2012 autism research review on Questioning Answers

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What y'mean those stories about the end of the world weren't true after all? They what... they forgot about the leap years? And the whole idea, which just happened to converge on the date of the Winter Solstice, was a little far-fetched?

I digress.

Speaking of time, once again we reach the end of another year and have a nostalgic look back at some of the highlights of the blogging year that was 2012 on Questioning Answers. Because the World is still here, all 7+ billion of us and Blogger remains active, similar to last year, month by month, let's takes a sentimental journey through what happened in autism and other research in 2012. So cup of tea in hand (no milk, two sugars please), feet up, and onwards...

January

My research mix tape @ Wikipedia  

Well just before the New Year set in, Drs Dan Rossignol and Richard Frye produced their excellent review of autism research trends discussed in this post. It was heartening to see that so much more research these days is looking at the more concrete somatic / physiological features of autism over the slightly more abstract psychological theories of times gone by. I don't have an issue with psychology trying to describe what autism might be, but don't particularly like quite a few of the sweeping generalisations that it has made thus far. Brent Williams and colleagues also published their very novel findings on the potential role of Sutterella bacteria in cases of autism with comorbid gastrointestinal (GI) symptoms which remains one of my most read blog posts. Heather Close and colleagues asked the question: can you grow out of autism? and opened up a can of worms in the process, and my fascination with epigenetics and autism blossomed.

February
A speculative but interesting paper published by T. Andrew Clayton on gut bacteria and amino acids in relation to autism caught my eye and continued the interest in all things gut microbiota. One of the first ever controlled trials of N-acetylcystine (NAC) for autism was also published potentially opening up some very interesting areas for intervention and further study. Discussions on the role of glutamine and glutamate in autism also made for similar engaging reading continuing the amino acid theme.

March
I'd like to think my research home primarily circles the various investigations into the hows and whys of a gluten- and casein-free diet for cases of autism. So when Pennesi and Cousino Klein published their survey of parental experiences of the diet I was always going to be interested (yes, I know it's not a randomised-controlled trial). I should also at this point tip my hat to the consensus statement published by Anna Sapone and colleagues on the spectrum of gluten-related disorders (outside of just coeliac disease). The paper by Momeni and colleagues describing the basics of a blood-based biomarker for autism also grabbed my blogging attention given the focus on the use of metabolomics. It wasn't a perfect study by any means, but it is a good start. The question of how common autism might be in cases of schizophrenia was of interest, but the main event for March must be the release of the latest CDC estimates for autism in the US: a very sobering 1 in 88 8-years olds with an autism spectrum disorder (ASD) up from 1 in 110 in 2009. Debate still rages on as to why the change (hint: it's likely to be lots of factors) and the implications.

April
Lots and lots of research discussed in April 2012. Gastrointestinal inflammation and immune activation in schizophrenia from Emily Severance and colleagues (keep her name in mind for now) seemed to mirror some of the findings reported in autism; six developmental trajectories and autism bloomers; quickly followed by some research on maternal obesity and risk of offspring autism as part of the CHARGE initiative. De novo mutations and autism filled some column inches, although there is still some confusion about SES and which parental age is a risk factors for autism. For me, April also carried one of the autism research papers of the year with the meta-analysis by Main and colleagues confirming that we really need to start looking more seriously at glutathione and related metabolites with autism in mind.

May
I never thought I would be talking about the bowel habits of Star Wars characters but that's what I did in this post on how poo tells a story in autism. Indeed there was more discussion of the inner workings of the bowel in this speculative post on polycystic ovary syndrome (PCOS), GI bacterial dysbiosis and autism. If you're a little bit sick and tired of poo and bacteria, there was this post on maternal fever and offspring autism risk (CHARGE once again) or if you like, some important data on parental pre-diagnostic experiences of their children.

June
Here in the UK, NICE - the National Institute for Health & Clinical Excellence - published the second strand of their guidance on autism, detailing their response for adults with autism. Elsewhere, CHARGE again published another vits and SNPs paper with autism in mind, this time focused on folic acid and everyone's favourite Scrabble enzyme classic, MTHFR. Low serum IgA in cases of autism was also discussed, as was some interesting work on autism's environmental exposome detailing some preliminary results on fish exposure to drug residues. June also closed with a summary post on the dangermouse that is the BTBR mouse model of autism. Just on the periphery a very important announcement was made with the first publications from the Human Microbiome Project (HMP).

July
More evidence for a role for glutathione in cases of autism nestled amongst other research looking at the possible overlap between autism and autoimmunity. A possible link between childhood anxiety and autistic traits was also the source of some discussion. Outside of autism, there were some interesting findings on mitochondrial dysfunction in cases of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) (followed up here) from which I would like to see similar methods applied to autism. And then there was the fascinating research from Prof. Paul Patterson's laboratory on mouse modelling of autism and immune function, a very definite 'watch this space' piece of research bearing in mind the increasing interest in stem cells and autism (see here).

August
'No single SNP associated with autism' was a real talking point for quite a few people. Micah Mazurek's paper linking functional GI problems, anxiety and sensory issues in cases of autism also brought in some interesting ideas about how physiology, psychology and behaviour might be linked in autism. The weather in August here in my part of the UK was not as wet as the wash-out of previous 'summer' months this year, so it was quite apt that the Saudi-Egyptian research tag-team of Mostafa and Al-Ayadhi published on vitamin D levels in cases of autism and their possible link to autoimmunity. There was more de novo mutations and older dads too. Although not a peer-reviewed paper, an opinion piece in the New York Times created a bit of a stir and some suggestions about the immune system and autism.

September
Quite an interesting month for autism research. There was the suggestion of a new inborn error of amino acid metabolism potentially being related to a presentation of autism. Indeed amino acids or rather one amino acid in particular, glutamate and its receptor and signalling functions was a real topic of conversation as per the report on the use of arbaclofen and a role for endocannabinoids at least in autistic symptoms associated with Fragile X syndrome. Maternal IgG antibodies and offspring autism also cropped up. Slightly to the left (or right!) of autism research was the grand XMRV de-discovery paper by Ian Lipkin and colleagues, which on the bright side, now means a bank of blood samples are available for research from quite a well-defined group of people with CFS. I should also point out that just because XMRV is not linked to CFS doesn't mean that viruses are completely off the hook for this range of conditions.

October
Continuing the autism-schizophrenia link, Kenneth Gadow reported some thought-provoking results on the presentation of schizophrenia spectrum disorder symptoms being present in cases of autism. The issue of wandering and autism has been discussed for quite a few years in the autism community, although Connie Anderson's paper represents one of the more thorough research-based investigations on just how widespread it might be. In a similar vein, the prevalence of bullying in cases of autism also got some research attention. October 2012 was also a month of leaky gut speculation as (again!) Paul Patterson and his team elaborated on their immune-activated mouse model and some very preliminary discussion of gut hyperpermeability (which I'm reliably informed is under submission for peer-reviewed publication some time soon).

November (or even Movember)
It started with a metabolomics bang following some very interesting research from Xue Ming and colleagues following up earlier investigations on urinary amino acid and other differences present in cases of autism. Interestingly, the amino acid glycine was a target compound which makes me wonder about its possible involvement with things like sleep. It was also mightily pleasing to me to see the paper from Francis Bowling and colleagues appear looking at sulphation (sulfation) and autism and revealing some very interesting systems biology tie-ups. Both the journals Nature and Pediatrics had special editions on autism (and open-access too) including reference to some future work on vitamin D and autism which neatly slotted into that paper by Ann Neumeyer suggesting a role for the sunshine vitamin in the bone density findings recorded in cases of autism. I've got to mention the study on HERVs and autism because this adds a whole new dimension to the whole genes-environment discussions and how methylation issues might potentially have some really important knock-on effects. And then there was that absolutely fascinating study on Toxoplasma gondii infection potentially setting up immunological issues with gluten by Emily Severance and colleagues...

December
DSM-V was accepted by the American Psychiatric Association (APA) and into unknown territory we all head. Some interesting data by Walter Zahorodny and colleagues were published on the ever increasing prevalence rate of autism in New Jersey, USA with the absolutely "startling" figure of 1 in 35 boys diagnosed with an ASD. With comorbidity in mind, I also looked at the similarly startling statistic of 40% of people with autism estimated to have a problem with their eyes which might very well tie into a least some of the perceptual issues which are reported to be experienced by many people on the spectrum. Some very interesting data linking some of the genetics findings in relation to autism to immune function were also published. Indeed a very, very preliminary study from Bradstreet and colleagues reporting on nagalase and Gc-MAF added to the immune function link.

And rest.

Quite a year by all accounts but I'm not here to blow research trumpets when still many, many people with autism and their families see little or no benefit from this or the thousands of other research papers published in 2012 and further back.

I have though, no doubt that 2013 will provide even more scientific fodder for this blog and its discussions given that the big DSM change-over is scheduled for May 2013 and that NICE are due to report their final strand of guidance on the management of autism in children and young people here in the UK. Coupled with high expectations from autism research conferences like IMFAR 2013, 2013 is already destined to be a game-changer of a year.

Stay tuned, thanks for reading, seasons greetings to all and take it away Kirsty and Shane... (25 years old y'know).

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A research highlight from 2012.....

Main PA, Angley MT, O'Doherty CE, Thomas P, & Fenech M (2012). The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutrition & metabolism, 9 PMID: 22524510

Mortality and autism

I know the topic of this post is not exactly great dinner table conversation, particularly at this time of year during the season of goodwill to all.  Nevertheless I'm posting today on the paper by Deborah Bilder and colleagues* looking at mortality and causes of death in relation to autism spectrum disorder (ASD) simply because there are important lessons which can be learned and applied with relative ease as a result of some of their collected data.

Regular readers might know that one of my interests on this blog is the issue of health inequality when it comes to conditions like autism and indeed beyond. It's a sad fact that whilst autism generates quite a lot of discussion, research, politics and emotion, the message that people with autism are people first, and hence are at least facing the same risk (if not more) of developing health-related complications, can get a little lost in the noise. I'm as guilty as anyone in losing this message with my constant ramblings on the wonders of autism research.

Papers like the one from Bilder et al however reinforce the view that autism, in some cases, might very well place a person at increased risk of early mortality and outside of just seeing a person with autism, we could do a lot by putting the person and their physical health and wellbeing first and foremost.

A few bullet-points from the Bilder paper:

• The study was based in quite an important geographical area for autism research, Utah. Important because as I've blogged about before, Utah has been the focus of some milestone studies on autism, in particular the UCLA-University of Utah Epidemiologic Study of Autism. Indeed some of the original data from that initiative has quite recently become the source of some discussion as part of the autism numbers game and the transition from DSM-III to DSM-IV.
• In particular, the authors sought to follow-up the cases of autism identified during the UCLA-University of Utah study and estimate the mortality hazard rate ratio (HRR) whilst look at the patterns of mortality and what factors were linked to death. The authors define HRR as: "an estimate of the excess risk associated with the identified exposure (i.e. ASD case status) as a constant effect over a specific time period (i.e. interval since case ascertainment) while adjusting for selected covariates (i.e.birth risk factors)".
• Based on a cohort of 305 adults with autism (DSM-III and DSM-IV-TR diagnosed/reclassified participants), 29 people (9.5%) had died by the end of 2011. 
• Most of the deceased were male, and the age at time of death varied between 7 - 46 years old.
• The HRR overall was 9.91 compared to population controls (N=2466). When taking into account the different genders, the HRR for males was 7.92 and for women with an ASD a staggering 20.71 (without covariates).
• As one would expect, there were various causes of death indicated on death certificates, ranging from seizures to cardiac-related disorders. Epilepsy was a prominent feature for quite a few of the cohort as per the range of physical disease comorbidity observed in cases. That being said, and without making any judgements, death listed as a result of an "open wound of hip" in one case invites further investigation. 
• Death by unnatural causes were relatively few although "two individuals died from an adverse event related to medication".

The Bilder paper does make somber reading when you realise that behind every statistic there was a person and a family. Indeed looking at the list of deceased, their intellectual and autism classification, their cause of death and importantly, their accompanying physical disease, one is struck by the heterogeneity present.

With my cold, dispassionate research spectacles on a few points caught my eye.

It was interesting to note how many cases cite cerebral palsy (CP) for example, as a comorbidity to their autism diagnosis (I counted 6 cases of the 29 deceased). I'm not inferring that CP was the cause of death, even though it was listed as a factor in at least one case, but rather that those cases with comorbid CP might indicate some elevated risk of early mortality as per the literature on excess mortality in CP** alone.

Reports of comorbid Sanfilippo syndrome were also present in more than one case of autism, two actually. Given the rarity with which this syndrome appears - anywhere between 1 in 100,000 to 1 in 1,000,000 in the general population - to see even one case in the current cohort should automatically be a cause of some interest bearing in mind presentation can include autistic features and the syndrome previously being mentioned in the autism research literature*** (2 / 222 cases of autism). Given the poor prognosis of Sanfilippo syndrome, one might reasonably assume some impact on mortality where autism also appears alongside.

I also observed that cancers and neoplasms did not seem to prominently figure among the deceased as a cause of death. One could argue that given the relatively young mean age of the deceased, this might play a role in mortality and indeed the lack of accompanying information on things like cancer treatment and survival among this cohort. But I'm interested in this phenomenon, especially when one considers what the population at large - as in everyone whether with autism or not - generally tend to die of (see this post for more information).

The low prevalence of death by unnatural causes also caught my attention. I've talked fairly recently about the wandering and autism research which was published and how wandering can, in a few cases, lead to the very worst outcome when autism is involved. As far as I can surmise and allowing for the difference in age groups looked at, wandering was not implicated in any of the cases looked at by Bilder. I'm not able to provide an in-depth view of wandering leading to the circumstances of early mortality in autism, but one speculates whether an overall increase in cases of autism might be a factor in the very public recording of death implicating wandering. Same goes for issues like suicide, recently discussed with autism in mind****.

Finally, I can't leave this post without commenting on those two people where death was linked to medication use. In both cases, individuals were in their late 30s-early 40s, and one case also carried a diagnosis of schizophrenia. Accepting that medicines - particularly those with a psychotropic effect - are still a voyage of discovery in terms of their precise effects and mode of action, pharmacotherapy is as much about good medicines management as it is about the effects of the drugs themselves. I note for example one case where poisoning due to exposure to "unspecified" drugs is cited alongside the word 'obesity'. The relationship between these concepts has been discussed before including the important issue of side-effects.

The take-home message from this post is best left to another comment from the paper:

"The elevated mortality risk associated with ASD in the study cohort appeared related to the presence of comorbid medical conditions and intellectual disability rather than ASD itself suggesting the importance of coordinated medical care for this high risk sub-population of individuals with ASD."

I would struggle to disagree.

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* Bilder D. et al. Excess mortality and causes of death in autism spectrum disorders: a follow up of the 1980s Utah/UCLA Autism Epidemiologic Study. J Autism Dev Disord. September 2012.

** Strauss D. et al. Causes of excess mortality in cerebral palsy. Dev Med Child Neuol. 1999; 41: 580-585.

*** Ververi A. et al. Clinical and laboratory data in a sample of Greek children with autism spectrum disorders. J Autism Dev Disord. 2012; 42: 1470-1476.

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Bilder D, Botts EL, Smith KR, Pimentel R, Farley M, Viskochil J, McMahon WM, Block H, Ritvo E, Ritvo RA, & Coon H (2012). Excess Mortality and Causes of Death in Autism Spectrum Disorders: A Follow up of the 1980s Utah/UCLA Autism Epidemiologic Study. Journal of autism and developmental disorders PMID: 23008058

The hyposerotonemic mouse and autism

Dear readers, please don't be put of this post by the title. All it refers to is a mouse described by Kane and colleagues* (open-access) which was engineered with a null mutation in the TPH2 gene governing the production of tryptophan hydroxylase, a required step in the synthesis of the aromatic amino acid tryptophan to everyone's favourite neurotransmitter, serotonin (or as we Brits like to call it 5-HT). Said mouse was unable to produce serotonin and hence lacked it - hyposerotonemia - despite having all the necessary receptors et al.

Meeces to pieces... @ Wikipedia  

Kane and colleagues set about looking at mice "derived from matings of heterozygous (TPH2+/−) males and heterozygous (TPH2+/−) females on a mixed C57BL/6-Sv129 background".

This selective breeding produced offspring who were homozygous for the null mutation, basically carrying the null mutation on both chromosome pairs (TPH2-/-). They then set about testing the TPH2-/- mice on various measures across various ages corresponding to human years (infancy, juvenile, adulthood) and compared results with wild-type pups who were not serotonin deficient.

Their findings? Well, the TPH2-/- mice presented with some interesting developmental features. A delay in hitting certain developmental milestones, transient early brain overgrowth normalising into the equivalent teen years and adulthood, among other things.

When put to various tasks equivalent to looking at some of the core and peripheral features associated with human autism spectrum disorders - a kind of mouse ADOS if you will - the TPH2-/- mice showed some significant differences in their behaviours compared with wild-type mice. So less preference for mother mouse's scent interpreted as the "early signs of a social communication deficit", alongside other socialisation issues and lots of repetitive, compulsive behaviours persisting into mouse adulthood. I'm not going to get to heavily into each individual finding because it's all there in the full-text paper.

The authors conclude: "these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism" and certainly I am not going to disagree with them. Yes, you could again use the argument that this was a mouse and not a human being, and the fact us humans are very, very, very complicated creatures by comparison. You could also argue that quite a few of the behaviours described by Kane and colleagues are also associated with other behavioural and psychiatrically-defined conditions and need not be just necessarily construed as autism; depression for example, bearing in mind the timing of presentation. It's a complicated picture of inference and 'ifs and buts' not helped by the mixed bag of research on serotonin and autism.

I remain however interested in these findings and indeed in the whole area of mouse models and autism given previous discussions on the BTBR dangermouse and also how mouse models might be able to translate autism hypotheses into viable murine-based findings. Er, should I mention sulphation and leaky gut here too, or is that old news now? Bearing in mind that those TPH2-/- mice might also carry other mutations and indeed epigenetic differences too, I'll be keeping an eye on the hyposerotonemic mouse research and just how useful it might be to autism research.

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* Kane MJ. et al. Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PLoS ONE. 2012; 7: e48975.

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Kane MJ, Angoa-Peréz M, Briggs DI, Sykes CE, Francescutti DM, Rosenberg DR, & Kuhn DM (2012). Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PloS one, 7 (11) PMID: 23139830

Bumetanide for autism?

The paper by Lemonnier and colleagues* (open-access) reporting results from a randomised, placebo-controlled trial of the diuretic drug bumetanide in cases of autism has received quite a bit of publicity over the past few days. As with other big autism research news, the study was accompanied by quite a good write-up in Nature (see here) which very conveniently allows me to skip over the ins and outs of the study and pick out a few notable points in this brief post.

As always with the 'no medical advice given' caveat in full working order:

• This was a gold-standard trial insofar as similar to other research discussed on this blog it was randomised and also incorporated a placebo into the methodology which meant that participants were randomly assigned to treatment or not and the 'not' consisted of something that I assume, looked, smelled and tasted the same as bumetanide. Indeed the study lists 'lactose' as being the placebo which is fine as long as participants with autism did not have a lactose intolerance as per other autism research findings.
• Bumetanide as well as being a diuretic (increasing urine excretion) is a loop diuretic acting on a specific part of the kidney. Its uses are varied but mainly focus on reducing swelling and fluid retention following problems with the heart and other organs. It's also apparently quite good for treating hypertension (high blood pressure) too** and potentially useful for certain types of epilepsy*** (although I'd like to see more data on this effect). 
• Quite a lot of the focus on why the drug seemed to affect autistic behaviours has been on the GABA side of things and how "disruption of GABA is due to increased levels of chloride ions in the brain cells" in case of autism. The theory goes that bumetanide has an effect of decreasing levels of chloride in neuronal cells, which theoretically should positively alter that GABA disruption. In particular is the proposed action of bumetanide on NKCC1 an importer of chloride, where if I understand it correctly, bumetanide blocks NKCC1 from doing its duties. Indeed I might be confusing myself even further but NKCC1 also has something of a relationship with hypertension****.
• Why am I focusing on the hypertension side of things? Well, with all that we think we know about autism in terms of stress responses and comorbidity potentially focused on things like hypertension***** as part of the whole metabolic syndrome side of things, one might also be minded to look at whether this might have been part and parcel of any effect noted. Of course, I'm just speculating, bearing in mind that no measure of blood pressure for example, was seemingly reported during the trial. 
• As per this review by Ward & Heel****** (open-access), there are several other physiological changes/effects associated with taking bumetanide, all of which should remain at the back of one's mind when thinking about potential mechanisms of effect.  

I've not got too much more to say about this work aside from it being quite an interesting study and indeed (a) providing further support for how the myriad of pharmaceutical compounds we use might have many more uses than those cited on the patient information leaflet, and (b) how some of the effects of such medicines in cases of autism might be more evidence for the 'whole-body' nature of the condition, or at least some cases of the condition.

'Nuff said.

[Update: February 2014. Well it wasn't exactly 'nuff said as indeed, more was subsequently said on this topic... see this post on bumetanide, GABA, oxytocin and mouse models of autism].

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* Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Translational Psychiatry. 2012: e202.

** van der Heijden et al. A randomized, placebo-controlled study of loop diuretics in patients with essential hypertension: the bumetanide and furosemide on lipid profile (BUFUL) clinical study report. J Clin Pharmacol. 1998; 38: 630-635.

*** Eftekhari S. et al. Bumetanide reduces seizure frequency in patients with temporal lobe epilepsy. Epilepsia. October 2012.

**** Ye ZY. et al. NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension. J Neurosci. 2012; 32: 8560-8568.

***** Tyler CV. et al. Chronic disease risks in young adults with autism spectrum disorder: forewarned is forearmed. Am J Intellect Dev Disabil. 2011; 116: 371-380.

****** Ward A. & Heel RC. Bumetanide: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs. 1984; 28: 426-464.

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Lemonnier, E., Degrez, C., Phelep, M., Tyzio, R., Josse, F., Grandgeorge, M., Hadjikhani, N., & Ben-Ari, Y. (2012). A randomised controlled trial of bumetanide in the treatment of autism in children Translational Psychiatry, 2 (12) DOI: 10.1038/tp.2012.124

Cord blood testosterone and autistic-like traits: no link?

Prof. Andrew Whitehouse has featured quite a bit on this blog. The most recent occasion (aside from this post) was a piece of research on maternal vitamin D status and early adult offspring scores on the Autism Spectrum Quotient (AQ) which concluded no overall link despite some interesting details. Indeed quite a bit of his work derived from the Raine study focuses on recording factors during pregnancy and the very earliest days in the big, wide world and seeing how they might relate to results like those derived from the AQ some years later. Not wholly dissimilar from the ethos behind looking at archive dried blood spots it has to be said.

Cord clamping @ Wikipedia  

In a similar vein, I want to talk about another of his papers* (open-access), this time on perinatal testosterone exposure and once again, early adult offspring AQ scores. And in particular a lack of association between the two variables and some potentially important implications for one of the more widely cited theories of how autism might come about.

I've kinda covered testosterone and autism before on this blog with reference to the finger length ratio (2D:4D), apparently quite an interesting correlate of how much testosterone we might have been swimming around in in-utero, and also more speculatively on a post on PCOS.

Most people thinking testosterone and autism are brought back to the theory posited by Prof. Simon Baron-Cohen - see one of the papers here** - extending the so-called extreme male brain (EMB) theory of autism*** itself extending the systemising/empathising sex differences**** again extending good old Theory of Mind (ToM). It's quite a logical train of thought I must admit, and probably why so many people truly do believe testosterone may show some primary connection to cases.

That being said, regular readers perhaps know that I'm not really one for sweeping generalisations when it comes to autism (see pages 949-951), no matter how much the science of psychology loves to try and compartmentalise conditions like autism. And take my word for it, psychology has been pretty fanatical about compartmentalising autism, its core cognitive features, down the years, almost it seems searching for some kind of scientific closure.

Anyhow, the paper in question is open-access but here are a few bullet points:

• The study is part of the Raine initiative again, whereby out of 861 children where BioT (free testosterone & albumin-bound testosterone) taken from umbilical cord blood at delivery was available, 707 provided diagnostic data at any of the specified follow-up points through infancy and early adulthood.
• Testosterone analysis was made by mass spectrometry, so one can't really fault accuracy, and DNA analysis from a small sample of the cohort ensured that cord blood samples were not contaminated by maternal blood so as to rule out reading maternal testosterone levels over offspring.
• Five of those 707 offspring were eventually diagnosed with an autism spectrum disorder (ASD).
• Results: "no significant correlations between TT levels and scores on any AQ scale among males (rho range: -.01 to .06) or females (rho value range: -.07 to .01)". TT = total testosterone.
• Indeed, "no significant association between BioT or TT concentrations and AQ scores among males (rho value range: -.07 to .08) or females (rho value range: -.06 to .12)".
• When looking at those 5 who were diagnosed with ASD, four "had TT and BioT levels lower than the sex-specific BioT means of the broader cohort, and all cases were within one standard deviation of these means".
• Not surprisingly the authors conclude that "testosterone concentrations from umbilical cord blood are unrelated to autistic-like traits in the general population".

There have been a few murmurs about this study in cyberspace, its results and implications for the EMB theory; partly genuine scientific interest, partly prejudice it has to be said. I'm going to try and remain objective. Assuming there was no significant sample degradation given that cord samples were taken at parturition and then thawed out apparently some years later for analysis, there are a few other factors to take into account which might have more general implications of the EMB-autism work.

Fair-do to Prof. Whitehouse for not totally poo-pooing the other research literature built up on testosterone and autism based on his findings. Indeed an even more recent study again by Bonnie Auyeung and colleagues***** (including Prof. Baron-Cohen) looking at amniotic fluid foetal testosterone and Q-CHAT results in 18-24 months old found a more positive relationship; bearing in mind a much smaller sample size and the focus on infancy not adulthood.

Back to the Whitehouse study: he for example talks about concentrations of cord testosterone not necessarily being the sole factor of any relationship but rather "individual differences in biological sensitivity to testosterone". That and the fact that the AQ is not a comprehensive autism assessment but rather a screen, and quite a subjective screen by all accounts. Other authors have talked about testosterone within a wider context of other biological markers as per this study by Geier and Geier****** who bring in words like glutathione, cysteine and homocysteine. I think you can see where I'm going with this; similar to the increasingly distant prospect of an autism gene, so an individual biomarker for autism is also looking less and less likely. Then there's heterogeneity (autisms not autism), comorbidity, etc. Indeed comorbidity is something that really needs a lot more study with testosterone-autism in mind.

Finally, I was interested to see that poverty might have been an influence on the AQ scores reported in the recent trial, to quote: "Total AQ scores were significantly higher for those adults whose mother was 
living below the poverty line during pregnancy". Assuming that you share the same enthusiasm for epigenetics and things like the Barker hypothesis as I do, you can perhaps see that this might be an area ripe for some further investigation.

To finish, a bad moon rising... oh yeah, I see it now.

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* Whitehouse AJ. et al. Perinatal testosterone exposure and autistic-like traits in the general population: a longitudinal pregnancy-cohort study. J Neurodev Disord. 2012; 4: 25.

** Auyeung B. et al. Fetal testosterone and autistic traits. Br J Psychol. 2009; 100: 1-22.

*** Baron-Cohen S. The extreme male brain theory of autism. Trends Cogn Sci. 2002; 6: 248-254.

**** Baron-Cohen S. et al.  Is there a link between engineering and autism? Autism. 1997; 1: 101-109.

***** Auyeung B. et al. Prenatal versus postnatal sex steroid hormone effects on autistic traits in children at 18 to 24 months of age. Molecular Autism. 2012; 3: 17.

****** Geier DA. & Geier MR. A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders. Horm Res. 2006; 66: 182-188.

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Whitehouse AJ, Mattes E, Maybery MT, Dissanayake C, Sawyer M, Jones RM, Pennell CE, Keelan JA, & Hickey M (2012). Perinatal testosterone exposure and autistic-like traits in the general population: a longitudinal pregnancy-cohort study. Journal of neurodevelopmental disorders, 4 (1) PMID: 23110806

GcMAF, nagalase and autism

I think it might be worth starting this blog post with (a) reference to my very well-trodden caveat of not making any medical recommendations on this blog and (b) a little bit of a description of some of the key terms connected with the paper by Jeff Bradstreet and colleagues* (open-access) on nagalase, GcMAF and autism bearing in mind my amateur status in this area. I might also add, don't shoot the messenger.

I'm the big eater @ Wikipedia  

Macrophages. It all begins with monocytes, white blood cells produced in bone marrow from hematopoietic stem cells. Monocytes grow into different types of macrophages.

Macrophages, known as the big eaters of the immune system, are present in every cell of the body and include microglia (in the brain).

As part of their big eating duties, macrophages enjoy dining out on the odd invading pathogen or cell programmed for destruction as well as telling other immune cells what to do. A sort of Mr Creosote if you will (without the bucket). If you want the Star Wars version of macrophages (I'm not kidding) ... here you go (open-access).

Macrophages are activated by Gc-MAF (Gc Macrophage Activating Factor). The production of Gc-MAF is affected by nagalase (alpha-N-acetylgalactosaminidase) encoded by the gene NAGA. Nagalase affects the Gc protein (vitamin D3 binding protein) which has a knock-on effect blocking the production of Gc-MAF. The more nagalase activity, the less Gc-MAF is a rough-and-ready way to look at it. Less Gc-MAF equates as less macrophage activation according to this logic and some potential onward effects for immune function.

Why is it important? Well in cancer research, there is some preliminary chatter that tumors might be able to affect Gc-MAF function by way of altering nagalase activity (open-access)**. Such is the effect of increased nagalase and depressed Gc-MAF function that this has been put forward as a potential explanation of why cancers are able to 'avoid' the immune system and so develop unchecked. There is also some very preliminary evidence that giving supplemental Gc-MAF as an injection might affect cancer growth in animal models*** and human participants**** although this is still an area of some controversy given that one lab seems to be producing all the research.

So what's the logic of this area with autism in mind? I can't claim to be able to provide a definitive answer but one suggestion from press releases such as this one, are the reports of high levels of nagalase activity to be present in quite a few of the cohorts with autism looked at. Remember, nagalase negatively affects levels of Gc-MAF so potentially disrupting the activation of macrophages. Outside of malignant cells, there is a suggestion that elevated nagalase activity might be part and parcel of issues with immune function in cases of autism onwards to things like the presence of some kind of viral activity. Indeed this last point on viruses and nagalase I assume comes from other results on the use of Gc-MAF in the clearance of HIV infection***** bearing in mind replication is still required for this area of work.

So eventually we get back to the paper from Bradstreet and colleagues and in more detail:

• Described as a chart review, 40 participants with autism who sought testing for nagalase activity, pre- and post assessment of nagalase following Gc-MAF injections were followed.
• Diagnosis of participants was determined by having already received a DSM-IV diagnosis of autism independent of the study together with some in-house assessments on the severity of presentation.
• Blood draws signalled the start of the nagalase activity assessment which was shipped to a lab already versed in looking for the enzymatic activity. 
• Gc-MAF was injected on a weekly basis covering an average of 14 injections to get those macrophages stimulated, and nagalase activity assessed again.
• Results: nagalase activity was generally higher in the autism group than the various reference ranges cited by the assaying laboratory.
• Nagalase activity levels dropped in quite a few participants following Gc-MAF administration (24 of 40 decreased to within laboratory reference ranges) and "uncontrolled observations of GcMAF therapy indicated substantial improvements in language, socialization and cognition". Before we get too carried away though, lets remember those words "uncontrolled observations". 
• Importantly (very importantly) no significant side-effects were reported, bearing in mind reports of elevated body temperature occurred post infusion and words like "By the second month, no patients experienced significant febrile events" were used.
• The authors conclude that more research is required in this area.

OK. With the science hat on, one reiterates that this was a very, very preliminary case review and although Gc-MAF was "checked for sterility in-house and externally by the UK Health Protection Agency" apparently, this is still a compound under investigation and is still very experimental. I've not specifically made mention of Gc-MAF on this blog before this post. That being said, I have talked about nagalase in relation to some speculations on the now de-discovered work on XMRV and chronic fatigue syndrome (CFS).

There are some obvious questions raised from the findings reported by Bradstreet. So, assuming all that Gc-MAF does and how it apparently does it, the whole 'underactive immunity' side of autism comes into play. Indeed I'm immediately drawn back to the work by Harumi Jyonouchi and colleagues on SPAD and immunodeficiency detected in their cohort and the possible link with gastrointestinal (GI) dysfunction. That and the low IgA findings also observed on more than one occasion in cases of autism. Of course balancing all that with other findings indicative of other issues with immune function in cases of autism such as an overactive immune system and the whole autoimmunity side of things. I should perhaps also stress that I am not equating autism with HIV or cancer or anything else based on the description of these findings.

Perhaps just as important is the whole viral infection link being implied in some cases of autism by this work. I know this starts to take us into some quite uncomfortable territory with autism in mind as per the study by Mady Hornig and colleagues****** (including virus hunter Ian Lipkin) on a (mostly) lack of measles virus in reply to studies like the one from Kawashima and colleagues*******. I'm not really in a position to offer an expert opinion as to whether this is proof positive that specific viruses are or aren't involved in autism, over an above the multitude of viruses everyone comes across in a lifetime, albeit with an immune response in full working order and the focus being on autisms not autism. Think also back to that most classical autism-viral connection which looked at rubella******** quite a few years back. And then all those ancient remnants of viruses which we all carry in our genome and have been recently looked at with autism in mind and whether there are any connections to be made or not.

Irrespective of any controversy this might unearth - which I assume it probably will - the Bradstreet results are peer-reviewed results and hence worthy of further independent analysis. Perhaps Prof. Lipkin might once again step up to this task?

[Update: you may also want to have a look at the second time Gc-MAF has cropped up on the autism  research circuit too.]

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* Bradstreet JJ. et al. Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein—macrophage activating factor injections. Autism Insights. 2012. 4: 31-38.

** Korbelik M. et al. The value of serum alpha-N-acetylgalactosaminidase measurement for the assessment of tumour response to radio- and photodynamic therapy. Br J Cancer. 1998; 77: 1009-1014.

*** Yamamoto N. & Nataparaju VR. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor. Cancer Res. 1997 Jun 1;57(11):2187-92.

**** Yamamoto N. et al. Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Int J Cancer. 2008; 122: 461-467.

***** Yamamoto N. et al. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF). J Med Virol. 2009; 81: 16-26.

****** Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS ONE. 2008; 3: e3140.

******* Kawshima H. et al. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci. 2000; 45: 723-729.

******** Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977; 7: 69-81.

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James Jeffrey Bradstreet, Emar Vogelaar, & Lynda Thyer (2012). Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein—macrophage activating factor injections Autism Insights

Autism, stress and cortisol

Stress is something that everyone, young and old, faces on a daily basis. Partnered with anxiety, stress has become part and parcel of the dictionary of modern day living despite the fact that even in times gone by, I'm pretty sure stress and anxiety were just as rife as they are today, if only under a different set of circumstances.

The stress Father @ Wikipedia 

My own personal view of stress is that it can be a double-edged sword. Particularly in these austere times that we all find ourselves living through, stress has generally taken on the most negative of connotations despite the fact that stress can often have a more productive side when linked to things like motivation and indeed in evolutionary terms, the 'fight-or-flight' response; I believe it falls under the term 'eustress'. Indeed some quite recent research suggests that it is the control factor of stress that might be important over the amount of stress and the concept of behavioural immunisation (UK-spelling) against future stress.

In trying to define stress as something tangible, physiological and measurable, one of the more widespread markers is that of cortisol, a primary stress hormone released in response to stress but also tied into our circadian rhythms. Issues with the cortisol response to stress are often associated with disruption of the hypothalamic-pituitary-adrenal (HPA) axis.

Measuring cortisol with autism in mind, has produced some interesting results so far. The earliest paper that I've found which looked at cortisol and autism is surprisingly one that has already been covered on this blog from Mary Goodwin and colleagues* and their introduction to the gut-brain axis as potentially being important in at least some cases of autism. I'm sorry that I can't link to the full-text of the Goodwin paper (which I recently mentioned in another piece on leaky gut and autism) but suffice to say that their initial measurement of plasma cortisol levels in autism vs. siblings was nothing to write home about. That being said, they did report some interesting findings based on supplementation with 1g of gliadin which "markedly decreased blood cortisol levels and abolished the normal circadian cortisol rhythm" in children with autism and their siblings. Food for thought bearing in mind that whole opioid-food-autism research and what opiates might do to cortisol levels.

Other research has reported other results when comparing autism with not-autism (and not siblings of children with autism either) as per papers like this one from Corbett and colleagues** (open-access) and this one from Kidd and colleagues***. These and other results suggesting that the usual patterns of cortisol were perhaps not followed in some cases of autism, alongside a heightened cortisol response as a reaction to novel stressor situations compared to not-autism.

Keeping in line with the autism-cortisol relationship I want to talk a little bit more about that paper from Kidd and colleagues as well as another paper published by Spratt and colleagues**** (open-access). A brief summary of both first:

Kidd paper:

• Comparing 26 children (mean age = 45 months) diagnosed with autism and confirmed by ADOS and ADI with 26 asymptomatic children  (mean age = 39 months), salivary cortisol and alpha-amylase (sAA) were measured 3 times a day over 2 consecutive days at three testing points (baseline, 3 and 6 months).
• Looking at both cortisol and sAA across the day (waking, midday, bedtime), mean levels were higher in the autism group than controls across each period although not significantly so.
• When participants with autism were divided into groups based on 'functional IQ status', those categorised as extremely low functioning children (authors words not mine) consistently presented with an elevated cortisol response across the day (although again, not significantly different from other functioning groupings). 

Spratt paper:

• Comparing 20 children with autism (mean age = 84 months) with 28 asymptomatic controls (mean age = 66 months), various measures of cortisol were analysed based on collection in urine, saliva and plasma (the blood draw for plasma cortisol analysis also serving as a stressor event too).
• Results: first production morning urine samples analysed for cortisol revealed no significant mean difference between the groups, although urinary cortisol levels were higher in the autism group taken as whole.
• Serum concentrations of cortisol were however significantly different between the groups (p=0.014). 
• Salivary cortisol showed some interesting trends in that, although presenting with a higher initial mean level of cortisol, the autism group did not differ significantly from controls at first testing prior to the blood draw stressor. That all changed following the next salivary cortisol test period 20 minutes after the blood draw, where the autism group registered a significantly elevated cortisol reading compared with controls. Indeed with the final salivary cortisol reading taken 40 minutes after the blood draw, the control group had already dipped below their baseline measurement, whereas the autism group as a whole remained elevated compared with their original baseline.
• Gender nor other items based on specific psychometric measures showed any significant correlation to  cortisol levels although there were some suggestions of links between the various testing medium (saliva, plasma, urine) at various periods of testing.

Based on these papers, one could surmise a few things:
(a) children with autism may present with an overall increase in cortisol levels, although not necessarily significantly outside the range seen in asymptomatic children,
(b) the effect of a novel stressor (novel insofar as children don't generally take part in blood draws everyday) seemed to correlate with a greater elevation in cortisol levels in cases of autism, and
(c) the regulation of stress, as in the stressor has passed and so cortisol levels should drop, seems to be affected in cases of autism, leaving a persistence of the stress state as per the findings of another study***** (open-access). Issues with habituation? I dunno.

Such important findings reported on cortisol and autism might potentially [and partially] explain some of the more debilitating aspects to the condition such as issues with responses to new and novel situations outside of those expected (the so-called repetitive behaviours domain) and maybe even the rates of anxiety that often accompany a diagnosis of autism. The implications resulting from an unusual pattern of production of glucocorticoids like cortisol noted in autism might also have some interesting links back to things like immune function too. Dare I even suggest a potential tie-in with findings related to things like hypertension too? How about something similar to that noted in depression with stress affecting neurogenesis?

Assuming some role for stress and the cortisol response to cases of autism, the final question should really be what can be done to mitigate its effects? Many parents and professionals have talked about routines and the various ways of planning for events and functions which might take a person with autism outside of their comfort zone as per things like trips to the doctors or even dentists. There's even been some speculation that dog ownership might positively affect the stress response in cases of autism, highlighting yet another effect from the pets win (prosocial) prizes potentially also following the Jedi massage route. It might also sound a little out of left field but I'm taken back to the work  by Julia Rucklidge and colleagues on micronutrients and stress (after earthquake) and whether or not similar mechanisms and modes of action might also pertain to autism? How about looking to control our bacterial masters too?

To conclude, it is rather quiet here, how about something a little big band from Iceland?

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* Goodwin MS. et al. Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. J Autism Child Schizophr. 1971; 1: 48-62.

** Corbett BA. et al. Variable cortisol circadian rhythms in children with autism and anticipatory stress. J Psychiatry Neurosci. 2008; 33: 227–234.

*** Kidd SA. et al. Daytime secretion of salivary cortisol and alpha-amylase in preschool-aged children with autism and typically developing children. J Autism Dev Disord. April 2012.

**** Spratt EG. et al. Enhanced cortisol response to stress in children in autism. J Autism Dev Disord. 2012; 42: 75-81.

****** Corbett BA. et al. Comparing biobehavioral profiles across two social stress paradigms in children with and without autism spectrum disorders. Mol Autism. 2012; 3: 13.

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Spratt EG, Nicholas JS, Brady KT, Carpenter LA, Hatcher CR, Meekins KA, Furlanetto RW, & Charles JM (2012). Enhanced cortisol response to stress in children in autism. Journal of autism and developmental disorders, 42 (1), 75-81 PMID: 21424864

Immune function: a critical role in autism?

The headline to this post is not my own but rather taken from the conclusions of the study published by Vishal Saxena and colleagues* (open-access) who undertook some computational analyses of some of the various genomic findings detailed in cases of autism spectrum disorders (ASDs).

Rather than me bore you with all the details of their study, I'll instead refer you to the ScienceDaily entry for this study (see here) which gives a far better overview than I possibly could. In essence it all boiled down to systems biology (looking at genes and their various pathways) and the application of something called Linkage-ordered Gene Sets (LoGS) which "takes pre-existing gene sets and ranks them in terms of their importance in autism".

As per their paper and the accompanying press release suggest, genes involved in immune function featured heavily in their results. In particular was the suggestion of some involvement for genes related to cytokine activity (see this post), the interferons (see this post) and the genetics of virus response (see here). Also appearing in the top 20 pathways turned up was an old friend, glutathione transferase activity, which one has to wonder might fit in with some other results on glutathione and autism which were published in recent months (see here and here). Just speculating...

There's other possibilities arising from the data produced by Saxena et al, some of which the authors start to discuss with reference to things like autoimmunity, which at least one of the co-authors has kinda hinted at before in the famous "significantly over-represented" paper discussed not so long ago. That and mention of the words "in-utero infections" and "mouse models of autism" which 'might' take us back to the work of Paul Patterson and colleagues (see here).

Regular readers might know that I'm not exactly enamoured by the results of the multitude of genetics studies which have been completed with autism in mind given both the heterogeneity of the condition and also the seeming lack of appreciation that autism does not exist in a vacuum but instead might significantly elevate the risk of other conditions co-occurring. As we also found out recently, we all carry quite a few mutations around with us, whether diagnosed with autism or anything else and even those don't necessarily mean anything. That and the rise of epigenetics... What I am however drawn to in this paper is the focus on the 'bigger picture' outside of just genes encoding for one protein; as the study authors put it in terms of pixels and zooming out. The question now is: who are these results most pertinent to on the autism spectrum and is this yet more evidence for the autisms?

But enough for now, aside from a final quote from the paper: "The results presented in this paper show that immune function may play a critical role in the genesis, development, or manifestation of autism". Who am I to argue?

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* Saxena V. et al. Structural, genetic, and functional signatures of disordered neuro-immunological development in autism spectrum disorder. PLoS ONE. 2012; 7: e48835.

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Vishal Saxena, Shweta Ramdas, Courtney Rothrock Ochoa, David Wallace, Pradeep Bhide, & Isaac Kohane (2012). Structural, genetic, and functional signatures of disordered neuro-immunological development in autism spectrum disorder PLoS ONE

The eyes have it for autism?

Twenty-twenty @ Wikipedia 

There were a few reasons why I wanted to talk about the paper from Ikeda and colleagues* on ophthalmologic (eye) disorders noted in cases of autism.

First and foremost is my continued, unwavering, interest in all things comorbidity with autism in mind. Probably the next reason was the quite astonishing rate of ophthalmologic disorder reported by Ikeda, in "40% of patients with autism or a related disorder".

A final reason? Well without wishing to plug anyone, a friend of mine is making some waves in this whole area of vision and perception and he's talked quite a bit about the value of appropriate eye examinations for people with autism and lots of related developmental conditions, partly so as not to reflect yet another health inequality.

Indeed having very recently seen him lecture again and talk about problems with vision, face perception and descriptions of eyes, nose and mouth seemingly not being where they were supposed to be alongside faces morphing into animals and vegetables, I'm more convinced than ever about the value of looking at vision processing for some cases of autism and other conditions too.

During a past post titled: Do you see what I see? I talked about the sensory and perceptual link to autism and how even the proposed revisions to the DSM V description of autism spectrum disorders have recognised just how important issues with visual, auditory and other sensory modalities might be to cases.

The Ikeda paper is slightly different insofar as they were looking for specific issues with the eyes following a retrospective review of their caseload.

The main points:

• Based on a total cohort of 407 pediatric attendees diagnosed with an autism spectrum disorder at a medical centre, a chart review revealed that 154 had documentation pertaining to an ophthalmologic examination by a suitably qualified person.
• Most children were male, white and diagnosed with mild/moderate autism. Over half of the children (57%) "presented with an eye-related concern" in the majority noted by parents.
• Results: only 40% of the cohort were cooperative for recognition visual acuity testing (the well-know eye chart test) and of those other 60% not cooperative, upwards of a third were found to have an ophthalmologic disorder. 
• That original 40% quote used in the beginning of this post included a variety of ophthalmic issues, many of which I can't even pronounce never mind give you detailed information about. The main issues were: strabismus (irregular aligning of the eyes) (21%) and "significant refractive errors" including hyperopia (long-sightedness) and myopia (short-sightedness) as being primary.
• Other less commonly described conditions include: nystagmus (voluntary or involuntary eye movements) and ptosis (a drooping or falling of the eyelid), and something linked to the autoimmune neuromuscular condition myasthenia gravis.

There are a few quite important points of discussion to take from this work and some other related study. Aside from reiterating the percentage of children with autism with verifiable issues with their eyes and vision (40 PERCENT), the point made about those who were least cooperative during examination carrying quite a high burden of ophthalmologic disorder is a worrying trend. That coupled with other data from this study on the role of comorbid intellectual disability (ID) also potentially being a risk factor for eye problems, really does make you sit up and think. I'm not for one minute suggesting that those in the uncooperative category are somehow cajoled into undertaking an eye examination (indeed whether it would be possible) but certainly the onus might be on the clinician and other professionals to engage in a little creative thinking about how uncooperative participants can be more readily catered for.

There is also a question about the relationship between ophthalmologic disorders and some of the various perceptual issues reported in cases of autism. Again my lack of expertise in this areas shines through as I cannot readily say whether issues like strabismus might have the potential to impact on visual perception or indeed whether some kind of cognitive correction might be at work**. I assume like everything, there is probably going to be a degree of individuality to such eye issues and any adaption made or not where timing might also be an important factor.

Meandering (a lovely word!) through the other research on ophthalmologic disorders and autism, there seems to be snippets of information about for example, various genetic conditions manifesting eye disorders and autism (see this paper by Strömland and colleagues*** for example). Such papers pose some interesting questions about whether within the autisms spectrum (plural again), there may be cases whether eye anatomy and physiology might share underlying issues (genetics, epigenetic or environmental) with the appearance of autistic characteristics**** in the same way that some people get quite excited about facial phenotypes and autism.

"Just one last thing"... I also chanced upon an interesting case series described by Pineles and colleagues***** (open-access) on something called vitamin B12 optic neuropathy presenting in cases of autism. I've kinda touched upon vitamin B12 and methlymalonic acid (MMA) issues appearing in autism in a previous post. Pineles et al suggest that a deficiency in vitamin B12 might indeed be an important correlate for things like decreased visual acuity in some cases of autism. This in itself asks a few further questions about why such deficiency might be present and indeed whether there may be some good reasons to look more closely at vitamin supplementation (thinking back to Jim Adams' study) where certain eye problems might be present as a comorbidity.

Oh, and I assume you have seen this paper?

To close, always remember Apollo Creed and the Eye of the Tiger. Respect.

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* Ikeda J. et al. Brief report: Incidence of ophthalmologic disorders in children with autism. J Autism Dev Disord. February 2012.

** Economides JR. et al. Perception via the deviated eye in strabismus. J Neurosci. 2012; 32: 10286-10295.

*** Strömland K. et al. Oculo-auriculo-vertebral spectrum: associated anomalies, functional deficits and possible developmental risk factors. Am J Med Genet A. 2007; 143A: 1317-1325.

**** Miller MT. et al. The puzzle of autism: an ophthalmologic contribution. Trans Am Ophthalmol Soc. 1998; 96: 369-385.

***** Pineles SL. et al. Vitamin B12 optic neuropathy in autism. Pediatrics. 2010; 126: e967-e970.

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Ikeda J, Davitt BV, Ultmann M, Maxim R, & Cruz OA (2012). Brief Report: Incidence of Ophthalmologic Disorders in Children with Autism. Journal of autism and developmental disorders PMID: 22350452