Sunday, 30 September 2012

Pets win (prosocial) prizes?

Miss Ellie Dog @Wikipedia
Pets have never really been a great part of my childhood it has to be said. Aside from a cat allergy which sort of ruled out any would-be Top Cat staying at ours, the family home just wasn't graced with enough space to accommodate other animal companions.

I did have a goldfish called George for a short period of time; that is until he/she(?) passed away and went to the great WC in the sky. Sad memories indeed.

This lack of animal contact during my childhood is probably why I am a little ambivalent towards children keeping pets at home (that and a very unfounded phobia of T.gondii) whilst, at the same time, being thankful for school pets who undoubtedly 'earn their keep' in the petting stakes.

Where autism is in mind however some recent research by Grandgeorge and colleagues* (full-text) suggests that pet arrival might very well have prosocial prizes.

The study is open-access so only a brief summary needed:

  • From quite a large bank of participants (N=260), two studies were carried out on two very much smaller groups: study 1: arrival of a pet at age 5 years (n=12) vs. never owned a pet (n=12); study 2: owned a pet since birth (n=8) vs. never owned a pet (n=8).
  • Alongside a questionnaire on human-pet relationships, parents of participants undertook questioning based on the ADI-R (see recent post) across two time periods (T0 and T1) primarily unaware of the reason for study participation.
  • Results: based on study 1, pet arrival between the ages of 4-5 years was associated with significant changes to 2 algorithm items on the ADI-R (53) offering to share and (55) offers comfort which "reflect prosocial behaviors". Having a pet from birth (study 2) did not seem to bestow the same changes.

There are a few obvious caveats to these findings based on the sample size and sole reliance on ADI-R to assess change at the same time of pet arrival. As with all studies of association, people don't generally live in a vacuum outside of real life, so one has to be slightly cautious about linking just pet arrival to the reported changes in behaviour particularly over quite a long period of time.

All that being said, I am really quite interested in these findings. I know some have talked about the whole theory of mind (ToM) issue as accounting for the results (see here). Whilst this remains a possibility, I have to say that I still remain unconvinced of a major link between animal associated prosocial behaviours and perspective-taking or vice-versa in this particular instance. Such cold hard psychology fails to take into account the concept of 'enjoyment' in having a pet and also the responsibility that comes with ownership outside of trying to understand the mental state or what their pet might be thinking.

On the other hand, I do rather like the idea that stress, and importantly a reduction/moderation in stress and anxiety responses following the introduction of a pet might be part and parcel of the results seen as per suggestions like this one from Virués-Ortega & Buela-Casal**. If there's one thing we know about autism, it's that stress and anxiety are very often in the background.

This study also reminds me of an earlier blog post concerning some research on animal magic and the amygdala which suggested that the amygdala might the place to be when it comes to animal identification and recognition. Exactly what role the amygdala might play is still unclear in autism but one can speculate that neuronal functioning may have potentially been affected by pet companionship in a sort of 'pet brain training scenario'. Let's wait for more evidence of this first though.

Whilst perhaps being a more outlandish link, my post on the appeal behind Thomas the Tank Engine to some cases of autism might also be relevant. Think about it: cats, dogs, hamsters, guinea pigs, etc. are fairly uncomplicated creatures by human standards. They don't talk (aside from the odd 'sausages' here and there), they don't use a wide variety of facial or other gestures, and in most cases, they pretty much like, and are responsive to, interaction without other complications. Just a thought.

I would like to see more investigation on this topic with autism in mind; a call echoed by an even more recent review of the use of assistance and therapy dogs for autism***. I hold back from suggesting that every child with autism should be automatically handed a pet at aged 4 or 5 years given that not every child probably wants a pet, but for some it might be a useful aid to their development. Dare I even suggest that the introduction of a pet to the family home might also have some knock-on effects to immune functioning as per articles like this one by Tse and Horner**** (full-text) in light of autism and the immune system research or am I just being a little bit silly?


* Grandgeorge M. et al. Does pet arrival trigger prosocial behaviors in individuals with autism? PLoS ONE. 2012; 7: e41739.

** Virués-Ortega J & Buela-Casal G. Psychophysiological effects of human-animal interaction: theoretical issues and long-term interaction effects. Journal of Nervous & Mental Disease. 2006; 194: 52-57.

*** Berry A. et al. Use of assistance and therapy dogs for children with autism spectrum disorders: a critical review of the current evidence. Journal of Alternative & Complementary Medicine. September 2012.

**** Tse H. & Horner AA. Allergen tolerance versus the allergic march: the hygiene hypothesis revisited. Current Allery & Asthma Reports. 2008; 8: 475-463.

---------- Grandgeorge M, Tordjman S, Lazartigues A, Lemonnier E, Deleau M, & Hausberger M (2012). Does pet arrival trigger prosocial behaviors in individuals with autism? PloS one, 7 (8) PMID: 22870246

Friday, 28 September 2012

Pretend play and autism

A lightsaber in production @ Wikipedia
I'm leaving the heavy biochemistry of late behind in this post with a link to an interesting paper recently posted on Twitter by Prof. Graham Davey (Twitter: @GrahamCLDavey) reviewing the current evidence on the impact of pretend play on child development*.

To quote: "...existing evidence does not support strong causal claims about the unique importance of pretend play for development".

Whoa there... pretend play over just play might not be such a vital component to child development? Y'mean all those hours honing my Vader-like lightsaber skills with those stuck together toilet roll tubes were wasted?

On reading such a paper my mind almost immediately wanders back to autism and publications like this one from Christopher Jarrold** reviewing the pretend play research base in autism alongside quite a few hours learning about play - imaginative and/or pretend play - through schedules like the ADOS. Indeed, isn't a problem with imagination and, by inference, imaginative/pretend play supposed to be a key hallmark of an autism diagnosis separating autism from not-autism? That was one of the findings from the artificial intelligence boiling down ADI-R paper published recently. So logically, does this mean that an absence/limitation of pretend play in cases of autism might not necessarily have such dire consequences for future development?

OK, I don't want to get too carried away here on the basis of one review. Indeed even the lead author, Prof. Angeline Lillard in this media piece admits that whilst pretend play probably doesn't have the final say in aspects such as creativity and problem-solving, it might very well aid in skills like language and social development - both key points to diagnosing autism; indeed social affect rolled into one according to the DSM-V suggestion. She also notes the very fuzzy issue in linking how specifically pretend play contributes to child development independently and outside of all the other factors which combine in that process called growing up.

It does however make me wonder whether the rigidity with which psychology has seemingly applied the importance of pretend play both in the context of autism and more generally in child development has been 'overstated'. Indeed, if we go back to the pretend play -- perspective-taking link as described by articles like this one by Doris Bergen*** for example, which makes mention of Theory of Mind (ToM), it makes me also wonder whether one could also question the global importance of ToM for 'proper' development too?

Individual differences? Compensation strategies? Have I said too much? Should I perhaps also not mention the recent paper by Sachse and colleagues on executive dysfunction and (adult) autism****?


* Lillard AS. et al. The impact of pretend play on children's development: a review of the evidence. Psychological Bulletin. August 2012.

** Jarrold C. A review of research into pretend play in autism. Autism. 2003; 7: 379-390.

*** Bergen D. The role of pretend play in children's cognitive development. Early Childhood Research & Practice. 2002; 4.

**** Sachse M. et al. Executive and visuo-motor function in adolescents and adults with autism spectrum disorder. JADD. September 2012: PMID: 23011252

---------- Lillard AS, Lerner MD, Hopkins EJ, Dore RA, Smith ED, & Palmquist CM (2012). The Impact of Pretend Play on Children's Development: A Review of the Evidence. Psychological bulletin PMID: 22905949

Thursday, 27 September 2012

Endocannabinoids and fragile X syndrome

Fragile X syndrome (FXS), one of the known causes of autism or rather autistic behaviours, has been receiving quite a lot of research and media attention lately. Arbaclofen (STX209) with FXS in mind was the topic of the most recent post (see here); now we have the article by Kwang-Mook Jung and colleagues* (open-access) on endocannabinoid signalling. There may be quite a few similarities between this latest endocannabinoid research and the growing interest in glutamate and its receptors with FXS in mind, but more on that shortly.

OK let's get it out of the way. Thinking about cannabinoids, I assume some people might initially make the connection back to cannabis and the chief psychoactive substance, delta-9-tetrahydrocannabinol (Δ9-THC), associated with that (in)famous plant. Indeed with the Jung study in mind, it was perhaps inevitable that a headline like: "Cannabis chemical combats chief genetic cause of autism" complete with the necessary picture of a cannabis plant would appear (all that's missing is Bob Marley and some 'herb' music just in case readers required a little more atmosphere).

Suffice to say that the Jung paper focuses on the functioning of the endogenous (endo)cannabinoid system over and above its external chemical relation.

  • In particular how in a mouse model, issues with the fragile X mental retardation protein (FMRP) associated with FXS might have some potentially important effects on endocannabinoid signalling by way of metabotropic glutamate receptor-5 (mGluR5) depression. 
  • Mention is made of something called 2-arachidonoyl-sn-glycerol (2-AG), a "retrograde endocannabinoid (eCB) transmitter" but other than saying that this is one of the more abundant endocannabinoids seemingly tied into mGluR5 and related to arachidonic acid (AA), I wouldn't pretend to know much more about it. The suggestion is that loss of FMRP has knock-on effects to mGluR5-dependent release of of 2-AG.
  • Aside from the basic science of endocannabinoid signalling in said mouse model of FXS, a particularly interesting part of the Jung study is the suggestion of pharmacological 'rescuing' of 2-AG signalling and the subsequent positive impact on some of the mouse subjects displayed behaviours. 
  • The pharmacological agent in question was something called JZL184, an inhibitor of the enzyme which usually degrades 2-AG (monoglycerol lipase, MGL) bearing in mind that said inhibition was irreversible. 

Hopefully I've got the main features of the study and its findings right and not confused you with all the terminology. Jung et al including Daniele Piomelli are no strangers to research on the endocannabinoid system and glutamatergic signalling as per papers like this one (full-text) and this one (full-text).

There are a few very obvious caveats to this latest work; not least that mice were the lucky participants and questions on those all-important extrapolations from mice findings to human findings which still need much greater investigation outside of the range of mouse models available to autism research. Emphasising also that this was a study of fragile X syndrome and the mutations associated with this autism-presenting condition, which may not be directly transferable to the range of other non-FXS autisms.

Having said all that I'm interested in this work for a few other reasons. As mentioned earlier on, fragile X syndrome and its relationship with glutamate and glutamate signalling is fast becoming a hot topic. If I were a betting man, I'd probably put a few quid/bucks/euro on a long-shot for glutamate and its receptors turning up as a commonality in quite a few behaviourally-defined conditions. Not necessarily as a core 'reason' but an important factor nonetheless.

I note also that MGL-inhibitors such as JZL184 have been discussed with concepts like protection from neuroinflammation (as a consequence of altering prostaglandin production) in mind** and indeed with another interesting topic in mind, intestinal permeability as per this study by Alhamoruni and colleagues***. All that outside of the possible inflammatory bowel disease link**** (open-access) too. On the basis of these and other research, I'm wondering about the centrality and specificity of the brain to any effects and indeed whether maintaining 2-AG levels may also be affecting other organs as part and parcel of any therapeutic, or indeed non-therapeutic, effect.

Enough with all this science and stuff. Ladies and gentlemen, welcome to paradise...


* Jung KM. et al. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nature Communications. 2012; 3: 1080. PMID: 23011134

** Nomura DK. et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011; 334: 809-813.

*** Alhamoruni A. et al. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. British Journal of Pharmcology. 2012; 165: 2598-2610.

**** Alhouayek M. et al. Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. FASEB J. 2011; 25: 2711-2712.

--------- Kwang-Mook Jung, Marja Sepers, Christopher M. Henstridge, Olivier Lassalle, Daniela Neuhofer, Henry Martin, Melanie Ginger, Andreas Frick, Nicholas V. DiPatrizio, Ken Mackie, Istvan Katona, Daniele Piomelli, & Olivier J. Manzoni (2012). Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome Nature Communications, 3 DOI: 10.1038/ncomms2045

Wednesday, 26 September 2012

Glycine as a sleep aid?

Sleeping beauty @ Paul Whiteley
When it comes to sleep and autism, or more specifically suggestions on how to improve sleeping patterns and sleep duration in cases of childhood autism, one compound crops up time and time again: melatonin.

I've talked about melatonin quite a bit on this blog; running through the current evidence for effect (here) and also speculatively discussing some of the ways and means that melatonin is made (here) and where the various findings on alterations in levels of the stuff in cases of autism might be derived from. 

All very interesting for the 'miracle' that is melatonin, bearing in mind that even melatonin supplementation might have a downside for some (including some pretty important drug interactions).

Having said all that, and again pronouncing my mantra: no medical advice given or intended, I was very interested to hear about another area of possible interest specifically with sleep in mind, supplementation with the amino acid glycine.

I don't know if you know or not but I'm a bit of a fan of amino acid chemistry and the myriad of ways that amino acids influence our health - somatic and psychiatric - and wellbeing. I've tended to focus quite a bit on the aromatic amino acids (tryptophan, tyrosine, phenylalanine) simply because of the various important links that have been made with for example serotonin (5-HT) chemistry and the in-born errors of metabolism such as PKU. I was also very interested in the whole branched-chain amino acids and rare cases of autism connection made quite recently.

Glycine is a little bit different in that it is categorised as a non-essential amino acid (i.e. the body can make the stuff itself); the body being capable of synthesising glycine from another amino acid serine (see here for a really small and complicated picture of how this happens).

The University of Wikipedia(!) reports that glycine is, quite importantly, also an inhibitory neurotransmitter; a point included in this overview by Bowery & Smart* (full-text) who also discuss the links with another important inhibitory neurotransmitter, GABA (see recent post). Mention of the words 'inhibitory' and 'GABA' immediately get me thinking about the sleep connection to glycine based on what an inhibitory neurotransmitter like GABA (and its receptors) has been suggested to be able to do.

Believe it or not, there is actually some peer-reviewed literature on the potential usefulness of glycine supplementation with sleep in mind. This paper by Bannai & Kawai** (full-text) is as good as any in outlining this fact, together with some speculation on the mode of action being linked to a lowering of body temperature normally experienced during sleep. Indeed the lead author, Makoto Bannai, seems to be quite interested in the whole glycine-sleep area as per another article*** suggesting that glycine supplementation might also cut down on perceived "daytime sleepiness and fatigue induced by acute sleep restriction" during a placebo-controlled trial. I hasten to add that this effect seemed independent of any findings related to melatonin.

Appreciating that quite a bit more research might need to be done on glycine and the link with sleep, I can't help but wonder whether glycine might also show some favour in cases of autism with sleeping issues. I stress that I am not advocating this or any other position without the appropriate medical advice and guidance. In view however of the speculations on glycine and body temperature - something also noted in cases of autism - and some very, very soft evidence on glycine supplementation and peripheral features like hyperactivity (here), one has to at least wonder whether more investigation is warranted.

Indeed bearing in mind that products such as dimethylglycine (DMG) and trimethylglycine (TMG) have already been discussed with autism in mind, could there be a greater effect over just altering stomach pH and the delivery of methyl groups to a potentially hypomethylating population?

To finish, somebody that I used to know? I dunno him but maybe you do.


* Bowery NG. & Smart TG. GABA and glycine as neurotransmitters: a brief history. British Journal of Pharmacology. 2006; 147: S109-S119.

** Bannai M. & Kawai N. New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep. Journal of Pharmacological Sciences. 2012; 118: 145-148.

*** Bannai M. et alThe effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers. Frontiers in Neurology. 2012; 3: 61.

---------- Bannai M, & Kawai N (2012). New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep. Journal of pharmacological sciences, 118 (2), 145-8 PMID: 22293292

Monday, 24 September 2012

Antibiotic exposure and inflammatory bowel disease

MRSA @ CDC #7820
I mentioned in a previous post how some reading on the gut microbiome is taking up some of my time recently. I've been quite lucky in writing some of the literature for that particular project now because papers seem to be cropping up left, right and centre making the whole task a little less taxing.

So it was recently when this paper by Kronman and colleagues* was published in the journal Pediatrics, and their assertion of a possible link between childhood antianaerobic antibiotic exposure and subsequent risk of developing an inflammatory bowel disease (IBD).

A few descriptions and details:

  • For those who might not know, bacteria can usually be classified as falling into one of two groups: aerobic = requiring oxygen to survive and function and anaerobic = not requiring oxygen. There is a third group, facultative bacteria which kinda like oxygen but don't necessary need the stuff to grow. Bacteria can also be categorised according to their colour on the Gram stain test but that's a slightly different story.
  • In the current study, antibiotic prescription and usage pertinent to those anaerobic bacteria was the topic of study including various antimicrobials such as "penicillin, amoxicillin, ampicillin, penicillin/β-lactamase inhibitor combinations, tetracyclines, clindamycin, metronidazole, cefoxitin, carbapenems, and oral vancomycin". 
  • Based on data for quite a large group (+1 million patients) derived from The Health Improvement Network (UK), a big database derived from General Practitioner (GP) records covering quite a few health outcomes, nearly two-thirds of the patient group aged up to 17 years old had taken some kind of antibiotic. Indeed most of these prescriptions were for an antianaerobic antibiotic.
  • Over the course of the study period, 748 participants developed an IBD including Crohn's disease and ulcerative colitis. When assessing the risk of an IBD amongst antibiotic exposed vs. unexposed participants, there was some disparity, equalling an 84% higher relative risk of IBD following a history of antibiotic use. Very early exposure (before 1 year of age) seemed to be associated with a higher risk of IBD and there seemed to be a dose-dependent relationship too.

I note that the authors have been quite cautious in press reporting their findings; in particular, cautioning against a definitive case for 'cause-and-effect'. Discussing also that antibiotics, when prescribed to children, are generally prescribed with good reason where indicated and not just willy-nilly.

Still, this work adds to a growing collection of data that suggests a possible link between gut bacteria, gut dysbiosis, immune function, antibiotic use and IBDs as per studies like this one and this one and an interesting editorial by De Vroey and colleagues**.

There's another reasons why this paper was of particular interest to me and this blog outside of just the gut microflora connection. I've talked about the potential double-edged sword of antibiotics use and autism in a previous post and although it might not be a popular topic to talk about, IBDs comorbid to autism seem to show a slightly more prevalent relationship than would perhaps be expected as per the Chen findings and the Kohane 'significantly over-represented' results. By saying this, I stress that I am not making any judgements on the connection or not between antibiotics, bowel issues and autism based on the lack of research literature currently available. But it is an interesting area nevertheless.

I imagine the Kronman paper will generate quite a bit more interest in this area particularly in light of the changing pattern and prevalence of IBDs over fairly recent years and the rise and rise of gut microbiota in relation to lots of different states and conditions. Personally, I'd be happy to see such investigations continue if only to see what can be done to ameliorate such conditions and whether things like probiotic therapy or even that therapy that should never be mentioned (fecal transplants) might hold some promise for something more than just recurrent C.diff infection.


* Kronman MP. et al. Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics. September 2012.

** De Vroey B. et al. Editorial: Antibiotics earlier, IBD later? Am J Gastroenterol. 2010; 105: 2693-2696.

---------- Matthew P. Kronman, Theoklis E. Zaoutis, Kevin Haynes, Rui Feng, & Susan E. Coffin (2012). Antibiotic exposure and IBD development among children: a population-based cohort study Pediatrics : 10.1542/peds.2011-3886

Micronutrients for stress and anxiety after earthquake

Lycosthènes @ Wikipedia
The junction between stress, anxiety and environment is of particular interest to this blog. I don't pretend to be an expert on the various mechanisms at work in such a relationship but, based on quite a thorough reading of some of the autism research literature in this area, I am beginning to understand how anxiety, chronic anxiety in particular, is a debilitating condition and plays a primary role in the reduction in quality of life for many, many people.

Moving slightly away from the autism link, I've talked before about some interesting research by Julia Rucklidge and colleagues at the University of Canterbury, New Zealand and their studies following the 2011 earthquake described at the time as " New Zealand's darkest day".

The main premise of that research was that supplementation with various micronutrients - vitamins, minerals and other compounds - may increase 'resiliance' to stress and anxiety associated with highly stressful events like earthquake in individuals diagnosed with ADHD and asymptomatic groups. Quite a bold claim I'm sure you would agree.

Today I'm following up that earlier post as a result of the fairly recent publication of this paper by Dr Rucklidge and colleagues* looking at different micronutrient formulations and their impact on stress and emotions linked to the 2011 earthquake (see trial database entry here). I apologise that I cannot post a link to the full-text paper but hope a short summary from me will suffice:

  • Two formulations were evaluated which, to save any commercial advertising issues, I will refer to as B and C, dispensed to 91 participants exhibiting heightened anxiety or stress a few months after the earthquake (B: n =30; C low dose: n=31; C high dose: n=30) based on a random allocation. A separate group of 25 people who either initially declined to participate or did not meet inclusion criteria acted as a non-randomised control group.
  • Various measures of anxiety and stress were delivered and completed at baseline and 4-weeks (study end). Measures included: the Depression Anxiety & Stress Scale (DASS), the Traumatic Exposure Severity Scale (TESS) and the Impact of Event Scale (IES) alongside other measures.
  • Results: all three treatment groups showed a significant decrease in measures of anxiety and stress following supplementation (based on change in scores between baseline and 4-weeks active treatment). Comparisons with the non-supplemented control group also revealed significant improvements in "stress, anxiety, avoidance, and arousal after 4 weeks of consumption of micronutrients".
  • Across the two preparations and different dosages, there were a few differences related to mood, anxiety and energy which have been put down the slightly broader spectrum of nutrients included in formulation C over formulation B. 

Appreciating that there are a number of potential forms of bias to be had in this type of research including a lack of blinding and no placebo as a control, I have to say that I am quite impressed with the reported findings. The authors have gone to some lengths to control for as many factors as possible (being free of psychotropic medication, exclusion of various conditions/states including neurological disorders) and looked at various angles including SES, alcohol/caffeine/smoking/drug use, mental health history, etc as potential influencing variables. Also importantly reporting potential adverse effects from supplementation.

I kinda like the suggestion that the stress and anxiety of being involved in such a horrific natural act might to some degree be abated by simple supplementation with an off-the-shelf micronutrient supplement. Even if it is purely a placebo action - 'take this pill it will help with your anxiety and stress' - giving a daily vitamin-mineral supplement after a disaster like that knocking out infrastructure and interfering with access to food for example, is probably not such a bad idea also in light of the increased risk for disease following such natural disasters (see the Haiti earthquake for a good example). It has to be slightly less expensive and more easy to administer than a few sessions of behavioural therapy or a course of more traditional pharmacotherapy even just as an emergency measure?

The authors do discuss some of the research on how certain components of the micronutrient preparations used might potentially be able to affect symptoms like stress. I'm taken back to the work of David Kennedy and colleagues at Northumbria University and their reports on high-dose vitamin B and vitamin C supplementation on perceived stress in healthy volunteers** (under placebo-controlled, double-blind conditions). There are several hundred more references on this topic also.

Finally, one has to wonder how deep the rabbit hole goes with regards to micronutrient supplementation and stress and anxiety. Outside of the natural disaster bit, could this work imply that nutritional supplementation might be an alternative route to treating anxiety and stress in the general population? (or at least some cases of anxiety and stress). Physiologically what are the mechanisms of effect, acknowledging snippets of research of interest to me on things like gut hyperpermeability and stress (see here)? What about those trillion or so bacteria which reside in our deepest, darkest bowels; how do they respond to stress and what action can they exert? (I note that this same team are going to be looking at a probiotic formulation in a subsequent trial). Even the possibility of trauma being transmitted across generations as per this interesting post on pregnant 9/11 survivors and the emerging field of epigenetics? Lots and lots of questions to answer.

To finish, how about a little piano genius from Ben Folds Five (and Fraggle Rock?).


* Rucklidge JJ. et al. Shaken but unstirred? Effects of micronutrients on stress and trauma after an earthquake: RCT evidence comparing formulas and doses. Human Psychopharmacology. July 2012.

** Kennedy DO. et al. Effects of high-dose B vitamin complex with vitamin C and minerals on subjective mood and performance in healthy males. Psychopharmacology. 2010; 211: 55-68.

--------- Rucklidge JJ, Andridge R, Gorman B, Blampied N, Gordon H, & Boggis A (2012). Shaken but unstirred? Effects of micronutrients on stress and trauma after an earthquake: RCT evidence comparing formulas and doses. Human psychopharmacology PMID: 22782571

Saturday, 22 September 2012

No clinically meaningful differences: gut bacteria and autism?

Who's stool? @Wikipedia
I've been in heavy gut microbiome reading mode these past few days as a result of helping to write some overview material on the topic (and various other -omics) for some collaborations. Autism spectrum disorders have not been a specific focus for most of the work, but I've been drawing heavily on the collected research so far as per the Lipkin Sutterella findings and the Aussie Akkermansia muciniphila observations.

It was with great interest therefore that I read the abstract to the paper by Gondalia and colleagues* and quote: "Results did not indicate clinically meaningful differences between groups. The data do not support the hypothesis that the gastrointestinal microbiota of children with ASD plays a role in the symptomatology of ASD." Strong words indeed from a study based on just over a hundred participants.

So with a little more detail:

  • The paper originates from the Swinburne Autism Bio-Research Initiative (SABRI) and a few names attached to autism research that I've come across before, including David Austin who last year published some correlative research suggesting a link between Pink disease and autism** (full-text) (see media on the paper here).
  • Pyrosequencing of (stool) samples was completed for 23 children with autism (no gastrointestinal (GI) dysfunction), 28 children with autism (accompanied by GI dysfunction) and neurotypical siblings (n=53). Keep in mind that neurotypical siblings bit for now.
  • Results: the dominant phyla in descending order were "Firmicutes (70%), Bacteroidetes (20%) and Proteobacteria (4%)" with no "clinically meaningful differences between groups".

I'm going to try and remain objective about these findings. Science is science and even though I might be less than most predisposed to the view that "other explanations for the gastrointestinal dysfunction in this population should be considered including elevated anxiety and self-restricted diets", despite the recent paper by Micah Mazurek linking gut problems to anxiety, that's the author's take on their results and it should be respected. The Aussie group did look at endophenotypes within the autism spectrum based on comorbidity and did take into account various SES variables. Fair do's to them.

A few factors however potentially intersect with the current findings:

  • If we've learned anything from the first results to come from the Human Microbiome Project (HMP) and related research, it's that there's probably more uniting us in bacterial terms, than divides us. By saying this I'm not saying that we are identical when it comes to bacteria, but rather like our genome (and epigenome) and indeed our brain gene maps, the similarities across populations probably outweigh the differences. From this perspective, I don't think such general results are too unexpected.
  • When undertaking controlled studies, it's always wise to see who and what controls are used. For this study, the control group was comprised solely of asymptomatic siblings. There was no external non-family control group (age and sex matched), just a group who probably lived with, ate similar food to, drank similar fluids to, etc and were genetically similar to the target participants. In this respect, I'm taken back to quite a bit of the other research on gut bacteria and autism, where most significant differences seem to be reported compared with external controls. So as per this study by Helena Parracho and colleagues*** (full-text) and of course, the Wang study**** (full-text) on short chain fatty acids and A.muciniphila. Note also in both these studies the suggestion of more similarities than differences between participants with autism and their sibling controls. 
  • The current findings are based on stool analysis; something which this group have published on previously with autism in mind***** (full-text). I'm perfectly happy to accept that stool analysis is a viable (non-invasive) route to speculating on gut bacteria in different groups, mindful however that different bacteria can populate different parts of the gut and that genetic regulation by bacteria can differ in different parts of the (mouse) gut. Probably the only study done so far looking at bacteria derived from biopsy samples in autism, and therefore reflective of the different areas of the gut, is the Brent Williams / Ian Lipkin Sutterella study****** (full-text) and I 'aint going to argue with their results following their recent XMRV de-discovery.

I hope this post hasn't turned into a rant. I for one am happy to see that gut bacteria and indeed the whole microbiome area is starting to receive some research interest with autism in mind. Accepting that Australia has recently been introduced to the 'Autism Enigma' programme (Jon Brock talked about it in a recent post), there is perhaps quite a bit of chatter Down Under about the ins and outs of gut bacteria with autism in mind. It is coincidental that this paper appears when it does from where it does.

I'm not quite ready to give up on the possibility of a gut bacterial role to some cases of autism. One cannot simply assume that the previous research carried out in this area is null and void on the basis of one study. Even if those little beasties are not a central facet to the condition and apply only to a specific sub-group of those on the spectrum, gut bacteria are just too important to health to just push out of the autism research agenda for now as per another great word by a familiar name:  pharmacometabonomics - gut bacteria affecting drug metabolism (see here*******).

Speaking of Down Under....


* Gondalia SV. et al. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Research. September 2012.

** Shandley K. & Austin DW. Ancestry of pink disease (infantile acrodynia) identified as a risk factor for autism spectrum disorders. Journal of Toxicology & Environmental Health A. 2011; 74: 1185-1194.

*** Parracho H. et al. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. Journal of Medical Microbiology. 2005; 54: 987-991.

**** Wang L. et al. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol. 2011; 77: 6718-6721.

***** Gondalia SV. et al. Faecal microbiota of individuals with autism spectrum disorder. Electronic Journal of Applied Psychology. 2010; 6: 24-29.

****** Williams BL. et al. Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio. 2012; 3: e00261-11.

******* Clayton TA. et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. PNAS. August 2009.

---------- Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D, & Austin DW (2012). Molecular Characterisation of Gastrointestinal Microbiota of Children With Autism (With and Without Gastrointestinal Dysfunction) and Their Neurotypical Siblings. Autism research : official journal of the International Society for Autism Research PMID: 22997101

Thursday, 20 September 2012


I assume quite a few people have already read the various reports about STX209* (most definitely not to be confused with ED-209) otherwise known as arbaclofen with Fragile X syndrome in mind. Hailed as 'The First Drug that Could Ease Social Withdrawal in Autism' according to one news source, the headlines are based on the results of this study by Elizabeth Berry-Kravis and colleagues** complemented by this study by Henderson and colleagues*** published on the same day in the same journal.

OK reverse please.

Seaside Therapeutics, yet another pharmaceutical company with autism or autistic behaviours in their sights, had been working for quite a while now on a new formulation, a derivative of baclofen, itself a derivative of everyone's favourite inhibitory neurotransmitter, GABA - gamma aminobutyric acid (see here for a description) as a possible therapeutic for certain behaviours associated with autism. Baclofen is normally indicated for the treatment of spasticity resulting from conditions like multiple sclerosis and cerebral palsy.

GABA is the yin to glutamate - an excitatory neurotransmitter - the yang. The balancing act between excitatory and inhibitory neurotransmitters has, on more than one occasions, been suggested to be slightly skewed in some cases of autism (and other conditions and states) as glutamate takes centre stage.

So then STX209 is, as its chemical relations are, recognised as an agonist for GABAB receptors which in turn inhibits the release of glutamate (and aspartate). You can perhaps see therefore where the interest lies.

I know quite a lot of the press around STX209 has focused on autism, but to be more accurate, Fragile X syndrome  - which presents with autistic features - is the target patient group based on the trials completed so far. The suggestion being that the primary mutation associated with Fragile X syndrome - FMR1 gene - has some knock-on effects**** including "activation of mGluR5, a metabotropic glutamate receptor". Avid watchers of the autism research landscape might remember mGluR5 as being a target for other pharmaceutics with autism/autistic characteristics in mind, including another interesting compound, GRN-529***** (at least in mice).


  • The recent trial of STX209** relied on human participants rather than mice, 63 of them in all, mostly male and all carrying "a full mutation in the FMR1 gene". 
  • Randomised, double-blind, placebo-controlled (all the things that science really likes to hear about) was the study design and outcome-wise, the Aberrant Behavior Checklist (ABC) and the Vineland Adaptive Behaviour Scales (VABS) are listed.
  • The primary endpoint of the study was a focus on irritability, which actually didn't come up trumps over placebo. 
  • Having said that, there were some significant positive effects noted on areas of social avoidance in the treatment group acknowledging that the absolute number of participants in the study was relatively small and actually got even smaller following some post-hoc analysis.
  • Importantly also, a few side-effects were noted, particularly in the treatment group including URTIs (13%) and headaches (8%).

I note that Seaside Therapeutics have quite recently agreed some terms over STX209 with pharmaceutical giant Roche which suggests to me that things might potentially get quite big for arbaclofen rather quickly. By saying that, I'm not in anyway endorsing the medicine. Quite a bit more data is required on long-term safety, efficacy and best responder characteristics.

With that in mind, I'll be quite interested to see the results of further trials of STX209 as are apparently planned and/or getting underway including a trial specific to children and young adults diagnosed with an autism spectrum disorders (see here). As to the mechanism of STX209 to GABAB receptors to improving social avoidance... more investigation needed I assume.


* Hopkins CR. ACS Chemical Neuroscience Molecule Spotlight on STX209 (Arbaclofen). ACS Chem Neurosci. 2011; 2: 381.

** Berry-Kravis EM. et al. Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with Fragile X Syndrome: a randomized, controlled, phase 2 trial. Science Translational Medicine. 2012; 4: 152ra127

*** Henderson C. Reversal of disease-related pathologies in the Fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Science Translational Medicine. 2012; 4: 152ra128

**** Dölen G. et al. Correction of fragile X syndrome in mice. Neuron. 2007: 56: 955-962.

***** Silverman JL. et al. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Science Translational Medicine. 2012; 4: 131ra51.

---------- Elizabeth M. Berry-Kravis, David Hessl, Barbara Rathmell, Peter Zarevics, Maryann Cherubini, Karen Walton-Bowen, Yi Mu, Danh V. Nguyen, Joseph Gonzalez-Heydrich, Paul P. Wang, Randall L. Carpenter, Mark F. Bear, & Randi J. Hagerman (2012). Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with Fragile X Syndrome: a randomized, controlled, phase 2 trial Science Translational Medicine DOI: 10.1126/scitranslmed.3004214

Wednesday, 19 September 2012

Lenalidomide and autism?

Lenalidomide @ Wikipedia
Of the thousands of medicines which have been or are currently in use, a few really enter the mainstream public consciousness for a variety of different reasons.

That little blue pill which now graces many a man's medicine cabinet worldwide is probably the best example, as any email spam folder can readily confirm.

One drug, suggested to treat morning sickness during pregnancy in the late 1950s, is however synonymous with the darker side of pharmaceutics; illustrative of the failings of appropriate medicines testing: thalidomide.

If you don't know the story of thalidomide this article offers quite a succinct timeline, and how only recently the company responsible for the invention of thalidomide has formally apologised to all those affected by this medicine.

You would perhaps think that after such a torrid history, this drug would and should be consigned to the annals of history, never to be used in medical practice again. You might however want to think again; as thalidomide is re-emerging as a medicine for various conditions including certain cancers, inflammatory diseases and even persistent cough, albeit with a few tweaks and heaps more pharmacovigilance particularly when administered to females of reproductive age.

OK so what's all this got to do with autism? Well, my attention was grabbed by the publication of this proof-of-concept study by Michael Chez and colleagues* (open-access) and the suggestion that lenalidomide, an analogue of thalidomide, might (might) show some promise in cases of autism. I had seen mention of this study, or something like this study, in a previous abstract from IMFAR 2010 (see here). The entry for the study can also be seen here.

The keen eyes out there might recognise the name Dr Michael Chez and the Sutter Institute for some other recent publicity regarding the first FDA-approved stem cell trial for autism (see trial details here) which has created some column inches among mainstream media and bloggers alike (including me). It seems that this research group is intent on creating scientific waves.

Back to the paper, which is open-access, for a summary and few comments:

  • The basic premise of the trial was the recognition of quite a bit of research which has indicated the immune system and various features of immune function might correlate with the presence of autism in some cases. Mention for example of that dastardly cytokine, interleukin-6 (IL-6) is made, but the main protagonist in this particular study is tumor necrosis factor - alpha (TNF-α), another inflammatory cytokine, and a target for lenalidomide (see here). The authors cite the focus of TNF-α as an outcome measure "because other cytokines were not always available in all patients" referring to tested parameters.
  • A daily dose (2.5mgs) of lenalidomide was given for 12 weeks to 7 males (aged 6-12 years) diagnosed with autism and with parental report of regression being associated with symptom onset. Autoimmune "dysfunction" (I assume this means autoimmune disease) was reported in first-degree relatives of all participants, although prospective participants with various diagnosed autoimmune conditions were excluded from the present study.
  • Various measures of behaviour and cognitive functioning were used during the study (baseline - 6 weeks - 12 weeks) including ADOS, CARS and the Receptive and Expressive One-Word Picture Vocabulary Test. This accompanied measurement of both serum and CSF levels of TNF-α (CSF levels collected via that most invasive of methods, lumbar puncture - don't click on this link if you are squeamish). 
  • To ascertain the pharmacokinetics of the drug (drug metabolism), blood draws at 1, 2, 4 and 8 hours after the first dose of the lenalidomide were administered. 
  • Results: well, mixed is probably the best description. Safety-wise, two participants were withdrawn from the study following their developing a rash. Another participant discontinued when their neutrophil count (white blood cells) dipped; albeit transiently. 
  • Four participants registered a drop in TNF-α levels in both serum and CSF at study end. Whilst on the surface of things this might be considered an interesting finding, one has to bear in mind that analysis of CSF levels of the cytokine were accepted anywhere up to 8 months before the baseline testing started.
  • Behaviourally, there was some suggestion of improvement on the various measures included for study, particularly at 6 weeks, but alas none of these changes were statistically significant. Indeed with the attrition (drop-out) rate (n=3) mentioned at study end, I'm not really surprised that nothing was found to be significantly improved. It would have to be an almost spectacular change in behaviour for 4 participants to register a significant change from baseline to study end.
  • Conclusion: some interesting trends from the various data but nothing concrete probably as a function of the small participant group.

The science-y types out there may very well look at this trial and its results and focus on its failings and weaknesses. Whilst not trying to defend the study, I would draw your attention to several keywords in the title like 'pilot study' as a clue to the very preliminary nature of this investigation. Indeed, the authors do mention that this was not a randomised trial (i.e. participants randomly allocated to treatment or not), did not include a placebo group and neither was it double-blind; everyone knew that participants were taking lenalidomide and nothing else. It's more of case series description than a scientific trial.

Before any chatter arises about me somehow endorsing thalidomide derivatives to 'treat' autism by highlighting this study, I just want to say that I'm not. My mind keeps wandering back to the devastating teratogenic effects that thalidomide bestowed, and still I can't help but wonder if this is indeed one of those drugs which given its history perhaps should have been consigned to the great pharmaceutical rubbish tip, never to be used again.

I'll let you form your own opinion on whether this is an area requiring further research with autism in mind or not. Bear in mind however that for some people with certain conditions, lenalidomide has probably had some real benefit for them (see here) and its adoption reflects, quote "the pressing need to develop molecules with enhanced immunomodulatory and antitumor activity". Not that there may not be alternatives as per this study however.


* Chez M. et al. Safety and observations in a pilot study of lenalidomide for treatment in autism. Autism Research & Treatment. 2012; 291601.
DOI: 10.1155/2012/291601

---------- Michael Chez, Renee Low, Carol Parise, & Tammy Donnel (2012). Safety and observations in a pilot study of lenalidomide for treatment in autism Autism Research & Treatment DOI: 10.1155/2012/291601

Tuesday, 18 September 2012

XMRV and chronic fatigue syndrome: the results are in...

Drummer boy @ Wikipedia
Drum roll please maestro.

It's been on the horizon for quite a while. The speculation about what will be found, the teaser announcements pinpointing Tuesday 18th September 2012 as the big day, the excitement was building.

And finally here it is.

The big multi-centre study initiated by the US National Institute of Allergy and Infectious Diseases headed by the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health to once-and-for-all answer the question on many a person's lips:

Is XMRV linked to chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)?

And the answer....

Very probably not.

The study by Harvey Alter and colleagues* is open-access and published in the the journal mBio.

OK, a quick recap first. XMRV (xenotropic murine leukemia virus-related virus) was initially suggested to be present in quite a number of cases of Chronic Fatigue Syndrome (CFS). It was followed by lots of media attention including some questions over the blood supply, a not altogether successful line of experimental replication, some pretty strong indications of contamination** affecting results, a backstory like something out of a soap opera, and now the final say-so study headed by Prof. Ian Lipkin, microbe and virus hunter extraordinaire (see this previous post on Sutterella and autism).

The study is open-access for all to see and has been covered by a number of sources so far (here) but a quick summary of the results, bearing in mind my considerable non-expertise in the very complicated world of virology:

  • Blood samples were taken from 147 participants diagnosed with CFS and compared with samples from 146  asymptomatic controls. CFS diagnoses were confirmed by several of the criteria available for describing CFS. Said cases had been ill with CFS for an average of 16 years.
  • Blinded analysis of peripheral blood samples was conducted for the genetic footprints of XMRV and pMLV (polytropic murine leukemia virus). 
  • Results: none of the samples (CFS or controls) showed evidence of XMRV or pMLV. The various labs involved in the trial as well as being pretty meticulous in avoiding any contamination, used both positive and negative controls as part of their analytical methods so knew what to look for.
  • There was a suggestion that nine of samples from each group showed a positive result to XMRV / pMRV reactive antibodies but this result is accompanied by some questions about accuracy and specificity to CFS cases.

What's more to say other than the headline by the NYTimes "Chronic Fatigue Syndrome Back to Square 1". Actually no, I wouldn't agree that we are back to square one. As per the comments from Prof. Lipkin, lessons have been learned and also now some very valuable biological samples from quite a well-defined group of people with CFS are available to science to test other theories as and when they come along (as they inevitably will).

I do have one remaining question for the whole XMRV story as per the results reported by Paolucci and colleagues discussed recently. They reported finding something that looked like XMRV/MLV in two of their patient group with CFS. Do the Lipkin findings then mean that they were wrong? Is yet another scientific retraction on the horizon?

Outside of the science bit, I imagine that quite a few people with CFS/ME will carry a sigh at the publication of these results as again, hopes and dreams of getting to the bottom of this mysterious, unexplained condition take another set-back. For their sake, one can only hope that the XMRV episode will at least stimulate more research interest into CFS/ME as per other US Government departments talking about CFS with drug development in mind. Not forgetting also that there are several areas of research into CFS which seem really quite interesting such as the recent mitochondrial findings and the whole immune functioning area.

OK, that's enough for now. 

I was pondering what song to finish this post with. Something related to the post? Nah, instead something completely unrelated... the Noisettes and That Girl.

Update (18/09/12): The association between XMRV and prostate cancer has also been questioned as per this study by Lee and colleagues (full-text).


* Alter H et al. A Multicenter Blinded Analysis Indicates No Association between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus. mBio. 2012; 3: e00266-12.

** Stieler K. et al. XMRV induces cell migration, cytokine expression and tumor angiogenesis: are 22Rv1 cells a suitable prostate cancer model? PLoS ONE. 2012; 7: e42321.

---------- Harvey J. Alter, Judy A. Mikovits, William M. Switzer, Francis W. Ruscetti, Shyh-Ching Lo, Nancy Klimas, Anthony L. Komaroff, Jose G. Montoya, Lucinda Bateman, Susan Levine, Daniel Peterson, Bruce Levin, Maureen R. Hanson, Afia Genfi, Meera Bhato, HaoQiang Zheng, Richard Wang, Bingjie Li, Guo-Chiuan Hung, Li Ling Lee, Stephen Sameroff, Walid Heneine, John Coffin, Mady Hornigo, & W. Ian Lipkino (2012). A Multicenter Blinded Analysis Indicates No Association between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus mBio : 10.1128/​mBio.00266-12

Saturday, 15 September 2012

The major histocompatibility complex and autism

Fancy a beer son? @Lucasfilm
"Your destiny lies with me Skywalker". So said Darth Vader as he tried his very best to work on his father-son relationship skills (shortly after chopping off his son's hand).

I don't necessarily see it as my destiny to keep talking about the immune system in connection to autism and other conditions but there was perhaps an air of inevitability that I would eventually end up talking about the major histocompatibility complex (MHC) and autism. Indeed two quite recent papers by Needleman & McAllister* and Torres and colleagues** (full-text) bring the MHC into full view with autism in mind.

What is the MHC?

It's all about identification and communication. In effect the very flexible MHC lets the immune system know what is 'self' and what is 'other' by promoting 'self' peptides on the surface of all cells. This means that when 'other', foreign peptides from an invading pathogen are presented on some cells by the MHC, the immune system knows that these are not-self and acts accordingly. So lymphocyte recognition and the presentation of antigens represent two quite big tasks of the cell-surface molecules which make up the MHC (also called the human leukocyte antigen). When things go wrong with the MHC and 'self' gets confused with 'other' you get autoimmunity; something which has been speculatively linked to some cases of autism (see here).

"Always two there are" (well two main ones).

Two classes of MHC molecules play a big role, MHC class I and MHC class II although there are others; all genetically encoded for on various regions of chromosome 6. I don't really want to get too bogged down by structure and different chains between the two classes but if you want a good review have a look at this paper by Hewitt*** (full-text) and this paper by Wang and colleagues**** (full-text). A big difference seems to be where each class of glycoprotein is found; MHC class I are present on most cells in the body, MHC class II glycoproteins are only found on antigen-presenting cells such as T cells and B cells. That and the different types of 'antigen' being presented (endogenous vs. exogenous) and to what (cytotoxic T cells vs. helper T cells) respectively.

Involvement of the MHC with regards to health and ill-health is never more prominent than in the example of coeliac (celiac) disease (CD). There, CD is strongly associated with the the presentation of specific genetic alleles of the MHC known as the (HLA) DQ2 and DQ8 haplotypes (see here for a description of haplotypes). This page is about a good an explanation that there is showing how HLA DQ2 and DQ8 fit into CD; the watchwords are: glutamine and prolamin rich gluten peptides, binding to HLA DQ2 / DQ8 haplotypes, initiation of an inflammatory response, tissue damage, flat mucosa and so forth.

Assuming that I've understood and conveyed all that information accurately, the next step is to discuss where autism may (or may not) fit into the MHC story.

And autism?

If I said that the late Reed Warren was there pretty much at the beginning when it comes to looking at the MHC in cases of autism would you be surprised? Indeed if ever there was a loss to autism research, it was the fact that Dr Warren passed away far too soon leaving us all wondering what he might have accomplished had he still be on the scene.

I've posted previously about his work on the C4B null allele (here) and more recently on his IgA deficiency findings in cases of autism (here). His paper from 1992***** suggested, quote: "a gene related to, or included in, the extended major histocompatibility complex may be associated with autism". In later work, Warren together with another big name in the immune side of autism Vijendra Singh, even talked about a possible association between issues with the MHC in autism and elevations in levels of serotonin (here******). Indeed Singh still holds some scientific interest with his notion of 'autoimmune autistic disorder'.

So what did Warren and colleagues find? Well it all boils down to quite a few cases of autism presenting with the "extended or ancestral haplotype B44-SC30-DR4". That and similar findings being reported in first-degree relatives as per this study by Lee and colleagues******* and this study by Johnson and colleagues********. I interpret this as meaning that within the class II MHC - the one involved in presenting exogenous (outside-derived) antigens from bacteria and such like - where the HLA-DR4 haplotype features, cases of autism might show a link. Bear in mind also, that HLA-DR4 is also a risk factor for conditions such as type 1 diabetes (see here) thus extending the autoimmune side of things too. 

I assume you are perhaps wondering where all this MHC talk is going when it comes to a behaviourally defined condition like autism outside of just autoimmunity. Well, this is where the tie up between the immune system and other organs like the brain come into their own and the suggestion that MHC molecules might do much more than just offer antigens to the immune system. Wekerle********* (full-text) provides an excellent overview of the MHC with neurons in mind, reviewing the suggestion that the MHC may regulate important processes like synaptic pruning.

Indeed with plasticity and pruning in mind, Belmonte and colleagues********** (full-text) talked about the possibility that a decreased expression of class 1 MHC molecules may impair pruning in cases of autism, pertinent to the early brain 'overgrowth' noted in some cases. There is also another potential side to the MHC story in autism as per the suggestion of  "an increased proportion of MHC class II-expressing microglia" at least in a mouse model of autism; indeed a mouse model already covered on this blog. I'm not however going any further with this at this time but would refer you to a recent post on microglia and autism.

Based on all this and other research, I'd like to think that there is a case for involvement of the MHC at least in some cases of autism. I can't really offer a sound explanation as to the how and why outside of speculation on things like the autoimmunity comorbidity or possibly some contribution from maternal infection during pregnancy (on the basis of the familial MHC connection) as being involved. All I can say is that there is some degree of likelihood of MHC involvement at least for some diagnosed with autism. Perhaps another potential research avenue in need of further investigation?

To end, readers in the UK whether interested or not, will have probably heard about the departure of Chris Moyles from BBC Radio 1. I'm more of a Radio 2 man myself (particularly when Ask Elvis is on) but Chris Moyles played some good tunes on Friday to bow out to, one of which I always really enjoyed in a melancholic way ... The Streets and Dry your eyes


Needleman LA. & McAllister AK. The major histocompatibility complex and autism spectrum disorder. Developmental Neurobiology. July 2012.
DOI: 10.1002/dneu.22046

** Torres AR. et al. HLA immune function genes in autism. Autism Research & Treatment. 2012; 959073.

*** Hewitt E. The MHC class I antigen presentation pathway: strategies for viral immune evasion. Immunology. 2003; 110: 163-169.

**** Wang P. et al. A Systematic Assessment of MHC Class II Peptide Binding Predictions and Evaluation of a Consensus Approach. PLoS Computational Biology. 2008; 4: e1000048.

***** Warren R. et al. Possible association of the extended MHC haplotype B44-SC30-DR4 with autism. Immunogenetics. 1992; 36: 203-207.

****** Warren RP. & Singh VK. Elevated serotonin levels in autism: association with the major histocompatibility complex. Neuropsychobiology. 1996; 34: 72-75.

******* Lee LC. et al. HLA-DR4 in families with autism. Pediatric Neurology. 2006; 35: 303-307.

******** Johnson WG. et al. HLA-DR4 as a risk allele for autism acting in mothers of probands possibly during pregnancy. Archives of Pediatrics & Adolescent Medicine. 2009; 163: 542-546.

********* Wekerle H. Planting and pruning in the brain: MHC antigens involved in synaptic plasticity? PNAS. 2005; 102: 3-4.

********** Belmonte MK. et al. Autism and abnormal development of brain connectivity. The Journal of Neuroscience. 2004; 24: 9228-9231.