Suggested Pathology of Systemic Exertion Intolerance Disease [...] (2019) Bohne

Title:Suggested Pathology of Systemic Exertion Intolerance Disease: Impairment ofthe E3 Subunit or Crossover of Swinging Arms of the E2 Subunit of the Pyruvate Dehydrogenase Complex Decreases Regeneration of Cofactor DihydrolipoicAcid of the E2 Subunit

Abtract:Systemic Exertion Intolerance Disease (SEID) or myalgicencephalomyelitis (ME) or chronic fatigue syndrome (CFS) has an unknown aetiology, with no known treatment and a prevalence of approximately 22 million individuals (2%) in Western countries.

Although strongly suspected, the role of lactate in pathology is unknown, nor has the nature of the two most central symptoms of the condition –post exertional malaise and fatigue.

The proposed mechanism of action of pyruvate dehydrogenase complex (PDC) plays a central role in maintaining energy production with cofactors alpha-lipoic acid (LA) and its counterpart dihydrolipoic acid (DHLA), its regeneration suggested as the new rate limiting factor. Decreased DHLA regeneration due to impairment of the E3subunit or crossover of the swinging arms of the E2subunit of PDC have been suggested as acause of ME/CFS/SEID resulting in instantaneous fluctuations in lactate levels and instantaneous offset of the DHLA/LA ratio and defining the condition asanLA deficiency with chronic instantaneous hyperlactataemia with explicit stratification of symptoms.

While instantaneous hyperlactataemia has been suggested to account for the PEM, the fatigue was explained by the downregulated throughput of pyruvateand consequently lower production of ATP with the residual enzymatic efficacy of the E3subunitor crossover of the E2as a proposed explanation of the fatigue severity. Functional diagnostics and visualization of instantaneous elevations of lactate and DHLA has been suggested.

Novel treatment strategies have been implicated to compensate for chronic PDCimpairment and hyperlactataemia. This hypothesis potentially influences the current understanding and treatment methods for any type of hyperlactataemia, fatigue, ME/CFS/SEID,and conditions associated with PDC impairment.

Full text: https://sci-hub.tw/10.1016/j.mehy.2019.109260

Link to the abstract: https://www.sciencedirect.com/science/article/abs/pii/S0306987718312994?via=ihub

 

Alternative sci-hub link: https://sci-hub.se/10.1016/j.mehy.2019.109260

 

In brief, these were the guys that created the special drink that a few folks took and got better. Has to be made fresh and in the right amounts as it can have negative effects if not made right. They have a theory, applied for patents, reckon to be working on a test but never got ethical approval. Because of that they have been shunned. It's an oxolate drink - patent has the formula.

PR thread for history 2016-2018. Page 4 is where the patent discussion starts
https://forums.phoenixrising.me/thr...victoria-bohne-in-norwegian.44871/post-982807

They did have a Facebook page and website. They killed the Facebook page although Victoria Bohne still has her own personal page, and the website domain expired this year I believe.

I'll read the paper later when I have more spoons....... Thanks @Marky

EDIT : Patent discussion here as well
https://www.s4me.info/threads/paten...r-treatment-of-chronic-fatigue-syndrome.4530/

 

Thanks for the links @wigglethemouse, I read through it but don`t have the education for assessing how energy metabolism works besides basics.. Hopefully someone who do can chime in on the hypothesis!

 

Just to make it clear, they actually did studies and experimented on people - without ethichs approval. The ethics commitee reported them to the Department of Health.

Decline letter, for retrospective application - note, the studies they did wouldn't have been approved anyhow:
https://www.s4me.info/threads/paten...onic-fatigue-syndrome.4530/page-2#post-103358

Also theres been a lot of drama and odd behavior, that's made it hard to engage in their idea. That's not to say the idea in itself may not be valid, and should be discussed for it's own merrits.

 

The theory for this reads like that AI thread we had recently. I cannot compute. I doubt many here can understand either. Anyone up to the challenge to?

Here are some excerpts from the paper describing possible tests from "Evaluation of the hypothesis" section. The killer really to all this is that instrument to measure DHLA and LA in healthy people doesn't exist yet as described in the text (If I read that right).

DHLA = dihydrolipoic acid
LA = alpha-lipoic acid
IFL = instantaneous fluctuations of lactate

Test 1

There was a paper recently that continuously measured lactate levels under aerobic conditions. Did I remember right @Michiel Tack?
https://www.s4me.info/threads/physi...xercise-testing-in-me-cfs-by-lien-et-al.9826/

Test 2

Test 3

Test 4

I take this to mean enzyme E3 which in Figs 1 & 2 is DLD. From Genetics Home Reference
"the DLD gene provides instructions for making an enzyme called dihydrolipoamide dehydrogenase. This enzyme forms one part (subunit), called the E3 component, of several groups of enzymes that work together (enzyme complexes). These complexes are essential for the breakdown of certain molecules to produce energy in cells."

Summary so far

Genetic Causes Tests 5 & 6

DLD gene info (not in paper)
https://ghr.nlm.nih.gov/gene/DLD

DLAT gene info (not in paper)
https://ghr.nlm.nih.gov/gene/DLAT

Be interesting to get thoughts from Mito experts even with the controversy . Do you think Karl Morten would be interested @Andy. Paul Fisher in Australia is the other one I can think of. Victora Bohne did say Ron Davis had seen the draft paper on testing last year (post since deleted on Facebook when the Bohne Askoy account was deleted).

 

I cannot get any grip on this idea. High blood lactate does not make you feel the way PWME feel. I have looked after people with very high blood lactate and it does not fit. SO the idea seems to be a non-starter.

With any idea like this you have to start off by asking how they answer questions like:

1. Why does the problem suddenly develop in mid life after a virus and go on for years.

2. Why are the symptoms different from other metabolic upsets with diabetes, renal or liver disease - PEM, sensory sensitivities etc.

3. Where is the evidence that PWME have an abnormality the theory predicts of sufficient level to account for symptoms.

And so on. I don't see this theory begin to answer any of these.

 

This is what the paper says about oxalates. LDH = lactate dehydrogenase

 

I think they are comparing it to DLD deficiency disease. This is what the Genetics Home Reference I linked to above for DLD says

EDIT : More info on DLD deficiency on the rare diseases site.
https://rarediseases.info.nih.gov/diseases/3263/dihydrolipoamide-dehydrogenase-deficiency

 

This is what the paper says about cause. Pretty vague and open ended.

 

Mid life rules out children

 

I wondered why the paper had no data to support the hypothesis. The only evidence they offer is

 

I know people I trust who has had a strong response, but as we know from experience we need the research. At the moment they weren't allowed by the regional ethics committee to publish the data after they were collected, mainly by the argument that the study was unethical. To be honest, I think that is too harsh, because it is not clear at all by norwegian law what counts as research, and what counts as experimental treatment on an individual level. This is why most clinicians here apply first anyway, to avoid any possible backlash. I don`t mind them publishing the hypothesis to generate interest when they have not been in a position to publish the data anyway.

 

I can attest to this, i tested at the hospital with a level between 2.5-3 mmo/l and did not feel any more different than normal. I think it`s a starter though, because it`s not supposed to be that high without doing anything. Fluge&Mella had several patients who had 8 mmol/l when standing up. When i read on it apparantly thats considered a medical emergency usually (for other reasons), so I got curious as to why this isnt the case when ME-patients gets these values

 

The frustrating thing about ME is that everything they test for is normal but our bodies aren't working in a very profound way. How can we be so ill when all the tests are normal?

It must be some widespread process that is very basic to biology but is just a little bit off.

I think of it as the difference between being burgled and being stalked. If you come home, the door is kicked in and the telly is gone everyone knows what has happened, it will get fixed and life will go on. If you tell people that the photos on your desk have been shifted one day and a drawer messed up the next they seem such a little thing they might not believe you but if it keeps happening your life will be turned upside down.

 

Interesting. Maybe patients have adapted to exist in a high lactate state?

 

If you look at blood lactate levels in patients they are not normal, but the critics say that they are high due to deconditioning.

 

I was not very clear in my previous post. Lactate does not fit with ME for me because it gives the wrong symptoms when it is up and it has to be vey up to give symptoms.

A local lactate rise in muscle may produce the symptoms you get when sprinting with a cramping pain (although I don't know if it is actually what causes that). But high blood lactate is often not associated with any specific symptoms and when it is high enough the symptoms don't look like ME. In severe lactic academia people have a change in respiratory pattern and become weak and then go in to coma. It is nothing like what PWME describe as far as I can see.

Either way symptoms of ME are not explained by the sorts of lactate levels recorded.

 

You say it needs to be very up to give symptoms so could increased lactate be an indication of something different happening within the metabolic process but not the cause of symptoms?