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

Caution: mitochondrial disorder learner ahead

Learner @ Wikipedia  

I mentioned in a post on acyl-carnitines quite recently how I would be looking to eventually take on the whole issue of mitochondrial dysfunction in relation to cases of autism spectrum disorder (ASD) on this blog. The day of that mega-post is still on the horizon, but for now I want to run through some important terms and issues which might eventually feature in that future post. This post will also help me get things straight about the basics of mitochondrial disorder but please, don't take my word as Gospel.

To save any charges of plagiarism, my main reference for this paper is the excellent review article by Mary Kay Koenig* (open-access) on the presentation of mitochondrial disorders in childhood, which at a recent visit to the dentist of all places, I actually managed to read in detail and make some (semi-) legible notes.

So here goes.

I have already set some of the scene for mitochondria and their important effects on our lives in a few previous post looking at high lactate levels in cases of autism (see here) and also detailing some interesting midi-chlorian, sorry mitochondrial findings in relation to chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) (see here). Aside from the detail that approximately 20% of children with autism are estimated to present with high lactate levels, I introduced some of the ways and means that mitochondria work and in particular, their primary energy production aim.

It's in your D-D-DNA
The first thing to note about mitochondria is that they contain their own DNA, and most of it (all of it?) comes from your mother. Dad's sperm it seems, does not stand a chance in the most part. This distinction from nuclear DNA, is an important one, particularly to things like the science of molecular phylogenetics. It also means that one can to some extent distinguish between mitochondrial issues as a consequence of mitochondrial DNA (mtDNA) and those as a result of issues with nuclear DNA. As Dr Koenig notes: "the majority of cases of mitochondrial disorders in children result not from mitochondrial DNA mutations, but from nuclear DNA mutations". That being said, mtDNA has been implicated in cases of autism as per this paper by Napoli and colleagues** (open-access).

The next thing worth pointing out is that there is a symbiotic relationship between mitochondria and our cells. Mitochondria provide usable energy to the cell but the cell also nurtures the mitochondria with proteins and nutrients it needs too. A sort of 'you scratch my back and I'll scratch yours' relationship.

Processes and signs
OK, the processes involved is next in line. There are lots, but the electron transport chain is the primary one attached to mitochondrial dysfunction, all related to the production of adenosine triphosphate (ATP). ATP really is the bees knees when it comes to energy which cells need and use (as in the end product of cellular respiration). A shortage in the supply of ATP means that cells are not going to be able to complete their function optimally.

When it comes to the presentation of paediatric mitochondrial disorders, there are some interesting stats about the body systems most frequently showing signs and symptoms. To quote from the good Dr Koenig: "Approximately 45% of children present with neurologic signs" ranging from hypotonia to seizures. Additionally: "20% of patients demonstrate intellectual dysfunction or psychiatric disturbances". There are quite a few more somatic presentations in terms of liver and cardiac presentation but these seem to be slightly less frequently reported in the general literature apparently.

Diagnosis and assessment
Diagnosis of a mitochondrial disorder is not, it seems, totally straight forward. Without trying to make too much fuss, it also seems very 'spectrum-y' to me, in terms of the definition and laboratory diagnosis of a mitochondrial dysfunction which relies on various disciplines doing their diagnostic stuff and coming together to make the diagnosis.

Lactic acidosis is an important clinical finding, which includes measurement of plasma lactate as per that 1 in 5 kids with autism with high lactate levels. Lactic acidosis is all about what happens when there are low levels of ATP (that golden energy source) and how the body tries to compensate via up-regulation of glycolysis which in turn leads to an excess of pyruvate, which itself might lead to elevated levels of the amino acid alanine or lactate. As well as looking at lactate, one could perhaps therefore see some merit in looking at levels of pyruvate and alanine too.

Outside of just looking in blood/plasma, there is also some suggestion that looking at lactate levels in the brain might also be a good idea, as per the use of proton magnetic resonance spectroscopy. There are other potential markers and mediums to work with including lactate levels in urine and cerebrospinal fluid (bearing in mind how invasive this is) and muscle biopsy to look for ragged red muscle fibres using light microscopy. That alongside looking for mutations in nuclear and mitochondrial DNA. Indeed in saying all this, quite a nice roadmap of where and what to look at with autism and mitochondrial disorders in mind was provided by Weissman and colleagues*** (open-access) noting the high prevalence of gastrointestinal symptoms and indeed some more recent research**** including Dr Koenig on the authorship team.

I'm going to finish this very descriptive post at this point with a few choice pearls of wisdom from Dr Koenig. First, unexplained elevations of lactate in any medium "should raise suspicions for a mitochondrial disorder". Second, "mitochondrial disorders are progressive". Don't assume a one-off analysis rules anything out. Finally, "a mitochondrial disorder should be considered in any child presenting with nonspecific signs such as ... learning disorders [and] epilepsy".

'Nuff said (for now).

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* Koenig MK. Presentation and diagnosis of mitochondrial disorders in children. Pediatr Neurol. 2008; 38: 305-313.

** Napoli E. et al. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Molecular Autism 2013; 4:2.

*** Weissman JR. et al. Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS ONE. 2008; 3: e3815.

**** Bhardwaj J. et al. Impaired gastric emptying and small bowel transit in children with mitochondrial disorders. J Pediatr Gastroenterol Nutr. 2012; 55: 194-199.

***** Frye RE. et al. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Translational Psychiatry. January 2013.

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Koenig, M. (2008). Presentation and Diagnosis of Mitochondrial Disorders in Children Pediatric Neurology, 38 (5), 305-313 DOI: 10.1016/j.pediatrneurol.2007.12.001

Targeting mitochondrial dysfunction in ME/CFS?

Consider this post a bit of a follow-up to a previous one based on some interesting observations by Booth and colleagues looking at mitochondrial dysfunction in cases of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

Join the Stone Age dots? @ Wikipedia  

Same authorship group but this time around presenting the results of an audit of patients who underwent examination based on the ATP profile (no endorsement given) and what they did about it published by Sarah Myhill and colleagues* (open-access).

I will at this point just reiterate my caveat about not giving advice, medical or otherwise, on this blog and hence not advocating anything based on discussions about the Myhill paper. I'm just talking, nothing else.

So here goes:

• The paper is based on the same 138 participants diagnosed with ME/CFS as described on their previous paper and how, when a multi-faceted intervention regime was put in place, some of the participants fared in terms of their mitochondrial profiles and presented symptoms.
• I say that this paper describes some of the original cohort; in essence this boils down 34 of them who had more than one ATP profile "separated by some months" of which 30 followed the intervention regime with vigour and 4 participants who were a little more lax. Bear in mind this was reported as an audit not a clinical trial.
• What was the treatment regime? Well, (a) a stone age diet which I assume is similar to a Paleolithic diet(?), (b) a good sleeping routine, (c) a supplemental vitamin/mineral/other regime and (d) assuming an appropriate work-rest balance; pacing but not PACE.
• Elements of these interventions were specifically tailored for participants based on their mitochondrial and other tests of nutritional status. Interestingly the authors report on some familiar issues as per often finding "deficiencies in glutathione (GSH) and glutathione peroxidase (GSH-PX) which are needed  to protect cells from oxidative damage and to detoxify xenobiotics". Other elements that turned up on the various testing panels were slightly more contentious as per the suggestion that "High levels of heavy metals can be tackled using selective chelation therapy".
• Results: there are some case histories reported and quite a bit of data per participant per testing occasion. I'll let you draw your own conclusions from what is described but in essence, the authors observed that there was some degree of responsiveness to the interventions shown on the repeat testing profiles for some of the participants. The caveat being that there was as expected, some degree of variability in response potentially affected by lots of variables, not least because individuals are individuals, and also probably due to the intervention regime itself.
• The authors report that "All 30 of the multiple test patients who followed the treatment protocol have increases in the major parameters of mitochondrial function and in the Mitochondrial Energy Score".
• The co-factors involved in ATP production - niacinamde, L-carnitine, coenzyme Q10 - also saw some interesting changes between baseline and post-intervention testing as a function of "% within normal range" though not presented in absolute mean values (pre- and post).
• All that being said, there is little in the way of formalised description as to the presentation of symptoms, and whether and how these overlapped with such changes (perhaps reiterating the audit nature of this paper).

For those who might be rather sceptical of this area of functional medicine, mitochondria being involved in ME/CFS or even members of the authorship group themselves, it would be easy to dismiss this paper as being nothing more than an advert for the clinical services of the authors. It is not a formal study of mitochondrial function being assessed or 'modified' in cases of ME/CFS, it focuses on individuals not groups, and there are plenty of scientific holes in how and what results have been presented (or not).

But step back a little and consider a few things. ME/CFS is probably in an even worse clinical position that autism for example, is at the moment. Whereas autism (mostly) enjoys the recognition of being a biologically-based neurodevelopmental condition, ME/CFS is still, in some quarters, thought to be a purely psychiatric condition, where sufferers - yes, people do suffer from ME/CFS - are thought to be either mentally ill or perhaps just as bad, to be hypochondriacs. Labels such as yuppie flu didn't really help matters either.

The next hurdle to be faced is the fact that the presentation of ME/CFS is heterogeneous. Even the diagnostic criteria for the condition has not been fully agreed upon, or at least as a condition with universal diagnostic consensus. That even before we start talking about comorbidity and the like.

When taking these factors into account, it does start to make a little more sense as to why initial, preliminary investigations should reflect these factors. So that mitochondrial issues might be part and parcel of ME/CFS or at least some cases, that reporting and correcting mitochondrial dysfunction might involve different strategies for different people, and that sticking to an intervention regime is not always possible in an intention-to-treat analysis manner, particularly when you are dealing with a condition which impacts so centrally on a person. Don't get me wrong, I'm not standing up for the use of audits over clinical trials - randomised, controlled clinical trials - but do consider this paper, and the previous publications from the authors, to be a good first step of where further investigation should be carried out.

Of course I would very much like to see more formal study not just on what happened to biochemistry as a result of the interventions discussed by Myhill and colleagues but also on overt signs and symptoms and importantly overall quality of life (QoL) outside of just clinical measures. Dietary changes such as those discussed are no laughing matter and can, on occasion, negatively impact on QoL as a consequence of their restrictiveness. Indeed as per other mentions of diet and ME/CFS on this blog, one wonders whether there may be either certain elements of the Stone Age diet which might be more usefully connected to cases, or indeed whether underlying clinical comorbidity such as coeliac disease or non-coeliac gluten sensitivity might be important to symptoms and outcomes.

Whatever your views on this area of research or more generally the definition of what ME/CFS is or isn't, this is peer-reviewed research and therefore represents an addition to the scientific literature and a challenge to the scientific community to undertake further independent replication save any repeat of XMRV...

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* Myhill S. et al. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a clinical audit. Int J Clin Exp Med 2013;6 : 1-15.

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Myhill S,, Booth NE,, & McLaren-Howard J (2013). Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a clinical audit International Journal of Clinical & Experimental Medicine, 6 (1), 1-15