I know you have commented previously on the possibility that ME might be due to a signalling problem.

 

I don't know a lot about TRP channels but I cannot get a clear idea of what they think is the relation between these and the clinical features of ME. They talk about NK cell defects but it is not really clear that there is a consistent NK defect in ME or how it would relate to illness. An effect on sensory receptors might be of interest but I am not sure quite what would be expected.

 

They are very similar clinically. I know people who have been diagnosed with ME that turned out to have a channelopathy. My wife pretty much satisfies the criteria for ME, but all her symptoms can be ascribed to her channelopathy. Of course, her particular form of PP has characteristics that fall outside of ME as well.

 

I don't understand what you mean here. The bigger the sample the fewer false positives you are likely to get. The number of differences depends on how many things you test for, not the number of people you test, and if you don't test enough false positives will come up.

I would like to think there is an important observation here. But I think to get more funding they need to explain what they have found in a way that a scientist like myself, who gets asked to review grants on ME, can understand. I don't really follow what they think they have found.

I worry when a group say they have found abnormal SNPs in NK cells. Abnormal SNPs will be in every cell so there is no point in looking specifically in NK cells, unless you think you are looking for a mutant tumour line. The normal thing would be just to report the difference in frequency of SNPs, period.

I may be missing something simple and would like to be put right if so.

 

I wouldn't expect a TRP channel abnormality to produce effects at all similar to potassium channelopathy, if that is what you are referring to. My guess is that they are thinking of sensory sensitivities but it does not seem clear.

 

I read the study yesterday or the day before, but I have already pretty much forgotten it. I lump channelopathies together - I guess because my wife belongs to a channelopathy forum of sorts, and I read it. It has potassium channelopathies and calcium channelopathies. Maybe TRP ones too, but I do not recall them.

My point is, there is a core set of symptoms that surface: profound muscle weakness, sleep problems, cognitive issues, exhaustion and a sort of PEM that is maybe different than ours. You can see the potential overlap.

But your point about TRP channelopathies perhaps generating a different set of symptoms is a good one.

 

Can you say more about that kind of PEM?

 

It's more like episodes, I guess. But it's payback for overdoing things, similar to PEM. With channelopathies, in addition to physically doing too much and triggering an attack, eating the wrong things can elicit a sudden exacerbation of symptoms. Muscle pain, muscle weakness to the point of paralysis in some patients, stomach issues, balance issues, bad cognitive issues, exhaustion. Episodes can be short-lived or protracted, lasting days or weeks or longer. Some have POTS, as well.

But there are differences too. For my wife's brand of channelopathy, the most frequent time for her PEM is following prolonged rest. Her most dangerous time of day is immediately after sleep.

Also, there can be severe cardiac issues that are tied directly into the channelopathy, so any episode or PEM may involve that.

Sorry, I'm sure I am forgetting stuff.

 

So do I understand this correctly, in a channelopathy the symptoms would happen immediately after overdoing it? Or do they start the next day, like it's often the case with PEM?

And are all the symptoms clearly and directly linked to potassium dysregulation? As opposed to in PEM where walking too much can result in something as seemingly unrelated as flu-like symptoms?

 

There is no set rule that I am aware of. Too little is known. But based on the patients on the channelopathy forum I have read about, it's often the next day or so. The difference may be when food is involved, right? So if you are hyperkalemic, and you ingest something with too much potassium, the reaction could be brutally quick.

No way too know. My wife's cardiomyopathy may or may not be linked to her potassium channelopathy. We just don't know enough. But some of the symptoms we know are, eg, her muscle weakness and exhaustion and spaciness and the like.
The thing is, how do we know our own forms of PEM don't relate back to some type of channelopathy? I don't think they do, but they may. So little is known about channelopathies in general. If you parse down and try to differentiate them, it get's even weirder. Only 100 people or so in the entire world have been diagnosed with my wife's channelopathy.

ETA: Many are like my wife: normakalemic. Their potassium levels fall within normal range. Yet she is one of the worse. What if we are like that? What if our CBC values are all normal, even though we are technically sensitive?

 

Actually it was 12 patients and controls, link to paper here, but one article mentioned they repeated the patch-clamp experiment on each samples 6 times which ended with the exact result, which is that all patients were positive and healthy controls were negative.