Autism, gastrointestinal disorders and comorbidity clusters

I start this post with a few important observations. Please feel free to disagree with me (as long as you can provide peer-reviewed evidence for your alternate viewpoint).

Bunting @ Wikipedia 

(1) Comorbidity can, and quite frequently does, surround a diagnosis of autism.

(2) Gastrointestinal (GI) issues form an important part of that comorbidity spectrum.

(3) The relationship between autism and comorbidity is, at present, poorly understood insofar as which influences the appearance of which and how the two are related.

So, with those statements in mind, I offer some discussion today on two potentially very important papers which variably reference the above points.

The first paper is from Brittany Peters and colleagues* (with many, many thanks to Natasa for the paper) which suggests that there indeed may be an important relationship between GI issues and rigid-compulsive behaviours noted in cases of autism. The second paper is from Finale Doshi-Velez and colleagues** (again, with thanks to Natasa) who looked at 'comorbidity clusters' when it comes to the autism spectrum.

Both these papers come from groups who have some 'research form' in their respective areas. For the Peters paper it comes in the guise of the valuable research contribution from Gorrindo and colleagues*** which basically said that yes, parents might know when their children with autism present with bowel issues: "parents were sensitive to the existence, although not necessarily the nature, of GID [gastrointestinal dysfunction]". For the Doshi-Velez paper I'll link back to the paper by Kohane and colleagues**** (covered in this post) and their notion of 'significantly over-represented' when it comes to the comorbidity burden with autism in mind.

The more recent papers make for interesting reading. Starting with the Peters paper:

• The authors start with a hypothesis: "a possible association between rigid-compulsive behaviors and GI symptoms" based on their clinical experience of the autism spectrum conditions.
• They tested their hypothesis on data from participants (N=5076) in the Autism Treatment Network (ATN) and various measures collected from the ATN database. Alongside including diagnostic data, the database also contains data from a GI symptom questionnaire; both of which were used to collect information for their study analysis.
• Results: Nearly half of the total cohort (43.5%) "had at least one GI symptom". In light of other quite recent reports (see here and here) this finding is not totally unexpected.
• Based on data from children (aged 2-17 years) - nearly 3000 of which were in the 'no GI symptoms' group (n=2957) and 806 in the 'constipation plus diarrhea or underwear staining' - several other details emerged from the data. The latter GI symptoms group were "more likely to have a parental report of repetitive behavior.... or compulsive behavior... and OCD [obsessive compulsive disorder] diagnosis". Ritualistic behaviours were also picked up more frequently in the GI group by clinician report (ADOS) over the no GI symptoms group.
• A few other research nuggets: children in GI symptoms group were "more likely to have a family history of anxiety or OCD" and also more likely to have received "treatment with an atypical antipsychotic".
• The authors conclude that, allowing for potential issues with the use of the ATN database and missing values, "all five primary measures of rigid-compulsive behavior were significantly associated with constipation and diarrhea or underwear staining". 

And then we have the Doshi-Velez paper:

• This was a study looking at "patterns of co-occurence of medical comorbidities in ASDs".
• Electronic medical records or rather electronic health records (EHR) were the source material for the paper and in particular, the ICD-9 codes relevant to particular conditions derived from the i2b2 National Center for Biomedical Computing (N=13,740). This sounds to me like a similar job to that of SHRINE (used in the previous Kohane paper).
• "Key patterns" identified from this rather large participant group were then tested on a smaller, independent cohort comprising 496 participants from Wake Forest University Health Sciences.
• With the application of some technical and statistical wizardry, various subgroups were identified within the cases examined based on the clustering of comorbidity alongside the diagnosis of autism.
• Results: "Four subgroups were identified" based on medical comorbidity and the paper offers quite a bit of detail about the hows and whens certain comorbidity tend to present.
• Group 1. That old comorbidity nemesis seizures (I assume to indicate some kind of epilepsy) was the focus for the first group with a prevalence of 77% within this group. 
• Group 2. Then came in "multisystem disorders" to form group 2 which included GI disorders (distinct from just functional GI issues). That being said "early ear infections" seemed to stand head and shoulders above other comorbidities for this group particularly with preschool presentation. 
• Group 3. Next for comorbidity was group 3 "characterised by psychiatric disorders" (33%). This group "had the highest rate of individuals with Asperger syndrome and the lowest rate of intellectual disability" and included some familiar conditions including anxiety (see here). That being said (again!), "Hyperkinetic syndrome of childhood" also prominently featured in the group 3 comorbidity profile. 
• Group 4. Finally, there was a 'not' resolved group. Not much more to say there really.
• Buried in the text is the quite alarming suggestion that: "All of these subgroups had higher levels of cardiac disorders" which, similar to the example of schizophrenia (see here), implies that health screening should be high on any physician's list when someone presents with autism save any charges of health inequality being levelled.
• The authors conclude that the identification of these comorbidity subgroups centred on the autism spectrum may very well indicate "distinct etiologies with different genetic and environmental contributions". I'm minded to say that we have another possible piece of evidence pertinent to the plural concept of 'the autisms'.

Combined, both these papers offer some really quite important information about the autisms and their very complicated presentation including comorbidity. I would hasten to point out that there is still quite a bit of 'fuzziness' about these results as for example, seen in a quote from the Doshi-Velelz paper: "The 3 subgroups from our original clustering analysis consisted of <10% [less than 10%] of the overall sample". In short, it's complicated. But don't let that take anything away from these results...

Oh and since we're on the topic of 'the autisms' and comorbidity, I note from the recent-ish findings from Giardino and colleagues***** that GI comorbidity has been reported in cases of 22q11.2 deletion syndrome (22q11DS). Autism or autistic behaviours if you like, show more than a passing connection****** to 22q11DS... perhaps research fodder for another blogging day? (Er, yes, watch this space).

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* Peters B. et al. Rigid-Compulsive Behaviors are Associated with Mixed Bowel Symptoms in Autism Spectrum Disorder. J Autism Dev Disord. 2013 Nov 29. [Epub ahead of print]

** Doshi-Velelz F. et al. Comorbidity Clusters in Autism Spectrum Disorders: An Electronic Health Record Time-Series Analysis. Pediatrics. 2013. Dec 9.

*** Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8. doi: 10.1002/aur.237.

**** Kohane IS. et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One. 2012;7(4):e33224.

***** Giardino G. et al. Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. Scand J Gastroenterol. 2013 Dec 18.

****** Vorstman JA. et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J Am Acad Child Adolesc Psychiatry. 2006 Sep;45(9):1104-13.

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Peters B, Williams KC, Gorrindo P, Rosenberg D, Lee EB, Levitt P, & Veenstra-Vanderweele J (2013). Rigid-Compulsive Behaviors are Associated with Mixed Bowel Symptoms in Autism Spectrum Disorder. Journal of autism and developmental disorders PMID: 24293040

Finale Doshi-Velez, Yaorong Ge, & Isaac Kohane (2013). Comorbidity Clusters in Autism Spectrum Disorders: An Electronic Health Record Time-Series Analysis Pediatrics DOI: 10.1542/peds.2013-0819d

How many steps a day should I be walking?

Granted, this entry is a slight departure from the usual material to be found on this blog, but I'm going to post it nevertheless. I'm a big fan of walking. I know that probably sounds a little bit obvious, but I'm actually referring to the use of walking as a tool to keeping in shape rather than just getting from A to B.

Tudor-Locke C. et al (2011) Int J Behav Nutr Phys Act.

Here in the UK (and perhaps beyond) there is quite a lot of chatter about the '10,000 steps a day' challenge (see here) and how walking seems to confer quite a lot of physical (and potentially psychological) benefits.

I know it might seem a little arbitrary to say that we should all be working towards 10,000 steps (as many of our health standards seem to be) but there is some evidence emerging that the magic number of 10,000 might be an important standard*.

Anyhow, I stumbled across the paper by Catrine Tudor-Locke and colleagues** (open-access here) who seems to be quite an important name in the area of 10,000 steps. The paper as you'll see talks about how various ages and genders seem to vary in their daily step count and onwards produce some kind of population normative standards.

It's an interesting review but what particularly took my attention in these days of infographics was the picture attached (which can be found here that I've reproduced with all rights reserved to the authors and publishing journal).

There's not too much more for me to say about it aside from 10,000 steps is a nice universal number to aim for but bear in mind this figure might not reflect the daily goal for everyone. It's also interesting that as we age so our step count goes down, which to me at least, suggests that we should all be living life a little more like when we were children (from a walking perspective).

So, with my blogging caveats of not giving medical or clinical advice in full working order, don't be afraid to put on a comfy pair of walking shoes or trainers and go and enjoy the fresh air with a pedometer if you choose or with the knowledge that 10 minutes of fairly brisk walking is equivalent to about 1000 steps...

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* Tudor-Locke C. & Bassett DR Jr. How many steps/day are enough? Preliminary pedometer indices for public health. Sports Med. 2004;34(1):1-8.

** Tudor-Locke C. et al. How many steps/day are enough? for children and adolescents. Int J Behav Nutr Phys Act. 2011 Jul 28;8:78.

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Tudor-Locke C, Craig CL, Beets MW, Belton S, Cardon GM, Duncan S, Hatano Y, Lubans DR, Olds TS, Raustorp A, Rowe DA, Spence JC, Tanaka S, & Blair SN (2011). How many steps/day are enough? for children and adolescents. The international journal of behavioral nutrition and physical activity, 8 PMID: 21798014

HERVs and ADHD

HERVs. Human endogenous retroviruses. The remnants of our evolutionary struggle with the viruses of the times of our distant ancestors, now part and parcel of our modern-day genome. Yes, genetically, we are all part virus to various extents [so embrace your viral self].

HMS Beagle @ Wikipedia

I've talked HERVs on a few occasions on this blog, in relation both to the autism spectrum conditions (see here) and myalgic encephalomyelitis (ME) (see here).

Without getting too technical, the crux of those posts was to suggest that although those bits of virus in our genomes are not necessarily 'active viruses' (i.e. not able to produce infectious virus or replicate) they may have implications for things like autoimmunity given that HERV proteins are supposedly recognised as 'self' by the almighty MHC [1] and seem to be able to provoke autoimmunity (in mice) [2]. That and the fact that the expression of HERVs may be kept in check by epigenetic means (methylation) [3] and 'hypomethylation [of DNA] = more genomic instability' [4] so, theoretically under certain circumstances could mean HERVs get a chance to start expressing (something). Or that's the theory (I think)...

With all that in mind, I move to the paper by Balestrieri and colleagues [5] (yes, the same group who completed the HERV paper with autism in mind) who discussed some very preliminary data on the expression of certain families of HERVs. Indeed, they reported: "The expression levels of HERV-H are significantly higher in patients with ADHD [attention-deficit hyperactivity disorder] compared to healthy controls".

I can't pretend to know all the ins-and-outs of how one goes about assaying for the expression of HERVs - "expression of retroviral mRNAs from the three HERV families was evaluated in peripheral blood mononuclear cells (PBMCs)" apparently. It was however interesting to see that HERV-H 'over-expression' was "significantly higher in patients with ADHD compared to healthy controls". HERV-H was also the same family reported to be 'more abundantly expressed' in cases of autism.

A search of some of the literature covering HERV-H reveals that it is a gamma-retrovirus (yes, similar to those letters X-M-R-V and that de-discovery issue). In terms of associations and roles, it "contributes to pluripotency in human cells" according to the paper by Santoni and colleagues [6] and their finding of high levels of HERV-H RNA in human embryonic stem cells. The HERV-H family have also been suggested to have immunosuppressive properties [7].

HERV-H has been linked to conditions such as multiple sclerosis as per papers like this one by Christensen [8] which also hinted at how other viruses may 'interact' with HERVs; in that paper concluding that: "retroviruses and herpes viruses have complex interactions". That being said, not all results have arrived at the same conclusion.

I was also particularly interested to read the paper by Shuvarikov and colleagues [9] who seemed to suggest "HERV-H elements as a mechanism of deletion formation", as in genetic deletions. I might be making mountains out of molehills but their case report that HERV-H elements seemed to flank "recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31" could potentially lead down some very important paths as intimated in a previous post. The fact that they mention autism as being part and parcel of some of their participant group description is likewise intriguing.  As I've indicated in other posts on this blog where the term 'de novo' has been used, the uncertainty or chance finding of de novo now, might not be so in X numbers of years time. And the future may already be here [10] with schizophrenia in mind.

I'm going to stop there with this quite heavy going post and the chatter about HERVs and ADHD (or autism or anything else). Science is to quite a large extent still feeling it's way around the HERVs and their role - if any - in health and wellbeing. The reported link between the expression of HERVs and a condition as complicated as ADHD needs a lot more work on it before anyone can arrive at any firm conclusions. That being said, I find this to be a fascinating area of science which really does add a new layer of complexity to the whole genetics-environment relationship.

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[1] Lavie L. et al. CpG Methylation Directly Regulates Transcriptional Activity of the Human Endogenous Retrovirus Family HERV-K(HML-2). J. Virol. 2005; 79: 876-883

[2] Perron H. et al. Human Endogenous Retrovirus Protein Activates Innate Immunity and Promotes Experimental Allergic Encephalomyelitis in Mice. PLoS ONE 8(12): e80128. doi:10.1371/journal.pone.0080128

[3] Wilson AS. et al. DNA hypomethylation and human diseases. Biochimica et Biophysica Acta. 2007; 1775: 138–162.

[4] Tugnet N. et al. Human Endogenous Retroviruses (HERVs) and Autoimmune Rheumatic Disease: Is There a Link? Open Rheumatol J. 2013; 7: 13–21.

[5] Balestrieri E. et al. Human endogenous retroviruses and ADHD. World J Biol Psychiatry. 2013 Nov 28. [Epub ahead of print]

[6] Santoni FA. et al. HERV-H RNA is abundant in human embryonic stem cells and a precise marker for pluripotency. Retrovirology. 2012; 9: 111.

[7] Mangeney M. et al. The full-length envelope of an HERV-H human endogenous retrovirus has immunosuppressive properties. J General Virology. 2001; 82: 2515-2518.

[8] Christensen T. Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses. Rev Med Virol. 2005 May-Jun;15(3):179-211.

[9] Shuvarikov A. et al. Recurrent HERV-H-Mediated 3q13.2-q13.31 Deletions Cause a Syndrome of Hypotonia and Motor, Language, and Cognitive Delays. Hum Mutat. 2013 Oct;34(10):1415-23.

[10] Bundo M. et al. Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia. Neuron. 2014. 2 Jan.

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Balestrieri E, Pitzianti M, Matteucci C, D'Agati E, Sorrentino R, Baratta A, Caterina R, Zenobi R, Curatolo P, Garaci E, Sinibaldi-Vallebona P, & Pasini A (2013). Human endogenous retroviruses and ADHD. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry PMID: 24286278

Treatable inborn errors of metabolism in cases of autism

Happy New Year! Καλή Χρονιά (in Greek).

Welcome back to Questioning Answers in 2014. Let's continue our journey across the autism research landscape.

Party time, excellent @ Wikipedia 

Holidays. Whilst never regretting the opportunity to go on holiday/vacation, I am the type of person who has a strong desire to stay connected to the (research) world. I wouldn't necessarily say that I'm a product of the age of social media, more of late convert who ran enthusiastically towards the light.

A few months back however, I missed something important. It was the chance to peer review the paper by Martha Spilioti and colleagues* (open-access here) and some very interesting information following the screening of 187 children presenting with an autism spectrum disorder (ASD) for the signs and symptoms of various inborn errors of metabolism.

Actually it wasn't all my fault that I didn't accept this review. Granted I didn't access my email on holiday as often as I do when working, but more than that, the publishing journal seemed to expect quite a prompt reply on whether or not I was willing to review. I didn't reply in time, so I missed out. That's what happens in August, the holiday month, the time the kids are off school, y'know, the summer (at least here in my part of the World). No mind, I am happy to see that the Spilioti paper has seen the light of scientific day and hence become fodder for this blog.

Anyhow, inborn errors of metabolism. I've talked about them before in relation to autism (see here and here) and how at least some of them might actually be pretty revealing when it comes to at least some autism (as per those interesting findings in relation to the branched-chain amino acids). More recently I've been reading the paper by Stockler-Ipsiroglu and colleagues** talking about outcomes with regards to a diagnosis of guanidinoacetate methyltransferase (GAMT) deficiency which included some chatter on autistic behaviours (or should that just be autism?) as being involved.

The Spilioti paper evaluated 187 Greek children diagnosed with an autism spectrum condition on the basis of quite a few parameters. We're told that alongside taking quite a bit of information about family history and dietary habits, quite a few laboratory investigations were initiated, too numerous to all mention here. I have to say I was particularly impressed by the authors talking about a glucose loading test (with mitochondrial issues in mind) alongside serum and urine amino and organic acid screens; even looking at carnitine levels. The Greeks seem to be taking a lead in this 'look-see' approach when it comes to the autisms.

Their results: well, only a small proportion of their cohort turned up an inborn error of metabolism. Two participants with Lesch-Nyhan syndrome linked to the overproduction of uric acid (see here for a post of impulsivity and uric acid). Two further participants were identified with succinic semialdehyde dehydrogenase (SSADH) deficiency (which is a very, very rare condition indeed). One child was also diagnosed with PKU (see here).

Perhaps of more interest were the findings related to that glucose loading test and the suggestion that there was an increase in serum beta hydroxybutyrate (β-OH-b) in around 8% of participants. Although not an expert on this particular metabolite, I understand that elevations can indicate one or several possible scenarios (see here). The authors elaborate that some of those with elevations in β-OH-b also "manifested exacerbation of symptoms during high carbohydrate intake" which brings in an interesting dietary element. Indeed, further when a ketogenic diet (high fat, low carbohydrate intake) was initiated in [some of] those with increased β-OH-b, some interesting behavioural changes were reported; one participant was reported to show "remarkable improvement" in his CARS scores, which was followed by a cessation of medication and attendance at a "public elementary school without clinical problems". Yes, I know this was a case series (an optimal outcomer?) and not a controlled trial of the ketogenic diet where increased serum β-OH-b levels have been identified. Perhaps this is the next experimental step?

Other interesting findings. Well, yes. Around 7% of participants also showed elevated levels of urinary 3-hydroxyisovaleric acid (3-OH-IVA). Assuming that these child participants were not smokers (see here***) we are also told that none of these 7% were also "undergoing valproate intervention" which is another potential way of elevating 3-OH-IVA (see here****). And when it came to intervening with biotin as a function of the connection between 3-OH-IVA and biotin*****, authors again reported some interesting outcomes leading to "clear therapeutic benefit" noted in CARS scores for some. Please note I'm not suggesting anything based on these findings as per my caveat about no medical or clinical advice given or intended.

There is a lot more, data-wise, in the Spilioti paper which I've not been able to include in this post. As per the growing literature on autism perhaps being better defined as the 'autisms' I would echo the sentiments of Spilioti and colleagues when they say: "further consideration be given to the selected analysis of IEM [inborn errors of metabolism] in ASD". That dietary and nutritional supplementation might also be a road to improvement in the presentation of symptoms for some on the spectrum with identified metabolic parameters is also a very important consideration too.

Some music to close, and for those of who watched the New Year festivities from the comfort of your own home like I did to the tune of offspring chatter of 'can I stay up late please?', Alfie and Gary sing a classic...

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* Spilioti M. et al. Evidence for Treatable Inborn Errors of Metabolism in a Cohort of 187 Greek Patients with Autism Spectrum Disorder (ASD). Front. Hum. Neurosci. 2013; 7:858. doi: 10.3389/fnhum.2013.00858

** Stockler-Ipsiroglu S. et al. Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 2013 Nov 7. pii: S1096-7192(13)00366-1. doi: 10.1016/j.ymgme.2013.10.018.

*** Sealey WM. et al. Smoking accelerates biotin catabolism in women. Am J Clin Nutr. 2004 Oct;80(4):932-5.

**** Mock DM. et al. Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroenterol Nutr. 1998 Mar;26(3):245-50.

***** Mock NI. et al. Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased biotin status in experimental biotin deficiency. Am J Clin Nutr. 1997; 65: 951-958.

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Martha Spilioti, Athanasios Evangeliou, Despoina Tramma, Zoe Theodoridou, Spyridon Metaxas, Eleni Michailidi, Eleni Bonti, Helen Frysira, Katerina Haidopoulou, Despoina Asprangathou, Aggelos Tsalkidis, Panagiotis Kardaras, Ron Wevers, Cornelis Jakobs, & Michael Gibson (2013). Evidence for Treatable Inborn Errors of Metabolism in a Cohort of 187 Greek Patients with Autism Spectrum Disorder (ASD) Front. Hum. Neurosci.

2013 autism research review on Questioning Answers

So, we're here again.

The end of another year and time to look back on some of the highlights of the blogging year that was 2013 on Questioning Answers. The question is: are we any further forward when it comes to the autism spectrum, it's aetiology, nature and improving quality of life?

Penshaw monument @ Paul Whiteley 

I'm going to be optimistic this year and say yes in some respects we are. But there is still much further to go...

Month by month here's a few posts on research that I thought were pretty important.

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January
Well it all started with a bang. Deborah Fein and colleagues published their optimal outcomes paper detailing how in a well-defined group of children with a previous diagnosis of autism, their autistic symptoms had abated. As you can imagine, the notion that at least some autism might not be as immutable as was first thought caused quite a stir (see here) but the evidence is starting to pile up for at least one developmental trajectory fitting this optimal outcome grouping. Further evidence for a correlation between air pollution and autism was also published. And I was also involved in publishing a review paper on the use of gluten- and casein-free (GFCF) diets for autism (see here) which is a topic I'll be coming back to later in this post.

February
Functional gastrointestinal (GI) problems do seem to be over-represented in cases of autism according to the study by Susie Chandler and colleagues. I know that this is not necessarily new news but from a UK perspective, the source of the message was an important part of this paper, which also applies to later research talked about in December. This month also saw the start of a whole slew of papers in 2013 suggestive of an increased risk of offspring autism where certain antiepileptics were used during the nine months that made us (see here). Maternal autoantibodies to foetal brain tissue also registered on the research radar which again, I'll be coming back to. Personally, I was saddened to hear about the death of Prof. Ann-Mari Knivsberg who was there from the start when it came to the whole GFCF diet and autism research. Rest in peace Ann-Mari.

March
Common ground was a key message from the consortium looking at the genetic overlap between conditions like autism, ADHD, schizophrenia and the like. In many respects that conclusion set the tone for many debates on clinical nosology vs. real-life presentation which were aired during 2013. Parent-reported autism prevalence figures in the United States suggested that 1 in 50 children presented with an autism spectrum disorder (ASD) in 2011-2012. Transgenerational effects were put forward as another variable influencing autism risk as per the paper by Emma Frans (see here). And that most contentious of topics, bowel disorders and autism, received some welcome attention from Stephen Walker (see here).

April
Autism or the autisms? was a questioned posed by Andrew Whitehouse continuing the theme of real-life autism and all that heterogeneity that accompanies presentation. Many authors have seemingly begun to realise that whilst common symptoms unite under the diagnostic label of autism, the cause and path of those symptoms may very well be numerous. The paper by Chloe Wong and colleagues looking at the methylome and autism continued the rise and rise of epigenetic research in relation to those autisms. The question of a connection between Lyme disease and autism also came under the research spotlight, as did the folding placenta (see here) and some interesting speculations on gut bacteria (see here) though not necessarily portrayed accurately in the accompanying media.

May
IMFAR 2013 was held in the beautiful Basque Country. One talk in particular seemed to capture those changing perspectives about autism (sorry, the autisms) as the world was introduced to ESSENCE (see here) by Prof Gillberg. May also saw one of the most significant changes to autism for many years as the latest update to DSM - the DSM-V - came into being, and with it a reshape of how we come to define the condition. Alongside, we were introduced to RDoC (see here) and the diagnostic vs. research battle commenced. Whilst slightly outside of core autism, but nevertheless potentially relevant as comorbidity, Mary Rogers and colleagues talked about depression and its correlation with C.diff infection.

June
Flaming June certainly lived up to its name this year here in the UK. The prevalence of autism in Canada took up two posts in June (see here and here). I was particularly interested to read the paper by Lau and colleagues on immune reactivity to gluten in cases of autism (see here). The implication from their results of a non-coeliac gluten sensitivity as potentially being present in cases set the tone for further interesting work in this area in the following months. Indeed continuing that dietary strand, the study by David Ruskin and colleagues describing the results of a ketogenic diet on a mouse model of autism also provided some rather informative reading.

July
The gold-standard trial by Cheryl Claiman and colleagues looking at the use of tetrahydrobiopterin (sapropterin or BH4) for cases of autism reported some rather interesting results in terms of a positive impact on presented autism traits. I'm becoming quite interested in what BH4 might be able to do for some cases of autism building on its potential for the archetypal 'diet can affect behaviour' condition that is Phenylketonuria (PKU). Gut bacteria also emerged again as a target for autism research based on the work by Kang and colleagues (see here) suggestive that gut bacterial diversity differences might be linked to the presentation of autism outside of just any GI comorbidity. Similar research on those trillions of passengers we all carry was also detailed with regards to Myalgic encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS). And there was the introduction of maternal autoantibody-related autism or MAR autism for short (see here). More on that shortly.

August
August was definitely a 'leaky gut' month. I posted a sort of overview of where autism research is currently up to when it comes to intestinal hyperpermeability and lo and behold, Laura de Magistris and colleagues go and add to the literature (see here). Still there was more to come. In other research news, there was an interesting update to the body of work looking at recurrence risk of autism in siblings (see here) and a nice case study on the potential value of NAC (N-acetylcysteine) for at least some autism (see here). Just outside of autism, the association between schizophrenia and everyone's favourite marker of inflammation, C-reactive protein also received some attention (see here). August also saw an important step forward for autism practice here in the UK with the publication of the last strand of guidance from NICE on managing children and young adults with autism (see here).

September
MAR autism y'say? Well, storm clouds appeared at the suggestion that such research might be translated into something like a commercial test (see here). Indeed, with that notion of maternal immune activation and offspring signs and symptoms in mind, observations from monkeys (not just rodents) suggested similar issues to be present (see here). The presentation of autistic-like symptoms in cases of eating disorders was reported. As was yet more discussion on the use of certain antiepileptics during pregnancy potentially impacting on offspring behaviour (see here). October however had two main highlights for me though: (i) the publication of our first follow-up paper to the ScanBrit study of a GFCF diet (see here) on potential best-responder characteristics, and (ii) the study from Jonas Ludvigsson and colleagues on issues with gluten in autism probably not being coeliac (celiac) disease but potentially something just as interesting (see here). The rise of non-coeliac gluten sensitivity? Indeed, the Ludvigsson paper prompted one Alessio Fasano to say something pretty monumental on his analysis of the study which I'll quote again: "In the past, we have had the believers and nonbelievers when it came to the role of gluten in autism ... Hopefully this paper can clarify, once and for all, that a subset of those with autism has gluten sensitivity, a condition triggered by gluten but distinct from celiac disease." [source is here].

October
Continuing the theme of dietary intervention and autism (I'm not obsessed honest!), the paper by Graf-Myles and colleagues caught my attention and their notion that, assuming correct nutritional support, the horror that is the GFCF diet might not be as rotten a diet as first thought. I was also interested in the review by Xu and colleagues who upon meta-analysing all the relevant data concluded that maternal diabetes did seem to show a connection with a heightened risk of offspring autism (see here). Parental stress and the various ways and means that autism research has suggested it could be tackled was also covered in October (see here); as was the news that the autism numbers game here in the UK might be showing a plateau in prevalence and incidence rates (see here). Scientific replication also played it's part in autism research as per the 'failure to replicate' paper from Robinson and colleagues when looking at SNPs predicting autism (see here). Oh and MAR autism also showed an autoimmunity side...

November
I was very interested to read the paper by Lynne Wang and colleagues replicating some earlier findings on a possible role for Sutterella in cases of autism (see here). That and the suggestion of a particularly high prevalence of autism associated with cases of Neurofibromatosis 1 (NF-1) from Garg et al. A possible role for iodine and autism was also the topic of some preliminary research chatter (see here) as was paracetamol exposure, albeit not exactly with autism in mind (see here). And then there was the suggestion of overlap between a specific part of the autism spectrum and the issue of synaesthesia (a mixing of the senses) to consider.... bearing in mind a few gaps in the presented study.

December
Two pretty big papers started the month of December. Beginning with one of, possibly the, largest study so far looking at the presence of functional bowel issues in cases of autism we were again reminded that autism does seem to be over-represented when it comes to such problems. This was followed by the paper by Elaine Hsiao and Paul Patterson (see here) and others which brought their earlier conference proceedings on the presence of leaky gut in the maternal immune activated mouse model to the peer-review arena. Words like 'incredible' were used to describe the potential of altering the gut microbiota and impacting on both gut permeability and presented 'autistic-like' symptoms in their mice. I was enthused but remind readers that mice are mice not humans. Indeed that same sentiment distinguishing mice from humans was similarly applied to some interesting work suggestive of GI issues in the valproate mouse model of autism. That all being said, we also got some more confirmation that leaky gut can appear in real people with autism as per the Dalton findings. I'd hazard a guess that I'll be blogging about gut permeability and autism further in 2014 and beyond.

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And rest. Of course there was lots more research considered in 2013 but I assume you'll be too busy eating those turkey left-overs for me to overload you any further.

I think I am justified in repeating my optimistic appraisal that we know a little bit more about autism at the end of this year than we did at the beginning. The main themes as I see it are:

• autism is probably better described as 'the autisms' with various different develomental trajectories present in different people,
• there is so much more to autism than it just being related to 'the brain',
• comorbidity is important; often very important, and
• 'immutable and lifelong' are words which might not necessarily apply to every single case of autism bearing in mind we don't yet know for who and the precise reasons why. 

Finally, if you noticed the picture at the top of this post, it's one of my own taken back in September this year, of Penshaw monument (see here for more information) here in the bracing North-East of England. Oh and there's some legend to accompany this splendid structure... about a worm and no, not those kinds of worms, which I assume we'll be hearing more about in 2014 (see abstract T177).

And with that, here is to 2014 and no doubt, another interesting year for autism research ahead. Thanks for reading and a Happy New Year to you and yours.

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It's a difficult task but my autism research paper of the year (2013) goes to....

Fein D. et al. Optimal outcome in individuals with a history of autism. J Child Psychol Psychiatry. 2013 Feb;54(2):195-205. doi: 10.1111/jcpp.12037.

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Fein D, Barton M, Eigsti IM, Kelley E, Naigles L, Schultz RT, Stevens M, Helt M, Orinstein A, Rosenthal M, Troyb E, & Tyson K (2013). Optimal outcome in individuals with a history of autism. Journal of child psychology and psychiatry, and allied disciplines, 54 (2), 195-205 PMID: 23320807

Heightened anxiety in children with autism

Given that a certain portly chap with a white beard (yes, one of those fat yet fit types) is heading the way of many a household over the coming hours, I'm going to be quite brief in this post about the paper by Victoria Hallett and colleagues* who concluded that their "findings support previous reports of heightened anxiety in children with ASDs [autism spectrum disorders]". The realisation that Christmas can itself be a significant source of anxiety to many people as per the BBC article (here) is perhaps also worth directing your attention to, given the potential for overlap when discussing autism.

By Emile not Santa [Claus] @ Wikipedia 

I've talked (and talked) about how various forms of anxiety do seem to be over-represented when it comes to autism (see here for the mega-post) and the various ways and means that science has so far offered when it comes to helping to manage or relieve such issues, acknowledging that we still have some distance to go on this topic.

The Hallett paper in respect of finding 'parent-reported' anxiety to be present in children with autism is no new thing. That being said, their analysis based on data from TEDS (Twins Early Development Study) adds a new twist to the research in this area, as does their suggestion that "Unaffected co-twins of children with ASDs also showed increased anxiety, generating questions about the potential etiological overlap between ASDs and anxiety". Yes it certainly does generate questions, and in particular, whether the broader autism phenotype (BAP) might have another potential diagnostic string to add to its bow.

I note that at least some of this authorship group have previously talked about autism, twins and issues like anxiety (as part of the so-called internalising traits) as per papers like this one** and this one***. I was drawn to a particular quote in one of those papers: "these traits may serve to exacerbate each other over time" suggestive that intervention-wise at least, treating something like anxiety might have some interesting knock-on effects on the presentation of core autism traits and vice-versa. Another discussion for another time methinks, perhaps alongside the recent paper by Boulter and colleagues**** on intolerance of uncertainty in relation to anxiety present in cases of autism?

Anyhow, without further ado, I wish you all Happy Christmas or Seasons Greetings if you prefer. Stay tuned for the mega-roundup post of autism research that has appeared on this blog during 2013 coming up in the next few days. I leave you with some sound advice when it comes to cooking that over-sized turkey that you've probably bought to avoid any unfortunate incidents or undesirable trips to the smallest room in the house. Oh, and some research news that will hopefully raise a smile to any Hobbit fan...

And just before I go, yet again Shane and Kirsty perform for you the best Christmas song ever...

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* Hallett V. et al. Exploring anxiety symptoms in a large-scale twin study of children with autism spectrum disorders, their co-twins and controls. J Child Psychol Psychiatry. 2013 Nov;54(11):1176-85.

** Hallett V. et al. Association of autistic-like and internalizing traits during childhood: a longitudinal twin study. Am J Psychiatry. 2010 Jul;167(7):809-17. 

*** Hallett V. et al. Investigating the association between autistic-like and internalizing traits in a community-based twin sample. J Am Acad Child Adolesc Psychiatry. 2009 Jun;48(6):618-27.

**** Boulter C. et al. Intolerance of Uncertainty as a Framework for Understanding Anxiety in Children and Adolescents with Autism Spectrum Disorders. J Autism Dev Disord. 2013 Nov 24. 

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Hallett V, Ronald A, Colvert E, Ames C, Woodhouse E, Lietz S, Garnett T, Gillan N, Rijsdijk F, Scahill L, Bolton P, & Happé F. (2013). Exploring anxiety symptoms in a large-scale twin study of children with autism spectrum disorders, their co-twins and controls J Child Psychol Psychiatry, 54 (11), 1176-1185 DOI: 10.1111/jcpp.12068