Friday, 29 March 2013

Antigen content exposure and autism: no link

I'm hopefully not setting myself up for a fall by discussing the study published by Frank DeStefano and colleagues* (open-access) suggesting no link between the 'too many too soon' argument of vaccination and risk of autism. As probably would be expected with such study results, there has been a flurry of interest on this paper (see here and here for example) and so once again I'm not going to add too much to the details which have already been reported.

The basics:

  • Based on a final comparison of 256 children diagnosed with an autism spectrum disorder (ASD) with an asymptomatic control group of 752 children (all born between 1994 -1999), vaccination histories were examined and exposure to "total antibody-stimulating proteins and polysaccharides from vaccines was determined by summing the antigen content of each vaccine received". 
  • For those like me, who are not too well-versed in the immunological principles of vaccination, the antibody-stimulating proteins and polysaccharides bit basically refers to the constituents of vaccines designed to invoke an immune response and the production of antibodies to recognise and fight the bacteria/virus being vaccinated against. Quite by coincidence, the BBC recently carried an interesting article about new vaccines potentially coming from some analysis on the UK synchrotron, the Diamond Light Source (see here - click on the interactive video) which quite neatly sums up the hows and whys of vaccination. 
  • The study produced odds ratios (ORs) for ASD 'outcomes' during the first 2-years and found no evidence for any increased risk of autism based on antigen exposure. 
  • Bearing in mind quite a few other potentially interfering variables were also collected (maternal exposures, child birth conditions, etc.), the results similarly suggested "no associations when exposures were evaluated as cumulative exposure from birth to 3 months, from birth to 7 months, or from birth to 2 years, or as maximum exposure on a single day during those 3 time period". In short, no statistical association between too many vaccines too soon and autism.

There's little more to say about the findings that hasn't already been said. I've talked before about immunisation uptake in siblings of children with autism (see here) and how the general topic of vaccination has been a real source of discussion/debate/argument in some quarters of the autism landscape; more often than not as a result of the disparity between personal experiences vs. the scientific literature.

Appreciating that quite a few people want to draw a line under the whole vaccination-autism affair in light of this and other data quite explicitly detailing no population-wide link between the two, I'm always open to further scientific inquiry on any aspect of autism. Take for example the work by Harumi Jyonouchi and colleagues on SPAD - specific polysaccharide antibody deficiency - in relation to cases of autism (see here) which may or may not be relevant and which is crying out for further independent replication. Or even the suggestion that post-vaccination paracetamol (acetaminophen) use might be tied into risk of autism as per the paper by Schultz and colleagues** (thanks Jen).

And then there are the various reports on cases being conceded on vaccination and 'autism-like symptoms' developing as per Hannah Polling. Indeed, with the n=1 very firmly in place, I note from the linked Time article "she received an unusually large number of vaccines in 2000 (when thimerosal was still in use). Because of a series of ear infections, Hannah had fallen behind in the vaccine schedule, so in a single day she was given five inoculations covering a total of nine diseases: measles, mumps, rubella, polio, varicella, diphtheria, pertussis, tetanus, and Haemophilus influenzae." According to the DeStefano results, the total antigen load was not an issue? So what might have been the issue/s? Did a mitochondrial problem show some involvement or not? (see the CDC FAQs on this topic).

I'm going to finish this post by highlighting just how important vaccination is (see here, again from the CDC), save any charges of irresponsible blogging being levelled against me. At the same time though, realising that no medicine is infallible and that continued vigilance and monitoring is required as per the article by Roberta Kwok*** and the recent flu vaccination - narcolepsy example.


* DeStefano F. et al. Increasing Exposure to Antibody-Stimulating Proteins and Polysaccharides in Vaccines Is Not Associated with Risk of Autism. J Pediatrics. March 2013.

** Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008; 12: 293-307.

*** Kwok R. Vaccines: The real issues in vaccine safety. Nature. 2011; 473: 436-438.

Frank DeStefano, Cristofer S. Price, & Eric S. Weintraub (2013). Increasing Exposure to Antibody-Stimulating Proteins and Polysaccharides in Vaccines Is Not Associated with Risk of Autism The Journal of Pediatrics

Thursday, 28 March 2013

NICE on managing autism in children & young people: draft

A very quick post to direct readers to the draft version of the final strand of guidance from NICE (National Institute for Health & Care Excellence) on managing autism in children and young people here in Blighty. The guidance documents can be found here and include the rather sizeable draft version of the full guidance (here) alongside a more condensed summary version (here).

These are draft documents (at the time of this post) so there may yet be some movement in some of the wording. Consultation closes on May 10th 2013 and is only open to stakeholders.

I'm not offering any opinion on these at the moment (I'm employed by one of the stakeholder organisations) but please feel free to download, read and take in. And don't forget those other strands of guidance which have already been published by NICE: (a) pathways to diagnosis (here) and (b) diagnosis and management of adults with autism (here).

Inflammation, oxidative stress and autism: Saudi style

Saudi Arabia and autism research appearing on this blog? Regular readers know that this can mean only one thing: Laila Al-Ayadhi and special guests - in this case Afaf El-Ansary - and their fairly recent paper* (open-access) on plasma lipid mediators in autism.
Kingdom Tower @ Wikipedia  

You might already know that I'm a bit of a fan of the Saudi autism research group which also on occasion includes Gehan Mostafa. Their papers have an exquisite range of topics around autism, the most recent being that vitamin D and autoimmunity paper** which I recently blogged about (see here). This is a group on an autism research mission which rivals that of the all-powerful MIND Institute in terms of scope if not participant numbers.

This time around there was a familiar sound to the topic in question: inflammation and autism (yes that old hat), and some interesting observations based on some players in lipid mediation.

A few choice points to make bearing in mind the paper is open-access and goes off in quite a few directions:

  • Impaired lipid metabolism was a focus, based on the measurement of three compounds in plasma which in a round-about kinda way tie into lipids, oxidative stress and inflammation: 8-isoprostane, cysteinyl leukotriene and prostaglandin E2.
  • Actually another old favourite, arachidonic acid (AA), is the starting point for these compounds in a roundabout sort of way.
  • As is usual with this research group, the participant numbers were not exactly all that impressive (autism: n=19, controls: n=20) but at least the autism group were well-defined and seemingly crossing over with some of their other research observations.
  • Results: group analysis of all three compounds showed that they were elevated in the autism group compared with controls; indeed in all compounds,  the means and standard deviation (SDs) showing some clear statistical water between the groups, and some significant correlations between levels of the compounds (the leukotriene - PGE2 correlation reaching 0.926).
  • As is also seemingly a pre-requisite for this research group, ROC analyses were also conducted and under certain circumstances showed 100% sensitivity but rather less in terms of specificity as predictive biomarkers for autism.

What more needs to be said? Well, further evidence that oxidative stress might be part and parcel of some cases of autism as per other research in this area***. Also, some support for further investigations into fatty acid metabolism in autism. And indeed inflammation... need I say much more about this?

Having said all that I'm not as sure that their suggestion about this suite of biomarkers informing the use of omega-3 fatty acids as a strategy to ameliorate inflammatory and oxidative stress in autism is necessarily reflected in the current evidence. Yes omega-6 fatty acids might play some role in autism as per (mouse) studies like that of Jones and colleagues**** but questions remain as to whether omega-3 supplementation really is cutting the mustard bearing in mind the heterogeneity and comorbidity present in autism.

Just before I go and hopefully not too far off-topic, did I mention the paper by McNamara and colleagues***** on fatty acid profiles in cases of schizophrenia?


* El-Ansary A. & Al-Ayadhi L. Lipid mediators in plasma of autism spectrum disorders. Lipids Health Dis. 2012; 11: 160.

** Mostafa GA. & Al-Ayadhi LY. Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: Relation to autoimmunity. J Neuroinflammation. 2011; 9: 201.

*** Ming X. et al. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids. 2005; 73: 379-384.

**** Jones KL. et al. Maternal diet rich in omega-6 polyunsaturated fatty acids during gestation and lactation produces autistic-like sociability deficits in adult offspring. Behav Brain Res. 2012; 238C :193-199.

***** McNamara RK. et al. Adult medication-free schizophrenic patients exhibit long-chain omega-3 Fatty Acid deficiency: implications for cardiovascular disease risk. Cardiovasc Psychiatry Neurol. 2013: 796462.

---------- El-Ansary A, & Al-Ayadhi L (2012). Lipid mediators in plasma of autism spectrum disorders. Lipids in health and disease, 11 (1) PMID: 23170784

Monday, 25 March 2013

The gut microbiome and chronic fatigue syndrome

I've hinted before on this blog and its sister blog about how one of the most unappealing of interventions - fecal bacteriotherapy - is starting to make some waves in managing various conditions. I know its not everyone's cup of tea but the concept of transplanting whole stools or specific types of enteric bacteria from one person to another is actually providing some well needed relief for quite a few people.
Insert here.... @ Wikipedia  

If it sounds like an undesirable treatment option, put yourself in the shoes of someone who for example is suffering as result of infection due to C. difficile and the potential consequences that this can entail after other treatment options have been exhausted and then wonder again. Better still, have a look at that probiotic yoghurt drink that is sitting in your fridge and ponder the question: where did the 'special' bacteria included in this drink originally come from? (hint: 'donor zero' is probably smiling at all of us).

Whilst fecal bacteriotherapy is moving into more mainstream medicine circles for conditions linked to things like C.diff, various other states and diseases are also starting to be discussed with the s--t transplant in mind. One person in particular is leading these discussions, Dr Thomas Borody, following his groundbreaking work on triple therapy for H.pylori infection (see here), and some discussions on 'emerging' applications* (no pun intended). Indeed Dr Borody is quite the leading light when it comes to fecal bacteriotherapy.

I was particularly interested to read the paper by Borody and colleagues** looking at the potential application of bacteriotherapy to cases of chronic fatigue syndrome (CFS). Regular readers might already know of my tendency to stray into the research domain of CFS (and ME) on this blog and beyond not least because quite a bit of the research there seems to overlap with what I talk about with autism in mind (e.g. immune function, mitochondrial issues, even HERVs..).

Anyhow, with many thanks to Sarah Finlayson, one of Dr Borody's co-authors, for sending me a copy of their paper, a few points are worth noting:

  • This is a paper which kills two birds with one stone. On the one hand, there is quite a nice summary of CFS and the gut microbiome (hopefully this link still works for non-members). On the other hand, the paper describes the experiences of 60 patients with CFS attending Dr Borody's clinic some time in the mid-1990s and in receipt of transcolonoscopic (TC) and rectal infusions of "anaerobic bacterial culture". Distinct from the 'full works' of of a stool transplant or 'fecal microbiota transplantation (FMT)', bacteriotherapy involves the 'fusion of a mixture of 13 non-pathogenic enteric bacteria" which include those of the Bacteroidetes, Clostridia and E.coli families/phyla/species.
  • Every participant received at least one TC infusion; most also received a second rectal infusion (n=52); a small number received two days of additional rectal infusion (n=3). Actually, as you'll see in a minute, there was a bit more to this than what is mentioned in the methods section of the paper.
  • Results: it is slightly difficult to gauge what specific results were achieved from this trial given that participants were judged to be responders or non-responders at 4 weeks based on some fairly nebulous criteria. So for example, responders signified "a resolution of CFS symptoms (sleep deprivation, lethary/fatigue)" but without the paper actually saying how these outcomes were measured or what tools were used. I'd hazard a guess that it was a case of participant interview or questionnaire but I can't confirm this. 
  • On the basis of this responder / non-responder coding, 35 (58%) were judged responders to bacteriotherapy. This figure improved when initial non-responders (n=15) were given a second TC infusion "followed by rectal infusion (n=4) or an oral course of cultured bacteria (n=6)"; up to 42 / 60 (70%) responders.
  • Gastrointestinal (GI) symptoms were reported to be resolved in 37 of the 42 final responders.
  • Follow-up of participants some 15-20 years later (12 of the original cohort) suggested that over half of them remained free of their CFS symptoms; although importantly, some relapsed (5/12) between 18-36 months post-bacteriotherapy.

I probably don't need to highlight the fact that this was very much an observational case-series study over anything like a clinical trial. My initial excitement at reading this paper was very slightly dampened by the way results were reported and those all-important missing details regarding how the authors measured change over the period of baseline vs. bacteriotherapy. Even the reported resolution of GI symptoms leaves me asking questions like: what GI symptoms, how were they measured and who did the measuring? There are gaps in this work, make no mistake of that. Bear however in mind issues such as when this study was initially carried out and how the diagnostic criteria of CFS might not necessarily have been as well-defined as they are today. Just sayin.

I can also imagine some people are reading this post and thinking what the .... ! How can a condition like CFS be sensitive to a bacterial transplant, and what about those methods used to introduce such a therapy... yeah right. Bear in mind however that our nether regions are actually quite good routes of drug administration bypassing for example, hostile environments like the stomach and onward the first-pass effect. Indeed the question should be: would you prefer this to the insertion of a naso-gastric tube as is the other option when delivering bacteria to where it is needed? Your choice...

Having said all that I am still interested in this line of inquiry. The authors for example, suggest a possible link between "the resolution of gastrointestinal and CFS symptoms" and how this "supports the theory of a possible gastrointestinal-associated etiology, potentially arising from alterations to the bowel flora". I kinda speculated about the many faces (Man-E-Faces?) of CFS in a previous post on HERVs and ME (see here) and how the spectrum of CFS/ME might be just that, a spectrum. It strikes me that one could very easily investigate this possible sub-types issue within a well-defined population.

There is obviously more to do in this area of endeavour. As per a recent article I played a small hand in writing, the gut microbiome is a relatively uncharted area of medicine in terms of its links to health and wellbeing and indeed our often varied response to the pharmaceutics we all take potentially as a result of our gut bacterial composition. There are obvious important questions to ask about safety (the gut virome anyone?) and efficacy of interventions like bacteriotherapy particularly when applied to conditions of unknown origin like CFS/ME. Indeed, the desperation of some sufferers makes them very vulnerable to all kinds of potential intervention options which might not necessarily be right for them.

But that's not to say there isn't already research movement (no pun intended) in the area of the gut microbiome and CFS/ME as per Sanjay Shukla study (detailed here) which should be reporting quite soon. That added to the Michael Maes suggestion of issues with gut permeability in cases of CFS/ME (sound familiar?) makes for quite a few hypotheses being open for testing with much greater focus on rigour in research methodology.


* Borody TJ. & Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol. 2011; 9: 88-96.

** Borody TJ. et al. The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy. Journal of the Australasian College of Nutritional and Environmental Medicine. 2012; 31: 3-8.

----------- Thomas Borody, Anna Nowak, & Sarah Finlayson (2012). The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy Journal of the Australasian College of Nutritional and Environmental Medicine, 31 (3)

Friday, 22 March 2013

Advancing grandparental age and autism risk

The paper by Emma Frans and colleagues* looking at autism risk across the generations is the focus of this post. Published in the journal JAMA Psychiatry alongside a provocative article by Andrea Roberts and colleagues** on maternal exposure to child abuse being "associated" with elevated risk for offspring autism (see here and here), the theme is transgenerational effects and quote: "that your father's and grandfather's lifestyle choices can affect you" as per some of media on this paper.
Ο Κακός Εγγονός @ Wikipedia  

I'm not going to head too heavily into the Frans study because others have already discussed it far better than I ever could (see here and here). Indeed NHS Choices carries a particularly good run-down of the study which is well worth a read (see here).

The main details were that based on an analysis of nearly 6000 cases of autism spectrum disorder (ASD) in Sweden, grandfathers who had fathered their daughter when aged 50 or above were 1.79 times more likely to have a grandchild diagnosed with autism than younger fathering grandfathers.

If grandfathers fathered a son when aged 50 or above, they were 1.67 times more likely to have a grandchild diagnosed with autism (again compared to grandfathers having children when they were younger).

The magic word 'epigenetics' is also mentioned to potentially account for results alongside the mutation side of things. I should also point out that Frans has published on similar things before with schizophrenia in mind***.

I'm interested in studies like the current Frans one despite their reliance on association and relatively limited increased risk of autism. Interested because alongside the 'older dads and autism risk' research (see here), I have actually talked about grandparents and risk of autism and schizophrenia previously on this blog (see here) based partly on some interesting data derived from ALSPAC published by Jean Golding and colleagues**** (open-access) and also that 2011 Frans study. In particular was the emphasis on the Golding 3M - meiotic mismatch methylation - hypothesis used to account for their results on grandmother's age as potentially being relevant to grandchild autism risk (please read the Golding article for more information on 3M complete with nice diagram).

I know it might sound a little far-fetched that the lives of our grandparents might so profoundly be able to affect the lives of subsequent generations but before we put this down to mere coincidence, let me draw your attention to some work that was done on a dark period of quite recent history: the Hongerwinter. The basics: the Dutch famine of 1944, where a Nazi blockade led to the deaths of thousands. As per the often cruel twists of fate, science actually learned something from the suffering of the Dutch people in these dark days. Not only the confirmation that wheat was tied into coeliac (celiac) disease but also the suggestion that famine exposure during a critical period of gestation *might* potentially affect offspring physical and mental health. I've kinda talked about something similar before with 'thin-fat bodies' and David Barker in mind (see here).

Granted in the current Frans study we are heading back even further through the germline as potentially hosting some effect, but to all intents and purposes, the theory is the same as per the intergenerational effects noted in other conditions like depression*****. I suppose one could ask whether specific types of autism might be more related to this grandparental age hypothesis over others. So for example, older grandparents at time of fathering or mothering impacting on the genome of their offspring - themselves then expressing certain traits associated with autism or the broader phenotype (not necessarily hitting the diagnostic threshold) - which are then transmitted (amplified?) to the next generation. Perhaps even some link to things like assortative mating theory too? I'm not saying that this is the only scenario and such 'transmission' works on its own to elevate risk of an autism diagnosis but the theory is an interesting one; even more so if we assume for example, that the autism and schizophrenia spectrums might not necessarily be poles apart (see here).

By the same token one might also extend such a hypothesis to include other variables other than just parental age at offspring conception. The availability of and exposure to certain food in these 'olden days', exposure events to pollutants, pharmaceuticals (yes, we did have them then) or lifestyle factors such as smoking and drinking habits, various psychological and somatic stressors; the list is seemingly endless. In at least some of these factors, there are subtle clues to potential future directions for autism research and beyond already being examined (see here and here). Assuming also that epigenetics might be tied into all of this, we also open up the concept of epigenetic reprogramming of the germline as per the very interesting article by Petra Hajkova****** (open-access); something which I think might be/have been discussed at the recent Environmental Epigenetics symposium hosted by the MIND Institute.

But let's not get too carried away with this area of inquiry or where it potentially leads in terms of the autism 'blame game'. Although I've not been able to find specific figures, I assume the actual numbers of grandfathers who fathered their children aged 50+ years is probably not going to be all that frequent if more current rates, at least here in the UK, are anything to go by (see this paper by Bray and colleagues*******). And then we have to wonder whether other variables might come into play such as the effect of paternal age at conception on birth factors such as birth weight or time of gestation even fecundity itself and how that might relate to autism risk.

Such transgenerational effects whilst interesting, should also not detract research attention away from other more here-and-now possibilities which might affect autism risk as per the recent valproate work or indeed all that immune activation research currently on-going. Neither should it deflect attention from the fact that the autism numbers are really starting to get quite serious - 1 in 50 US kids (with caveats) - and what needs to be done (a) asking why there is such an increase in cases and (b) to ensure the relevant help and support is available to all who need it.

To finish a very catchy tune from Jake Bugg - Lightning Bolt.


* Frans EM. et al. Autism risk across generations. A population-based study of advancing grandpaternal and paternal age. JAMA Psychiatry. March 2013.

** Roberts AL. et al. Association of maternal exposure to childhood abuse With elevated risk for autism in offspring. JAMA Psychiatry. March 2013.

*** Frans EM. et al. Advanced paternal and grandpaternal age and schizophrenia: a three-generation perspective. Schizophr Res. 2011; 133: 120-124.

**** Golding J. et al. Parental and grandparental ages in the autistic spectrum disorders: a birth cohort study. PLoS ONE. 2010; 5: e9939.

***** Warner V. et al. Grandparents, parents, and grandchildren at high risk for depression: a three-generation study. J Am Acad Child Adolesc Psychiatry. 1999; 38: 289-296.

****** Hajkova P. Epigenetic reprogramming in the germline: towards the ground state of the epigenome. Phil. Trans. R. Soc. B. 2011; 366: 2266-2273.

******* Bray I. et al. Advanced paternal age: How old is too old? J Epidemiol Community Health. 2006; 60: 851–853.

---------- Frans, E. (2013). Autism Risk Across GenerationsA Population-Based Study of Advancing Grandpaternal and Paternal AgeAutism Risk JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2013.1180

Wednesday, 20 March 2013

1 in 50 children with parent-reported autism in the US

An estimated 1 in 50 US children aged between 6 - 17 years old present with an autism spectrum disorder (ASD). Attention-grabbing isn't it?

Today's post is based on the source of that soundbite, the publication by Stephen Blumberg and colleagues* (open-access) describing results from data mining of the 2007 and 2011-2012 US National Survey of Children's Health (NSCH) relevant to the numbers of cases of ASD.
Testing 1, 2, 3 @ Wikipedia  

The autism-numbers game is something that has been discussed previously on this blog; most recently with the CDC 1 in 88 estimate in mind (see here) and the even more recent data from New Jersey (see here). The direction of the figures seems only one way - up - but the reason(s) for the increase still remain the source of discussion.

The Blumberg report is open-access, but a few pointers might be useful:

  • Based on 91,642 telephone interviews in 2007 and 95,677 interviews between 2011-2012, parental reports of receipt of an ASD diagnosis (autism, Asperger syndrome, PDD) in offspring were noted, alongside other variables such as age of the child, severity of presentation (mild, moderate, severe) and aged when first diagnosed.
  • Actually in the age range 6-17 years old, data were collected from 63,967 interviews (2007) and 65,556 (2011-2012).
  • Results: "based on parental reports, the prevalence of diagnosed ASD in 2011-2012 was estimated to be 2.00% for children aged 6-17". This compared with 1.16% or 1 in 86 for 6-17 year olds in 2007.
  • The increase in prevalence was noted across the age ranges when they were sub-categorised and perhaps not surprisingly, there was a greater increase in prevalence in boys (2007: 1.8% vs. 2011-2012: 3.23%) than girls (2007: 0.49% vs. 2011-2012: 0.70%). Reported severity also shifted between the various data points (and age ranges) indicating that there was a trend towards less severe presentation (milder ASD) post 2008 diagnosis.
  • The authors were able to some degree, rule out "survey-based measurement error" as being a major contributor to the prevalence increase and there is some discussion about the data not necessarily reflecting "factors that exist prior to or occur just after birth". Indeed the authors very firmly suggest that the changes are a consequence of either "recognition of ASD by health professionals or survey-based measurement changes over time". They also conclude that increases in the prevalence of parent-reported ASD especially for children aged 6-13 "was the result of diagnoses of children with previously unrecognized ASD".
  • As per the report on this story in USA Today "15% to 20% of children who were once diagnosed with autism no longer have the condition". Which raises similar questions as to that of the Fein study on 'outgrowing autism' and 'optimal outcomes' which created so many column inches recently (see here and here).

Bearing in mind that this was a prevalence study not an incidence study (see here for the difference) and issues with regards to response rates (2007: 46.7% vs. 2011-2012: 23.0%), and the sole reliance on parental judgement of variables like severity, the data being presented are indeed stark.

That the rates of autism have seen an inordinate shift from what was once considered a rare condition to something which theoretically should [almost] appear in every school classroom at least once is an eye-opener. As mentioned, the debates rumble on about factors such as better awareness of autism, better case ascertainment, diagnostic switching and broadening, etc. as being the source of the increase. A real increase in cases? Hardly a mention in this latest data. The implication that for example our screening methods and skilled professionals have been able to miss or mis-diagnoses a staggering number of children presenting with an ASD is truly mind-boggling and worthy of an inquiry or two in the US and beyond. Indeed better be quick with that investigation with the DSM-V revision deadline fast approaching and the potential impact that might have on the autism numbers game (including adult numbers**).

So 1 in 50 children with an ASD. What happens next? Sure, many children were described as falling into the mild and moderate ability ranges but as I've said before, terms like 'high-functioning' don't necessarily mean 'can function' with regards to daily living skills, quality of life and onwards translating into positive outcomes in adulthood. Certainly society has to play its role in helping people with autism reach their potential (I have a post scheduled on job interviews and autism coming up soon) and changes are indeed on-going (e.g. the implementation of the Autism Act here in the UK). But let's not be too proud of the achievements done in this area, as still many people on the autism spectrum, their families and concerned others have to fight daily for appropriate recognition, provisions and services.

Another important issue also springs to my mind on the basis of the new prevalence figure. Comorbidity, of which autism is by no means immune from, are not mentioned. The realisation that autism is often very much more than the sum of its triad - soon to be dyad - in terms of comorbidity must surely factor into the potential impact of the latest figures. Not least because of the quite startling health inequalities which seem to be present when an ASD is diagnosed and how as was very recently detailed in the CIPOLD report, such inequality can in some cases, have the most profound and far-reaching effects. I'm not trying to scare anyone; just sayin' that we need to be mindful of the whole person not just their autism.


* Blumberg SJ. et al. Changes in prevalence of parent-reported autism spectrum disorder in school-aged U.S. children: 2007 to 2011–2012. National Health Statistics Reports. 2013: 65.

** Wilson CE. et al. Comparison of ICD-10R, DSM-IV-TR and DSM-5 in an adult autism spectrum disorder diagnostic clinic. J Autism Dev Disord. March 2013.

---------- Wilson, C., Gillan, N., Spain, D., Robertson, D., Roberts, G., Murphy, C., Maltezos, S., Zinkstok, J., Johnston, K., Dardani, C., Ohlsen, C., Deeley, P., Craig, M., Mendez, M., Happé, F., & Murphy, D. (2013). Comparison of ICD-10R, DSM-IV-TR and DSM-5 in an Adult Autism Spectrum Disorder Diagnostic Clinic Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-013-1799-6

Monday, 18 March 2013

Folic-ing around in schizophrenia

I seem to have been focusing a lot on folic acid (vitamin B9) and vitamin B12 these days. It's not that I'm in anyway choosing the direction taken, it just happens that the published papers are appearing that way.

And as if to prove my point, enter the paper by Joshua Roffman and colleagues* (open-access) reporting results from a gold-standard, randomised, double-blind, placebo-controlled study on the addition of folic acid and vitamin B12 supplement to antipsychotic medication for a group of adults with chronic schizophrenia.
MTHFR, FOLH = word score @ Wikipedia  

The paper is open-access but a few summary points are worth mentioning bearing in mind Dr Emily Deans has already discussed this research:

  • One hundred and forty participants diagnosed with schizophrenia but psychiatrically stable were included for initial study. They were all taking an antipsychotic for 6 months "but displayed persistent symptoms despite antipsychotic treatment".
  • As per the study protocol, participants were randomly split into folate-vitamin B12 supplementation or placebo. Actually whilst it was random, it was stratified random, meaning that randomisation took into account serum folate levels which were measured at baseline and formed an important part of the study outcomes. Indeed, the split was also not 50:50 in each group; instead weighted towards the supplementing group. 
  • On most other variables the groups showed no significant difference (age, gender splits, medications, SES). That is aside from serum vitamin B12 levels, where the experimental group showed a significantly higher mean level at baseline compared to the placebo group (631 pg/ml vs. 511 pg/ml respectively).
  • The primary outcome measure was the change in negative symptoms as judged by the SANS. Not being an expert on schizophrenia, I was interested to read about the characterisation of positive and negative symptoms in schizophrenia and, as the authors put it, "considerable disability is associated with negative symptoms and cognitive deficits, for which effective treatment is not available".
  • Results: after 16 weeks of study, there were lots and they were mixed in with some DNA genotyping data pertinent to genes involved in the folate metabolism cycle. So our old Scrabble friend MTHFR (see here) got a look in, as did MTR (methionine synthase) - as per my previous post
  • One gene in particular seemed to get quite well caught up in the study results: FOLH1 - which among other things is involved in folate transfer and absorption. Mention of the words 'glutamate excitotoxicity' alongside FOLH1 also stirs up some interesting thoughts
  • So, yadda, yadda, "folate and vitamin B12 improves negative symptoms of schizophrenia" but only modestly given the "15% difference in SANS scores" between the experimental and placebo groups. Importantly in these days of personalised medicine, the FOLH1 gene was the focus, in that FOLH1 484C>T variant seemed to tie into treatment response. This was slightly at odds with what had been noted on another occasions**.
  • So, if a participants was homozygous - as in identical copies of the same allele - for FOLH1 484T,  they were more likely to show greater benefit from the supplements. I'll come back to this shortly.
  • That's not also to say that there weren't other gene related findings tied into intervention response. As the authors note about MTHFR 677C>T "only T allele carriers exhibited a significant benefit for active treatment over placebo for negative symptoms". Thankfully in line with what has previously been discussed***.

Every paper covered on this blog is a learning journey for me and this one is no exception. Likewise, it is always interesting to see when results don't exactly pan out as they are predicted to. In the case of the Roffman paper, it was the FOLH1 gene findings which didn't go to plan, and how contrary to the expected role of the 484C variant, the so-called low-functioning variant which one would expect to have reduced folate absorption - as was demonstrated in a separate asymptomatic cohort - it was actually the presence of the high-functioning variant (484T) which governed a positive treatment response.

In light of these findings, and the fact that red blood cell (RBC) levels of folate grew and grew in the experimental group over the course of the trial (although not significantly related to the change in negative symptoms), one starts to ponder other explanations to account for the results.

I've gone over MTHFR so won't say much more on that. The authors touch upon one potentially pertinent issue - DNA methylation - which is where I always seem to end up back to when talking about folate and MTHFR and the like. That for example, the supplementation of folic acid and vitamin B12 might, just might, impact on important reactions such as the recycling of homocysteine back to methionine onward to the production of SAMe is one possible effect. Indeed, it is a shame that elements of the methionine cycle were not measured over the course of the current trial.

I could go on. I could ask what kind of vitamin B12 was used as a supplement, whether the oral dosage form is the ideal way to get vitamin B12 into the body, whether outside of the reported symptoms, there may have been other variables affected by the results and whether despite increasing levels of folate, there were corresponding increases to levels of the active form of folic acid, 5-methyltetrahydrofolate? Indeed on that last point apparently there are plans afoot to look at the use of 5-methyltetrahydrofolate (or as the authors call it 1-methylfolate)...

Please stop now... and so I shall.


* Roffman JL. et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. March 2013.

** Roffman JL. et al. Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia. Schizophr Bull. 2013; 39: 330-338.

*** Hill M. et al. Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophr Res. 2011; 127: 41-45.

---------- Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, & Goff DC (2013). Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia. JAMA psychiatry (Chicago, Ill.), 1-9 PMID: 23467813

Friday, 15 March 2013

Autism, maternal immune activated mice and suramin

Avid followers of the autism research circuit must have noticed the increasing tide of studies looking at a possible role for maternal immune activation (MIA) in relation to risk of offspring autism spectrum disorder (ASD). It's a topic I've covered more than once on this blog; predominantly in relation to the work of people like Paul Patterson and his colleagues (see here), observations on things like C-reactive protein (see here) and the various ways to experimentally mimic such MIA in the mouse model of autism / schizophrenia / other for example (see here).
Squeakers @ Wikipedia  

So it is in this post that I'm serving a double helping of the MIA model of autism as per the publication of studies from Jared Schwartzer and colleagues from the MIND Institute* (open-access) and Robert Naviaux and colleagues** (open-access).

Both studies looked at the effects of artificial induction of MIA in the mouse model following poly I:C use as an immunostimulant. Thereafter the two studies went their separate ways as Schwartzer looked at the variable of mouse strain on the after-effects of MIA on offspring and Naviaux looked at the role of purinergic signaling.

I'll say right now that I am neither qualified nor experienced enough to go into these papers with any great detail. So I won't; instead a brief overview of each - bearing in mind their open-access status - and some interesting factoids which have already been mentioned in the autism research peer-reviewed domain which might tie into results.

The work of Schwartzer and colleagues basically "indicate[s] the need to consider how genetic predisposition may exacerbate or protect against the effects of environmental insults in the etiology of ASD". In other words, based on a mouse model looking at different strains of mouse, the specific genetic make-up of that mouse model might impact on offspring presentation after an artificial MIA event.

In their case they looked at the C57BL/6J and BTBR T+tf/J inbred mouse strains and concluded that the dangermouse that is the BTBR strain combined with the poly I:C stressor seemed to "be synergistic resulting in greater behavioral impairment than from either factor alone" when compared with the C57BL/6J mouse strain. Some interesting variables are noted including elevations in cytokines like IL-6 (see here) and IL-17 (see here) in the BTBR offspring mice compared to C57BL/6J mice alongside some sex specific behavioural differences. All in all, some very interesting observations; and on that sex-specific notion, not completely at odds with other work in this area (see here).

The work of Naviaux and colleagues - summarised quite well here - has definitely taken the interest of the media as per headlines such as 'New drug that may help reverse autism' or should that be 'Century old drug could beat autism'. I'm confused. The long-and-short of it is that based on the analysis of the MIA mouse model - C57BL/6J mice - there was a suggestion that "hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders". Treatable via "antipurinergic therapy (APT)" which in this study was via the drug suramin. The observant reader should immediately be comparing Schwartzer and Naviaux and the MIA mouse models chosen and results obtained.

Anyhow, Naviaux et al continue in their observations on how MIA affected offspring mice and how the administration of suramin seemed to have some pretty wide-ranging effects on offspring mice. Alongside various behavioural effects on social and coordination issues, suramin administration was reported to show important effects such as "the preservation of cerebellar Purkinje cells", which as I discussed in a recent post, have more than a token link to cases of autism. "Suramin treatment strongly increased the expression of the nicotinic acetylcholine receptor subunit α7 (nAchRα7) in cerebral synaptosomes of MIA animals" was another potentially important finding in view of other work in this area. In all, "16 multisystem features of this model were either corrected or improved by suramin treatment".

Impressive stuff I hear you say. Indeed all the more impressive given that the authors on purpose did not start suramin treatment until 6 weeks because they "wished to test the hypothesis that many of the autism-like features of the MIA model were treatable after they appear". And apparently there is more to come according to the authors, with the promise of human trials of suramin...

But just before you pop down to your local doctor or pharmacist to ask for suramin (off-label), it might be worth pointing out a few things. Mice. Yep, this was a study of mice and as per the Schwartzer study, not necessarily the best and only mouse model of autism from an MIA point of view. Indeed if I needed to go back to the BTBR mouse and its overlap with autism, I might also recall some work looking at that most forgotten of autism research parameters, sulphate (sulfate) and findings related to the BTBR model (see here). Mice are not humans and suramin is to be added to a growing list of mouse findings with an autism slant (see here and here).

That the US National Cancer Institute holds an entry for suramin should also give you some idea as to what uses the drug has and why bearing in mind it was injected into the study mice. Alongside its anti-parasitic effects related to things like sleeping sickness, the activity of suramin has been linked to its blocking of various growth factor binding which might yet hold some clue to other effects of the drug outside of competitive inhibiting of purinergic signalling (see here and here). As with most medicines, there are other effects to keep in mind which might also tie into results. And then there are the reported side-effects...

I'm not by any means trying to belittle the Naviaux results of suramin in the MIA mouse model of autism so please do not take this post as such. I am very keen to see some replication studies done in other mouse and other animal models, just to see if the results stack up before progressing to human trials with the all-important focus on 'first do no harm' and whether other meds have similar actions. As such I'll keep my eye open for suramin and autism and perhaps post some updates.

In the meantime, the maternal immune activated hypothesis grinds forward...


* Schwartzer JJ. et al. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Translational Psychiatry. 2013; 3: e240.

** Naviaux RK. et al. Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PLoS ONE. 2013; 8: e57380.

---------- Schwartzer JJ, Careaga M, Onore CE, Rushakoff JA, Berman RF, & Ashwood P (2013). Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Translational psychiatry, 3 PMID: 23481627

Naviaux, R., Zolkipli, Z., Wang, L., Nakayama, T., Naviaux, J., Le, T., Schuchbauer, M., Rogac, M., Tang, Q., Dugan, L., & Powell, S. (2013). Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model PLoS ONE, 8 (3) DOI: 10.1371/journal.pone.0057380

Wednesday, 13 March 2013

Just say NO to sapropterin for autism

Actually the title of this post is a bit of a misnomer.

I'm not really asking readers to say 'no' to sapropterin, otherwise known as tetrahydrobiopterin or BH4, for autism as if it were some kind of Zammo-esque drugs in the toilet scenario (note: for anyone born post-Grange Hill golden era or for my non-UK readers, you might want to follow this link to see what I'm going on about). But neither am I saying yes, as per my prime directive on this blog: no medical or clinical advice given or intended (resistance is futile... and all that).
Mr Bronson / Admiral Ozzel @ BBC News

The 'no' actually refers to NO - nitric oxide - and in particular the findings reported by Richard Frye and colleagues* (including Jill James yet again) on the potential involvement of NO metabolism in the behavioural changes noted when BH4 was introduced to a small cohort of children diagnosed with autism. I think we might have seen shadows of this study presented at IMFAR 2012.

OK, a quick description might be in order first. I've covered BH4 previously on this blog (see here) and some of the various roles that it plays; not least in its co-factor duties for the metabolism of some important aromatic amino acids eventually into things like neurotransmitters. Also not forgetting the potential role for BH4 in relation to managing conditions like PKU also (see here). Similarly, NO has also appeared on this blog before (see here). The Frye paper stresses the important role that BH4 has in the production of NO.

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

  • Starting with 10 participants (aged 2-6 years) diagnosed with an autism spectrum disorder (ASD) whose parents agreed "to not change any traditional or alternative medical or behavioral therapy during the study", various measures of behaviour and language function were charted over the course of a 16-week open-trial of BH4 (Kuvan).
  • Alongside the behavioural and psychometric measures used (which included the VABS and PLS), CSF samples were collected via lumbar puncture (not normally recommended because of its invasiveness) and blood samples used to measure for various marker compounds including BH4, the amino acids L-arginine and L-citrulline and everyone's favourite redox coverboy/covergirl, glutathione.
  • Results: bearing in mind that this was an open-trial and that no control group or placebo arm was used, the authors report some interesting changes to various parameters. So language (receptive at least) showed a significant improvement across the group across the testing periods (baseline, 8 weeks, 16 weeks). Some of the VABS subscales also indicated some positive changes (albeit one of them, VABS personal daily living, presented with a p-value of 0.061, I assume to denote Nick Berry style 'we nearly made it').
  • The biological stuff: well there was an increase in the reduced-to-oxidised glutathione ratio (good thing) and a decrease in levels of 3-Chlorotyrosine (3CT) (also a good thing) over the course of intervention, positive in terms of oxidative stress (redox status) and the presence of "reactive nitrogen species" respectively (see below).
  • Findings also pointed to "a fundamental change in pterin metabolism" coinciding with BH4 supplementation. I won't pretend to know all the ins-and-outs but it all has to do with supplementation modifying the reduced-to-oxidised pterin ratio and degradation of BH4 onwards to the appearance of something called peroxynitrite which is not particularly a good thing. I think this article** (open-access) might explain it a little better than I could.
  • The authors also reported that despite no significant change in NO metabolism markers (arginine and citrulline, and their ratio), it did appear that baseline levels of these compounds were allied to behavioural outcomes. Specifically improvements on the behavioural parameters "were related to higher baseline arginine and arginine-to-citrulline ratio".
  • Importantly, BHsupplementation was generally well tolerated with "only one patient discontinuing the medication because of mild adverse effects".

Yes, this was a very small trial, and yes again, there was no control group, no placebo and no blinding. It is preliminary work, of that there is no doubt. I find it a little unusual that the authors also chose HPLC with electrochemical detection when it came to the measurement of important metabolites like CSF levels of BH4. A little bit '80s' if you'll forgive me, given the startlingly increased precision offered by mass spec and NMR techniques as exemplified by papers like this one. Indeed even more odd that LC-MS was used for the analysis of amino acids: why not all metabolites? It should also be noted that Dr Frye is listed as having a potential conflict of interest in this paper via receipt of funding from the producers of Kuvan for this trial; not that this should or did influence the findings in any way, shape or form.

Nevertheless there are a number of interesting observations which might require some follow-up from this paper. That for example, a higher baseline level of arginine seemed to quite strongly correlate (r=0.91) with the PLS total raw score (language) as a result of BHsupplementation is a point worth following up, particularly in these days emphasising the identification of best- and non-responders to various interventions for the autisms. The implication being that "only some of the participants were able to significantly change their NO metabolism with the dose of Kuvan used in this study" potentially as a result of this correlate - or at least this studied and known about correlate. An endophenotype eh? Or even a biomarker for intervention response?

Given the body of work already published on BHsupplementation and autism and how BH4 levels might tie into lots of different areas outside of just being a co-factor (see this paper*** open-access) I'd like to see quite a bit more done on this compound and its relations. That it might also overlap with other conditions too - schizophrenia for example**** and other diagnoses***** - is also an important point given the genetic common ground being postulated between quite a few conditions (see here). One also wonders whether that recent vitamin B12-folate supplementation for schizophrenia paper****** by Roffman and colleagues (open-access) might also hint at some involvement of BH4 (more on that paper to come).

To finish, the old Grange Hill intro, including that sausage. Alongside due respect to actor Michael Sheard who played the unfortunate Kendal Ozzel ("he is as clumsy as he is stupid"). Steady on Darth.


* Frye RE. et al. Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Transl Psychiatry. 2013; 3: e237.

** Pacher P. et al. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87: 315-424.

*** Frye RE. et al. Central tetrahydrobiopterin concentration in neurodevelopmental disorders. Front Neurosci. 2010; 4: 52.

**** Richardson MA. et al. Evidence for a tetrahydrobiopterin deficit in schizophrenia. Neuropsychobiology. 2005; 52: 190-201.

***** Coppen A. et al. Depression and tetrahydrobiopterin: the folate connection. J Affect Disord. 1989; 16: 103-107.

****** Roffman JL. et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. March 2013.

---------- Frye RE, Delatorre R, Taylor HB, Slattery J, Melnyk S, Chowdhury N, & James SJ (2013). Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Translational psychiatry, 3 PMID: 23462988

Monday, 11 March 2013

Inflammatory bowel disease in autism: distinctive features?

Where to start with this very long post... where to start?

That autism, some cases of autism, also coincide with various comorbidities sometimes including severe gastrointestinal (GI) issues is a relatively undisputed finding these days. I'm actually getting a little bored of saying this myself on this blog and I'm sure some readers are getting bored of hearing it too.

Health inequality
Lymphocytic infiltration @ Wikipedia  
The reason why I continue to keep hammering away at this line however is because there is a substantial gap between what the peer-reviewed literature is saying about GI factors coexisting with cases of autism and the real-world experiences of many people (children and adults) with autism in terms of getting such symptoms/conditions investigated and properly treated.

A health inequality if ever there was one; indeed why else would the folks over at Treating Autism feel compelled to have to produce a document on the medical comorbidities in autism spectrum disorders highlighting such an issue?

An autism-specific IBD variant?
With this in mind, today's post concerns the paper published by Stephen Walker and colleagues* (open-access) which suggests that when it comes to the more GI disease-related aspect of bowel disturbance linked to autism - as in inflammatory bowel disease (IBD) - it appears that such GI disease might have "distinctive features" onwards to either an autism-specific IBD variant or "a prodromal phase of typical inflammatory bowel disease". We had seen a hint that this study was coming to publication based on an abstract presented as IMFAR 2012 (see here).

OK, I know that this paper takes some people into uncomfortable territory. Bowel disease - lymphoid nodular hyperplasia (LNH) and enterocolitis and autism - means 1998, Lancet and retracted paper and Lord Voldemort style 'he who must not be named'. Indeed search through the Walker paper and you will see that 'he' is definitely not named among the references, or not at least as first author on any paper. This despite the fact that other, well-renowned teams have no issue in citing the retracted paper in question (see here). I'll also point out that the authorship list on the Walker paper includes Dr Arthur Krigsman who has published work in this area** (open-access) previously. Just sayin'.

Anyhow, a few details from the Walker paper bearing in mind it is open to all:

  • The name of the game was "transcriptome profiling of gastrointestinal mucosal biopsy tissue from ASDGI children and three non-ASD control groups (Crohn's disease, ulcerative colitis, and histologically normal)" to ascertain just how similar/different gene expression was. In other words, whether the molecular signature noted in cases of autism and bowel pathology (autism-GI) matches what it seen in other well-known, and relatively well characterised bowel diseases.
  • The focus of analysis was differentially expressed transcripts (DETs) noted in ileal and colonic tissue samples from the various groups under study. The tool of analysis was microarray followed up by quantitative real-time PCR (qPCR) to "validate representative transcripts that showed differential expression by microarray". A sort of scatter gun, see what hits we make approach, followed by a more precise confirmation of said hits. Results were organised according to PCA "to determine similarity among biological replicates". 
  • Participants were 25 children diagnosed with an autism spectrum disorder (mean age around 5 years old) who all presented with a regression in previously acquired skills and some kind of inflammatory-related condition of the bowel (ileitis, colitis, ileocolitis). Indeed all presented with LNH. Most of children with ASD were following a gluten- and casein-free (GFCF) diet. Control groups were rather smaller in number and there was a bit of an age difference between them and the autism-GI group.
  • Results: Lots. Bearing in mind the authors were looking at tissue from two different parts of the GI tract, across quite a few groups, so this is probably not unexpected. For the autism-GI group, not everyone was included in all the analyses based on the two different regions of the gut because of quality/quantity of the RNA derived from them. 
  • For both colonic and ileal mucosa gene expression profiles, the asymptomatic control group (histologically normal) tended to cluster tightly together. Not so when it came to the symptomatic groups, where the autism-GI group in particular showed quite a bit of variability "suggestive of some potential subgroup(s)". Mmm, interesting.
  • Various comparisons were made between the groups based on the DETs identified in the two regions. I would be here all day and night listing the results of all this, so I'm cherry-picking a few bearing in mind it was a mix of up-regulated and down-regulated gene expression. (a) Autism-GI vs. asymptomatic controls (ileal mucosa): "1409 DETs unique to ASD-GI samples". DETs tended to link back to things like inflammatory bowel disease and colitis genes and the inflammatory response. Then we get down to genes related to humoral immune response, antibody production and digestive system development and function. (b) Autism-GI vs. asymptomatic controls (colonic mucosa): "1189 DETs unique to ASD-GI samples". DETs were linked to things like again gastrointestinal disease and also "neurological disease" including schizophrenia (50 genes) (see this post) and "hyperactive disorder" (16 genes) (which I take as meaning something like ADHD).
  • Again focusing on the autism-GI group and the DETs which overlapped both ileal and colonic tissues (178 transcripts), the top associated biological functions were in relation to inflammatory disease, endocrine system development and function, and digestive system development and function. Interesting also that 3 genes also cropped up in the pathway analysis linked to "Valine, Leucine and Isoleucine Degradation".  Did someone say branched-chain amino acids and autism
  • A very large quote: "Taken as a whole, the picture that emerges is one in which GI symptomatic children with ASD in whom cellular infiltrate is present in the ileum and colon have a distinct molecular signature that is consistent with the larger disease categories of gastrointestinal disease, and more specifically, overlaps with Crohn's disease, ulcerative colitis, and autoimmunity".

What can we surmise from these results? Well potentially quite a bit but with the very strong requirement for replication, replication, replication with a greater number of participants over a longer period of inspection. That all children with ASD included in the Walker study also presented with defined bowel disorder (including LNH) is an important findings. I've talked about inflammatory bowel disease and autism in a previous post based on the paper by Chen and colleagues*** which concluded that LNH was not an inconsistent finding - "apart from intestinal lymphonodular hyperplasia, the majority of these findings were not consistent" - among the various papers looking at bowel disorder in cases of autism. The Walker paper adds to that feeling.

Carbohydrate metabolism
I was interested to read about the potential overlap between the Walker findings and those reported in the Brent Williams paper on carbohydrate metabolism**** in autism (see here and here reloaded). Williams and colleagues reported decreased mRNA expression in cases of autism related to important carbohydrate metabolising enzymes alongside signs and symptoms indicative of things like dysbiosis. Walker says 'yes'; they found similar evidence in their cohort, particularly when it came to the down-regulation of CDX2.

Politics and kingdoms aside, and bearing in mind the heterogeneity present within the autism spectrum (and its fuzzy boundaries), this paper is an important one. Re-opening scientific investigation into how autism is not just the sum of its dyad, and how a diagnosis of autism is seemingly protective of nothing when it comes to comorbidity, are important elements to this work. Realising the very real and very significant pain and discomfort which can occur when such bowel conditions are present alongside autism is a good first step to bringing this particular branch of GI research out of the shadows, and finally asking the question: what can we do about it?

If indeed people want to see real equality when it comes to healthcare access and use for people with autism, continued investigation on the topic of GI disease and autism inclusive of both functional presentation and underlying pathology is absolutely implied.

To close, Blondie and One Way or Another....


* Walker S. et al. Identification of unique gene expression profile in children with regressive autism spectrum disorder (ASD) and ileocolitis. PLoS ONE. 2013; 8: e58058.

** Krigsman A. et al. Clinical presentation and histologic findings at ileocolonoscopy in children with autistic spectrum disorder and chronic gastrointestinal symptoms. Autism Insights. 2010; 2: 11.

*** Chen B. et al. Abnormal gastrointestinal histopathology in children With autism spectrum disorders. J Pediatr Gastroenterol Nutr. February 2011.

**** Williams B. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE. 2011; 6: e24585.

---------- Walker, S., Fortunato, J., Gonzalez, L., & Krigsman, A. (2013). Identification of Unique Gene Expression Profile in Children with Regressive Autism Spectrum Disorder (ASD) and Ileocolitis PLoS ONE, 8 (3) DOI: 10.1371/journal.pone.0058058