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Mitochondrial enzymes discriminate between mitochondrial disorders and CFS

Discussion in 'Latest ME/CFS Research' started by Marco, Feb 26, 2012.

  1. biophile

    biophile Places I'd rather be.

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    Reminds me of Wessely's recent reminiscence about an early study of his involving comparisons of CFS vs depression vs neuromuscular disorders (http://jnnp.bmj.com/content/83/1/4.full.). Conducted in the late 1980's with no official CFS criteria, instead Wessely sourced "cases of unexplained fatigue" (ie an absence of abnormalities on conventional neurological testing including muscle testing) from neurologists at a hospital for nervous diseases using an ad hoc criteria which seems remarkably similar to what the 1991 Oxford criteria would turn out to be: 6 months (unexplained) fatigue as the primary complaint.

    The "striking" overlap of chronic fatigued patients with depressed patients compared to muscle disorder patients would be an unsurprising methodological artifact when considering that the criteria/symptom of fatigue has known overlap with depression and those with evidence of neurological and muscular abnormalities were actively excluded from the study.
  2. Don Quichotte

    Don Quichotte Don Quichotte

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    Thanks for the link. It's amazing how much damage one young enthusiastic and well-meaning psychiatrist can create (I am sure he was genuinely interested in helping those patients who were referred to him by the neurologists after those decided there was nothing wrong with them) . It is also amazing how, many years later, he clings to his original hypothesis even when so much doesn't fit (and sees those as "minor" issues).

    I read the original article and was amazed to see the significant number of methodological flaws:

    First- you can't create your own questionnaire and use it in serious research without validating it first. (Not to mention that you don't usually diagnose diseases by questionnaires of this sort. quite likely if he used a similar questionnaire in patients with pancreatic cancer, lymphoma or thyroid disorders and not CFS patients, he would have reached similar conclusions, but he didn't validate his questionnaire on any control group of that sort).

    Second- when you compare one group of patients to another group of patients, you have to use clear criteria to define those groups. And as the distinction between normal sadness and depression is still not well-defined, using a group of patients with the diagnosis of depression as a group of comparisson is at the least problematic. (also as I have mentioned many diseases can be mistakes for depression, because of significant overlap in many symptoms; also to complicate matters even more, having a serious/debliltating illness is many times accompanied by a normal reactive sadness/depression).

    Third-the above is even more important when you have mixed and overlapping symptoms of diagnoses. Or else you can easily enter a loop of proving your hypothesis with what you have to prove. (which is basically what happened here).

    Fourth- you can't use a heterogenous group of patients with symptoms varying from mild eye symptoms to being on a respirator in the ICU (such as myasthenia gravis) as your group of comaparisson without clearly defining the severity of the illness in your group of patients. There is no mention of how many had a mild disease, how many had only limb involvement, how many had bulbar symptoms, how many had respiratory problems and sleep disturbances? He also didn't take into account (and probably didn't know) that myasthenia itself (now known to be an autoimmune and rarely a genetic disease) was initially thought to be a non-organic illness (hysteria) because there were no anatomic findings in this disease.

    Further more, patients with atypical variants of myasthenia, or unrecognized respiratory muscle involvement are often diagnosed as suffering from psychiatric problems. In general it is exceedingly common for patients with neurological illnesses to also "have" psychiatric problems. (which in other words means that some of their symptoms are atypical and can't be explained by the current knowledge and understanding of their illness).

    So, the only valid conclusions that can be reached from this paper are that patients with CFS are in many ways similar to patients with less typical forms of myasthenia. And that neurologists commonly attribute symptoms they do not have a good explanation for to psychiatric problems, such as "depression" and "anxiety".

    This does not prove or disprove the validity of this approach and only shows what was already known without this study.
    Without realizing it, the non-organic nature of the disease studied was based on the initial assumption of the non-organic nature of this disease. The fact that there was significant overlap with symptoms of patients with depression did not prove or disprove this assumption. This overlap was obvious without the study, as it was the original hypothesis based on wessley's (right or wrong) observations and impressions, which were validated by his own questionnaire.

    The fact that others readily agreed with his findings and this paper was cited numerous times, only proves (again) the ingeniousness of Lewis Carol in the "Hunting of the Snark" -

    "Just the place for a Snark!" the Bellman cried,
    As he landed his crew with care;
    Supporting each man on the top of the tide
    By a finger entwined in his hair.
    "Just the place for a Snark! I have said it twice:
    That alone should encourage the crew.
    Just the place for a Snark! I have said it thrice:
    What i tell you three times is true."
    MeSci, merylg, alex3619 and 2 others like this.
  3. IanHHH

    IanHHH

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    Histological studies show sporadic, but not uniform, abnormalities in muscle fibers
    and their mitochondria, (e.g., Behan, 1991). McCully et al. (1996) took the ambiguous
    position in their NMR studies of arguing for a defect in muscle oxidative metabolism while
    also maintaining the problems could be a result of muscle deconditioning. NMR studies by
    Lane and co-workers (1995, 1998a, 1998b), however, showed a significant subset of CFS
    patients with abnormal lactate responses to exercise, magnetic resonance characteristics
    indicative of excessive intracellular acidosis and impaired capacity for mitochondrial ATP
    synthesis, which could not be satisfactorily attributed to inactivity or deconditioning.

    Our studies using mononuclear leukocytes, which avoid the interpretative problem of the
    deconditioning phenomenon in muscle, support the reality of a defect in muscle oxidative
    metabolism. Further, mitochondria in mononuclear leukocytes look normal, which
    would explain many of the histological findings of small ultrastructural abnormalities. Our
    ability to examine individual cells and their mitochondria using confocal microscopy and
    our analytical methods (Sect. 2.3) also have an advantage over P-NMR, which inherently
    must average a great many cells in a given muscle area.

    From:
    Chazotte, B., and Pettengill, M., 1998, Cytokine effects on mitochondrial membrane potential and possible
    mitochondrial dysfunction in chronic fatigue and immune dysfunction syndrome, ASBMB J. May 1998.
    Chazotte, B., and Pettengill, M., 1999, Using membrane potential to follow cytokinc effects on mitochondria and
    possible dysfunction in chronic fatigue syndrome, Biophys. J. 76:A363.
    Chazotte, B., Loehr, J. P., and Hackenbrock, C. R., 1996, Quantitative analyses of membrane potential of
    mitochondria in individual living human cells related to chronic illness, FASEB J. 10:A1377.
    MeSci and Dolphin like this.
  4. nanonug

    nanonug Senior Member

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    Are you suggesting that ME is strictly a neurological disorder?
  5. alex3619

    alex3619 Senior Member

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    It is well established that mitochondrial deficits have the greatest impact in nerve tissue. The problem is that biopsies on nerves always cause damage. A brain biopsy gone bad would be a nightmare - and that would be most of them. Muscle is a convenient substitute, and SEVERE deficits should show up in muscle. Slightly less severe might not. Its problematic.

    Blood cells have access to the highest levels of nutrients. In theory they are the worst places to look for mitochondrial issues.

    These are complex issues.

    Bye, Alex
    merylg likes this.
  6. Dolphin

    Dolphin Senior Member

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  7. jace

    jace Off the fence

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    Dr Myhill et al have a paper out re Mito disfunction, which shows all her ME/CFS cohort have measurable abnormalities:


    http://www.ijcem.com/files/IJCEM1204005.pdf
    Int J Clin Exp Med 2012;5(3):208-220 http://www.ijcem.com /ISSN:1940-5901/IJCEM1204005
    Original Article

    Mitochondrial dysfunction and the pathophysiology of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)
    Norman E Booth1, Sarah Myhill2, John McLaren-Howard3
    1Department of Physics and Mansfield College, University of Oxford, Oxford UK; 2Sarah Myhill Ltd, Llangunllo, Powys UK; 3Acumen, Tiverton, Devon UK
    Received April 26, 2012; accepted May 21, 2012; Epub June 15, 2012; Published June 30, 2012

    The objectives of this study are to test the hypothesis that the fatigue and accompanying symptoms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis are in part due to defects in energy provision at the cellular level, and to understand the pathophysiology of the defects so that effective medical intervention can be implemented.
    We performed an audit of 139 patients (ages 18-65) diagnosed with CFS/ME and attending a private practice.
    The patients and 53 normal, healthy controls had the ATP Profile test carried out on neutrophils from a 3-ml venous blood sample. This test yields 6 numerical factors that describe the availability of ATP and the efficiency of oxidative phosphorylation in mitochondria. Other biomedical measurements, including the concentration of cell-free DNA in plasma, were made.
    The results of the audit are compared with the controls and a previous cohort of 61 patients. We find that all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness. The patients divide into two main groups differentiated by how cellular metabolism attempts to compensate for the dysfunction.
    Yet another biomarker?
    MeSci likes this.
  8. soulfeast

    soulfeast Senior Member

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    anyone understand this? results from a buccal swab: respiratory Complex 1 activity defienciey and Citrate Synthase deficiency.
  9. alex3619

    alex3619 Senior Member

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    Hi soulfeast

    Complex 1 deficiency is a serious worry and should be investigated. For one thing, how are your levels of CoQ10? How about NAD/NADH? Any problems with iron, sulphur, toxins? What is your intracellular pH? This can indicate a mitochondrial disorder, and it might be treatable. In symptoms such a mitochondrial disorder would look a lot like ME.

    http://www.umdf.org/atf/cf/{28038C4C-02EE-4AD0-9DB5-D23E9D9F4D45}/COMPLEX_1_DEFICIENCY.pdf

    Citrate synthase problems are also a worry. In particular you could have serious issues processing carbohydrates. This might, just might, lead to blood sugar spikes if you eat carbs.

    Either way these need to be investigated. A common cause would be nice, but might not be the case. Both of these have links with type 2 diabetes and obesity:
    http://ajpendo.physiology.org/content/298/1/E49.full.pdf

    http://en.wikipedia.org/wiki/Citrate_synthase
    http://en.wikipedia.org/wiki/Electron_transport_chain

    I hope this helps. Please contact me privately if you need more help unless you think it would interest the rest of us and is not too personal. I might be able to help you understand the science a bit better.

    However one thing to keep in mind is the swab might not be representative of what is happening in muscle or whereever.

    Best wishes, Alex
    merylg likes this.
  10. roxie60

    roxie60 Senior Member

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    Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder.

    Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E.
    Source

    Maes Clinics, Antwerp, Belgium. crc.mh@telenet.be
    Abstract

    INTRODUCTION:

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medical illness characterized by disorders in inflammatory and oxidative and nitrosative (IO&NS) pathways.
    METHODS:

    This paper examines the role of Coenzyme Q10 (CoQ10), a mitochondrial nutrient which acts as an essential cofactor for the production of ATP in mitochondria and which displays significant antioxidant activities. Plasma CoQ10 has been assayed in 58 patients with ME/CFS and in 22 normal controls; the relationships between CoQ10 and the severity of ME/CFS as measured by means of the FibroFatigue (FF) scale were measured.
    RESULTS:

    Plasma CoQ10 was significantly (p=0.00001) lower in ME/CFS patients than in normal controls. Up to 44.8% of patients with ME/CFS had values beneath the lowest plasma CoQ10 value detected in the normal controls, i.e. 490 microg/L. In ME/CFS, there were significant and inverse relationships between CoQ10 and the total score on the FF scale, fatigue and autonomic symptoms. Patients with very low CoQ10 (<390 microg/L) suffered significantly more from concentration and memory disturbances.
    DISCUSSION:

    The results show that lowered levels of CoQ10 play a role in the pathophysiology of ME/CFS and that symptoms, such as fatigue, and autonomic and neurocognitive symptoms may be caused by CoQ10 depletion. Our results suggest that patients with ME/CFS would benefit from CoQ10 supplementation in order to normalize the low CoQ10 syndrome and the IO&NS disorders. The findings that lower CoQ10 is an independent predictor of chronic heart failure (CHF) and mortality due to CHF may explain previous reports that the mean age of ME/CFS patients dying from CHF is 25 years younger than the age of those dying from CHF in the general population. Since statins significantly decrease plasma CoQ10, ME/CFS should be regarded as a relative contraindication for treatment with statins without CoQ10 supplementation.
    PMID:
    20010505
    [PubMed - indexed for MEDLINE]
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  11. Little Bluestem

    Little Bluestem Senescent on the Illinois prairie, USA

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    EEEK! :eek: 25 years is a lot.
  12. Valentijn

    Valentijn Activity Level: 3

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    You just have to think of it like "dog years", but instead of multiplying by 7, you add 25 to determine your "ME years".

    Hey, that means I'm almost old enough to retire! :thumbsup:
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  13. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Hopefully it is only those with specific abnormalities who are risk of premature death. This 2009 paper:

    http://www.rediviva.sav.sk/51i34/106.pdf

    says:

    "A study reported that among ME/CFS patients the causes of death cluster in three general domains: heart failure, suicide, and cancer (Jason et al 2006). Approximately 20% died from each of these three causes."

    There's a lot of other interesting stuff in there, but I haven't read it all.

    I tried Co-Q10 but it made me dizzy - felt like hypoglycaemia. Maybe the dose was too high (100mg, I think) or maybe I am not deficient.
    Valentijn likes this.
  14. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    It means I only have about 5 years to live if I don't have ME, but I do, so maybe I have beaten the odds! :)
  15. roxie60

    roxie60 Senior Member

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    I am taking ubiquinol 100mg. Also I have 'improved' (I'm leaning to not use the word ' better' since people seem to interpret that as meaning getting over this whatever I have) in the last few months. Still tired, get fatigued if do too much but the fatigue is no longer major 24x7, sleeping more but not refreshed, the muscle twitching, nerv explosions, internal shaking vibrating has decreased significantly (unless I overdo it, symp comees back.), pain has decreased but still get those out of nowhere without warning sharp pains,usualy in legs and torso and feet. The cognitive and memory has not improved except marginally, still have tinnitus 24x7, still sore stiff all over. Now Im torn, I now I apear to be getting back to about 50% and am trying to decide if I can try to go back to work but....I have no confidence in my abilities, is this just a calm before another storm (this has been my pattern - slowly get real sick and back off work to recovery, get back to 50%. The new Dr Ben Lynch webinar I watched last night made me realize I have been very sick for a long time, I have just been pushing though al these years and I am fearful if I go back to work this time getting more sick could just kill me. I have worked all my life so it is not a matter of not wanting to work. I was kinda down after watching Ben's new presentation (I need to watch again, my brain was tired) it seemed most of what he was saying is with my polymorphisms I should not be as sick as I am and have been. I'm still hunting the elusive key to why I am sick all th time, most of the time.
  16. roxie60

    roxie60 Senior Member

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    he also has some additional genes i want to get rsnumbers, GAMT is one
  17. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    I think that it is best to take a precautionary approach re work. Almost all of us are tempted to try to do too much. All your symptoms are typical ME symptoms, and I have had most of them for years, excluding the limb pain, but they have decreased a lot since I cut out gluten, cut down on grains and sugar, established a regime of supplements that seem to suit me, and became more careful about pacing and resting. You seem to be making progress, but going back to work could well set you back again.

    I've got that annoying quivering again at the moment, which I suspect is due to a bit of over-exertion and disruption resulting from having builders working on the house, and also having to water a lot of plants in the hot sun. Interestingly, although it feels like the physical symptoms of anxiety, I don't feel anxious.
    roxie60 likes this.
  18. alex3619

    alex3619 Senior Member

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    I have been doing this for many years in thinking about how old I am! I am 77! Ooops, not good for a male, life expectancy is atrocious! :aghhh: ;) On the flip side I still feel like I am 25 years younger in many ways - though a very mature 25 years younger. That would make me 27. Hmmm, so which am I, 77, 52 or 27? Is biology, chronology or psychology more important?
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  19. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Add them up and divide by three! :D
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  20. Little Bluestem

    Little Bluestem Senescent on the Illinois prairie, USA

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    A few years ago my mother heard that the life expectancy for women in this country (U.S.) was less than her current age. She seemed to think that this meant that she would not live much longer (she has dementia). I looked up life expectancy to show her that the longer you live, the longer you can expect to live. This is what I found (2004 U.S. data, for all people):

    Age - Life Expectancy
    birth - - - 78
    21 - - - - 80
    50 - - - - 82
    65 - - - - 84
    80 - - - - 90
    85 - - - - 92
    90 - - - - 95
    95 - - - - 99
    100 - - - 103
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