Canada and the autism prevalence rate continued

So, in my last post this morning I was talking about the paper by Hélène Ouelette-Kuntz and colleagues* on the autism numbers game in various regions of Canada. Thanks to Natasa, I now have the full-text of the paper and just wanted to pass some further comments on the findings reported and potentially how important they might be.

• OK, three regions in Canada were scrutinised based on the NEDSAC initiative for cases of autism: Newfoundland and Labrador (2003-2008 period), Prince Edward Island (2003-2010) and Southeastern Ontario (2003-2010) and a total of 2377 cases of autism were identified across various age groups (2-5 years, 6-9 years, 10-14 years). Response rates - to get more detailed information about the children identified with an autism spectrum disorder (ASD) - per region were not exactly great but ranged between 32% and 45%.
• The prevalence of autism "increased significantly among all age groups" over the various surveillance periods. There were however some variations across the different regions such that for example, prevalence in the age group 2-5 years old in Southeastern Ontario did show something like a plateau in the later years of study. The authors however do not rule out "incomplete capture of preschool children with autism" as accounting for their results there. Indeed Southeastern Ontario was reported to also have contributed a "larger proportion of false positive" diagnoses based on some small-scale case validation investigation using ADOS or ADI as the standards which may also have accounted for some of the final figure they report.
• Age of diagnosis and the issue of diagnostic delay are covered in the data presented. Another quote: "in all three regions many children were not diagnosed until they were older". So much for the practical application of all those 'catch 'em early' sentiments.
• The authors pass comment on the issue of age at diagnosis as affecting any prevalence estimates using the Parner paper** as an example and the suggestion that a younger age at diagnosis would artificially inflate the prevalence rate for that age group. Allowing for potential bias in the reporting of age at diagnosis they concluded: "it does not appear that an earlier age at diagnosis contributed in any meaningful way to prevalence increases in the youngest age group".
• The sex ratio also came under scrutiny. Interestingly that Icelandic study*** also looking at autism prevalence rates which I mentioned in my last post seemed to take an interest in one of my studies on the topic (see here****). The Icelanders decided that their results did not accord with our own where we talked about an widening gap in the gender ratio towards boys over the years. The Canadian study reported that "the boy:girl prevalence ratio increased between the first and final years of the surveillance period". Indeed in one region Prince Edward Island the ratio went from 3.7:1 in 2003 to 6.7:1 in 2010 (peaking at 6.9:1 in 2009). I'm don't want to say too much about this for now bearing in mind all the possible confounders which could account for results, but certainly if I were an official based somewhere in Prince Edward Island I'd be minded to ask a few questions about the hows and whys of these findings. 
• The authors admit that the various explanations they've looked at as accounting for the increase in cases "appeared to account for only a small portion of the increases observed". In other words, the numbers are going up but to say that it is better awareness or just that kids are being diagnosed earlier or that it is diagnostic reclassification (which doesn't really cover the period of this study in terms of DSM or ICD changes for example) doesn't really cut the mustard when looking at the size of the increase they uncovered. I'll leave you to determine what else might be able to account for the increase they reported.

I'll finish by reiterating that the autism numbers game is a complicated area. One has to be careful not to make too many sweeping generalisations on how figures, and the potential reasons for those figures, in one area are necessarily representative of autism prevalence in all other areas. 

That being said, the Ouelette-Kuntz paper does perhaps indicate that we should perhaps be widened the debate about why autism is on the rise above and beyond the notion that we're just better at finding it. Yes, there are factors like socio-economic status (SES) to consider but dare I even mention that we might also start to take seriously how environment (however you wish to define this) might also be impacting on the numbers of cases being diagnosed and indeed the concept of gene - environment interactions***** (open-access)?

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* Ouellette-Kuntz H. et al. The changing prevalence of autism in three regions of Canada. J Autism Dev Disord. 2013 Jun 16.

** Parner ET. et al. A comparison of autism prevalence trends in Denmark and Western Australia. J Autism Dev Disord. 2011 Dec;41(12):1601-8. doi: 10.1007/s10803-011-1186-0.

*** Saemundsen E. et al. Prevalence of autism spectrum disorders in an Icelandic birth cohort. BMJ Open. 2013 Jun 20;3(6). pii: e002748. doi: 10.1136/bmjopen-2013-002748.

**** Whiteley P. et al. Gender Ratios in Autism, Asperger Syndrome and Autism Spectrum Disorder. Autism Insights. 2010:2 17-24.

***** Chaste P. & Leboyer M. Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci. 2012 September; 14(3): 281–292.

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Ouellette-Kuntz H, Coo H, Lam M, Breitenbach MM, Hennessey PE, Jackman PD, Lewis ME, Dewey D, Bernier FP, & Chung AM (2013). The changing prevalence of autism in three regions of Canada. Journal of autism and developmental disorders PMID: 23771514

Canada and the autism prevalence rate

[Update: 01/07/13: Further discussion on this topic can be found here].

The autism numbers game has been a long running discussion in many quarters. Even with estimates now suggesting that anywhere between 1 in 88 children or 1 in 50 children (or 1 in 57 if you prefer) in the United States (depending on who and how you count) might present with an autism spectrum condition, arguments still rage about the hows and whys, often over and above the question: 'what are we going to do about it'.

Waterloo Bridge @ Wikipedia 

I'm sitting on the fence a bit about why the numbers are increasing as they are. I appreciate that we are better at detecting autism than we were 30 or 40 years ago and all the related opinions about changes in diagnostic schedules (see here) and reclassification from other conditions in favour of the autism spectrum. There is little doubt that these factors exert an effect and are probably going to be significant ones.

Having said that though I'm not yet ready to give up on the idea that some of the increase in cases is due to other factors including being representative of a true and real increase in cases. My reasoning for this opinion is multi-faceted but includes the fact that we have, at least in the Western world, more than adequate provisions for the detection of [pediatric] autism and to say that its all about reclassification or awareness really brands our autism diagnosticians as being pretty incompetent over the years. They're not by the way; indeed they do a sterling job often in very, very difficult circumstances. What I should also point out is that the reasons for the increase might not necessarily be the same for every part of the world.

Just before also you tell me there is no evidence that the incidence - not prevalence - of autism is increasing, I beg to differ as per some of my previous posts which can be seen here and here. Indeed this leads into an interesting paper that has recently appeared by Hélène Ouelette-Kuntz and colleagues* on the prevalence rate of autism in several regions in Canada which forms the topic of this post.

I'll admit to not having the full-text of the Oueltte-Kuntz paper so you might need to do some further fact-checking on any conclusions that I reach. Actually, the chances are that I'm probably not going to reach any conclusions on the paper so maybe this is a moot point.

The first thing that we do get from the abstract to the paper is that based on an analysis of data from the National Epidemiologic Database for the Study of Autism (NEDSAC) (yes same author) autism prevalence is increasing in this study. That increase in annual prevalence ranges from 9.7% up to 14.6% I assume because of the differing prevalence rates among the different regions of Canada the study authors looked at.

The next thing to glean from the abstract are some of the reasons put forward to account for the increase: previously unidentified cases being identified and the issue of "in-migration" which concerns movement between regions of the same country/territory.

Finally, a quote: "we cannot rule out the possibility of a true increase in incidence, particularly given the lack of a leveling-off of prevalence among the 6- to 9-year olds". In other words, the door is still open to a 'real' increase in cases being contributory to the numbers.

I'm sure the arguments will continue about the hows and whys of the autism numbers game. One thing is abundantly clear from most of the emerging data: autism is fast becoming a 'common condition' as per another recent report on the autism numbers game from Evald Saemundsenand and colleagues** (open-access) and a particularly interesting table. As we stand at the moment, we don't really know all the reasons why and what to do about it.

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* Ouellette-Kuntz H. et al. The changing prevalence of autism in three regions of Canada. J Autism Dev Disord. 2013 Jun 16.

** Saemundsen E. et al. Prevalence of autism spectrum disorders in an Icelandic birth cohort. BMJ Open. 2013 Jun 20;3(6). pii: e002748. doi: 10.1136/bmjopen-2013-002748.

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Ouellette-Kuntz H, Coo H, Lam M, Breitenbach MM, Hennessey PE, Jackman PD, Lewis ME, Dewey D, Bernier FP, & Chung AM (2013). The changing prevalence of autism in three regions of Canada. Journal of autism and developmental disorders PMID: 23771514

Antibiotics and autism: a case study

OK you got me.

Another case study of autism is being discussed in this post. It's not that I'm moving away from good ole' evidence-based medicine - double-blind, placebo-controlled group studies like this one if you please - but rather that as I've discussed before, there is often merit in looking at autism from the N=1 perspective. After all, it is a heterogeneous condition and we have all that 'autisms' chatter of late (see here) coupled with some elevated risk of comorbidity (see here). Indeed why else would medicine still enjoy the odd case report or two more generally?

Go fish @ Wikipedia  

The case study in this case(!) is reported by P. Lucas Ramirez and colleagues* (open-access) and concerns an interesting outcome following the use of antibiotic therapy for a young man diagnosed with autism.

I have, as it happens, covered the potentially double-edged sword that is antibiotics and autism in a previous post (see here) alongside some discussion on specific preparations with autism in mind (see here). The whole gut bacteria side of things comes into play in the Ramirez paper given the reasons why antibiotic therapy was initiated (encopresis) and the subsequent results of a stool analysis.

A few points of note:

• Whilst antibiotics were the name of the game, there is some interesting history about this particular young man with autism and his dietary history focused on the use of a gluten- and casein-free diet. Those who follow the autism research scene will probably have come across some recent interest in the whole autism-diet link as per the paper by Nga Lau and colleagues (see here) on immune reactivity to gluten (see here also). In this case, there was the 'suggestion' that diet might have impacted to some degree on various core and other facets of this chap over the years.
• So: "A ten-day course of metronidazole and a subsequent twenty-day course of ketoconazole were prescribed for management of the Clostridium spp. and G. klebahnii, respectively". Clostridia has already been talked about (quite a few times) with autism in mind. Geotrichum klebahnii is not something I'd come across before so I can't really say too much about it.
• Suffice to say that alongside some bowel-related effects, positive effects following antibiotic therapy: "Parental reports indicated that his aggressive and self-injurious behaviors significantly improved and his self-stimulatory behaviors decreased dramatically during the course of the treatment".
• Alas, the completion of the antibiotic / anti-fungal course did not herald a major permanent shift in the presentation of behaviour for this young man as per the reports of a regression in his behaviour after antibiotics had finished.

I find this to be an interesting case report. Not least that the report of 'doing well' on antibiotics / anti-fungals was followed by a return of behavioural symptoms after course completion in line with other reports of antibiotic therapy such as that of Sandler and colleagues**. You might argue that there was some kind of placebo effect from the antibiotic use but I have to say that I have some issues with the suggestion that the presentation of aggression and self-injury would be so fundamentally altered. Indeed when one hears that aggression and SIB between cycles of treatment included things like "breaking a teacher’s nose with a head butt, and breaking the rear windshield of a vehicle by head banging" I have to say that I'm not convinced that the placebo effect would be so effective as a sole explanation. Of course, if science wanted to prove me wrong, there is a placebo-controlled study waiting to be done there....

Insofar as the fungal connection and any effect this might have had with regards to symptoms, I'm not going to make too much of this at the present time. I note that Julia Rucklidge, she of the vitamins after earthquake research, has asked a similar question of late with yet another case report about whether yeast infection could "impair recovery from mental illness"***. Without trying to approximate autism with mental illness (they are not the same), the common denominator is the effect of such bacterial or fungal beasties on overt behaviour. Indeed Rucklidge presents an interesting hypothesis about how certain fungal elements might impair nutrient absorption and onwards what effect this might have on behaviour; which as far as I can see could easily also be asked about autism too.

I know that for some the report by Ramirez is going to be of little interest; a fluke and nothing more than correlation and association perhaps even with a dash of controversy around one of the authors and some previous monkey business****. So be it. What perhaps should be taken into consideration is that at least the presentation of encopresis for this young man was taken seriously and not just put down to that old chestnut - 'it's all part of the autism'. That and reiterating what effects gastrointestinal / bowel symptoms can have for a person with autism and all that potential gut-brain axis stuff that I seem to keep going on about.

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* Ramirez PL. et al. Improvements in Behavioral Symptoms following Antibiotic Therapy in a 14-Year-Old Male with Autism. Case Reports in Psychiatry. 2013: 239034.

** Sandler RH. et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000 Jul;15(7):429-35.

*** Rucklidge JJ. Could yeast infections impair recovery from mental illness? A case study using micronutrients and olive leaf extract for the treatment of ADHD and depression. Adv Mind Body Med. 2013 Summer;27(3):14-8.

**** Hewitson L. et al. Influence of pediatric vaccines on amygdala growth and opioid ligand binding in rhesus macaque infants: A pilot study. Acta Neurobiol Exp (Wars). 2010;70(2):147-64.

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Ramirez, P., Barnhill, K., Gutierrez, A., Schutte, C., & Hewitson, L. (2013). Improvements in Behavioral Symptoms following Antibiotic Therapy in a 14-Year-Old Male with Autism Case Reports in Psychiatry, 2013, 1-2 DOI: 10.1155/2013/239034

What does autism with mitochondrial dysfunction mean?

I don't mind admitting that I'm a little bit baffled by mitochondrial function. Yes, I know all about the 'powerhouse' label which they have been given. But still, it's a topic which confuses me quite a bit.

Masquerade - Beardsley @ Wikipedia 

With autism in mind, I've skirted around the edges of the growing literature suggestive of some mitochondrial dysfunction being present in cases (see here and here) but to be honest it's always seemed a little bit too big of an area for me to tackle. That and the fact that some authors have already written some pretty good (peer-reviewed) review papers on the topic as per the example of Rossignol & Frye* (open-access) and Frye & Rossignol** (open-access) (yes, the same authors).

Indeed it is with the name Dr Richard Frye that I'm talking today about a new paper of his*** (open-access) published in what seems to be a favourite journal, Translational Psychiatry (that and its sister journal, Molecular Psychiatry). The latest offering with possibly the longest abstract I've seen in a while looked at a group of children diagnosed with an autism spectrum disorder (ASD) "who met criteria for probable or definite MD" [MD = mitochondrial disease] to see whether there was any tie-in with another interesting area of autism research looking at abnormal redox metabolism and all that oxidative stress work.

This is quite a big paper in terms of the wealth of data which has been included. Quite a lot of it goes well above what I would consider myself comfortable with explaining so you'll have to excuse me if I use quite a few quotes and perhaps skip over certain reported findings. The paper is open-access so please do read it.

Data are presented from 18 children who fitted both the autism and MD bill compared with 18 kids with autism but no MD. Immediately I'm struck by the focus on a specific subgroup of the autisms which is definitely the way ahead for autism research. Bearing in mind the small participant numbers and although there were some differences on things like the VABS, the groups were fairly consistent when it comes to the presentation of autistic behaviours and language abilities. Most of the differences (significant differences) were noted in the biochemistry looked at, and not exactly the way most people would have figured.

So for example, when it came to that elephant in the room that is glutathione and autism, there were indications of a "more favourable glutathione redox status in the ASD/MD group" as a function of the balance between reduced and oxidised levels (see here). Bearing in mind though that when compared with an asymptomatic control group - typically developing controls - both the MD and non-MD autism groups were quite a bit below what the glutathione balance should have been which accords with other work.

I was interested also to see that 3-chlorotyrosine (3CT), a marker of chronic inflammation was also looked at in the latest study. 3-CT was discussed in another Frye paper on another pet topic of mine, tetrahydrobiopterin or BH4 talked about recently with autism in mind (see here). A long quote: "Both ASD groups demonstrated significantly higher 3CT levels than control subjects, suggesting that chronic inflammation was present in both groups of children with ASD". Irrespective of the MD side of things, this finding in particular is of potentially real interest to autism research.

Levels of another compound "3-nitrotyrosine (3NT), a biomarker of oxidative damage to proteins" were also tied into a few interesting findings between and across the groups examined. Again perhaps slightly counter to what would be expected was the suggestion that higher levels of 3NT "were associated with more favourable adaptive behaviour, language and ASD-related behavior". Again I was drawn back to another study from this authorship group suggesting 3NT was a feature of post-mortem brain specimens linked to autism (see here).

So as not to get you and I even more confused I'm moving to some of the paper conclusions. That for example, there is more uniting the autism-MD and autism non-MD groups than which divides them is perhaps not so surprising. Another quote: "both ASD groups manifested abnormal redox and immune metabolism, but in slightly different ways".

The issue of inflammation as a consequence of those 3CT levels being elevated in autism cases is really interesting. The authors cover this point well by speculating that the chronological age factor in this relationship (younger children presented with higher levels) is potentially reflective of early life inflammation triggering a cascade of events which "initiated the mitochondrial dysfunction and damage". The speculation continues that even though the inflammatory issues become 'resolved' as children get older, the mitochondrial damage remains. I'm intrigued at this notion of how specific biological events might appear during a window of infancy and development but not necessarily persisting yet leaving a lasting impression. That and the very preliminary evidence talking about markers of inflammation in mums of children with autism (see here) asks some interesting questions about the value of functional here-and-now testing if the 'damage has already been done'.

I've not done justice to the Frye paper in this post simply because I freely admit that I don't understand all of it. To the question which forms the title of this post about what MD might mean to autism, I'm minded to say quite a bit but not necessarily as centrally as we might have first thought. Perhaps also encompassing quite a bit of other research as per some other recent results on tryptophan metabolism in relation to autism**** (open-access) and quote: "Our findings support a possible mitochondrial dysfunction as a result of impaired tryptophan metabolism in cells from patients with ASDs". That and endorsing their idea that 'compensation' is an attribute of our wonderfully engineered bodies that we would do well not to forget about.

To close, I've talked about the Richard Linklater film 'Dazed and Confused' before on this blog. I'm going to leave you with another classic featured in the film.... Rock and Roll All Nite by a group with a very famous tongue.

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

** Frye RE. & Rossignol D. Mitochondrial physiology and autism spectrum disorder. OA Autism. 2013; 1: 5.

*** Frye RE. et al. Redox metabolism abnormalities in autistic children associated with mitochondrial disease. Translational Psychiatry 2013; 3: e273. doi:10.1038/tp.2013.51

**** Boccuto L. et al. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism. 2013 Jun 3;4(1):16. doi: 10.1186/2040-2392-4-16.

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Frye, R., DeLaTorre, R., Taylor, H., Slattery, J., Melnyk, S., Chowdhury, N., & James, S. (2013). Redox metabolism abnormalities in autistic children associated with mitochondrial disease Translational Psychiatry, 3 (6) DOI: 10.1038/tp.2013.51

Immune reactivity to gluten in autism

When I first saw the paper from Nga Lau and colleagues* (open-access) looking for markers of gluten sensitivity and/or coeliac (celiac) disease in children with autism I have to admit to raising a smile. I smiled because in a previous post on this blog I talked about a 'wish-list' for autism research specifically focused on the gluten and casein-free dietary intervention**. Part of that wish list was some further inquiry into why, biochemically, some people on the autism spectrum might benefit from dietary intervention. My prayers it seems have started to be answered.

Smiler @ Wikipedia  

When it comes to the area of dietary intervention for conditions like schizophrenia (no really), there seemed to be a lot more enthusiasm for looking at why some cases of schizophrenia might overlap with dietary issues over investigations into autism. I can't pretend to know why schizophrenia research took the lead; maybe something to do with Dohan and his original discussions on diet and schizophrenia or that schizophrenia research has some very talented people like Emily Severance and colleagues (see here and here and here) taking an interest. One might also speculate that some of the politics of autism - diet, gastrointestinal (GI) issues = (see here) - might also creep into this lack of autism research interest too? Who knows.

No mind, Lau et al did look at immune reactivity to gluten (or rather a fraction of gluten called gliadin) in a group of children with autism (n=37) compared with their asymptomatic siblings (n=27) and typically developing controls (n=76). They looked for anti-gliadin antibodies (IgA and IgG). They looked for antibodies to deamidated gliadin (that is where gliadin has already been subjected to some kind of enzymatic modification). They looked at antibodies to tissue transglutaminase (tTG). They even examined HLA genotype for the DQ2 and DQ8 haplotypes (linked to the genetics of coeliac disease). All in all, the primary bases were covered.

Results: well, the serum samples all came from AGRE - the Autism Genetic Resource Exchange - so no quibbling about the diagnosis of autism. They also subdivided the autism group up into those with GI symptoms and those without and remarked on those who were following a gluten-free diet too.

The authors report that levels of IgG anti-gliadin antibody were elevated in the autism group compared to siblings and controls. This differences lasted even when certain confounders such as age, gender and race were taken into account and the calculated odds ratio of an having an elevated IgG antibody levels to gliadin was not to be sniffed at either (OR 4.97; CI 1.39 - 17.8). That being said, there was cross-over between the relatively small participant groups and levels of IgA antibody to gliadin were not significantly different between the groups. Very interestingly, the presence of comorbid GI symptoms appearing alongside autism seemed to be linked to that elevated IgG antibody response to gliadin compared with no comorbid GI symptoms.

Just short of 50% of the children with autism were "positive for HLA-DQ2 and/or -DQ8 (6 DQ2, 12 DQ8)". I probably didn't explain this well, but a significant proportion of people with coeliac disease carry these haplotypes which all relates back to the almighty MHC and antigen presentation (see here for explanation).

Insofar as the other parameters on antibodies to deamidated gliadin and tTG, there was little difference to write home about. Although not wholly relevant, I'll refer you back to some interesting work down on tTG with autism in mind from a while back (see here).

A few choice quotes from the authors: "The findings indicate that the observed anti-gliadin immune response in patients with autism is likely to involve a mechanism that is distinct from celiac disease, without the requirement for TG2 activity or antigen presentation through DQ2/DQ8 MHC molecules". Well, we know that coeliac disease, when it is tested for in cases of autism, is probably not greatly over-represented in ASD despite some interesting evidence (see here). The Lau study kinda confirms that fact. But.... with all the talk about non-coeliac gluten sensitivity which has surfaced over the past few years (see here and here) one has to wonder whether for some on the autism spectrum, a similar mode of action might pertain outside of the more classical coeliac serology and markers?

It's interesting also that the authors talk about issues like the potential cross-reactivity of gluten as one implication of their findings. I'm taken back to the work of Ari Vojdani and colleagues*** on this matter. Oh and those Emily Severance findings about critters like T.gondii mixing it up with gluten reactivity (see here). I'm not necessarily saying that everyone with autism who presents with gluten antibodies has been in contact with the gondii but merely that the infection connection is an interesting one as per all that autoimmunity chatter with autism in mind.

It's interesting too that the authors also make mention of intestinal permeability as potentially being a factor to be looked at further. I know some people still look on things like 'leaky gut' as being the stuff of tree-huggers, but the evidence is growing for some effect in cases of autism (see here) with the promise of more investigations to come (see here for the Paul Patterson mouse work and here for a video from everyone's favourite autism - gut specialist researcher, Alessio Fasano).

Whilst I am pretty buoyed by seeing that this area is starting to get some research interest, I'm containing my excitement for now. It's still a long haul from gluten antibodies to suggesting that gluten may 'cause' or 'exacerbate' a complex set of conditions like the autisms even with all that gut-brain chatter which I'm certainly guilty of elevating. But due credit where it is deserved, at least Lau and colleagues have started asking some questions about this interesting area of autism research and the potential links with diet....

To finish, how about a song about Alejandro? (something for everyone in that video...)

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* Lau NM. et al. Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS ONE 8(6): e66155. doi:10.1371/journal.pone.0066155

** Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2013; 6: 344.

*** Vojdani A. et al. Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci. 2004 Jun;7(3):151-61.

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Lau, N., Green, P., Taylor, A., Hellberg, D., Ajamian, M., Tan, C., Kosofsky, B., Higgins, J., Rajadhyaksha, A., & Alaedini, A. (2013). Markers of Celiac Disease and Gluten Sensitivity in Children with Autism PLoS ONE, 8 (6) DOI: 10.1371/journal.pone.0066155

Autoimmune disease as a risk factor for mood disorder?

Autoimmunity, the process by which the immune system fails to recognise self as self and subsequently targets those self tissues and cells, is something talked about quite a lot on this blog with autism specifically in mind. Part of the very wide and diverse immune-related features which have been discussed with at least some of the autisms in mind, it's not yet altogether clear exactly how and why autoimmunity is linked to behaviour but the association is an interesting one.

Sally? @ Wikipedia  

The paper by Michael Benros and colleagues* expands that autoimmune - behaviour interest and their observations suggesting: "Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis". Their conclusion is based on the analysis of a huge patient set from which nearly 100,000 people had a hospital contact for mood disorder. Mood disorder by the way, is an overarching term for quite a few conditions (see here) which as the name suggests, affect mood; be it an unusual 'high' or an unusual 'low'.

"A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45%". To me this is a really interesting association. OK I know correlation does not equal causation, but added to the association they made between hospitalisation for infection and subsequent mood disorder (62% increase) and the large participant numbers, there is lots to ponder here.

I've gone on a few times on this blog about the bi-directional link between our physiology and the presentation of more psychiatric or behavioural 'symptoms'. Be it C.diff infection and depression or the skin-brain axis (see here), the connections are starting to be formed and examined. I'm just remembering back to some interesting research on allergic disease and neurodevelopment as also potentially being relevant to this post (see here) with the focus on allergy and its potential developmental effects and indeed the implication of some interesting potential interventions too.

So what could be the mode of action for this autoimmune-infection-mood disorder link? Well, we have some contenders but at the moment nothing concrete. That the immune system might be doing so much more than protecting against disease is already pretty well known about as for example with the rise and rise of research into microglia (see here) and some other areas of interest** particularly with a focus on a very nebulous term: inflammation.

Regular readers might know about my views and opinions on the role of food and the gut to behaviour - no really -  and certainly when it comes to certain autoimmune conditions like coeliac (celiac) disease, we have a body of research suggesting how food, certain elements of food, under the right circumstances might be able to affect behaviour. Think Marios Hadjivassilliou for example.

Even more outlandish, how about some role for those HERVs - human endogenous retroviruses - which seem to be cropping up with lots of conditions in mind (see here) and in particular autoimmune conditions***? Too speculative? Whether any of these areas overlap with the Benros paper is something as yet unknown. But the association posited between autoimmune conditions / infections and subsequent mood disorders is really, really interesting.

To close, with the new Stone Roses inspired movie on the horizon, how about a song about Sally Cinnamon?

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* Benros ME. et al. Autoimmune Diseases and Severe Infections as Risk Factors for Mood Disorders. JAMA Psychiatry. 2013;():1-9. doi:10.1001/jamapsychiatry.2013.1111.

** del Rey A. et al. A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning. Brain, Behavior, and Immunity. 6 June 2013. http://dx.doi.org/10.1016/j.bbi.2013.05.011

*** Dreyfus DH. Autoimmune disease: A role for new anti-viral therapies? Autoimmun Rev. 2011 Dec;11(2):88-97. doi: 10.1016/j.autrev.2011.08.005.

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Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, & Mortensen PB (2013). Autoimmune Diseases and Severe Infections as Risk Factors for Mood Disorders: A Nationwide Study. JAMA psychiatry (Chicago, Ill.), 1-9 PMID: 23760347

Autism, fetal alcohol syndrome and thyroid hormone?

Alcohol is the drug of choice for many people these days. For most, it's a case of the odd glass of wine here or there or a beer whilst sat outside in the garden during the summer we're supposed to be basking in at the moment.

The grape @ Wikipedia 

But there is no getting away from the fact that alcohol is a drug, and by all accounts, a drug which very readily impacts on the lives of many, many people. Outside of all the social ills associated with excessive alcohol consumption, there is also in some cases, a price to pay for infants born to those who drink alcohol to excess during pregnancy. The condition is called fetal alcohol syndrome or fetal alcohol spectrum disorder.

I've talked about FAS / FASD previously on this blog (see here). The crux of that post was the often confusing message sent out about how much alcohol is 'safe' to consume when a woman is pregnant and how one has to be very careful when presenting a potential link between FAS / FASD and a condition like autism.

Enter then a new study by Elif Tunc-Ozcan and colleagues* on the topic of a rodent model of FASD and some potentially interesting findings. There has already been some press discussion about this paper as per entries like this one.

Given the overlap between the presentation of FASD and autism (being very careful here), Tunc-Ozcan et al set out to see if they could identify some of the "molecular characteristics related to ASD in an animal model of FASD" to further inform both conditions. Rats were the participants of choice and as a starting point feeding pregnant rats one of a number of diets, one of which included supplementation with ethanol - the fancy chemical name for alcohol.

They then looked at the offspring of the various groups of rats based on examination of memory and social behaviours alongside the expression of certain genes tentatively related to autism in the hippocampus. They also looked at some of the facets of thyroid functioning as a function of supplementing one of the rat groups consuming ethanol with thyroxine. This last part stems from a body of work suggesting that in-utero exposure to alcohol might affect thyroid function which then subsequently impacts on facets of brain development**.

The results: well, keep in mind that this was a study of rats not humans, but alcohol did indeed impact on thyroid chemistry in exposed offspring. Males seemed to be particularly sensitive on measures of the behavioural effects of alcohol exposure. Talk about your fragile male. Quite a few of those candidate genes potentially involved in autism were also "significantly increased in the hippocampus of male offspring" exposed to alcohol.

Importantly, it seemed that co-administration of thyroxine with the inclusion of alcohol in the maternal diet seemed to have something of a protective effect on the areas studied in offspring. The word 'normalized' (North American spelling) is used to denote the various changes described.

As you might imagine, there is some interest in these results. I'll stress again that this was a study of rats and how rats are rats and not humans with all their complexities. The study authors have also made the important point that: "The study does not mean alcohol consumed by the mother is the cause of autism". With all the potential for stigma based on such results, I'll reiterate again that the authors are not saying that autism is caused by mothers drinking alcohol.

Again, I've talked about thyroid function with autism in mind quite a while back (see here). Within that entry was the suggestion (evidence-based suggestion***) that levels of thyroxine (T4) in the newborn might be to some degree linked to the risk of a later diagnosis of autism. One could also put this in the perspective of the results by Tunc-Ozcan and colleagues too.

I had a few additional thoughts about this study. I'm speculating so please humour me. I wondered for example, whether maternal consumption of alcohol talked about in this rat study might have had some more generalised effects on things like gut bacteria. It's quite widely known that alcohol is not great news for gut bacteria as per reports on consumption of alcohol and SIBO (see here). I'm speculating that this might also translate into potential effects for offspring too? Another even more outlandish thought for your consideration: auto-brewery syndrome. I know that this is not exactly an idea with a great deal of legal merit (see here) but the scientific literature is dotted with case studies suggesting that it can, and does happen**** as a consequence of some unusual fermentation in the deepest, darkest recesses. With all the focus on gut bacteria and autism, is it beyond the realms of possibility that something like this might show some subtle effect?

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* Tunc-Ozcan E. et al. Low-Dose Thyroxine Attenuates Autism-Associated Adverse Effects of Fetal Alcohol in Male Offspring's Social Behavior and Hippocampal Gene Expression. Alcohol Clin Exp Res. 2013 Jun 13. doi: 10.1111/acer.12183.

** Kornguth SE. et al. Impeded cerebellar development and reduced serum thyroxine levels associated with fetal alcohol intoxication. Brain Res. 1979; 177: 347-360.

*** Hoshiko S. et al. Are thyroid hormone concentrations at birth associated with subsequent autism diagnosis? Autism Res. 2011 Dec;4(6):456-63. doi: 10.1002/aur.219.

**** Dahsan A. & Donovan K. Auto-Brewery Syndrome in a Child With Short Gut Syndrome: Case Report and Review of the Literature. J Ped Gastroenterol Nutr. 2001; 33: 214-215.

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Tunc-Ozcan E, Ullmann TM, Shukla PK, & Redei EE (2013). Low-Dose Thyroxine Attenuates Autism-Associated Adverse Effects of Fetal Alcohol in Male Offspring's Social Behavior and Hippocampal Gene Expression. Alcoholism, clinical and experimental research PMID: 23763370

The Autism Impact Measure and more

It's the usual excuse from me, "the dog ate my homework sir", no not that one, the one about me having a busy week so not being able to post a particularly detailed blog entry this time around. Indeed although there is the usual plethora of research material to pick from, only a few studies have really caught me eye so far this week. But those studies are pretty interesting....

Must try harder @ Wikipedia  

I'm starting with the paper by Stephen Kanne and colleagues* and their description of the Autism Impact Measure or AIM for short. Yes, we knew this study was coming as per an entry at the 2012 IMFAR conference. Including one Micah Mazurek on the authorship list who was involved in that really rather interesting article about gut problems potentially being linked to anxiety and sensory issues in relation to autism (see here), I was really quite interested in the AIM proposal. I've said it before and I'll say it again, one of the very big holes in autism research is a measure which has the appropriate power and accuracy to determine change in autism (see here) so we can start to reliably assess what interventions might work and indeed for who. Very possibly also to be used to pick up what might be different about those optimal outcomers (see here) as per more information on this group being revealed. There's not much more for me to say on this study aside from it certainly looks like the AIM has passed the initial hurdles in terms of reliability and robustness. Fingers are definitely crossed that it continues across clear water.

Next up the paper from Kristelle Hudry and colleagues** talking about language profiles in infants at high-risk for autism. Part of the BASIS network, the idea here was to look at language profiles across infancy in these high-risk kids compared with low-risk controls and then compare across groups of children from the high-risk grouping who were subsequently diagnosed with autism, "other atypicality" and nothing (typically developing). The important part of the results outside of "few group differences appeared on direct assessment of language and parent-reported functional communication" was the issue of reduced receptive vocabulary 'advantage' present in the high-risk group and maintained in the autism and other atypicality group. I know this might not sound like much but identifying red flags, any potential red flags pointing towards a propensity to develop autism, has to be a good thing even from a screening point of view.

Finally is the paper by Sarah Sullivan and colleagues*** which is well outside of the autism research domain, looking at prenatal vitamin D status and offspring risk of psychosis at 18 years of age. I say outside of autism research but maternal vitamin D levels in relation to offspring risk of autism or autistic traits have been talked about before (see here) and very little found on that occasion. Actually that's about the sum total of the findings from Sullivan et al replacing autism or AQ scores for psychosis in early adulthood, at least in their birth cohort. But just before you say to yourself words to the effect of "y'mean vitamin D isn't linked to something' I'll draw your attention to the work of Barbara Gracious and colleagues (open-access) which I talked about in a previous post (see here) suggesting vitamin D levels, first-person levels, might show a connection to psychotic features. Unfortunately the Sullivan paper doesn't seem to ask about first person vitamin D levels...

So AIM, language profiles in children at high-risk for autism and maternal vitamin D levels in relation to offspring risk of psychosis (or rather not). Surely there can't be many places on the web that you'd get all that together?

To close, a song by Badly Drawn Boy - something to talk about anyway. We miss you Richard Whiteley (no relation by the way).

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* Kanne S. et al. The Autism Impact Measure (AIM): Initial Development of a New Tool for Treatment Outcome Measurement. J Autism Dev Disord. 2013 Jun 8.

** Hudry K. et al. Early Language Profiles in Infants at High-Risk for Autism Spectrum Disorders. J Autism Dev Disord. 2013 Jun 8.

*** Sullivan S. et al. Prenatal vitamin D status and risk of psychotic experiences at age 18 years-a longitudinal birth cohort. Schizophr Res. 2013 Jun 6. pii: S0920-9964(13)00270-3.

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Kanne, S., Mazurek, M., Sikora, D., Bellando, J., Branum-Martin, L., Handen, B., Katz, T., Freedman, B., Powell, M., & Warren, Z. (2013). The Autism Impact Measure (AIM): Initial Development of a New Tool for Treatment Outcome Measurement Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-013-1862-3

Asthma increases risk of ADHD?

Asthma increasing the risk of ADHD? With a title like that derived from the paper by Mu-Hong Chen and colleagues* I couldn't resist posting an entry about it. Indeed the paper has one or two of the elements that I've come to love over my couple of years of blogging; in that we have two seemingly disparate conditions - one physiological, one behavioural - yet within the confines of the old 'correlation does not equal causation' quote, some possibility of a connection.

Breathe @ Wikipedia  

ADHD - Attention Deficit Hyperactivity Disorder - has been on my blogging radar a few times in the past few months. Not only with regards to the numbers (see here) which seem to be going up all the time** but also with some rather curious associations in mind, such as solar intensity (see here). Stay with me on this one.

The Chen paper is an interesting one based on a surprisingly large body of research supportive of some link between the two conditions***. Their specific take on this issue was to look at the temporal relationship between asthma and ADHD, which they did by means of a case - control study. Trawling a national database, which is something they are seemingly rather good at in Taiwan (see here) they came up with a very nice sample size of children with asthma (n=2294) and controls (n=9176) and looked at how many kids were subsequently diagnosed with ADHD.

The results:
"Children with asthma had a higher incidence of developing ADHD (7% vs. 4.6%, p < .001)".

OK the difference in ADHD rates might not appear startling but bear in mind the numbers of cases and controls that they looked at. Indeed the overall risk - hazard ratio - after controlling for various other factors was 1.31 (95% CI: 1.07-1.59).

Browsing through older posts on this blog it appears I've talked about some of Chen's work previously with an entry on allergic and autoimmune conditions being more readily diagnosed in cases of autism (see here). This tells me that this research group have some interest in the area of physiology and behaviour being linked and have the means to look at some quite big samples to test the correlations.

So with correlation put to the test and potentially something found, the next questions: how and why? Given how close and cosy ADHD seems to be getting to diagnoses like autism - see the Rao & Landa study**** and accompanying press - on top of all that ESSENCE chatter (see here), one might speculate at potentially similar mechanisms being involved. Indeed, when I wrote about asthma and autism a while back (see here) a few themes emerged based on familial genetics and some overlap for immune function which may be relevant. More recent speculations on things like the hygiene hypothesis (and see here) become even more relevant when it comes to conditions like asthma. I wish I could give a more definitive answer about any connection but it's all rather complicated. One last thought to mention is that rather interesting study by Barbara Stewart (see here) on some anatomical differences found in the airways of children with autism. I'm no expert on the physiology of the lungs and asthma but wonder whether this might also be relevant (or not) to cases of ADHD too.

And finally(!) another quote from the Chen study: "Further studies are required to investigate whether the prompt treatment of asthma and comorbid allergic diseases could prevent the development of ADHD or decrease ADHD symptoms". Food for thought?

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* Chen MH. et al. Asthma and attention-deficit/hyperactivity disorder: a nationwide population-based prospective cohort study. J Child Psychol Psychiatry. June 2013.

** Getahun D. et al. Recent trends in childhood attention-deficit/hyperactivity disorder. JAMA Pediatr. 2013; 167: 282-288.

*** Mogensen N. et al. Association between childhood asthma and ADHD symptoms in adolescence--a prospective population-based twin study. Allergy. 2011; 66: 1224-1230.

**** Rao PA. & Landa RJ. Association between severity of behavioral phenotype and comorbid attention deficit hyperactivity disorder symptoms in children with autism spectrum disorders. Autism. June 2013.

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Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, Chen TJ, & Bai YM (2013). Asthma and attention-deficit/hyperactivity disorder: a nationwide population-based prospective cohort study. Journal of child psychology and psychiatry, and allied disciplines PMID: 23730913

Autism, the ketogenic diet and Dangermouse

I'm proud of my quite 'unusual' area of autism research interest focused primarily on whether diet might, in some way, shape or form, be linked to or impact on some cases of the autisms. It's not been a particularly popular area of research down the years it has to be said. Most of which I've put down to its links to areas far outside of the behavioural dyad (as its known these days). That and all the gastrointestinal (GI) baggage inevitably associated with diets like the gluten- and casein-free (GFCF) diet: leaky gut, gut bacteria, etc. which have been allied with other 'factors' leading to a sort of scientific death-by-association in some quarters.

Penfold  @Wikipedia  

Outside of the considerable politics, there is an evidence base to diet and autism. It's not a particularly strong scientific base it has to be said, but there are a few randomised controlled trials (RCTs) to be found, and in agreement with Tim Buie's latest take on gluten-free dietary intervention and autism* "There may be a subgroup of patients who might benefit from a gluten-free diet". Though we still don't know who.

Dr Buie, by the way, has also talked about things like lactose (the sugar in milk) intolerance and gut dysbiosis in cases of autism extending the potential of a dietary link. Assuming you adhere to the notion of the autisms - with all their heterogeneity and comorbidity - you might be inclined to also think that autism might not just be a condition of the grey-pink matter floating in the skull. Or maybe not....

Hopefully not being too 'me, me, me', I'm actually involved in writing a book about the area of diet and autism as we speak. It's been an interesting journey and allowed me to dig deep into the available science behind diet including some gems such as per this paper**. Outside of just GFCF diets, a variety of other food changes have also been on the research menu with autism in mind, including the ketogenic diet.

I've talked about the ketogenic diet before - what it is and how it is starting to enter mainstream medicine when it comes to managing certain types of epilepsy. Briefly, it's all about high fat (no, not that Hai Fat) and low carbohydrates and putting the body into a state known as ketosis. Indeed how this state seems to affect seizure patterns for some people. Yes, I know a similar sort of diet, sorry nutritional approach, has also been suggested as a weight loss measure but I'm not really that interested in that sort of thing on this blog.

With autism in mind and outside of any seizure-linked effect, there has been a suggestion, a small suggestion, that a ketogenic diet might also be able to affect certain behaviours linked to autism too as per the paper by Evangeliou and colleagues***. In a more case-study fashion, I'll also draw your attention to my fairly recent discussions on the paper by Martha Herbert and Julie Buckley (see here) on similar things. Other than that, we've got a bit of a scientific black hole when it comes to the question of whether such a very restrictive dietary intervention could 'help' where autism is present and who might be best responders.

The paper by David Ruskin and colleagues**** (open-access) which I'm finally getting to after quite a long-winded introduction, represents an addition to that autism-ketogenic diet literature and their observations of the BTBR 'Dangermouse' when on a ketogenic diet. OK I've exaggerated slightly. The BTBR mouse model of autism is not really Dangermouse; just a name I've assigned from my mis-spent youth watching far too much TV (see this post). But it is still quite a good mouse model of autism despite some recent criticism.

The Ruskin paper is open-access so I'm not going to go over the top with any description. It went something like: take several BTBR mice. House them with other mice (C57Bl/6). At 5 weeks of age, feed some of the mixed caged mice a ketogenic diet (KD) and others a control diet. Test mouse behaviour at 3-5 weeks of diet. Report results.

The results: well, the KD mice were certainly showing signs of ketosis as per some blood chemistry results including some much lower blood glucose levels (interesting!*****). There were also some interesting differences recorded to elements of mouse behaviour as a function of the use of the KD or not and mouse strain: "the KD did not affect behavior in C57Bl/6 mice". Importantly "the beneficial behavioral effects of the KD are not secondary to its well-known efficacy against epilepsy and seizure activity".

OK, it's another study of mouse behaviour and making the quite considerable leap from a proposed mouse model of autism to real-life autism. Mouse behaviour is not human behaviour (he says cleaning his whiskers). I'm no expert on how one goes about examining and testing mouse behaviour so I'll have to assume that the authors knew what they were doing and did it to the best of their abilities. I'm not necessarily expecting the Ruskin study to mark any substantial shift in opinion on how people view the research area of diet and autism it has to be said.

What this study does offer though, is another potentially fascinating glimpse into how diet might be related to some cases of autism. Indeed, whether the whole or facets of the intervention are worthy of much greater study. For example, I earlier mentioned Tim Buie's work on carbs and autism. The question is whether the lower carbohydrate load attached to a ketogenic diet might be the more important variable over and above fat, bearing in mind that there might be issues there too? Similarly, the authors ask whether the ketogenic diet might be something to consider where autism and certain types of epilepsy exist; as per another quote: "a KD could offer dual benefits in this difficult clinical population". Bear in mind however, I offer nothing like medical or clinical evidence by suggesting all this. Just speculating.

To close and paying homage to the era of Dangermouse (1980s), here's Neneh and Buffalo Stance.. ("know wot I mean?")

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* Buie T. The relationship of autism and gluten. Clin Ther. 2013; 35: 578-583.

** Asperger H. Psychopathology of children with coeliac disease. Ann Paediatr. 1961; 197: 346-351.

*** Evangeliou A. et al. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol. 2003; 18: 113-118.

**** Ruskin DN. et al. Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS ONE. 2013; 8: e65021.

***** Yancy WS. et al. A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutrition & Metabolism. 2005; 2: 34.

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Ruskin, D., Svedova, J., Cote, J., Sandau, U., Rho, J., Kawamura, M., Boison, D., & Masino, S. (2013). Ketogenic Diet Improves Core Symptoms of Autism in BTBR Mice PLoS ONE, 8 (6) DOI: 10.1371/journal.pone.0065021

Toe walking and autism

Whilst grazing, as one does, on the plains of the Internet savanna, I stumbled across an interesting article by Williams and colleagues* (open-access) describing a protocol for a study looking at toe walking. As what normally happens with me, memories of autism research times gone by started to flood back, culminating with the question: what ever happened to research looking at toe walking in cases of autism?

En Pointe @ Wikipedia  

Going back quite a few years now, I remembered one occasion when I had research reasons to be in contact with the family of a young girl diagnosed with autism. I quite vividly remember this youngster because of her almost ballet-like gait, hoisting her body weight (which it has to be said was only a very slender frame) on the front portion of her feet; her heels almost never touching the ground for the duration of my visit. The parents I recall, described how she would spend literally hours toe walking; her gait intertwined with various stereotypies depending on her mood and disposition at the time.

Most people will know about the links suggested between autism and issues with gait as per studies like the one from Fournier and colleagues** and the one from Green and colleagues***. Indeed just flicking through an old copy of the ADI (Autism Diagnostic Interview) which I have to hand, I note that in the general behaviours section there is an entry under gait and the words 'up on toes' and 'toe-walking' detailed as part and parcel of the schedule, even if not part of the diagnostic algorithm.

So what evidence is there for toe walking being linked to cases of autism?

• I was actually quite taken aback as to how few references there were for toe walking research in relation to autism as listed in PubMed. One the more important studies seems to be this one from Barrow and colleagues**** which was also discussed on a SFARI entry (see here). Barrow et al suggested that toe walking might be a facet of quite a few cases of autism - during childhood - and raised "the possibility of a secondary orthopedic deformity" to be present. Barrow also reported a disparity in results between the autisms (autism vs. Asperger syndrome) which might also tie into the various research looking at toe walking from a language point of view (see here) or the possibility of a cognitive developmental issue (see here).
• The possibility that toe walking might be a 'red flag' for the presentation of autism had been previously discussed as exemplified by the paper from Mandell and colleagues***** (open-access). As a parcel of behavioural presentations including 'hand flapping' and 'sustained odd play', they suggested that toe walking was associated with a decrease in the age of diagnosis. Someone it seems, has been taking its presence quite seriously.
• The paper by McDougle and colleagues****** (who is talking about some very interesting concepts these days) on tryptophan depletion in cases of autism offers some interesting links between everyone's favourite aromatic amino acid and behaviours such as toe walking. Their results, based on the very complicated area of tryptophan and serotonin chemistry in relation to autism, might have some connection back to more recent mouse model results (see here).

Of course there are other papers looking at toe walking and autism (even with a potential mitochondrial slant to them) but I'm not going to bore you with all the details. Obviously one has to keep in mind that toe walking is not an exclusively autism-linked trait and that some children can present with such a behaviour without presenting with other features linked to a diagnosis of autism or anything else.

I do wonder about a few things based on this collected work: whether we should, following Barrow's suggestion, be screening for orthopaedic issues where sustained toe walking presents in cases of autism, and indeed whether this heralds any link (or not) to things like joint hypermobility (see this post). Whether also toe walking might correlate with other signs and symptoms around either comorbidity (such as cerebral palsy) or even other slightly less well-defined motor-related behaviours are important questions too. That also, for the most part, examination of toe walking in cases of autism has tended to concentrate on the early years of childhood, leaves quite a wide gap into how far maturity acts on such behaviours, and indeed the extent to which toe walking persists into adulthood in cases of autism.

To close, I don't do advice on this blog. But if you really want some life advice, then how about listening to this chap and starting with wearing sunscreen.... (dancing is also a good idea).

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* Williams CM. et al. Do external stimuli impact the gait of children with idiopathic toe walking? A study protocol for a within-subject randomised control trial. BMJ Open. 2013; 3: e002389.

** Fournier KA. et al. Motor coordination in autism spectrum disorders: a synthesis and meta-analysis. J Autism Dev Disord. 2010; 40: 1227-1240.

*** Green D. et al. The severity and nature of motor impairment in Asperger's syndrome: a comparison with specific developmental disorder of motor function. J Child Psychol Psychiatry. 2002; 43: 655-668.

**** Barrow WJ. et al. Persistent toe walking in autism. J Child Neurol. 2011; 26: 619-621.

***** Mandell DS. et al. Factors associated with age of diagnosis among children with autism spectrum disorders. Pediatrics. 2005; 116: 1480–1486.

****** McDougle CJ. et al. Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry. 1996; 53: 993-1000.

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Barrow WJ, Jaworski M, & Accardo PJ (2011). Persistent toe walking in autism. Journal of child neurology, 26 (5), 619-21 PMID: 21285033