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

[Marky]

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

 

[Lisa108]

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

 

[wigglethemouse]

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/

 

[Marky]

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!

 

[inox]

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/

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.

 

[wigglethemouse]

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

One particular, yet unreported, phenomenon, high-amplitude IFL, might reflect the dysfunctional in situ clearance of lactate. IFL is the difference between two consecutive measurements of capillary lactate levels. Detection of ‘up’ and ‘down’ peaks of lactate reflect the activity of the pyruvate/NAD+ shuttle in a two-tact mechanism of in situ clearance of lactate.

The hypothesis may be successfully assessed through functional analysis based on consecutive measurements of lactate levels within short intervals (5 min) before, during, and after the applied stimuli (test 1).

Stimuli should not generate anaerobic conditions within the cell and not be of muscular work by nature. Any physiological or cognitive functions, such as reading or digestion of a light meal could be examples of appropriate stimuli.

No studies have attempted to determine lactate levels in ME/CFS/SEID patients in response to stimuli under aerobic conditions; however, elevated lactate levels (22) and impaired proton homeostasis (23) after physical exertion, e.g. under anaerobic conditions, have been reported

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

We suggest that DHLA in addition to regenerative the proton flow path may have alternate systemic, extramitochondrial functions similar to the Cori cycle for lactate gluconeogenesis. Therefore, only short-term, instantaneous, elevations of DHLA might be expected, similar to lactate.

Measurements should be performed in the same manner as that in test 1, eventually reflecting only the consequence without identifying the cause (test 2). At the present time, the limit of DHLA and LA detection in healthy volunteers is higher than the physiological range (24) and therefore development of a new methodology is highly required.

Test 3

Therefore, by performing test 1 but with chemical stimulation by riboflavin instead of functional stimuli, in the same manner as glucose is used to diagnose diabetes, higher-amplitude IFL will be induced only in affected individuals (test 3).

Test 4

In addition, the degree of E3 impairment can be measured through analysis of enzymatic efficacy (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."

Thus, both the cause and the degree of impairment can be identified.

Summary so far

Therefore, by performing test 1 but with chemical stimulation by riboflavin instead of functional stimuli, in the same manner as glucose is used to diagnose diabetes, higher-amplitude IFL will be induced only in affected individuals (test 3). In addition, the degree of E3 impairment can be measured through analysis of enzymatic efficacy (test 4). Thus, both the cause and the degree of impairment can be identified.

Genetic Causes Tests 5 & 6

To exclude the inherited nature of DLD or swinging arms of DLAT impairment, the test for any alterations within corresponding encoding genes may be performed (test 5 and 6).

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

At least 17 mutations in the DLD gene have been found to cause dihydrolipoamide dehydrogenase deficiency. The signs and symptoms of this severe condition vary widely, but they most commonly include a potentially life-threatening buildup of lactic acid in the tissues (lactic acidosis), neurological problems, and liver disease.

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

At least two mutations in the DLAT gene have been identified in individuals with pyruvate dehydrogenase deficiency; mutation of the DLAT gene is a very rare cause of this condition. Pyruvate dehydrogenase deficiency is characterized by a potentially life-threatening buildup of a chemical called lactic acid in the body (lactic acidosis), delayed development, and neurological problems.

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).

 

[Jonathan Edwards]

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.

 

[Trish]

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.

I remember reading their stuff about some sort of juice they made including lots of spinach that they claimed made people's symptoms improve and their attempt to patent it. I wonder if this is an attempt to make a theory to fit the high oxalates in the drink. My biochemistry isn't sufficient to make sense of it. Given that too much oxalate is poisonous, I'm not keen and I won't be experimenting.

 

[wigglethemouse]

I wonder if this is an attempt to make a theory to fit the high oxalates in the drink. My biochemistry isn't sufficient to make sense of it. Given that too much oxalate is poisonous, I'm not keen and I won't be experimenting.

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

The therapeutic effect of nutritional oxalates on hyperlactataemia resulting from different aetiologies has been unveiled, which is currently pending a patent, probably owing to the favourable reversible enzymatic activity of LDH (Fig. 2 step 8).

Oxamate and oxalate inhibit LDH in different directions, in competition with pyruvate and lactate, respectively (20), and this activity is observed only with bound enzymes. Moreover, a precursor of oxalate, DCA, has reduced therapeutic effects in ME/CFS/SEID patients (21). Altogether, these findings strengthen our assumption.

Because enzymatic conversion of lactate to pyruvate does not affect DHLA regeneration, this therapy should be combined with a compensatory exogenous supply
of LA (step 11).

 

[wigglethemouse]

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

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

This accumulation is toxic to cells and tissues, particularly in the nervous system, and contributes to neurological problems in people with dihydrolipoamide dehydrogenase deficiency.

A reduction in pyruvate dehydrogenase function results in buildup of pyruvate, which is converted in another chemical reaction to lactic acid, contributing to lactic acidosis in affected individuals.

Impairment of αKGDH leads to the accumulation of alpha-ketoglutarate and likely also contributes to lactic acidosis.

Reduced function of these three enzyme complexes also diminishes the production of cellular energy.

The brain, which requires especially large amounts of energy, is severely affected, resulting in the neurological problems associated with dihydrolipoamide dehydrogenase deficiency.

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

 

[wigglethemouse]

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

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

Further, we believe that all symptoms from the list of the Canadian criteria (16) might be explained by the present hypothesis and either result from dihydrolipoyl dehydrogenase (DLD, E3) or dihydrolipoyl transacetylase (DLAT, E2) crossover impairment owing to
(a) altered levels of carbon matter (elevated lactate levels and lowered levels of signalling molecules);
(b) disturbances in electrochemical electron transport;
(c) allostatic offsets of PDC co-factors, including NAD (niacin), FAD (riboflavin), and TPP (thiamine) in addition to LA/DHLA;
(d) downregulation of PDC or any other yet unknown consequence.

 

[Amw66]

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.

Mid life rules out children

 

[wigglethemouse]

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

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

Clinical evidence regarding a successful treatment protocol based on the hypothesis presented herein will be published elsewhere.

 

[Marky]

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.

 

[Marky]

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.

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

 

[Mithriel]

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.

 

[Hoopoe]

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

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

 

[deleder2k]

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.

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

 

[Jonathan Edwards]

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

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.

 

[Adrian]

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?