Tuesday 26 February 2013

In relation to chelation and autism

OK, just to make sure we're straight on this matter:

I am not endorsing chelation therapy for autism in this post.

Carry on Private...

I might have said it before but a few areas of the autism landscape have been, and still, are a bit of a sticking point when it comes to their discussion. Mention for example bowel issues and autism and, in at least some quarters, you can see the eyebrows raising and the eyes beginning their short rolling journey around the eye socket. This despite the fact that bowel issues are to some extent entering the mainstream autism research consciousness as witnessed for example by that recent paper from Susie Chandler and colleagues (discussed here). Dare I even mention gut bacteria and autism as per the recent write-up of Paul Patterson's [pending] work in the New Scientist? Too much?
My hand @ Miss Whiteley  

So it is with some degree of eye-rolling anticipated that I set about discussing the paper by Eleonor Blaucok-Busch and colleagues* (open-access) describing the results of their small trial based on the use of the oral chelator meso-2,3-dimercaptosuccinic acid (DMSA) in cases of autism.

I'm not altogether sure, but I wondered whether we might have already seen some part of this trial published in another paper**.

In truth I wouldn't normally be minded to talk about something like DMSA and autism given that (a) chelation - with general health in mind - is still a bit of a hot potato in many science/medical circles even despite some evidence that the 'metal-snaring' intervention might have some effects, and (b) with autism in mind, chelation is even more of a hot potato given some safety concerns and its link to heavy metals - in particular one heavy metal - onward to a suggested role in the rising numbers of cases of autism by some.

But science is science, and the manuscript by Blaucok-Busch is peer-reviewed science (the journal also indexed in PubMed). Added to the fact that some people have reported positive changes to some features associated with autism following such intervention*** alongside some recent publicity for related work by people like Jim Adams (see this previous post), this post may be timely.

The Blaucok-Busch paper is open-access but a few details might be of some use:

  • I don't mean to be a stickler but the opening line of the abstract read slightly unusual to me: "the aim of this study was to provide evidence that DMSA detoxification treatments cause a reduction of the heavy metal burden in the autistic, and that this reduction lessens neurological symptoms associated with ASD". A research paper designed to provide evidence that something works? Mmm, I perhaps would have worded this differently with regards to things like hypothesis-testing over evidence-producing, but maybe that's just me.
  • Anyhow, 44 children diagnosed with an ASD - most boys and most diagnosed with autism - aged between 3-9 years old were included for study. The children were all attending a child development centre in Saudi Arabia. Quite a bit of background data were available for participants and in among the various entry/exclusion criteria were the none use of regular medication including neuroleptics and antiepileptics. 
  • The Childhood Autism Rating Scale (CARS) (translated into Arabic) was used to score the presence of autism-related behaviours; both before DMSA use and "six months after treatment". This actually translates as a single dose of DMSA per month (10mg/kg body weight) for a total of 6 months.
  • Prior to any use of DMSA, participants were provided with a nutritional supplement including "a multi-mineral-vitamin-amino acid complex" which included zinc gluconate given once-a-day for 3 months prior to chelation.
  • Baseline urine samples pre-chelation were collected and alongside (I assume first supplementation) post-DMSA administration urine samples (over 4 hours), analysis was conducted on them using everyone's favourite metal analysis technique, ICP-MS.
  • Results: based on analysis for a number of metals, urine samples showed a number of differences between pre- and post-DMSA administration, most notably for increases in cadmium (p=0.006) and lead (p=0.008) excretion. Mercury also showed some difference, but only just from a statistical point of view (p=0.049). Another quote: "For this autistic group, the baseline urine concentration of all metals tested exceeded the given reference range".
  • For the CARS, pre- and post-DMSA scores - bearing in mind we are talking 6-months after treatment - showed a few interesting trends in terms of items like sensory-perceptual issues and verbal and non-verbal communication, potentially indicative of positive changes to symptoms.
  • The authors conclude: "Our evaluation confirmed specific metals as neuro-developmental toxins, and we observed that a reduction in toxic metals is helpful in reducing some symptoms typically associated with autism".

OK first things first. This was a simple before-and-after study based on the use of DMSA. There was no control group, no randomisation, no placebo, and everything was unblinded. This is not a great example of providing evidence for a cause-and-effect relationship.

Aside from reporting that 2-3 days prior to the DMSA challenge "no fish was eaten" and "all nutritional supplements were stopped" we know very little about what else might have happened in that intervening 6 month period between CARS assessments. Without any sample control group to compare against, we might just as well say that the changes to the CARS might be down to maturation or some other intervention put in place. Indeed I don't know whether this cohort were more or less likely to be using other interventions which might have affected results as a result of their participation in the trial; not least whether anyone went back on to the nutritional supplement after the first chelation event. There are methodological holes in this trial; of this there is no doubt.

But... [cue any eye-rolling] I am particularly interested in the pre- and post-challenge DMSA urine results detailed. Interested that even in the pre-DMSA samples, children with autism were presenting with levels of heavy metals that exceeded reference ranges. Granted, one could ask: from where the reference range is derived and whether it is truly reflective of this particular participant group in terms of age, sex, ethnicity, etc. and the myriad of other potentially influential demographic and geographic factors. I have to take the authors' word for it that it is accurate although I would like to have seen the unit of measurement when it comes to reporting metal excretion levels displayed somewhere in the paper.

Of course this is not the first time that metals like lead have for example cropped up with autism and quite a few other conditions/states in mind. Even superman had problems with lead, so went a past post on this blog. Indeed my discussion on the paper by Yasuda and colleagues quite recently (see here) and their metallomic analysis of children with autism suggested that lead, cadmium and aluminium in relation to some cases of autism were of potential importance, particularly where zinc deficiency was present. This follows similar findings previously reported (yep that Jim Adams study again) and some case studies (see here for example).

I was also interested in the variation in metal excretion following DMSA challenge. Increasing mean levels of urinary lead in the cohort follow what DMSA is supposed to do and add to the evidence already presented with autism in mind**** (open-access). But, as the authors point out, several metals were actually lower in the post challenged samples. Even the mercury results whilst showing a mean higher level showed a vastly increased standard deviation pre- and post-challenge (3.35±3.81 vs. 16.12±36.57) which probably accounts for the relatively modest p-value reported. I assume this denotes that some children were better excretors of things like mercury than others following DMSA challenge? My next question would be: why?

Evidence for the use of chelation in cases of autism is still wanting in terms of research results as per the review by Davis and colleagues*****. This trial by Blaucok-Busch is, unfortunately, unlikely to add anything significant to the existing research literature. The tragic case of Abubakar Tariq Nadama who died following intervention with a chelating agent****** (albeit a different chelating agent) still also hangs over the whole area of metal removal and autism and serves as an important but very unfortunate reminder about what can happen; also re-emphasizing the first law of any intervention: do no harm. No doubt why the NIH trial fell as it did (see here).

That's not however to say that the research door should be slammed shut, bolted, padlocked and alarmed, as several questions still remain unanswered: why for example some kids with autism present with elevations in certain heavy metals in the first place (see the paper by Levallois et al******* for one possibility) and what their relationship might or might not be to presented symptoms. One could argue that getting to the bottom of these questions is the first step, and thereafter to the question of what can or can't be done about it in a more scientifically-rigorous fashion bearing in mind safety first and the fact that not all chelating methods are the same********.

To finish, a final mention: I am not endorsing chelation therapy for autism in this post. Just in case I hadn't got my message across.

Now away from metal, how about listening to The Specials and 'Gangsters' including one of the best lines in music... "Don't call me Scarface". So, don't.... (and as it happens, thanks to a childhood prank gone wrong, I do actually have a scar on my face).


* Blaucok-Busch E. et al. Efficacy of DMSA therapy in a sample of Arab children with autistic spectrum disorder. Maedica (Buchar). 2012; 7: 214-221.

** Amin OR. P-252 - Efficacy of oral dimercaptosuccinic acid (DMSA) therapy in a sample of arab children with autistic spectrum disorder. European Psychiatry. 2012; 27 (suppl 1).

*** Senel HG. Parents' views and experiences about complementary and alternative medicine treatments for their children with autistic spectrum disorder. J Autism Dev Disord. 2010; 40: 494-503.

**** Adams JB. et al. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A--medical results. BMC Clin Pharmacol. 2009; 9:16.

***** Davis TN. et al. Chelation treatment for autism spectrum disorders: a systematic review. Research in Autism Spectrum Disorders. 2013; 7: 49-55.

****** Baxter AJ. & Krenzelok EP. Pediatric fatality secondary to EDTA chelation. Clinical Toxicology. 2008; 46: 1083-1084.

******* Levallois P. et al. The impact of drinking water, indoor dust and paint on blood lead levels of children aged 1–5 years in Montréal (Québec, Canada). Journal of Exposure Science and Environmental Epidemiology. January 2013.

******** Cohen JP. et al. Plasma and Urine Dimercaptopropanesulfonate Concentrations after Dermal Application of Transdermal DMPS (TD-DMPS). J Med Toxicol. 2013; 9: 9-15.


ResearchBlogging.org Blaucok-Busch E, Amin OR, Dessoki HH, & Rabah T. (2012). Efficacy of DMSA Therapy in a Sample of Arab Children with Autistic Spectrum Disorder. Maedica (Buchar), 7 (3), 214-221

Sunday 24 February 2013

Memantine and autism

As part of their review of autism research in 2012, the Simons Foundation Autism Research Initiative (shortened to the very catchy SFARI) had an interesting blogpost on all things drug development with autism spectrum disorders (ASD) in mind.

It was an interesting entry insofar as they had categorised the various medicines potentially indicated for some of the symptoms of ASD according to the stage of drug development including some formulations that have previously been fodder for this blog such as arbaclofen (see here), NAC (see here), minocycline (see here and here) and of course melatonin (see here). Without wishing to nit-pick, there was one important omission from the list - at least when I looked at it (29/12/12) - in the form of Dr Joan Fallon's CM-AT preparation which has also started making waves, but I'll put that to one side for now.

Tacuinum Sanitatis @ Wikipedia
Another compound which I've been hearing rumblings about for some time now was also included as a drug in phase II development.

The name: memantine, known under various trade names but with autism in mind, specifically Namenda by Forest Laboratories.

Searching through my blogpost archives I have made brief mention of memantine in a previous entry on some research looking at amyloid precursor protein in cases of autism. In that context, memantine was discussed with the management of symptoms related to Alzheimer's disease although touching upon the open-label study by Chez and colleagues* with autism in mind.

Given the very visible focus on glutamate and autism (see my post on GABA for an overview) it was always likely that memantine would get a look in when it comes to autism and autistic-like conditions. Memantine, I am reliably informed, blocks the action of glutamate by binding to NMDA receptors. That and a few other potentially important modes of action including some effect on cholinergic activity which I've always thought to be a rather interesting area as per articles like this one from Elaine Perry and colleagues** (open-access) and some potential synapse formation effects*** (open-access). It's probably no surprise that memantine has also been tentatively suggested for quite a few more psychiatric-based conditions**** including depression and schizophrenia.

I am rather interested in memantine and its possible uses (and misuses) when talking about autism. A quick trawl of the available literature suggests that an awful lot more needs to be done on this medicine with autism in mind as per its inclusion in the very useful pharmacologic autism treatment review by Doyle & McDougle***** (open-access) and its proposed effects particularly on the social interactive side of autism. Indeed trials are on-going (see here). Not least to also bear in mind are the various contra-indications and side effects (see here) which as always need to be balanced against potential therapeutic gains as required by good medicines management.

We wait and see... And while waiting, let's do some jammin' with Bob.


* Chez MG. et al. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol. 2007; 22: 574-579.

** Perry EK. et al. Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am J Psychiatry. 2001; 158: 1058-1066.

*** Wei H. et al. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome. PLoS ONE. 2012; 7: e36981.

**** Zdanys K. & Tampi RR. A systematic review of off-label uses of memantine for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 1362-1374.

***** Doyle CA. & McDougle CJ. Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan. Dialogues Clin Neurosci. 2012; 14: 263–279.


ResearchBlogging.org Chez MG, Burton Q, Dowling T, Chang M, Khanna P, & Kramer C (2007). Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. Journal of child neurology, 22 (5), 574-9 PMID: 17690064

Thursday 21 February 2013

Myalgic encephalomyelitis (ME) and HERVs

Viruses. Apparently there are quite a lot of them on this old rock we call home and I've started to become quite interested in some of them, or at least how we as a species have, and continue to interact with them down the ages.

I must start by thanking Natasa for bringing me into contact with the paper by Kenny De Meirleir and colleagues* (open-access) looking at human endogenous retrovirus (HERV) expression in a small cohort of patients diagnosed with myalgic encephalomyelitis (ME). I'm going to try and talk about this potentially quite important paper as best I can, bearing in mind my considerable non-expertise in all things HERVs and indeed, ME. And just in case you want another viewpoint on this study, the article by Joel (Snowathlete) is pretty good.
Voyage of Discovery @ Wikipedia  

OK, so HERVs. Think ghosts of viruses past, bits of which are communicated down the generations and comprise a very surprising 8% of the human genome. I've talked about HERVs before with autism and schizophrenia in mind (see this post) and the involvement of epigenetic means in keeping HERVs in some kind of check. Consider this post a bit of an extension of that discussion albeit with ME in mind. Consider also how some of the De Meirleir results might also be potentially investigated with autism and schizophrenia in mind.

Before progressing to the findings, the first thing that struck me about this paper is its point of origin: the Whittemore Peterson Institute. While this name probably means very little to many people, those with a particular interest in ME (and Chronic Fatigue Syndrome, CFS) will perhaps know about some of the recent history which included the WPI, and those magic letters X-M-R-V (see this post). I might add that this point should not in any way, shape or form alter or affect the findings or conclusions offered by De Meirleir et al. This is peer-reviewed stand-alone science. And science is after all [mostly] self-correcting; the XMRV story is quite a good example of that.

So back to the paper, and a very quick summary:

  • The proposed connection between HERV expression in various conditions with an 'autoimmune' element** (systemic lupus erythematosus, SLE for example) led the authors to look at the expression of HERV proteins in gastrointestinal biopsies taken from 12 participants diagnosed with ME compared with those from 8 asymptomatic (at least for ME) control participants.
  • Punch biopsies came from the stomach and duodenum and were analysed for "the presence of HERV and gamma-retroviral Env and Gag proteins" based on immunohistochemistry.
  • Results: well alongside "the presence of substantial disruption of gut microbiota composition" in all ME cases (dysbiosis to you and me) and "a lympho-plasmatic infiltrate in the submucosa in all specimens"(question?), 8 of the 12 duodenal samples from participants with ME were immunoreactive to antibodies "raised against HERV proteins" compared with none of the controls. 
  • Another quite important quote from the paper: "These observations suggest that the presence of the HERV protein in pDC's [plasmacytoid dendritic cells] may be associated with a pathological manifestation in at least a subset of individuals with ME".

I've probably not done justice to the final paper and the work that went into producing it with such a short summary. Nonetheless, I find these to be some quite exciting preliminary findings for quite a few reasons. I should point out that HERVs are seemingly becoming quite fashionable where ME and CFS are concerned as evidenced by the paper from Oakes and colleagues. I'll maybe come back to their findings on HERV-K in a later post.

Back to the De Meirleir paper and a few comments...

First is the suggestion that words like 'autoimmunity', 'antigen-presentation', 'inflammation' and 'gastrointestinal' might actually be part and parcel of the pathology of at least some cases of ME or at the very least, significant comorbidity. Accepting the continuing issue of definition and criteria for definition when it comes to ME (and CFS), and that there is still lots of debate as to what the underlying causes of ME might be and best treatment options are, I find myself drawn back to some of the work done in autism research; particularly that connected to the almighty MHC. Without going over already trodden ground, the MHC is perhaps best described as the way the body tells the immune system what is self and what is a foreign contaminant (to borrow a phrase from Disney's WALL-E). I note for example that MHC class II antigens have been talked about before, at least in CFS, as per the paper by Smith and colleagues*** (open-access).

As Meirleir points out, HERV proteins should normally be treated as 'self' by the MHC. They speculate however that several elements combine: (i) "Inflammation is known to increase HERV expression", (ii) "some HERV proteins act as superantigens", (iii) "pDCs are most remarkable for their ability to produce copious amount of type-1 IFN" and how an issues with pDC response might impact on interferon production with some potentially important knock-on effects****. Perhaps some food for thought?

Next is the possibility of a relationship between ME and that bright new discipline of epigenetics, bearing in mind the concept of jumping genes and the mantra: hypomethylation = more genomic instability with the connection back to HERVs. I should caution that nothing is specifically mentioned about epigenetics in the De Meirleir paper given their focus on identifying immunoreactivity to HERV protein in cases. Indeed I was very surprised to see that a PubMed search of the keywords 'myalgic encephalomyelitis and epigenetics' showed only 2 hits (20/02/13). An unexplored area if ever there was one....

Finally, I can't end this post without referencing the gut bacteria findings and indeed the fact that "Gastritis (mainly antritis) was present in all cases". Some years ago, two colleagues of mine speculated that within the spectrum of ME/CFS there seemed to be two primary phenotypes: one where symptoms appeared to coincide with gastrointestinal (GI) issues; another with a more neurological presentation - the word 'brain fog' seemed to be quite a well-used description. Now I'm not saying that these categorisations are entirely accurate, but certainly the GI symptoms element does seem to cropping up in quite a bit of the ME/CFS literature as for example in the paper by Clark and colleagues***** (full-text) on reports of things like childhood gastrointestinal symptoms potentially being risk factors for a diagnosis. Indeed, the overview provided by Lakhan & Kirchgessner****** (full-text) on gut inflammation and CFS covers quite a lot of the material in this area and again, a call for quite a bit more research to be done too.

The De Meirleir paper, whilst small in participant numbers and preliminary in nature is an interesting one; of that there is no doubt. The next stage of the HERV-ME journey - learning the lessons of XMRV - is independent replication with the appropriate statistical power and relevant control groups (fibromyalgia and various other autoimmune related conditions for example) and then, depending on those results, the real adventure can begin.

But also I would caution that we not forget all the other areas of potential importance to ME and CFS... (see here and here and here and here) in our prospective new-found fixation with HERVs and ME.


* De Meirleir KL. et al. Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins. In Vivo. 2013; 27: 177-187.

** Balada E. et al. Molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity. Rev Med Virol. 2009; 19: 273-286.

*** Smith J. et al. Association of chronic fatigue syndrome with human leucocyte antigen class II alleles. J Clin Pathol. 2005; 58: 860–863.

**** Martinet J. et al. Altered functions of plasmacytoid dendritic cells and reduced cytolytic activity of natural killer cells in patients with chronic HBV infection. Gastroenterology. 2012; 143: 1586-1596.

***** Clark C. et al. Premorbid risk markers for chronic fatigue syndrome in the 1958 British birth cohort. Br J Psychiatr. August 2011.

****** Lakhan SE. & Kirchgessner A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). 2010; 7: 79.


ResearchBlogging.org KENNY L. DE MEIRLEIR, SVETLANA F. KHAIBOULLINA, MARC FRÉMONT, JAN HULSTAERT, ALBERT A. RIZVANOV, ANDRÁS PALOTÁS, & VINCENT C. LOMBARDI (2013). Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins In Vivo, 27 (2), 177-187

Tuesday 19 February 2013

Ann-Mari Knivsberg: an autism research pioneer

Prof. Ann-Mari Knivsberg
Dear readers, this is a short post to communicate the passing of a great woman and celebrate her life and achievements in the field of autism research and beyond.

On Sunday 17th February 2013, Prof. Ann-Mari Knivsberg died peacefully. An obituary has been posted on the University of Stavanger website which can be translated into other languages.

All who had the pleasure of meeting Ann-Mari will know that she had a real warmth about her which shone through in her professional life and her ground-breaking work examining the potential effectiveness of a gluten- and casein-free (GFCF) diet for people on the autism spectrum and beyond.

Ann-Mari was a pioneer in her various studies looking at GFCF diets with autism in mind, publishing one of the very first scientific accounts examining dietary intervention (see here). Her passion for autism research continued over the years; to many earning her the title of 'godmother of dietary intervention research for autism'.

I had the very great pleasure of working with Ann-Mari on our ScanBrit project and feel honoured to have been a part of one of her final works on diet and autism (see here). She was a great teacher and a good friend. My condolences go to her family and friends.

Amino acids and autism in China

Many happy returns @ Paul Whiteley
Questioning Answers is 2 years old today (19th February 2013). Happy Birthday to 'me', or should that be 'it'?

Still a relative newcomer to the blogosphere but still churning out posts on all things autism research and beyond. Just in case you thought that I did actually bake a cake for the occasion, I didn't. But if I had have done (and yes a man can make a cake), it would have looked like the cake shown alongside. So please loyal readers, take an imaginary bite and enjoy.

To task. I've had hold of the short paper by Wen-Jun Tu and colleagues* (open-access) for a few weeks/months but have only now have got round to posting about it. It continues some familiar themes on this blog on (a) the focus on the -omics and application of technologies like mass spectrometry to autism and (b) amino acids revealing some really quite interesting differences in cases of autism vs. not-autism, as they are doing in conditions like schizophrenia and chronic fatigue syndrome also. A bit out of left field but I was also interested to read the paper by Shingyoji et al on plasma amino acid profiles potentially predicting lung cancer too. Wow, these guys get around.

Anyhow. I say it is a short paper but actually the Tu paper is a letter, and although there is relatively little novelty in just looking at amino acid chemistry in autism - what's up and what's down - these days, it does look at autism in quite a different ethnic population (Chinese) compared to quite a lot of the other papers in this area.

Indeed China, as well as emerging as a world superpower albeit with some peculiarities, is also starting to put quite a bit more effort into autism as per papers like this one from McCabe** with the very interesting title: Bamboo shoots after the rain... (hence the cute picture of the baby panda shown below looking so inquiring).

The net findings reported by Tu and colleagues reflect a few things:

  • Based on quite a small participant group of children diagnosed with DSM-IV autism (n=20) compared with asymptomatic controls (n=20), there were some very distinguishing plasma amino acid results found.
  • Tandem mass spectrometry was the main analytical method for determining amino acids complemented by immunoassay for detecting circulating neurotransmitters such as plasma dopamine.
  • Levels of some amino acids were significantly elevated (lysine, glutamate - glutamic acid and homocysteine); others were depressed (tryptophan, tyrosine, glutamine) in the autism group compared with controls.
  • Ailuropoda melanoleuca @ Wikipedia  
  • When it came to the level of significance, the biggest group differences were in the elevated levels of leucine (p=0.000 apparently), higher homocysteine (same p-value again) and elevated plasma dopamine (ditto on the p-value).

Of course I don't really need to say too much about these findings that have not already been said. Glutamate and glutamine are already on the autism research radar for quite a few reasons; same goes for homocysteine and it's link into things like methylation and the folate metabolic pathway. Tryptophan is a potentially important one bearing in mind its metabolism into things like melatonin among other things. Leucine? Well think branched chain amino acids and that rather interesting study by Novarino and colleagues*** (see this post) in relation to autism, and one cannot help but wonder if there might be some overlap.

Interestingly, one of my papers on the gluten- and casein-free (GFCF) diet (open-access) gets a mention in the text, with the authors seemingly worried about how their results might be further worsened if and when a GFCF diet is instigated following on from some similar suggestion by Arnold and colleagues****. Indeed this is an issue which has more recently been discussed in the meta-analysis by Sharp and colleagues*****. I'm minded to respond that rather than worry about how things could 'get any worse', a closer inspection of why they have the results they have and indeed, dealing with what they actually found, might be a good starting point, accepting the study by Jim Adams and colleagues (see this post) on what might be achieved by micronutrient supplementation. That and the fact that they reference gastrointestinal (GI) issues as potentially being involved with their results which begs the question: why not try and 'sort out' the GI issues or least one of them?

From the ethnicity point of view, the Tu study is an important one given the overlap between their observations and what has been found in other more Western populations allowing for the genetic, environmental and epigenetic differences that one might envisage and the eternal question of whether autism is presented the same worldwide. Such research actually makes a really good case for doing a little bit more cross-collaborative work among different peoples in different countries with autism, based not just on genetics as seems to have been the case so far, but also more functional biochemistry too.

Because this blog is the big 2 now, and given the association between this age and the word 'terrible', a song which I always thought best encapuslates a toddler tantrum from Nirvana (sorry about the language). Toodle pip.


* Tu WJ. et al. Application of LC-MS/MS analysis of plasma amino acids profiles in children with autism. J Clin Biochem Nutr. 2012; 51: 248-249.

** McCabe H. Bamboo shoots after the rain: Development and challenges of autism intervention in China. Autism. November 2012.

*** Novarino G. et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012; 338: 394-397.

**** Arnold GL. et al. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord. 2003; 33: 449-454.

***** Sharp WG. et al. Feeding Problems and Nutrient Intake in Children with Autism Spectrum Disorders: A Meta-analysis and Comprehensive Review of the Literature. J Autism Dev Disord. February 2013.


ResearchBlogging.org Tu WJ, Chen H, & He J (2012). Application of LC-MS/MS analysis of plasma amino acids profiles in children with autism. Journal of clinical biochemistry and nutrition, 51 (3), 248-9 PMID: 23170055

Saturday 16 February 2013

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).


* 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.


ResearchBlogging.org 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

Wednesday 13 February 2013

MIND the maternal autoantibodies in autism

It's been a few weeks since I posted on research coming out of the MIND Institute. Regular readers will probably already know that I'm quite interesting in the various investigations on autism from UC Davis, and in particular how they are very usefully starting to think about subgroups and endophenotypes when it comes to autism as per the quite significant heterogeneity (and comorbidity) present across the spectrum.
By your command @ Wikipedia  

Today's offering is focused on the paper by Nordahl and colleagues* looking at how the presence of specific maternal IgG autoantibodies to foetal brain protein might be (a) linked to cases of autism and (b) form a specific endophenotype of autism with a focus on brain enlargement.

Before wandering through the latest offering, I should point out that both the concept of maternal autoantibodies and brain enlargement have been talked about before on this blog with the MIND link in mind(!) Indeed the last time I posted about the work of Christine Wu Nordahl was on how regression (yes it does happen) might link into brain overgrowth in cases of autism (see here) bearing in mind the complexity and heterogeneity within the field of looking at head size (see here).

As for maternal autoantibodies, well I've talked before about what happens to the offspring of pregnant mice (yes, mice) when they receive a transfusion of IgG brain reactive antibodies derived from mums with a child diagnosed with autism (see here) but I should also say that I'm very glad that I MET you... (see here). Other related findings on this topic are also worth mentioning (see here).

  • The latest Nordahl paper reports that in an independent cohort of mums of 181 young children (most of whom had a child diagnosed with an autism spectrum disorder, ASD; n=131), there were some interesting findings related to the presence of specific maternal IgG autoantibodies (37 + 73-kDa) overlapping with offspring ASD. 
  • A reported 7% of children (n=10) with ASD were "born to mothers with the 37/73kDa IgG autoantibodies" compared with none in the control, typically developing group. 
  • More than that, when the ASD-IgG (those born to IgG positive mothers) were compared with the non ASD-IgG-ers, there were some differences between the rate of abnormal brain enlargement (12.1% vs. 4.4%) compared to controls. 
  • Without professing any knowledge or wisdom on the specific structure of the pink stuff floating in our skull (yes, pink), I note the authors reported that "the frontal lobe is selectively enlarged in the ASD-IgG group and that both gray and white matter are similarly affected". 

I'm interested in these findings. Interested because not only was there a subgroup of mums with children with autism who were positive for these autoantibodies but also because "all TD [typically developing] controls were negative for these paired autoantibodies".

Of course such interest needs to be balanced; and in particular the temptation to make too much out of these findings based on the numbers reported on this particular occasion. So for example, 10/131 (7%) of the ASD group were reported to be born to IgG positive mothers. Applying this rate to the control group (n=50) would, by my crude calculations, mean that 3 or 4 of those 50 typically-developing children would have been expected to show the same rate had there been no differences between the groups. You can perhaps see that the difference in the numbers of cases is not exactly overwhelming from this point of view. Indeed, similar principles go for the reported rate of brain enlargement between the IgG positive and negative ASD groups. More shades of grey over a stark black-and-white difference. Even the MRI findings on brain enlargement need to be brought into context with other reviews on structural issues being related to autism as per my post on the Vasa paper (see here).

All that being said and following the whole sub-group / endophenotypes mantra, I'm taken back to some interesting commentary by another of the study authors, David Amaral elsewhere, and his notion of "autism type A, or type B, or type C" as the endpoint of much of this autism subtype research.

I suppose the next set of questions should be something along the lines of how such antibodies come about, how exactly maternal autoantibodies to foetal brain might lead to brain enlargement, and what if anything can be done to mitigate any effect on the developing child. Without wishing to speculate too much, the family of IgG antibodies are normally part and parcel of the on-going struggle against the various bacterial and viral infections which we're all faced with day-to-day. They also have the quite exceptional ability to cross the placenta from mum to baby which the Braunschweig study** seemed to reiterate. Certainly knowing all that, there seems enough to go on with as to where research should be looking with regards to a potential source. The peer-reviewed literature also suggests a couple of other potential angles which may or may not be important (see Zhang and colleagues*** for example) but like everything linked to autism research, it's probably going to be complicated.

Again with my non-expert hat on, and armed with that pinch/dollop of salt, one has to wonder whether for example, there is a role for maternal autoimmune disease in the formation of such autoantibodies as per the research in other autoimmune conditions such as systemic lupus erythematosus (SLE). I was particularly taken by the paper from Lee and colleagues**** (open-access) who reported a really interesting connection between maternal SLE and N-methyl-D-aspartate receptor (NMDAR)-specific autoantibodies (in a mouse model). Indeed Palmeria and colleagues***** (open-access) present quite a good overview of IgG placental transfer with some discussion on maternal autoimmunity and its possible effects. Likewise whether maternal immune activation during critical periods of pregnancy might have some role in this process of IgG brain autoantibodies remains to be seen, following the recent maternal C-reactive protein findings published by Prof. Alan Brown and colleagues (see here).

Speculations aside, the Nordahl results add to the growing body of literature on immune function showing some connection to cases of autism and how the earliest days might well be important for at least some of the autisms and beyond (stress on some of the autisms) as per the news recently on folic acid. The precise mechanics of this biological relationship currently still remain, in the most part, hidden from view, and complicated by all that heterogeneity and comorbidity present in cases. The continued focus however on subgroups and endophenotypes represents the way forward in autism research, combining also with the notion that the presentation of autism may be much greater than the sum of its behavioural dyad.

Final note: the pretty picture of a cylon included in this post, which bears no relation to the content of the post, is simply there because I've recently been revisiting some of the golden days of TV Sci-Fi and wanted to share some of them with you. The original Battlestar Galactica series with Lorne Green was a favourite, but then again so was another series about a chap returning to earth some 500 years later, give or take a year or two, and making some new friends.


* Nordahl CW. et al. Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder. Brain Behav Immun. February 2013.

** Braunschweig D. et al. Maternal autism-associated IgG antibodies delay development and produce anxiety in a mouse gestational transfer model. J Neuroimmunol. 2012; 252: 56-65.

*** Zhang Y. et al. Induction of autoimmunity to brain antigens by developmental mercury exposure. Toxicol Sci. 2011; 119: 270–280.

**** Lee JY. et al. Maternal lupus and congenital cortical impairment. Nat Med. 2009; 15: 91–96.

***** Palmeria P. et al. IgG Placental transfer in healthy and pathological pregnancies. Clinical and Developmental Immunology. 2012: 985646.


ResearchBlogging.org Nordahl, C., Braunschweig, D., Iosif, A., Lee, A., Rogers, S., Ashwood, P., Amaral, D., & Van de Water, J. (2013). Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder Brain, Behavior, and Immunity DOI: 10.1016/j.bbi.2013.01.084

Tuesday 12 February 2013

Folic acid and autism: a micropost

There is currently a lot of chatter about the study by Pål Surén and colleagues* (open-access) reporting that "Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder".

Since the paper is open-access and opinions already abound about the findings (see here and here and here), there is little point in me adding to the column inches. So instead, I'll direct you to a previous post on the topic of maternal folic acid use during pregnancy being linked to offspring autism risk and some words of caution....


* Surén P. et al. Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children. JAMA. February 2013.


ResearchBlogging.org Pål Surén, Christine Roth, Michaeline Bresnahan, Margaretha Haugen, Mady Hornig, Deborah Hirtz, Kari Kveim Lie, W. Ian Lipkin, Per Magnus, Ted Reichborn-Kjennerud, Synnve Schjølberg, George Davey Smith, Anne-Siri Øyen, Ezra Susser, & Camilla Stoltenberg (2013). Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children JAMA : doi:10.1001/jama.2012.155925

Sunday 10 February 2013

Metallomics analysis and autism

As an avid follower of several of the -omics, I was interested to read the report by Hiroshi Yasuda and colleagues* (open-access) on the application of a new -omics to me, metallomics - think metals affecting cellular functions - and in particular, the application of metallomics to autism.

This is not the first time that the work of Hiroshi Yasuda has appeared on this blog, as per my previous entry on 'the link with zinc' highlighting some interesting findings of zinc deficiency in quite a sizable proportion of their cohort diagnosed with an autism spectrum disorder (ASD).
Mick's home or 'ome Mick's? @ Wikipedia  

The autism metallome?

Yasuda's latest paper - published in the same Nature family journal, Scientific Reports - extend their analysis of the metals outside of just zinc to include quite a few more and likewise report on what looks like the same cohort of participants as their previous paper.

A few details bearing in mind the paper is open-access:

  • Quite a big cohort (N=1967) of Japanese children diagnosed with an ASD were included for study.
  • Hair samples taken from as close to the scalp as possible (I assume denoting a more current metallomic profile) were analysed by everyone's favourite metal analysis technique, ICP-MS. I might add that not everyone is convinced that hair analysis is a great way of testing for metal status or anything else. 
  • Results: well we know that zinc levels were already reported on the low side; indeed a zinc deficiency was present in over 40% of the 0-3 years age group (43%), getting a little better as the age ranges increased: 4-9 year olds (28%) and 10-15 year olds (3%) in males (who comprised most of the cohort). Females also showed a similar pattern across the age ranges (52%, 28%, 3% respectively).
  • Magnesium and calcium deficiency were also highlighted as being present among a proportion of their cohort; albeit not to the same extent of the rates of zinc deficiency.
  • A quote: "high toxic metal burden of aluminium, cadmium and lead of over their +2 S.D. level was observed in 339 (17.2%), 168 (8.5%) and 94 (4.8%) individuals".
  • A few examples are given showing the metallome of individual participants which seem to lead to an interesting suggestion that zinc deficiency (together with magnesium deficiency) might correlate somehow with a "high toxic metal burden".

Link with zinc

I'm not going to offer too much in the way of discussion about the zinc part of these results given my past reporting on the previous paper** by Yasuda et al alongside some background on zinc. A few additions perhaps are worthy of mention in light of the suggestion of an epigenetic role of zinc deficiency. Regular readers will already know that I'm getting quite enamoured with the whole 'your genome is not your destiny' revolution that seems to be occurring these days. I note for example the paper by Kurita and colleagues*** which in a mouse model at least, points to a possible epigenetic effect from zinc deficiency occurring in-utero. The assumption being that especially in that 0-3 age group where zinc deficiency was highest in the Yasuda study, gestational zinc deficiency might have preceded infantile deficiency? And then there's the whole inflammation side of things as per the paper by Wessels and colleagues**** bearing in mind what we call inflammation and also infection (see here).


The rates of magnesium deficiency were also quite striking in their Japanese cohort. I assume most people with some interest in autism will know all about the whole vitamin B6-magnesium connection stretching back some years now. Granted the evidence base looking for example, at supplementation with B6 and magnesium is still a little incomplete as per the Cochrane review from Nye and Brice***** but I would also draw your attention to some interesting studies in the decade of big hair and electro-pop (the 80's) by Lelord and colleagues******* (who are also credited with devising the rather nice Behaviour Summarised Evaluation Schedule). I might add that this is not the first time that magnesium deficiency has been reported in cases of autism, illustrated by the papers by Wecker and colleagues******** and Lakshmi and Geetha*********, although not universally so. The causes and effects of such deficiency? Well, lets just say that I have a few ideas outside of just faddy diets affecting intake but I'm not fooling myself that this process would be so simple and universal.


As for the other findings, well, let's just say that I've done lead before (see here) so I'm not heading down that path again. Calcium deficiency is something that I am quite interested in as a result of the use of things like a casein-free diet as a possible intervention measure for some cases of autism. As discussed in other posts, calcium seems to have its own relationship to some cases of autism and especially the view that such dietary intervention might impact on calcium levels. Indeed calcium intake is known to often be a little lower in cases of autism*********. That being said, I'll also draw your attention to some other recent literature on the calcium-autism link (see here) and on whether or not the sunshine vitamin might also play some role in this complex relationship.

Yasuda and colleagues conclude their paper by talking about the possibility of "a critical term “infantile window” in neurodevelopment and for its therapy" in light of the deficiencies and elevations they found. I'm not sure that we are quite there yet so as to be able to suggest that supplementing with zinc or magnesium or calcium during the very earliest days is somehow able to mitigate the risk of autism onset. Certainly I'd be wary of seeing anyone make any general recommendations on such supplementation strategies during such early development without both confirmatory evidence of deficiency in specific cases (including whether seasonality might for example affect results**********) and some further safety work looking at optimal dosage and delivery. Oh, and a good explanation as to why the deficiency was there in the first place might also be a good idea...

To finish and to celebrate Rolf Harris continuing to wow audiences, a classic... Jake the Peg (with his extra leg).


* Yasuda H. et al. Estimation of autistic children by metallomics analysis. Sci Rep. 2013; 3: 1199.

** Yasuda H. et al. Infantile zinc deficiency: association with autism spectrum disorders. Sci Rep. 2011; 1: 129.

*** Kurita H. et al. Prenatal zinc deficiency-dependent epigenetic alterations of mouse metallothionein-2 gene. J Nutr Biochem. 2013; 24: 256-266.

**** Wessels I. et al. Zinc deficiency induces production of the proinflammatory cytokines IL-1β and TNFα in promyeloid cells via epigenetic and redox-dependent mechanisms. J Nutr Biochem. 2013; 24: 289-297.

***** Nye C. & Brice A. Combined vitamin B6-magnesium treatment in autism spectrum disorder. Cochrane Database Syst Rev. 2005; 4: CD003497.

****** Lelord G. et al. Clinical and biological effects of high doses of vitamin B6 and magnesium on autistic children. Acta Vitaminol Enzymol. 1982; 4: 27-44.

******* Wecker L. et al. Trace element concentrations in hair from autistic children. J Ment Defic Res. 1985; 29: 15-22.

******** Lakshmi P. & Geetha A. Level of trace elements (copper, zinc, magnesium and selenium) and toxic elements (lead and mercury) in the hair and nail of children with autism. Biol Trace Elem Res. 2011; 142: 148-158.

********* Sharp WG. et al. Feeding problems and nutrient intake in children with autism spectrum disorders: a meta-analysis and comprehensive review of the literature. J Autism Dev Disord. February 2013.

********** Teresa M. et al. Trace element concentrations in blood and hair of young apprentices of a technical-professional school. Sci Total Environ. 1997; 205: 189-199.


ResearchBlogging.org Yasuda H, Kobayashi M, Yasuda Y, & Tsutsui T (2013). Estimation of autistic children by metallomics analysis. Scientific reports, 3 PMID: 23383369

Thursday 7 February 2013

More GI symptoms reported in cases of autism

The real Star Wars... @ Wikipedia  
The paper by Susie Chandler and colleagues* adds to the quite voluminous literature on bowel issues and autism by suggesting that "Parents report more GI symptoms in children with ASD than children with either SEN or TD children".

A translation if it is needed: according to mums and dads, kids diagnosed with an autism spectrum disorder (ASD) have more toilet-related issues than those without autism or those with a physical / learning disability (SEN) which does not include a diagnosis of autism.


If there's one thing comorbidity-wise that the autism research community is starting to realise when it comes to the autism spectrum disorders (ASDs) it's that gastrointestinal symptoms - whether functional bowel issues or more chronic disease pathology - do seem to be a feature of quite a few cases of autism but not all, particularly in children with autism. Perhaps even forming a specific endophenotype of autism?

And quite a few parents with children with autism have been saying that for many, many years.

A few details from the Chandler study:

  • Three groups of children participated in the study: ASD (n=132), SEN (special educational needs) but no autism (n=81), and typically developing kids (n=82) based on the snappily titled SNAP (Special Needs and Autism Project) cohort. The ASD group were also subdivided into broad (n=89) and narrow autism (n=43).
  • A questionnaire was used to collect parental views on offspring gastrointestinal (GI) symptoms (vomiting, constipation, diarrhoea, etc.) during the course of interviews for diagnostic assessment. This was accompanied by a food diary type questionnaire (over 3 days) and a blood draw from some of the participants to look for some of the signs and symptoms of GI-related pathology such as coeliac (celiac) disease (CD).
  • Quite a few results: one child with ASD (1/68) came up positive for anti-endomysial antibodies and was subsequently diagnosed with CD.
  • Almost half of the kids with ASD were reported to have at least one GI symptom in their lifetime compared with around a quarter of kids from the other groups.
  • Children with ASD also had significantly higher rates of current GI symptoms than the other groups, especially things like soiling. Same goes for rates of past GI symptoms among the ASD group.
  • Things can only get better? Well, it did appear that "fewer GI symptoms were reported currently compared to the past in all groups" but there's not very much in the way of information as to why this might have occurred (maturity? intervention?).
  • Gender, a history of regression, "faddy diet" or autism severity showed no significant association with the reported presence of GI issues.


Those with a keen eye on the autism research field might recognise some of the authorship group on the Chandler paper as being the same which, for example published on the 1% prevalence rate of autism in London, UK** and an important 'regression happens in some cases of autism' paper*** to name just a few. Oh, and this paper****...

The notion of a GI element comorbid to cases of autism still has the ability to exact some eye-rolling from some people based to a large extent on "that research paper" (now retracted but still cited by Chandler et al) or more precisely what happened following its publication. All I have to say is that the GI - autism link has been with us for at least 40 years (see this post on the paper by Goodwin published in 1971) probably longer, and as yet, no-one really knows the precise hows and whys, which are likely to be complex and possibly as multiple as autism is itself.

Who said it

Whilst the Chandler findings are not necessarily new news to the autism research world nor to many parents of children with autism, I personally do find them to be significant insofar as who reported them. Without hopefully speaking out of turn, I've touched upon the topic of hierarchy in autism research, and how the translation of research findings from lab to real-life is not necessarily just about what has been found but also by who. Both here in the UK and beyond, the SNAP group members comprise some of the movers and shakers in autism research as per not only the 1% autism prevalence study from 2006 but also the overlap with, for example the PACT trial (discussed in this post). Indeed even some of the UK NICE guidance on autism (final strand due August 2013) is chaired by a member and corresponding author of the Chandler study. Don't discount this important variable.

I'm also very happy to report that alongside their findings, Chandler et al carry reference to the very important paper by Phillip Gorrindo and colleagues***** which should answer some questions about how parental report of GI symptoms in cases of autism might not necessarily be a million miles away from "evaluations by pediatric gastroenterologists". In other words, parents might actually know when their children present with potentially significant bowel issues. A shocker, I know.


What's more to be said about the study? Well, that one case of CD comorbid to autism reiterates the fact that a diagnosis of autism is seemingly protective of nothing and further enhances the view that screening for CD should perhaps be undertaken when an autism diagnosis is given. The fact that the child's CD presentation was described as clinically silent: ".. but had no GI symptoms" should also figure in any discussions about CD screening. My mind also wanders back to that case study paper by Stephen Genuis****** on what happened to autistic symptoms when a gluten-free diet was installed, and whether any follow-up was made on the child identified with CD during the Chandler study. Don't even get me started on the whole non-coeliac gluten intolerance area requiring further investigation; something which some other important movers and shakers seem to be taking quite seriously.

I've also talked previously about the Kushak paper (see this post) and their suggestion that bowel issues might also be indicative of lactose intolerance, or at least the requirement for another potential screening parameter following the autism diagnosis. Food for thought indeed, bearing in mind GI issues may intersect with other facets of autism presentation too.

Final words

But perhaps the take-home message from the Chandler study is that now we all know that GI issues can occur alongside quite a sizable proportion of children with autism, there really is no point in sticking our heads in the sand about this anymore. Assuming that one can see past autism as just being the sum of the dyad of presented symptoms (which didn't seem a problem when it came to that recent optimal outcome paper) and in order to correct some of those quite startling health inequalities that seem to be emerging, should we not be more widely implementing the Buie recommendations (here and here) and perhaps doing something about such bowel issues when they are present? Or at least committing a few more resources to looking at the hows and whys? Y'know for the sake of quality of life, self-dignity, self-esteem and such like?

To close, Jimi at his very best.


* Chandler S. et al. Parent-reported gastro-intestinal symptoms in children with autism spectrum disorders. J Autism Dev Disord. February 2013.

** Baird G. et al. Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet. 2006; 368: 210-215.

*** Baird G. et al. Regression, developmental trajectory and associated problems in disorders in the autism spectrum: the SNAP study. J Autism Dev Disord. 2008; 38: 1827-1836.

**** Baird G. et al. Measles vaccination and antibody response in autism spectrum disorders. Arch Dis Child. 2008; 93: 832-837.

***** Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012; 5: 101-108.

****** Genuis S. & Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2010; 2 :114-119.


ResearchBlogging.org Chandler S, Carcani-Rathwell I, Charman T, Pickles A, Loucas T, Meldrum D, Simonoff E, Sullivan P, & Baird G (2013). Parent-Reported Gastro-intestinal Symptoms in Children with Autism Spectrum Disorders. Journal of autism and developmental disorders PMID: 23371507