"Mitochondrial Modifying Nutrients" and chronic fatigue syndrome: a pilot study

"Recent evidence suggests that mitochondrial dysfunction may play a role in the pathophysiology of chronic fatigue syndrome (CFS)" was the starting point for the study results reported by Ranjit Menon and colleagues [1].

Detailing findings -  "open-label trial" findings - following use of a 'nutraceutical combination' in a small number of participants with CFS, researchers produced evidence that further investigations might be needed. The trial protocol for their investigation can be viewed here. The 'combination' under inspection included "primary nutrients: Coenzyme Q10, Alpha lipoic acid, Acetyl-l-carnitine, N-acetyl cysteine, B Vitamins"; many of which have been shown to act on various "mitochondrial targets" in the context that mitochondria might play a role in at least some cases of CFS (see here for example), but not necessarily all (see here). Indeed, I'll draw your attention when other groups have talked about nutraceutical 'intervention' (see here) in the context of mitochondria and CFS previously (see here and see here).

Over the 16 weeks of the trial period, researchers quite regularly assessed various parameters relating to the core feature of fatigue (based on use of the Chalder Fatigue Scale) and various mood, sleep and general health variables. They observed that alongside "a significant improvement in fatigue symptoms across [the] treatment period on the Chalder Fatigue Scale" there were also some potentially important differences noted in other measures too. Not least with "clinician-reported symptom-improvement" in mind.

Obviously the emphasis on the Menon results being an open trial (i.e. not blinded/masked, not randomised, with no control group), and very much, a small open trial, mean that these are preliminary findings and shouldn't yet be informing any research or clinical opinions. The additional fact that no objective 'actigraphic' measure of physical functioning was included for study is something else to bear in mind. Such results *should* support further research; indeed, one would hope that in this new era of interest and 'changing perspectives' with CFS in mind (see here), many more investigations in this thread would be forthcoming.

And whilst on the topic of clinical trials for CFS, the news out of Norway when it comes to the use of Rituximab is not looking too good despite a previously promising start [2]. No-one said it was going to be easy...

To close, I've nabbed a screenshot of a picture from the film Unrest that I think is starting to take on an almost iconic status...

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[1] Menon R. et al. Mitochondrial Modifying Nutrients in Treating Chronic Fatigue Syndrome: A 16-week Open-Label Pilot Study. Advances in Integrative Medicine. 2017. Nov 15.

[2] Fluge Ø. et al. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358.

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Mitochondria support for mitochondrial activity in [some] autism

"This study examined the effect of common mitochondrial treatments on specific mitochondrial components in a group of children diagnosed with ASD [autism spectrum disorder], some of which also were diagnosed with co-morbid mitochondrial disease."

That was the premise of the study results published by Leanna Delhey and colleagues [1] (open-access available here) and follows previous discussions suggesting that mitochondrial disease might not be totally unfamiliar to at least some autism (see here). Including some notable names on the authorship list previously linked to the area of mitochondrial functions in relation to autism (see here), the authors provide some important information about how specific mitochondrial function might be 'supported' by various interventions.

I'm not on this occasion going to venture into all the details discussed by Delhey but I do want to pick out some interesting titbits. First, of the 127 children diagnosed with an autism spectrum disorder (ASD), we are told that "15% of the sample was clinically diagnosed with mitochondrial disease." Bearing in mind this particular cohort might not be totally representative of the autistic population at large, 15% is not an insignificant figure. What this tells us is that as and when a diagnosis of autism is received, screening for a possible mitochondrial disorder should be initiated (yes, an autism diagnosis is a starting point not the finishing line and the diagnosis rarely exists in a diagnostic vacuum).

Next, various supplements were taken by participants, some of which have recognised effects on mitochondrial functions. Of particular note was the use of coenzyme Q10 (CoQ10) and carnitine; both of which have been discussed on this blog previously (see here and see here respectively) with the word 'mitochondrial' also being mentioned. Interestingly, a couple of other supplements are also included in the Delhey paper including fatty acids and folate; some of which I have to say, didn't immediately pop into my mind as being primarily mitochondrial-related (folate is though, still a hot topic when it comes to autism). The authors head into how said supplements might affect specific facets of mitochondrial function. It also reminded me that I really need to brush up on my knowledge of mitochondrial functions...

"This study provides empirical support for common mitochondrial treatments and demonstrates that the relationship between activities of mitochondrial components might be a marker to follow in addition to absolute activities." I'd agree that there is the beginnings of a roadmap for further study based on the Delhey results. That and including important parameters related to the presentation of autism and how it may/may not be affected by treating underlying mitochondrial disorder, and the scene is set for further recognition of how indeed, autism rarely exists in a diagnostic vacuum...

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[1] Delhey LM. et al. The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder. J Clin Med. 2017 Feb 13;6(2). pii: E18.

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Delhey LM, Nur Kilinc E, Yin L, Slattery JC, Tippett ML, Rose S, Bennuri SC, Kahler SG, Damle S, Legido A, Goldenthal MJ, & Frye RE (2017). The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder. Journal of clinical medicine, 6 (2) PMID: 28208802

On dietary and nutritional therapies for ME/CFS

ME/CFS in case you don't already know refers to Myalgic Encephalomyelitis / Chronic Fatigue Syndrome and, according to the findings reported by Nadia Campagnolo and colleagues [1], is in need of quite a bit more scientific investigation when it comes to the application of dietary changes and nutritional supplements to potentially alter the course of the condition(s).

Surveying the peer-reviewed literature "from 1994 to May 2016" the authors looked for peer-reviewed studies where "CFS/ME patients modified their diet or supplemented their habitual diet on patient-centred outcomes (fatigue, quality of life, physical activity and/or psychological wellbeing)." They found 17 studies that included 14 different interventions. Unfortunately they concluded that: "Many studies did not show therapeutic benefit on CFS/ME" alongside the observation that the methodological quality of the research in this areas 'could do better'.

But it was not all research doom-and-gloom as some approaches seemed to show promise: "Improvements in fatigue were observed for nicotinamide adenine dinucleotide hydride (NADH), probiotics, high cocoa polyphenol rich chocolate, and a combination of NADH and coenzyme Q10." Without wishing to toot my blogging trumpet, some of these approaches have been discussed before on this blog (Coenzyme Q10 and NADH supplementation for Chronic Fatigue Syndrome? and Coenzyme Q10 and NADH supplementation for Chronic Fatigue Syndrome continued) and beyond that, the target organ of something like the use of probiotics for CFS has made an appearance more than once too (see here for example). I might also add that just outside of the search dates used by Campagnolo et al was the suggestion that issues with a staple foodstuff - cows milk - might be over-represented in cases of CFS (see here) and that a milk-free diet could be useful [2] for some at least. By saying all that, I'm not giving any medical or clinical advice...

As science starts to move further away from the the biopsychosocial (BPS) model of CFS/ME (see here) and starts looking at genetics, biology and somatic disease processes with regards to the various presentations included under the banner of ME/CFS (see here) I foresee some interesting developments further down the line. Granted, dietary and nutritional approaches to CFS/ME are probably not considered 'mainstream' in terms of management strategies but that does not mean they aren't important or at least important in the context of a diagnosis of ME/CFS seemingly being protective of nothing. Central to any future studies in this or any related area is the idea that there may be lots going on under the 'plural' diagnostic umbrella of ME/CFS (see here). Indeed, something that even the PACE trial is starting to take on board [3].

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[1] Campagnolo N. et al. Dietary and nutrition interventions for the therapeutic treatment of chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review. J Hum Nutr Diet. 2017 Jan 22.

[2] Rowe PC. et al. Cow's milk protein intolerance in adolescents and young adults with chronic fatigue syndrome. Acta Paediatr. 2016 Sep;105(9):e412-8.

[3] Williams TE. et al. Heterogeneity in chronic fatigue syndrome - empirically defined subgroups from the PACE trial. Psychol Med. 2017 Jan 23:1-12.

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Campagnolo N, Johnston S, Collatz A, Staines D, & Marshall-Gradisnik S (2017). Dietary and nutrition interventions for the therapeutic treatment of chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review. Journal of human nutrition and dietetics : the official journal of the British Dietetic Association PMID: 28111818

Coenzyme Q10 and NADH supplementation for Chronic Fatigue Syndrome continued

In a previous post on this blog I briefly discussed the research paper from Jesus Castro-Marrero and colleagues [1] suggesting that "oral CoQ10 [Coenzyme Q10] (200 mg/day) plus NADH [nicotinamide adenine dinucleotide (NADH)] (20 mg/day) supplementation" might be something useful for some people diagnosed with Chronic Fatigue Syndrome (CFS).

Enter then a new paper from Castro-Marrero and colleagues [2] (open-access available here) building on the original findings by suggesting that "CoQ10 plus NADH supplementation for 8 weeks is safe and potentially effective in reducing max HR [maximum heart rate] during a cycle ergometer test and also on fatigue in CFS." The max HR by the way, is a measure of cardiovascular function as part of exercise performance. A cycle ergometer test is all about testing parameters such as max HR using a stationary bicycle.

"A proof-of-concept, 8-week, randomized, double-blind, placebo-controlled trial was conducted" whereby either CoQ10 plus NADH was given (n=39) or a placebo (n=34) over the study period. Baseline and end of study max HR was tested alongside self-reported changes to "fatigue, pain and sleep problems" based on scoring using the Fatigue Impact Scale (FIS) among other things.

Based on an intention-to-treat (ITT) analytical strategy, authors reported that: "statistically significant differences were observed in CoQ10 + NADH group during the study, with a reduction in max HR after 8 weeks of treatment compared with baseline max HR." That being said, when comparing max HR from baseline to 8 weeks between the groups (CoQ10+NADH vs placebo), no statistically significant group differences were noted despite a trend towards greater max HR reduction in the experimental group. Insofar as other biological parameters also measured over the course of the study period ("VO2, VCO2, maximal workload, respiratory quotient and arm systolic and diastolic blood pressure") no significant differences were noted between baseline and end of study.

Fatigue scores showed a similar trend in terms of intra- and inter-group comparisons. So, for the CoQ10+NADH group, comparisons between baseline, week 4 and week 8 scores suggested significant reductions in total FIS scores. When it came to comparisons with the placebo group however, no significant differences were reported (indeed, the placebo group also showed a reduction in FIS total scores at least between baseline and week 4). The authors suggest that a lack of study power might have contributed to the lack of significant effects when comparing the experimental and placebo groups.

These are interesting results and from an intra-group perspective (comparing across different testing occasions) suggest that there may be more to see from this preparation on this patient group. Bearing in mind the emphasis on actually looking at physiological parameters such as max HR and as the authors note: "the use of strict inclusion criteria based on 1994 CDC case definition ensures that the participants were appropriately selected and without confounding comorbidities" further research is indicated to further assess such claims and determine specific biological mechanisms pertinent to any effect.

Music: Ike & Tina Turner - River Deep Mountain High.

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[1] Castro-Marrero J. et al. Does oral Coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in Chronic Fatigue Syndrome? Antioxid Redox Signal. 2014 Nov 11.

[2] Castro-Marrero J. et al. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. Clin Nutr. 2015 Jul 17. pii: S0261-5614(15)00189-2.

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Castro-Marrero J, Sáez-Francàs N, Segundo MJ, Calvo N, Faro M, Aliste L, Fernández de Sevilla T, & Alegre J (2015). Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. Clinical nutrition (Edinburgh, Scotland) PMID: 26212172

Persistent hyperlactacidemia in cases of autism

The paper from José Guevara-Campos and colleagues [1] (open-access can be downloaded here) is fodder for today's short post, and a topic that has not been seen on this blog for quite a while: hyperlactacidemia (elevated plasma lactate levels) and autism.

Previous mentions of lactate and autism on this blog (see here and see here) were potentially pretty important; specifically, how elevated plasma lactate levels might (a) not be an unfamiliar finding for quite a few people on the autism spectrum [2] and (b) might provide further evidence for the involvement of mitochondria in cases of autism among other things [3]. Mitochondria and autism, I might add, is still quite a complicated topic but a research area in the ascendancy.

Guevara-Campos et al reported on case reports for "three patients diagnosed with developmental delay, ID [intellectual disability] and ASD [autism spectrum disorder], and also with a possible mitochondrial disease accompanied by an ETC [electron transport chain] deficiency accompanied by hyperlactacidemia." There are various data provided following some clinical investigations including that based on muscle biopsy data. Just as important are some of the details on 'pharmacological treatment' of said issues and the observed impact on presented symptoms. Without cherry-picking too much, carnitine, a vitamin B complex, co-enzyme Q10 and folic acid combined seemed to have quite an effect on participants, particularly on "intellectual abilities". Some of these interventions have been trialled in other conditions where mitochondria or their important processes are suspected to show involvement (see here). I say this without providing endorsement or recommendation.

Appreciating that there is quite a bit more to do (experimentally) when it comes to "suspected mitochondrial involvement" specifically where autism is mentioned, and in particular, the need for quite a bit more controlled study on how such interventions might impact on symptoms in this group, I'm interested in the Guevara-Campos report. How many people on the autism spectrum their results hold true for is as yet unknown. With the growth in this area of research however, I'd be minded to suggest that we should really start directing a lot more resources to trying to answer that question if we are indeed going to start taking the plural autisms a little more seriously. Oh, and as per the sentiments of the paper by Zilberter and colleagues [4] there may yet be related factors which might be of "potential therapeutic significance."

Music: Roots Manuva - Witness. Brilliant.

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[1] Guevara-Campos J. et al. Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia. Int J Mol Sci. 2015 Feb 11;16(2):3870-3884.

[2] Oliveira G. et al. Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol. 2005 Mar;47(3):185-9.

[3] Andersen LW. et al. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. 2013 Oct;88(10):1127-40.

[4] Zilberter Y. et al. A unique array of neuroprotective effects of pyruvate in neuropathology. Front. Neurosci. 2015. Feb 17.

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Guevara-Campos J, González-Guevara L, & Cauli O (2015). Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia. International journal of molecular sciences, 16 (2), 3870-3884 PMID: 25679448

Coenzyme Q10 and NADH supplementation for Chronic Fatigue Syndrome?

A quick post today to direct your attention to the paper by Jesus Castro-Marrero and colleagues [1] reporting results which seemed to suggest that under double-blind, placebo-controlled conditions "oral CoQ10 [Coenzyme Q10] (200 mg/day) plus NADH [nicotinamide adenine dinucleotide (NAD) + hydrogen (H)] (20 mg/day) supplementation" might have some positive effects for cases of Chronic Fatigue Syndrome (CFS). The NIH entry for the trial can be found here.

I volunteer as tribute! 

Reporting on both fatigue-related and "biochemical parameters in 73 Spanish CFS patients", researchers found that the NADH / CoQ10 preparation (ReConnect) was superior to a phosphoserine/serine plus vitamin C placebo based on fatigue scores derived from the Fatigue Impact Scale (FIS) [2]. Further, that "a recovery of the biochemical parameters was also reported. NAD+/NADH (p< 0.001), CoQ10 (p< 0.05), ATP (p< 0.05) and citrate synthase (p< 0.05) were significantly higher and lipoperoxides (p< 0.05) were significantly lower in blood mononuclear cells (BMCs) of the treated group."

Obviously there is quite a bit more to do in this area but these results are perhaps not so surprising given other more open-trial data as per the paper from Garth Nicholson and colleagues [3]. I'm also minded to refer you back to some other research discussed in this area with regards to mitochondria and CFS (see here) and mention of the paper by Maes and colleagues [4] which concluded: "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."

"Larger sample trials are warranted to confirm these findings." I couldn't have said it better myself.

Music: The Skatalites and Guns of Navarone based around a story by one of my favourite novelists.

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[1] Castro-Marrero J. et al. Does oral Coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in Chronic Fatigue Syndrome? Antioxid Redox Signal. 2014 Nov 11.

[2] Frith J. & Newton J. Fatigue Impact Scale. Occup Med (Lond). 2010 Mar;60(2):159.

[3] Nicholson G. et al. Lipid Replacement Therapy with a Glycophospholipid Formulation with NADH and CoQ10 Significantly Reduces Fatigue in Intractable Chronic Fatiguing Illnesses and Chronic Lyme Disease Patients. International Journal of Clinical Medicine. 2012; 3: 163-170.

[4] Maes M. et al. 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. Neuro Endocrinol Lett. 2009;30(4):470-6.

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Castro-Marrero J, Cordero MD, Segundo MJ, Saez-Francas N, Calvo N, Román-Malo L, Aliste L, Fernandez de Sevilla T, & Alegre-Martin J (2014). Does oral Coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in Chronic Fatigue Syndrome? Antioxidants & redox signaling PMID: 25386668

Organic acids as biomarkers of autism?

Whilst I am always a little cautious about the use of the word 'biomarker' when applied to a heterogeneous condition like autism, even the autisms, I am nevertheless always intrigued at any reasonable prospect reported in the scientific literature. So it was when I read the paper by Joanna Kałużna-Czaplińska and colleagues [1] and their assertion that "there is a significant metabolic difference between autistic and non-autistic children" and onwards that "21 metabolites were identified as potential biomarkers".

Let me expand on this a little...

• This was a small study looking at potential biomarker identification on the basis of the analysis of urine samples via gas chromatography-mass spectrometry (GC-MS). If you want some further background on this technique applied to autism research, have a look at a previous post (see here) where it has been utilised. Overnight urine samples from 14 children (aged 4-10 years) diagnosed with an autism spectrum disorder (ASD) undergoing "rehabilition" (whatever that means) were analysed in comparison to samples from 10 asymptomatic controls.
• Quite a bit of information is included about sample treatment and the analytical method. Each sample result was represented as a TIC (total ion count) and, as is often the case with such methods, data processing was an important part of the analysis. Most compounds were identified by cross-referencing with the NIST mass spectra library and via fragmentation patterns. Principal component analysis (PCA) was "applied to check the dataset structure and assess the variability of the profiles belonging to groups of autistic vs. non-autistic children". 
• Results: as indicated, 21 metabolites were deemed as "potential marker metabolites" some detected in higher quantities in the autism samples, and some lower. Fourteen of these compounds were described as organic acids. Without hopefully breaking any copyright, I've attached a copy of the table included in the paper with all the compounds differing between autism and control samples. The eagle-eyed will also note the big 'H' - homocysteine - to be a part of that list, and as expected, elevations in urinary homocysteine for the autism group as per other work in this area (see here).
• Given the title of this post I'll point out a few organic acids which seemed to be important differentiators between autism and control samples: (i) levels of beta hydroxybutyric acid were elevated in autism sample. This compounds has been talked about previously on this blog with regards to inborn errors of metabolism and autism (see here). (ii) Hydroxybenzoic acid was again elevated and perhaps ties into other findings from this group [2] potentially indicative of intestinal dysbiosis. (iii) Succinic acid levels were also generally elevated, and as the authors point out: "is considered a potential marker for deficiency of CoQ10 and riboflavin in children with autism". Co-enzyme Q10 y'say? I could go on, but won't.
• Various statistical models (PCA) were applied to the datasets which led authors to find: "The group of samples from non-autistic control children [were] more homogeneous than the group from autistic children". Further: "There is a clear distinction between those two groups of samples". ROC analysis looking at the performance of the PCA models was also applied leading authors to conclude that there may be something in their results from a diagnostic point of view.

Obviously the Kałużna-Czaplińska results are preliminary and in need of further independent replication. I note that quite a bit of the other literature in this area of biomarkers tend to use both training and test sets, where training samples provide your initial compounds of interest and test sets do just that, test your biomarker assumptions (see here). This wasn't the case in the current study but still leaves the door open to independent verification. That also the word 'comorbidity' does not seem to be mentioned as part and parcel of the autism group means the questions of how widespread comorbidity was in the autism participant group and whether this might have exerted an effect on the results obtained are unanswered. I might also quibble about the way that peaks in the TIC were assigned a compound name: "Peaks with the similarity index more than 80% were assigned compound names..." but now I'm just nit-picking.

That all being said, I do see some promise in the results obtained by Kałużna-Czaplińska et al. I note in another paper by some of the authors [3] they talk about how probiotic therapy might impact on both some of the behavioural measures of autism and also levels of one of the compounds picked up in their latest analysis, D-arabinitol. Again, I'd like to see more research done on this, alongside their other suggestion on the use of B vitamins (and magnesium) potentially affecting organic acids in cases of paediatric autism [4] talked about in a previous post (see here). The focus on the inner working of the gut, and particularly the trillions of gut bacteria which call us home, potentially being connected to some of these biomarkers, ties in well with an emerging autism research area (see here).

Music to close, and yet again my brood provide the inspiration as Bob Marley is fast becoming a YouTube favourite in our home with the classic One Love. You know you're getting old when your kids start listening to cooler music than you do...

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[1] Kałużna-Czaplińska J. et al. Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. Journal of Chromatography B. 2014. Feb 2.

[2] Kałużna-Czaplińska J. Noninvasive urinary organic acids test to assess biochemical and nutritional individuality in autistic children. Clin Biochem. 2011 Jun;44(8-9):686-91.

[3] Kałużna-Czaplińska J. & Błaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition. 2012 Feb;28(2):124-6.

[4] Kałużna-Czaplińska J. et al. B vitamin supplementation reduces excretion of urinary dicarboxylic acids in autistic children. Nutr Res. 2011 Jul;31(7):497-502.

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Kałużna-Czaplińska J, Zurawicz E, Struck W, & Markuszewski M (2014). Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences PMID: 24565890

Coenzyme Q10 and autism

The paper by Frederick Crane and colleagues [1] (open-access here) caught my eye recently and their suggestion that when it comes to autism there may be more research to do on coenzyme Q10. Indeed, the old grey-pinkish matter started grinding into action as to whether there may be a wider research literature on CoQ10 with a focus on autism...

A helping hand? @ Wikipedia 

Coenzyme Q10 otherwise known as ubiquinone, has appeared before on this blog for various reasons (see here and see here). Described as a fat soluble vitamin-like substance, there are apparently a few important steps in the production of CoQ10 implicating one to two old friends - aromatic amino acid friends - involving the "synthesis of the benzoquinone structure" from said aromatic friends (tyrosine or phenylalanine) alongside the "synthesis of the isoprene side chain from acetyl-coenzyme A (CoA) via the mevalonate pathway". It's then a case of marrying the two reaction products together to form something which as the name 'co-enzyme' suggests, is pretty important to quite a few enzymatic reactions.

In terms of the functions of CoQ10, well quite a few of them overlap with areas of interest when it comes to autism. The word 'mitochondria' springs up quite a bit and the important role CoQ10 plays in the production of energy or involvement with ATP (adenosine triphosphate) at least. The antioxidant activity that CoQ10 also seems to possess, at least in it's reduced form - ubiquinol - is also something pretty important. Both mitochondrial function and the concept of oxidative stress have surfaced in the autism research literature in recent years (see here and see here).

The Crane paper presents quite a bit of biochemistry pertinent to "a hypothesis that autism is controlled by a coenzyme Q-dependent redox system in the porin channels". Putting aside my reluctance towards grand, over-arching theories about autism (sorry, the autisms) I'll be honest and tell you that I found the reading pretty heavy going on this topic bearing in mind my very limited knowledge on porin channels and all-things when it comes to transportation in and out of cells. I'm not then going to provide some detailed critique of the author's hypothesis aside from mentioning the paper by Freedenfeld and colleagues [2] on the use "of ribose therapy and NADH therapy on children with autism" (NADH being oxidised by coenzyme Q). NADH is something that Crane et al have talked about in other papers too [3].

The wider autism literature on CoQ10 and autism is best described as limited at the moment. I came across the paper by Gvozdjáková and colleagues [4] (open-access here) talking about results from a preliminary open trial of ubiquinol in a small number of children diagnosed with an autism spectrum disorder (ASD). Following an initial daily dose starting at 50mg of "Liquid liposomal ubiquinol" increased to 100mg daily, authors reported on both behaviour and various biochemical measures including CoQ10 (total) and TBARS "the end product of lipid peroxidation in the body". Bearing in mind the study methodology, the authors reported that a: "Beneficial effect of ubiquinol in children with autism has been demonstrated for the first time". That being said, I note that only the 'CoQ10-TOTAL' biochemical measure came out as significantly affected by ubiquinol supplementation (which is kinda what one would expect) and as someone has already [slightly harshly] noted using PubMed Commons "There is no way in which these observations can be interpreted as a "demonstration" of a "beneficial effect".

I do however believe that there may be more to do from a research point of view when it comes to coenzyme Q10 and autism. Thinking back to the Jim Adams double-blind, placebo-controlled trial looking at a vitamin and mineral supplement for autism (see here) I note that their preparation included CoQ10 (see here) among lots of other things. Granted, lots of other nutrients might have been contributory to the effects they noted, but one cannot, at the moment, rule out any specific effect from CoQ10 either. This is something also mentioned in the new-ish paper from Frye & Rossignol [5]. I'm also minded to mention the various discussions about the use of CoQ10 in relation to cases of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) too (see here) as per papers like the one from Maes and colleagues [6]. Following my mantra about autism seemingly not being protective against any other condition or state, one might further consider additional research as to whether overlap or similar processes might unite at least some autism and at least some CFS/ME or not?

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[1] Crane FL. et al. Plasma membrane coenzyme Q: evidence for a role in autism. Biologics. 2014 May 29;8:199-205.

[2] Freedenfeld SH. et al. Biochemical Effects of Ribose and NADH Therapy in Children with Autism. Autism Insights. 2011; 3: 3-13.

[3] Löw H. et al. Putting together a plasma membrane NADH oxidase: a tale of three laboratories. Int J Biochem Cell Biol. 2012 Nov;44(11):1834-8.

[4] Gvozdjáková A. et al. Ubiquinol improves symptoms in children with autism. Oxid Med Cell Longev. 2014;2014:798957.

[5] Frye RE. & Rossignol D. Treatments for Biomedical Abnormalities Associated with Autism Spectrum Disorder. Front. Pediatr. 2014. doi: 10.3389/fped.2014.00066

[6] Maes M. et al. 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. Neuro Endocrinol Lett. 2009;30(4):470-6.

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Crane FL, Löw H, Sun I, Navas P, & Gvozdjáková A (2014). Plasma membrane coenzyme Q: evidence for a role in autism. Biologics : targets & therapy, 8, 199-205 PMID: 24920882

Mitochondrial dysfunction and ME/CFS

I continue my interest in research examining chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) in this post looking at what might turn out to be quite an important paper by Booth and colleagues* (full-text) on a potential role for mitochondrial dysfunction.


Where to start....

Mitochondria (plural) are not to be confused with the midi-chlorians of a Galaxy far, far away. A few associated words: organelles, eukaryotic cell, the power plant of cells, cellular respiration (this link carries a really easy to understand description of this process). In short, mitochondria provide energy to the cell in the form of ATP. Cells like most thing need energy to function properly; where insufficient energy is produced... well, cells don't work as well as they should and the results can be serious and wide-ranging.

I've kinda eluded to mitochondrial function, or rather dysfunction, in posts like this one on lactate levels in autism although I dare say that as some point I will come back to the topic in more detail. Indeed elevations in lactate levels do seem to indicate some potential issue with mitochondrial dysfunction as per studies like this one from Magner and colleagues**.

I digress. Booth et al have previously reported on mitochondrial dysfunction in cases of CFS/ME in this paper*** (full-text); the current study being a sort of extension and elaboration effort. I might add that they are by no means the first to suggest that there may be some mitochondrial 'involvement' in cases of CFS/ME (see here and here). Low carnitine levels? Now where have I heard that before?

Their latest paper is full-text and contains quite a bit of data but a short summary is perhaps in order:

• The ATP profile features quite strongly in the paper. This is described as containing among other things, ATP concentration in blood neutrophils (in the presence of excess magnesium, deficiencies of which have been linked to CFS) and is a part of a so-called mitochondrial energy score (MES). In their previous paper (***) the authors reported an impressive correlation between MES and CFS Ability as described using the Bell Ability Scale, a rough and ready measure of the level of disability as a consequence of the condition (see here). 
• It looks like there were a few elements to this paper including a reanalysis of the cohort reported in their previous paper - cohort 1 (minus 10 participants who were outside of the age range of controls, again taken from their original publication) and analysis of a new participant group - cohort 2 - made up of 138 participants aged between 18-65, mean age 41 years.
• Similar to the last paper, the MES showed a pretty good correlation with CFS Ability (correlation coefficient = 0.80). I have to admit that quite a lot of the rest of the results are beyond the limits of my biochemistry as various measures of ATP inhibition, functionality of the translocator proteins (e.g. ANT) and efficiency of oxidative phosphorylation are tested ( I think!). The end result is that the mitochondrial dysfunction noted by the authors in this patient group seems to (a) frequent, very frequent and (b) particularly involves issues with the translocator protein (TL) regulating the passage of ATP and ADP across mitochondrial membranes (see here - no endorsement intended). Other preliminary studies of oxidative phosphorylation capacity in CFS for example, suggested that this is probably not the main reason for mitochondrial dysfunction**** (full-text).
• The authors conclude: "Taken together, these measurements show that ME/CFS is a serious illness which may affect every cell in the body".

And relax. 

I should point out that my interpretation of the Booth results should not be taken as Gospel or anything like that. I do however believe that these results are important for CFS/ME and potentially represent at least one part of the puzzle that is this debilitating set of conditions. Independent replication of the Booth results is the next step.

I was drawn to the fact that other conditions presenting with a fatigue component such as fibromyalgia have also been suggested to be linked to issues with mitochondria as per this case study by Abdullah and colleagues***** (full-text). The 'solution' to their reported case was supplementation with various compounds including coenzyme Q10, creatine and carnitine among other things. Whilst I am not in a position to endorse anything like such a treatment protocol (please do speak to your healthcare provider first), I note that supplements like coenzyme Q10 have cropped up more than once in relation to CFS/ME as per articles like this one****** from a familiar name to this area of study, Michael Maes and colleagues.

ME/CFS are a heterogeneous set of conditions which, similar to the description of autism, probably include quite a few different paths to the development of symptoms. Whilst the area of mitochondrial dysfunction is an attractive potential marker showing involvement in cases - at least some cases - the question of whether this is a 'core' aspect of the conditions still remains to be seen alongside its connection with other pathways of interest. 


To finish, Kate Bush sings Wuthering Heights. A lesson in the art of dance and music (and its absolutely fantastic).

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* Booth NE. et al. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). International Journal of Clinical & Experimental Medicine. 2012; 5: 208-220.


** Magner M. et al. Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures. European Journal of Paediatric Neurology. 2011; 15: 101-108.

*** Myhill S. et al. Chronic fatigue syndrome and mitochondrial dysfunction. International Journal of Clinical & Experimental Medicine. 2009; 2: 1-16.

**** Vermeulen RC. et al. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. Journal of Translational Medicine. 2010; 8: 93.

***** Abdullah M. et al. Mitochondrial myopathy presenting as fibromyalgia: a case report. Journal of Medical Case Reports. 2012; 6: 55.

****** Maes M. et al. 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. Neuro Endocrinology Letters. 2009; 30: 470-476.