On mitochondrial DNA (mtDNA) changes and autism

Mitochondrial issues accompanying some diagnoses of autism have quite a bit of peer-reviewed research backing (see here for example). Not for everyone, but for some people diagnosed with an autism spectrum disorder (ASD), there seems to be something afoot with regards to these 'powerhouses of the cell' that could well impact on various aspects of their lives [1]. Indeed, keep that paper from Poling et al [1] in mind...

Although by no means an expert on mitochondrial issues in any context, I believe that there are a few ways in which mitochondrial dysfunction can manifest. It can present as a secondary disorder for example (see here), where some acquired biochemistry (non-genetic) provides some of the 'answers'. Or it can present as a primary mitochondrial disorder, a genetic condition "confirmed by a known or indisputably pathogenic mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutation" [2], where issues in the genetic code of mitochondria are present.

The recent findings reported by Noémi Ágnes Varga and colleagues [3] focused on that latter route looking at issues with mtDNA in the context of autism. They turned up some rather interesting results...

So: "The aim of the present study was to investigate the presence of the most common pathogenic mtDNA alterations in patients with ASD." Researchers screened 60 children with autism and 60 not-autism controls. One detail stuck out when it came to those controls: "Our control group for mtDNA screening consisted of 60 European adults (26 females and 34 males, median age = 28 years, IQR = 13.75) selected from our biobank." Compared with those participants diagnosed with autism, they were quite a bit older (median age = 7 years vs. median age  = 28 years) and indeed, the gender ratios were a little bit more balanced.

Anyhow: "Mitochondrial deletions were identified in 16.6% (10/60) of our patients with ASD." OK, 'patients' is not exactly the word I would use for participation in such a research project but that shouldn't distract from the findings. Varga et al also provide some further insights into those 10 'participants' with a diagnosis of autism and mtDNA deletion(s) which turned up some other interesting details, such as the finding that various other symptoms presented alongside autism. Quite a few of them were connected to muscle and movement functions (limb and truncal ataxia, hypotonia, dyspraxia) which ties into other independent findings [4]. I also noted the words 'gluten sensitivity' were mentioned in one case, which is guaranteed to perk my professional interest (see here) although I'm still a little unsure of whether this connected to mtDNA issues or not.

Another set of potentially important details were also observed by researchers when comparing those with autism with and without mtDNA deletion(s). Keeping in mind the small numbers falling into that autism with mtDNA deletion(s) category, developmental regression seemed to be an important facet of the clinical profile of this group. Regression of previously acquired skills is something else I've talked about quite a bit on this blog with regards to autism (see here and see here for examples). Going back to that paper by Jon Poling and colleagues [1] that I told you to keep in mind, it's interesting to note the overlap of regression reported by them and also reported by Varga in the context of mitochondrial disorder. And this isn't the only occasion that regression and mitochondrial issues have been talked about in the same breath as autism [5] and even with other potentially important clinical indicators [6]. Correlation is not necessarily causation but...

There are quite a few other details listed in the Varga paper that I'd encourage readers to pursue but I think I've gone on enough about this topic for now. It, yet again, appears that a diagnosis of autism is protective of nothing when it comes to other conditions/diseases/symptoms/labels appearing and perhaps implies that preferential screening for mitochondrial disorder should be more commonplace than it is as and when autism is diagnosed. I'm also inclined to draw your attention to other clinical labels where mitochondrial issues might be relevant for some (see here) albeit not always with genetics in mind (see here). How perhaps investigations need to be carried out looking at any possible intersection between *some* autism and something like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (see here) for example, also in light of other important data (see here). Indeed, I'll be coming to the findings reported by Bilevicute-Ljunger and colleagues [7] on this topic quite soon in a separate post...

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[1] Poling JS. et al. Developmental Regression and Mitochondrial Dysfunction in a Child With Autism. J Child Neurology. 2006;21(2):170-172.

[2] Niyazov DM. et al. Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment. Mol Syndromol. 2016 Jul;7(3):122-37.

[3] Varga NA. et al. Mitochondrial dysfunction and autism: comprehensive genetic analyses of children with autism and mtDNA deletion. Behavioral and Brain Functions. 2018. 14: 4.

[4] Ghaoui R. & Sue CM. Movement disorders in mitochondrial disease. J Neurology. 2018. Jan 6.

[5] Rossignol DA. & Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012 Mar;17(3):290-314.

[6] Shoffner J. et al. Fever plus mitochondrial disease could be risk factors for autistic regression. J Child Neurol. 2010 Apr;25(4):429-34.

[7] Bilevicute-Ljunger. I. et al. Patients with chronic fatigue syndrome do not score higher on the Autism-apectrum quotient than healthy controls: comparison with autism spectrum disorder. Scandinavian Journal of Psychology. 2018.

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"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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"abnormalities in mitochondrial activity in the lower GI tract of children with ASD"

The findings reported by Shannon Rose and colleagues [1] (open-access) continue a research theme by [some of] this authorship group looking at how mitochondrial dysfunction seems to be part and parcel of at least some autism (see here). Indeed, how when one talks about mitochondrial issues potentially accompanying [some] autism, one really needs to look at it in the context of other issues potentially also 'over-represented' in relation to autism (see here).

This time around, Rose et al set out to "determine whether mitochondrial dysfunction may contribute to GI [gastrointestinal] symptoms in children with ASD [autism spectrum disorder]" on the basis that GI symptoms (whether functional or more pathological) are no stranger to autism (see here). With this in mind, I note the name Tim Buie is included as part of the Rose paper authorship team and so should reference some of the sterling work he and his team have done on the topic of GI issues and autism and its importance down the years.

Researchers analysed mitochondrial function(s) in rectal and cecum mucosal biopsies in a small sample of children diagnosed with ASD (n=10) and compared results with those from "10 children with Crohn’s disease and 10 neurotypical children with nonspecific GI complaints." There are two points for me to make here: first, although it is an invasive procedure to collect them, those biopsies used for study were extracted on a clinical basis as part of "elective diagnostic colonoscopy." This was not a case of 'experimenting' on children for the sake of an experiment; rather that children were already undergoing investigations for their significant bowel issues, save any health inequalities appearing "just 'cos they were autistic" for example. Second, although the authors have chosen to use the term 'neurotypical' to reflect not-autism, I myself still find this terminology to be scientifically problematic (see here) in the context that no brain is seemingly typical or atypical according to current scientific evidence. Not least also on the basis that immune-based conditions such as inflammatory bowel diseases do seem to carry an increased 'risk' of psychiatric issues (see here) and what that might [eventually] mean for those children diagnosed with Crohn's disease (an inflammatory bowel disease) for example. Anyhow, two approaches are described in connection with the study of mitochondria in those biopsy samples looking at both the quantity and activity of various electron transport chain (ETC) complexes. Yet again, I can profess no serious expertise on the various elements of mitochondria but there is some good reading out there in the peer-reviewed science domain on the topic.

Results: "Differences in mitochondrial function were found in children with ASD as compared to the other control groups across several ETC complexes suggesting a difference in overall mitochondrial function rather than a change in one specific mitochondrial enzyme." Accepting the small participant numbers included for study, these are potentially important results. Not least because other work looking at such mitochondrial issues in relation to [some] autism has been predominantly based on activity in muscle; now it appears extending "this observation to altered ETC complex activity in the GI mucosa" too.

Then to some speculation: "The fact that increased ETC complex protein content was primarily seen in the cecum, an area where enteric microbiome fermentation products such as PPA [propionic acid] and BUT [butyrate] are abundant, suggests a role for the enteric microbiome in the evolution of mitochondrial abnormalities in children with ASD." An interesting perspective indeed and in need of some further investigation. Butyrate has, in recent years, been elevated to almost scientific sainthood (see here for example) so one has to perhaps be a little cautious about sweeping statements in the context of autism or any other label. I say this with particular relevance to an 'autism colon' discussed by the authors (see here) which I also think is perhaps a little premature to speculate on.

No mind, the results are what they are and add to the growing literature discussing mitochondria in the context of [some] autism. The implication once again is to screen for such issues within the context that a diagnosis of autism should represent a starting point for further investigations not the finishing line.

And finally, to another author on the Rose paper, I'm still waiting to read about some of your results...

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[1] Rose S. et al. Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study. PLoS One. 2017 Oct 13;12(10):e0186377.

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"mitochondrial dysfunction is involved in the pathobiology of GWI [Gulf War Illness]"

Among the various research distractions that I take on this blog away from the core material of autism science, one condition/diagnosis/state continues to particularly intrigue me: Gulf war syndrome or Gulf war illness (GWI).

I've covered this topic a few times on this blog (see here and see here and see here for examples); specifically how the hostile environment of the Persian Gulf during the 1990-1991 Gulf War perhaps aligns with this conflict being labelled as 'one of the most toxic wars in human history' (see here). If you think I'm overplaying that last sentence have a look at what was housed at one facility in Iraq under Saddam Hussain and then understand the nature of some of the compounds to which combatants were potentially exposed to.

The [small scale] findings reported by Yang Chen and colleagues [1] (open-access) adds to the still-growing research base suggesting that for the 25%+ soldiers who returned from theatre in ill-health, the biological nature of their symptoms is both wide-ranging and complex. The authors concluded that: "veterans with GWI exhibit greater mtDNA [mitochondrial DNA] damage which is consistent with mitochondrial dysfunction."

Looking at "21 cases of GWI (CDC and Kansas criteria) and 7 controls" (I told you it was 'small scale') researchers looked in blood samples in order to "quantify mitochondrial and nuclear DNA lesion frequency and mitochondrial DNA (mtDNA) copy number (mtDNAcn)" as well as to provide some information on "mitochondrial complex I and IV enzyme activities." In effect, covering both genetic and biological presentation in relation to any possible mitochondrial dysfunction (mitochondria being the 'powerhouse' of the cell).

"This study provides the first direct biological evidence of mtDNA damage in the blood of veterans with GWI." I'm always a little cautious when a study claims to provide 'first evidence' of anything but a quick search of PubMed seems to confirm that mitochondrial DNA (mtDNA) has not been discussed in the research literature before. Although not an expert on mtDNA or anything, the details being discussed by Chen et al point to an excess of mitochondrial and nuclear DNA damage in the GWI group compared with the small control group. This is however, not the first time that mitochondrial dysfunction has been discussed in the context of the GWI as per other peer-reviewed research outings [2].

"Mitochondrial dysfunction among veterans with GWI may help explain, in part, the persistence of this illness for over 25 years." This is an important observation made by the authors. Drawing on data from another area of [overlapping] research - chronic fatigue syndrome (CFS) - it's worthwhile noting that some fatigue-related conditions do have a mitochondrial element to them (see here) even if not universally linked to mtDNA (see here). The fact that this group with GWI did show some evidence of mtDNA damage begs the questions: how and why?

Minus any sweeping statements or the like, I would draw your attention to one particular 'toxic exposure' seen in the Gulf War - depleted uranium tipped munitions - and some research suggesting that particular radioactive particles emitted from something like depleted uranium might very well be able to impact on mitochondrial DNA [3]. I'm not saying this is 'truth', just a testable hypothesis in the context of GWI.

Of course, further investigations are required in this area, both larger in scale and also carried out by other, independent groups. There is also the possibility that certain mitochondrial and interconnected issues, if detected, could be treatable as per again, what has been talked about in CFS circles (see here). Our troops deserve the most thorough and best care we can possibly provide...

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[1] Chen Y. et al. Role of mitochondrial DNA damage and dysfunction in veterans with Gulf War Illness. PLoS ONE. 2017; 12(9): e0184832.

[2] Koslik HJ. et al. Mitochondrial dysfunction in Gulf War illness revealed by 31Phosphorus Magnetic Resonance Spectroscopy: a case-control study. PLoS One. 2014 Mar 27;9(3):e92887.

[3] Zhang S. et al. Mitochondrial alteration in malignantly transformed human small airway epithelial cells induced by a-particles. International Journal of Cancer. 2012; 132: 19-28.

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Mitochondrial mutations are not common in chronic fatigue syndrome but...

"We report the complete mtDNA [mitochondrial DNA] sequence of 93 CFS [chronic fatigue syndrome] patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations."

So said the results reported by Elizna Schoeman and colleagues [1] (open-access available here) who drew on other research previously covered on this blog (see here) suggesting that "symptoms of mitochondrial diseases and CFS frequently overlap and can easily be mistaken" to look-see whether issues with mitochondrial DNA might be important to at least some cases of CFS. Their investigation found no evidence that within this cohort at least, undiagnosed mtDNA disease was apparent. They do caution however that their findings do not "exclude a role for mtDNA population variation in the susceptibility to CFS", neither also did they provide any functional biological analysis of the presentation of mitochondrial function/disease in cases on this research occasion. I might add that the lack of an association between mitochondrial genomes and CFS is not a new finding [2].

Mitochondria represent the so-called 'powerhouse' of cells as a result of their link with compounds such as ATP (adenosine triphosphate) among other things. Functional issues with mitochondria are known to manifest as 'fatigue' on some occasions and so it stands to reason that they should be explored in conditions where fatigue is a primary symptom such as in CFS. Indeed, other authors have looked at 'targeting' mitochondria onward to tackling some of those fatigue-related symptoms present in cases of CFS (see here).

The Schoeman results are a bit of a blow to the idea that genetically speaking, issues with mitochondria are a core part of CFS such that "CFS does not fall within the spectrum of inherited mtDNA disorders." But I would perhaps draw your attention to some of the 'interventions' that have been talked about in relation to CFS that have a 'mitochondrial' edge to them (see here) and have 'helped' under experimental conditions. Further, how just because CFS is not an inherited genetic condition as a result of underlying [genetic] mitochondrial disease does not necessarily rule out the targeting of mitochondrial functions in at least some cases of CFS. This bearing in mind the typical onset age of something like CFS (see here) and that various 'trigger' factors have been implicated with onset in mind (see here).

To close, I also note that the Cochrane guidance on the use of exercise therapy in relation to CFS has been updated (again) recently [3]. Personally, I'm minded to be a little cautious about quite sweeping statements like: "We think the evidence suggests that exercise therapy might be an effective and safe intervention for patients able to attend clinics as outpatients" made by the authors, particularly when accompanying statements like: "Serious side effects were rare in all groups, but limited information makes it difficult to draw firm conclusions about the safety of exercise therapy" are made. 'First do no harm' and all that and then perhaps focus a little more on important concepts like PEM in light of other meta-analysed findings [4]...

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[1] Schoeman EM. et al. Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome. BMC Med Genet. 2017 Mar 16;18(1):29.

[2] Billing-Ross P. et al. Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2016 Jan 20;14:19.

[3] Larun L. et al. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2017 Apr 25;4:CD003200.

[4] Loy BD. et al. Effect of Acute Exercise on Fatigue in People with ME/CFS/SEID: A Meta-analysis. Med Sci Sports Exerc. 2016 Oct;48(10):2003-12.

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Schoeman EM, Van Der Westhuizen FH, Erasmus E, van Dyk E, Knowles CV, Al-Ali S, Ng WF, Taylor RW, Newton JL, & Elson JL (2017). Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome. BMC medical genetics, 18 (1) PMID: 28302057

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

Fatigue in adults with a 22q11.2 deletion syndrome

The genetic condition called 22q11.2 deletion syndrome (22q11.2DS) has, on occasion, provided some research fodder for this blog (see here and see here). The reason for its inclusion here has tended to be around the 'overlap' in the presentation of 22q11.2 and autism/autistic features and the importance of appropriate screening as and when an autism diagnosis is received (see here). Remember: receipt of an autism diagnosis is a starting point not the finishing line.

Today I'm once again talking about 22q11.2 and specifically the results reported by Vergaelen and colleagues [1] on the need for more research/investigation on fatigue as a potentially important symptom when it comes to 22q11.2. This work links into another area of interest to this blog: chronic fatigue (syndrome) (CFS).

OK, just for the record I'd like to point out that fatigue is not the same as chronic fatigue syndrome (indeed, as mentioned in a recent post, 'chronic disabling fatigue' is also not the same as chronic fatigue syndrome). Vergaelen et al relied on data from 29 people (adults) diagnosed with 22q11.2 who completed "the multidimensional fatigue inventory (MFI) measuring severity of fatigue." Results from the self-report schedule were "compared with published population norms" and suggested that: "Subscales and total MFI scores were significantly higher in adults with 22q11.2DS." Authors also noted that the presence of fatigue seemed to also affect scores on quality of life and depression in their cohort and recommend "a systematic clinical examination to exclude underlying somatic or psychiatric causes of fatigue."

There's little more to say on this topic aside from reiterating the point that further clinical examinations should be undertaken to assess the possible hows and whys of fatigue presenting alongside 22q11.2 deletion syndrome. Given for example, previous work suggesting that mitochondrial disease might manifest as fatigue (as part of CFS that is) (see here) and some work linking "some 22q11DS genes implicated in mitochondrial function" [2] that is one option to consider among [likely] many.

Music: and if like me, you watched the trailer to the new 'Logan' film and asked who 'sings that song?', well it was Johnny Cash and Hurt.

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[1] Vergaelen E. et al. High prevalence of fatigue in adults with a 22q11.2 deletion syndrome. Am J Med Genet A. 2017 Feb 12.

[2] Devaraju P. & Zakharenko SS. Mitochondria in complex psychiatric disorders: Lessons from mouse models of 22q11.2 deletion syndrome: Hemizygous deletion of several mitochondrial genes in the 22q11.2 genomic region can lead to symptoms associated with neuropsychiatric disease. Bioessays. 2017 Feb;39(2).

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Vergaelen E, Claes S, Kempke S, & Swillen A (2017). High prevalence of fatigue in adults with a 22q11.2 deletion syndrome. American journal of medical genetics. Part A PMID: 28190295

Low muscle tone and autistic traits

"This large study showed a prospective association of infant muscle tone with autistic traits in childhood."

So said the findings reported by Fadila Serdarevic and colleagues [1] who, looking at nearly 3000 children, were able to assess early motor development and muscle tone "between ages 2 and 5 months" and later parental ratings of autistic traits in children at 6 years of age. Said autistic traits were surveyed using the "the Social Responsiveness Scale (SRS) and the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist." Authors concluded that there was something of a connection between low muscle tone and autistic traits: "Low muscle tone in infancy predicted autistic traits measured by SRS... and PDP" and further: "early detection of low muscle tone might be a gateway to improve early diagnosis of ASD [autism spectrum disorder]."

Just before anyone gets ahead of themselves with this data, it is worth pointing out that despite the large participant group included for study and the prospective nature of the study design, this was a study only really looking at two sets of variables across quite a long time-frame. It's not beyond the realms of possibility that other factors might influence the presentation of [parent-reported] autistic traits outside of just early measures of muscle tone or anything related...

But let's set this research in some context. Muscle tone in a broader sense had been noted to be potentially 'linked' to autism in some of the earliest texts on the topic (see here). More recent discussions on how motor skill in the context of gait for example, might be something important to at least some autism (see here) add to the relevance. One might also look to the some of the typical reasons why low muscle tone (hypotonia) may present to see whether there are areas that could inform autism research too. I note for example, mention of Ehlers-Danlos syndrome (EDS) in some of the texts and this would perhaps appeal to further investigation on any overlap between EDS (or other connective tissues disorders) and autism (see here). Serious infections such as encephalitis and meningitis have also been mentioned in the context of hypotonia, and again, might be indicated in relation to hypotonia and some autism (see here). There is also a possibility that hypotonia could (in some cases) be tied into mitochondrial disease; something else that could be relevant to at least some 'types' of autism (see here). All of these areas are worthy of further research inspection added to the idea that muscle tone might be rather more core to autism than many people might appreciate.

'And the best picture goes to'...

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[1] Serdarevic F. et al. Infant muscle tone and childhood autistic traits: A longitudinal study in the general population. Autism Res. 2017 Feb 9.

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Serdarevic F, Ghassabian A, van Batenburg-Eddes T, White T, Blanken LM, Jaddoe VW, Verhulst FC, & Tiemeier H (2017). Infant muscle tone and childhood autistic traits: A longitudinal study in the general population. Autism research : official journal of the International Society for Autism Research PMID: 28181411

Yet more on potential biomarkers and chronic fatigue syndrome

'Thick and fast' is probably the best way that I can describe the flurry of peer-reviewed scientific papers recently appearing (see here and see here for examples) talking about how chronic fatigue syndrome (CFS) (also linked to the diagnosis of myalgic encephalomyelitis, ME) might have some important biological processes attached to it.

Now we can add the findings reported by Federica Ciregia and colleagues [1] (open-access) to the list and their observations that "the identification of biomarkers present in particular subgroups of CFS patients may help in shedding light upon the complex entity of CFS."

The Ciregia paper is open-access but well-worth a few inches of discussion on this blog. Not least because (a) the word 'mitochondria' is part and parcel of the their findings in line with other research in this area, (b) one of the gold standards of analytical chemistry - liquid chromatography mass spectrometry -  was used, and (c) some of the findings are based on a study of twins: "a patient suffering from CFS in comparison with his healthy monozygotic twin." This mirrors other similar published work from this authorship group [2].

So, using a discovery/training and validation approach similar to other biomarker studies in other areas, researchers initially set out to "study the mitochondria extracted from platelets of the twins" using "nano-liquid chromatography electrospray ionization mass spectrometry (nano-LC-MS)." They were looking for evidence of different compounds being presented/expressed in those twins diagnosed with CFS compared with their non-affected twin and eventually came up with 41 proteins - "34 were upregulated in CFS and 7 were downregulated" (see here for the list of compounds).

Using a process called Ingenuity Pathway Analysis (IPA) "to retrieve the known functions of each protein" authors were able to visualise where each compound 'fitted' in terms of specific biological functions. The top three included: "metabolism of isocitric acid..., metabolism of NADH... and metabolism of nucleic-acid component or derivative." Certainly NADH has some 'history' when it comes to CFS/ME (see here).

Then came the validation side of the study where "the most promising biomarkers were validated by western blot [WB] analysis in a big cohort of patients, using whole saliva (WS)." Here some 45 patients diagnosed with CFS ("based on the classification criteria of Fukuda et al") were recruited alongside 45 not-CFS controls and spit samples from all were analysed for "aconitate hydratase (ACON), ATP synthase subunit beta (ATPB) and malate dehydrogenase (MDHM)." Two proteins, ACON and ATPB. were replicated or at least "consistent with the results from nano-LC-MS."

Finally, researchers looked at whether presented clinical features as described in various questionnaires delivered to participants might play a role in the presentation of their biological results. They did see something (see here) - "For each marker, the values were actually higher in the group of patients who had clinical features similar to the ill twin" - but I would be minded to suggest that quite a bit more work is needed before anyone reads too much into this as the results stand.

So, there you have it. A little bit more evidence to suggest that science is edging a little closer to potentially identifying some of the biology behind (or least associated with) at least some CFS (and ME). A little bit more peer-reviewed evidence moving the discussions away from 'psychosomatic' [3] to something a little more testable/analysable with CFS/ME in mind (I'll be coming to the paper by Geraghty & Esmail soon enough on this blog by the way). Independent replication is the next step, onwards to potentially "developing tailored treatments." That bearing in mind, we already have some emerging data in this area too (see here) (with no medical advice given or intended).

And just in case you want yet more potential biomarker research for CFS, here's another paper that has just been published [4]. Thick and fast people, thick and fast.

So, there is a new trailer for Rogue One (A Star Wars story)...

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[1] Ciregia F. et al. Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome. Transl Psychiatry. 2016 Sep 27;6(9):e904.

[2] Ciregia F. et al. A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers. J Transl Med. 2013 Oct 2;11:243.

[3] Geraghty KJ. & Esmail A. Chronic fatigue syndrome: is the biopsychosocial model responsible for patient dissatisfaction and harm? Br J General Practitioners. 2016. Aug 1.

[4] Yamano E. et al. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Scientific Reports. 2016; 6: 34990.

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Ciregia F, Kollipara L, Giusti L, Zahedi RP, Giacomelli C, Mazzoni MR, Giannaccini G, Scarpellini P, Urbani A, Sickmann A, Lucacchini A, & Bazzichi L (2016). Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome. Translational psychiatry, 6 (9) PMID: 27676445

The effects of acute exercise on ME/CFS/SEID meta-analysed

Accepting that the science recipe that is a meta-analysis is only as good as the research ingredients that go into it, I was interested to see the results published by Bryan Loy and colleagues [1] who concluded that: "preliminary evidence indicates that acute exercise increases fatigue in people with ME/CFS/SEID more than in control groups, but effects were heterogeneous between studies."

ME - myalgic encephalomyelitis - and CFS - chronic fatigue syndrome - are conditions that I'm interested to talk about on this blog; specifically how after seemingly years and years in the research-clinical wilderness, science is starting to put some real effort into determining cause(s) and importantly, what might be done about ameliorating this quality of life-crushing condition. SEID - systemic exertion intolerance disease - by the way, is a rather newer description of symptoms (just in case you were not already confused enough).

Loy et al set about combing the peer-reviewed research literature for studies pertinent to their examination of the "population effect of a single bout of exercise on fatigue symptoms in people with ME/CFS/SEID." Interestingly, Google Scholar and not PubMed was there search engine of choice, where 7 studies "examining 159 people with ME/CFS/SEID met inclusion criteria" went on to be included for study. After some statistical analysis, authors concluded that: "Fatigue increases were larger for people with ME/CFS/SEID when fatigue was measured four or more hours after exercise ended rather than during or immediately after exercise ceased." They also suggested that more precise research is required in terms of the effects of exercise on this population.

If, like me, you assume that quite a lot of people who have been included under the headings of ME/CFS/SEID are actually suffering (yes, suffering) with an organic illness/illnesses [2] potentially affecting the way energy is created, stored or used in the body, such results are probably not unexpected. Words like 'mitochrondrial issues' are not totally unfamiliar to at least some parts of the ME/CFS/SEID continuum (see here and see here) and given the link between mitochondria and energy, may well provide at least one answer why post-exertional fatigue/malaise is present for some. The idea of immune system involvement in ME/CFS/SEID cannot also be left out of the equation (see here) although the precise relationship to fatigue is slightly less clear-cut.

I'd agree with the authors that more needs to be done on the hows and whys of post-exertional fatigue following acute exercise in this patient group including why other reviews [3] have reported contrary findings when it comes to exercise therapy lasting "from 12 to 26 weeks." And before you mention, yes, I'm well aware of the various goings-on with regards to a certain trial for CFS where exercise of the graded variety was used...

Of course acute exercise vs. chronic exercise (if I can call it that) are not one and the same thing so one has to be slightly cautious of making any direct comparisons. I would however like to see a little more research on the biological processes linked to fatigue post-exercise in this group; as per the suggestion by Rutherford and colleagues [4] that: "Bioenergetic muscle dysfunction is evident in CFS/ME" and what implications this might have. That also a few other favourite topics of mine (gut bacteria and bacterial translocation) might also be something to look at (see here) in the area of exercise effects and ME/CFS is worthwhile mentioning too...

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[1] Loy BD. et al. Effect of Acute Exercise on Fatigue in People with ME/CFS/SEID: A Meta-analysis. Med Sci Sports Exerc. 2016 May 17.

[2] Edwards JC. et al. The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem. Fatigue. 2016 Apr 2;4(2):63-69.

[3] Larun L. et al. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2015 Feb 10;2:CD003200.

[4] Rutherford G. et al. Understanding Muscle Dysfunction in Chronic Fatigue Syndrome. J Aging Res. 2016;2016:2497348.

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Loy BD, O'Connor PJ, & Dishman RK (2016). Effect of Acute Exercise on Fatigue in People with ME/CFS/SEID: A Meta-analysis. Medicine and science in sports and exercise PMID: 27187093

On genes, environment, broccoli and autism (again)

Picture: Carl Warner: http://www.carlwarner.com/

I'm serving up two peer-reviewed papers for your reading delight today which draw attention to the ideas that (a) the 'causes' of autism are likely complex and as heterogeneous as the label itself, (b) gene x environment interactions affecting risk of autism are starting to get some good scientific research airtime and (c) don't 'dis the broccoli [chemical] autism connection just yet...

The first paper by Brandon Pearson and colleagues [1] (open-access) has already found some media interest as per the Guardian headline: 'Agricultural fungicides are 'bad news for neurons', study suggests'. Exposing mouse neurons - "cortical neuron-enriched cultures" - to several hundred chemicals (careful of that word) found in the modern environment, researchers concluded that several compounds "produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer’s disease and Huntington’s disease)." That is, several types of chemicals quite commonly found in the modern environment seemed to alter gene expression in those mouse neuron enriched cultures that weren't a million miles away from that noted previously in conditions such as autism for example.

Mouse neurons, you might be thinking? Well, obviously one has to be a little cautious about extrapolating from mouse to humans (see here) but researchers did include some comparison analysis looking at "the gene expression profile of our cultures with brain cell-type-specific expression data sets and human brain gene expression data sets." The result: "cortical cultures show strong transcriptional similarities to the human brain."

Clustering chemicals based on "concordant gene expression changes", six groups emerged. Cluster 2 chemicals, containing such pesticides as rotenone, pyridaben and fenpyroximate  and also various compounds under the heading of the strobilurins seemed show some particularly interesting results insofar as they "mimicked the transcriptional changes of two post-mortem ASD [autism spectrum disorder] brain expression data sets in a bidirectional manner." The effects of this cluster of compounds also seemed to unite various conditions with autism including Alzheimer’s disease and Huntington’s disease and the "aging brain". My interest was particularly piqued by that last association in light of other research results (see here).

When it came to the 'effects' of those chemicals in terms of genetic and biological processes, researchers put forward some not unfamiliar potential roles: "These chemicals, most of which inhibit mitochondrial complex I or III, stimulated free radical production and disrupted microtubules." Words like 'oxidative stress' start to emerge as they have done in previous autism research (see here) and yet again, inflammation or inflammatory processes seem also to be indicated. Indeed, the authors also make mention of how effects such as free radical production "can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane." Yes indeed, sulforaphane - the chemical found in broccoli - might indeed be moving back up the autism research agenda (see here for some previous background).

There is obviously lots more work to do in this area before anyone gets too carried away. The authors note: "While usage and residue levels of cluster 2 chemicals on conventionally grown foods are increasing, in the absence of causality, it is premature to draw correlations with the increased prevalence of ASD and other brain disorders." Lessons could be learned from other blanket suggestions about 'chemicals' and autism (see here) as well as an appreciation for the concept of the the plural autisms (see here). Then there are the practicalities of whether ingesting such compounds on food or in water is the same as direct exposure to cortical neuron-enriched cultures? Or indeed, whether there may be other routes of contact? I might also suggest that further studies should focus on looking for the metabolites of such agents too [2] bearing in mind the concept of statistically significant thresholds...

If you're still here after all that, the second paper I want to talk about is that from Sarah Wong and colleagues [3] that has also received a bit of media attention. The focus this time was on a gene called p53 (see here for some background) and how issues with this gene might be 'over-represented' when it comes to autism following on from other work by some of the same authors [3]. First of all, please don't get too fixated by mention of the words 'cancer gene' when it comes to p53 given it's [protein] tumour suppressing capabilities. As I've discussed before, the risk of cancer does not seem to be elevated any more than the general population risk when it comes to autism (see here). Perhaps of greater relevance to the Wong findings is the idea that p53 has other 'activities' such as that related to oxidative stress (yes, that again) and "DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance."

Based on data from CHARGE (beincharge!), researchers garnered blood samples from 66 children diagnosed with an autism spectrum disorder (ASD) and "race-, gender-, and age-matched typically neurodeveloping children (n = 46)" (authors words not mine). They analysed for mtDNA copy number and deletions and p53 gene copy ratios and found them to be "more common in children with AU [autism] and their fathers." The authors translate their findings as pointing to "a role for deficient DNA repair capacity not driven by paternal age." They also suggest that environment might intersect with genetics in relation to 'severity' scores of autism obtained for their cohort: "gene x environment interaction seems to play a greater role in children with autism with less severe symptoms."

Taken together the Pearson and Wong findings point to some interesting 'associations' potentially relevant to [some] autism. The idea that certain components of the modern-day environment might increase the risk of autism is nothing new but the way that Pearson et al went about studying the possible relationship is. The results from Wong et al suggesting that there might be issues with the gene 'whose role is to suppress cellular damage from environmental stressors' suggests that exposure patterns might not necessarily be where it's all at when looking at compound/chemical X or Y in relation to autism risk. I'm also inclined to direct you to some previous discussion about the caspases and autism (see here) in light of the involvement of p53 with the process of apoptosis (programmed cell death) in mind. As I've mentioned before, the biological mechanisms for how people deal with various xenobiotics needs a lot more investigation in autism research circles (see here); something that might similarly extend to genetic mechanisms too.

Oh, and just in case you think that I'm pushing the either/or of genetic and environment when it comes to autism, I'm not, as words like epigenetics spring to mind and the idea that genomic instability might, for example, have quite a few different dimensions (see here)...

To close, I'm thinking of branching out... football (soccer) pundit perhaps?

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[1] Pearson BL. et al. Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration. Nat Commun. 2016 Mar 31;7:11173.

[2] Domingues VF. et al. Pyrethroid Pesticide Metabolite in Urine and Microelements in Hair of Children Affected by Autism Spectrum Disorders: A Preliminary Investigation. Int. J. Environ. Res. Public Health 2016; 13: 388.

[3] Wong S. et al. Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study. Pediatrics. 2016. March 31.

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Pearson, B., Simon, J., McCoy, E., Salazar, G., Fragola, G., & Zylka, M. (2016). Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration Nature Communications, 7 DOI: 10.1038/ncomms11173




Wong, S., Napoli, E., Krakowiak, P., Tassone, F., Hertz-Picciotto, I., & Giulivi, C. (2016). Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study PEDIATRICS, 137 (4) DOI: 10.1542/peds.2015-1888

Can mitochondrial disease be mistaken for chronic fatigue syndrome?

Very possibly, is the answer to the question that titles this post on how the diagnostic borders between mitochondrial disease and chronic fatigue syndrome (CFS) might be blurred. I bring to your attention the case report published by Fernando Galán and colleagues [1] (open-access available here) as an example.

Detailing the experiences of a 30-year old male who "appeared to meet the CDC-1994/Fukuda criteria for CFS [chronic fatigue syndrome]" and for whom 1 year of "cognitive behavioral therapy, graded exercise therapy, and antidepressants" resulted in only 'very slight improvement', authors eventually "considered the possibility of mitochondrial myopathy in this patient."

Screen and you may find, is the primary lesson offered by Galán et al, as "a severe deficiency of activity in complex I (nicotinamide adenine dinucleotide: ubiquinone oxidoreductase) and IV (cytochrome c oxidase) below 42% and 70% of the minimum reference of control value normalized to citrate synthase activity, respectively" is reported. Combined with several variants noted in the mitochondrial genome, and "adult-onset mitochondrial myopathy, with clinical manifestation of peripheral sensory neuropathy, autonomic symptoms, and occipital neuralgia" was the eventual diagnosis. Treatment, consisting of riboflavin (100 mg 3 times per day) and thiamine (300 mg/day) was begun, and coincided with "a marked and sustained improvement." Further clinical improvement was also noted following the use of pregabalin.

In these days of continued questioning about whether the suggested blanket psychological 'treatment' of CFS is actually cutting the scientific mustard (see here) I'm minded to reiterate how Galán et al were able to diagnose a biological reason as to potentially why this man was presenting with the symptoms he was. As far as I'm aware, cognitive behaviour therapy (CBT) is not normally indicated for treating mitochondrial disease and probably why it had such little effect in this case.

Yes this is a single case report and it would certainly be unwise to suggest that every case of CFS or ME is due to mitochondrial issues. That being said, the work from Sarah Myhill and colleagues - 'mitochondria, not hypochondria' - has been discussed before on this blog (see here). Combined with other preliminary results (see here) and I think quite a good case for screening for mitochondrial issues is being formed as and when CFS is diagnosed. Certainly following "the appearance of new symptoms and signs" one might consider putting additional screening resources in place, and indeed probably better to do said screening before any psychosomatic explanations are assumed or acted upon.

Oh, and without medical or clinical advice given or intended, the peer-reviewed literature 'around' this topic also has some other potential 'placebo-controlled' lessons to offer any interested ears (see here)...

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[1] Galán F. et al. Mitochondrial Myopathy in Follow-up of a Patient With Chronic Fatigue Syndrome. J Investig Med High Impact Case Rep. 2015 Sep 24;3(3):2324709615607908.

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Galán F, de Lavera I, Cotán D, & Sánchez-Alcázar JA (2015). Mitochondrial Myopathy in Follow-up of a Patient With Chronic Fatigue Syndrome. Journal of investigative medicine high impact case reports, 3 (3) PMID: 26904705

Mitochondrial response to BCKDK-deficiency and 'some' autism

I'll admit to being pretty fascinated by the Branched Chain α-Keto acid Dehydrogenase Kinase (BCKDK) gene. As per previous blog entries about this gene (see here and see here) and the important biological step it plays in the metabolism of the branched-chain amino acids (BCAAs), at least one 'form' of autism might be particularly sensitive to issues with it [1]. I take it you've heard of the idea that the autisms (plural) might be a better description of autism? If you haven't, here is a peer-reviewed take on it [2]...

I'm happy to report that science continues to study this gene; its biology and it's associations with "a novel dietary-treatable form of autism" as per the findings reported by Oyarzabal and colleagues [3]. The focus of the Oyarzabal paper was to study the "mitochondrial response to the BCKDK-deficiency" potentially brought about for example, when there are issues with the BCKDK gene given its links to the mitochondria matrix. This work also takes on particular relevance given the idea that mitochondrial issues - mitochondria: the powerhouse of cells - might not be something entirely new to at least some autism (see here for example).

Anyhow, fibroblasts were the starting material and the measurement of "bioenergetics, ultra-structural and dynamics parameters" of fibroblasts from those who had BCKDK-deficiency. Although not totally au-fait with all the science included in the paper, the authors report results on: "a general bioenergetics depletion that could affect the mitochondrial dynamics and cell fate." They even reported complementary findings following a: "Knockdown of BCKDK gene in control fibroblasts" and mention of some findings relevant to maple syrup urine disease (MSUD) in light of the involvement of the BCAAs there. In short: "All these data gives us a clue to understand the positive dietary response to an overload of branched-chain amino acids."

This is an exciting area of autism research pertinent to the idea that (a) there may be various types of autism characterised by various different genetic and biological factors being involved, and (b) the possibility that at least some autism might stem from one or more inborn errors of metabolism is gaining ground (see here) and hence might be potentially 'treatable'. For that last point I'm minded to take you back to a recent post on phenylketonuria and autism (see here) and some more recent [peer-reviewed] research talking about 'Succinic Semialdehyde Dehydrogenase Deficiency Presenting as Autism Spectrum Disorder' [4]. Dare I even present the idea of carnitine issues falling into this area?

Screening for such inborn errors of metabolism seems to be the important conclusion; screening not assuming nor guessing nor making grand generalisations. Just screening.

Music: the glorious music accompanying the film Interstellar has to be the one for today in light of new discoveries in recent days...

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[1] Novarino G. et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012 Oct 19;338(6105):394-7.

[2] Poot M. Towards identification of individual etiologies by resolving genomic and biological conundrums in patients with autism spectrum disorders. Mol Syndromol. 2013 Jun;4(5):213-26.

[3] Oyarzabal A. et al. Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochim Biophys Acta. 2016 Jan 22. pii: S0925-4439(16)30003-5.

[4] Gogou M. et al. Succinic Semialdehyde Dehydrogenase Deficiency Presenting as Autism Spectrum Disorder. Indian J Pediatr. 2016 Jan 25.

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Oyarzabal A, Bravo-Alonso I, Sánchez-Aragó M, Rejas MT, Merinero B, García-Cazorla A, Artuch R, Ugarte M, & Rodríguez-Pombo P (2016). Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochimica et biophysica acta PMID: 26809120