Asthma as a risk factor for autism?

I start with a quote from the paper by Po-Hsin Tsai and colleagues [1]: "This prospective study indicated a temporal relation between asthma and subsequent ASD [autism spectrum disorder] diagnosis, supporting the immune hypothesis of ASD pathogenesis". Based on a familiar collaboration residing in Taiwan (see here and see here for some discussions on previous data), yet more evidence is emerging of a correlation between immune function, physiology and behavioural / developmental conditions.

Chen Cheng-po @ Wikipedia 

I say more evidence because as per the links above, I've posted about other research from this group looking at the comorbidity of allergic and autoimmune diseases in cases of autism [2] and more recently evidence linking early life asthma with a heightened risk of subsequent attention-deficit hyperactivity disorder (ADHD) [3].

So here goes with yet more data from this group based on their analysis of the National Health Insurance Research Database (NHIRD) in Taiwan. Natasa also receives a thank you for bringing the full-text of this paper to my [virtual] desk.

• An asthma cohort was plucked from the NHIRD based on the random selection of 1 million persons on the database. Those aged between 0-3 years and with a physician diagnosis of asthma (ICD diagnosis) (n=2134) were age- and sex-matched with 4 control patients (1:4 ratio) with no asthma and no recorded history of psychiatric disorder (n=8536). Researchers then looked at the frequency of "Psychiatrists diagnosed ASD" (ICD-9 autism) up to some 8 years later. Other variables were also recorded for participants including other atopic/allergic diseases and level of urbanisation.
• Results: well, as per the headline: "The asthmatic group exhibited higher incidence rates of ASD (1.3% vs 0.7%, P=.007)". As perhaps one would expect, levels of other allergic diseases were also more frequently reported for the asthma group. Also, the asthma group were slightly more likely to be living in urban areas than controls, although urbanisation was not reported to significantly increase the risk of ASD (see a related post here).
• Interestingly, the authors also suggest that the presence of asthma "influences the manifestation pattern of ASD" based on the fact that asthmatics tended to be diagnosed with ASD later than those who were diagnosed with ASD in the control group (although this difference was not statistically significant: 5.6 years experimental group vs. 4.5 years control group).

As the authors point out, there is some noticeable methodological strength in their findings based on the database used, the numbers of participants included and the prospective nature of their inquiry. They do however caution that a cause-and-effect relationship between asthma and autism is not proved from their data. This same sentiment could also be applied to the recent attention given to the study by D’Onofrio and colleagues [4] on that age-old (pardon the pun) issue of older dads and autism risk.

I've talked about asthma and autism previously on this blog (see here) and how there may indeed be some overlapping features when it comes to the two conditions. I also hark back to some of the work by Kevin Becker (see this post) and his speculations on autism, asthma, inflammation and the Hygiene hypothesis [5] (open-access) which may well have been borne out to some degree by the Tsai data. If you want to get even more speculative, you might also have a look at my past post talking about the opinions of Moises Velasquez-Manoff and the immune roots of autism (see here)... [sorry for the sweeping generalisation by the way].

The only other things I'll add to the authors speculations about the 'mast cell activation' hypothesis (see here) as being linked to the findings is the possibility of a couple of other variables being potentially related too. So, how about medication being a common factor as per the preliminary work throwing prenatal paracetamol (acetaminophen) into the research limelight? Or, with my sunshine vitamin interest in mind, how about vitamin D as being something to tie the two conditions together [6]? And then there's the bank of evidence talking about maternal infection being linked to offspring asthma [7] which invites further study of a growing area of interest with autism in mind. Finally, there is all the chatter about environmental exposures and asthma [8] (open-access) some of which, without making a sweeping generalisation about the definition of 'environmental exposure', may overlap with some autism discussions [9]. Quite a few lines of potential further investigation methinks.

Outside of the need for quite a lot more study on this association (importantly, replication with other geographical datasets) including disentangling the very complicated issue of immune function and autism, there is a potentially important message to take from the Tsai data. Although perhaps only a small increased risk where early asthma is present, one might think about some additional screening for conditions like autism or ADHD just in case?

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[1] Tsai PH. et al. Increased risk of autism spectrum disorder among early life asthma patients: An 8-year nationwide population-based prospective study. Research in Autism Spectrum Disorders. 2014; 8: 381-386.

[2] Chen MH. et al. Comorbidity of allergic and autoimmune diseases in patients with autism spectrum disorder: A nationwide population-based study. Research in Autism Spectrum Disorders. 2013; 7: 205-212.

[3] Chen MH. et al. Asthma and attention-deficit/hyperactivity disorder: a nationwide population-based prospective cohort study. J Child Psychol Psychiatry. 2013 Nov;54(11):1208-14.

[4] D’Onofrio BM. et al. Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity. JAMA Psychiatry. 2014. February 26.

[5] Becker KG. Autism, Asthma, Inflammation, and the Hygiene Hypothesis. Med Hypotheses. 2007; 69(4): 731–740.

[6] Gupta A. et al. Vitamin D and asthma in children. Paediatr Respir Rev. 2012 Dec;13(4):236-43

[7] Illi S. et al. Perinatal influences on the development of asthma and atopy in childhood. Annals of Allergy, Asthma & Immunology. 2014; 112: 132-139.

[8] Matsui EC. Environmental exposures and asthma morbidity in children living in urban neighborhoods. Allergy 2014; DOI: 10.1111/all.12361.

[9] Grandjean P. & Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014 Mar;13(3):330-338.

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Po-Hsin Tsai, Mu-Hong Chen, Tung-Ping Su, Ying-Sheue Chen, Ju-Wei Hsu, Kai-Lin Huang, Wen-Han Chang, Tzeng-Ji Chen, & Ya-Mei Bai (2014). Increased risk of autism spectrum disorder among early life asthma patients: An 8-year nationwide population-based prospective study. Research in Autism Spectrum Disorders DOI: 10.1016/j.rasd.2013.12.022

Pregnancy paracetamol use and offspring ADHD traits?

Poor old paracetamol (acetaminophen if you wish).

Tablets (before tablets again) @ Wikipedia

First it was the Brandlistuen correlation [1] suggesting that sustained exposure in-utero may impact on childhood developmental outcome (see here for my take). Now another swipe has been taken at this pharmaceutical stalwart of pain relief / fever reduction with the publication of results by Zeyan Liew and colleagues [2] suggesting that: "Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children". HKDs by the way, refer to hyperkinetic disorders which includes the diagnosis of attention deficit hyperactivity disorder (ADHD) (see here).

Given what the Liew results suggested, together with the impact of the publishing journal (the journal family of which currently carries some interesting news about US pediatric obesity rates), it's little surprise that headlines such as: 'Acetaminophen use in pregnancy may be linked to ADHD ' and sub-headings like: 'Moms-to-be who relieve pain with acetaminophen may be setting their children up for hyperactivity' have appeared all around this work.

Reliant on data from another Scandinavian registry - the Danish National Birth Cohort [3] - (no, not MoBa), researchers looked at data covering nearly 65,000 children whose mothers were asked to report on paracetamol use during pregnancy and parent-reported "behavioral problems in [offspring] children 7 years of age". They used a variety of materials to ascertain the presence or not of those HKDs and ADHD-like behaviours including the Strengths and Difficulties Questionnaire and diagnostic and prescription information related to ADHD.

The results: "More than half of all mothers reported acetaminophen use while pregnant". Nothing particularly unusual about this fact given that paracetamol enjoys a place in most medicine cabinets as a drug of choice when it comes to pain relief and/or fever. But then the correlations: "Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27)". That and the fact that something like a dose-response relationship seemed to be emerging from the collected data, and one has a story that will make most readers sit-up to attention.

The accompanying editorial on the study [4] is also worthwhile reading so as to emphasise that correlation is not the same as causation and the important requirement to replicate this experiment before drawing too many conclusions at this time. As I mentioned in my post on the previous paracetamol - childhood outcomes study, asking participants about their use of commonly available medicines like paracetamol during pregnancy (even prospectively) is not the same as looking at prescriptions data based on frequency and dosage (as the authors did in relation to the use of something like methylphenidate as a proxy for subsequent offspring ADHD diagnosis/behaviours).

That being said, alongside the Brandlistuen results (which themselves have been discussed in the peer-reviewed forum [5]) this latest data add to a worrying trend when it comes to paracetamol use during pregnancy. How, just because it is an over-the-counter (OTC) medicine, this does not mean one should treat it with any less care than a prescription drug.

The good thing, if there is any good thing to come out of this study, is that unlike the growing pains of the emerging valproate - childhood development story, paracetamol is for pain relief and not a must-take medicine for a must-treat condition like epilepsy. Granted, one has to be careful about the alternatives to paracetamol (as per the dos and don't of ibuprofen use during pregnancy) but I'm sure that other solutions can be found during the nine months that made you? [6] (open-access).

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[1] Brandlistuen RE. et al. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013 Dec;42(6):1702-13.

[2] Liew Z. et al. Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders. JAMA Pediatr. 2014; February 24.

[3] Olsen J. et al. The Danish National Birth Cohort - its background, structure and aim. Scand J Public Health 2001; 29: 300-307.

[4] Cooper M. et al. Antenatal Acetaminophen Use and Attention-Deficit/Hyperactivity Disorder
An Interesting Observed Association But Too Early to Infer Causality. JAMA Pediatr. 2014; February 24.

[5] Cannell JJ. Paracetamol, oxidative stress, vitamin D and autism spectrum disorders. Int J Epidemiol. 2014 Feb 11.

[6] Lewis AJ. et al. Early life programming as a target for prevention of child and adolescent mental disorders. BMC Medicine 2014; 12: 33

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Zeyan Liew, Beate Ritz, Cristina Rebordosa, Pei-Chen Lee, & Jørn Olsen (2014). Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders JAMA Pediatrics DOI: 10.1001/jamapediatrics.2013.4914

The [universal] early identification of autism or not?

As I might have already intimated, whilst I'm all in favour of the very early identification of autism and the potential effects this might bring to a child in terms of something like benefiting from early intervention, I'm not overly enthused by the collected evidence which has been amassed so far in this area despite some promising data.

Under my umbrellas @ Wikipedia 

Most people with some knowledge of autism will know that it is an extremely heterogeneous condition, with presentation also seemingly tied up with the risk of various other comorbidity appearing alongside. That autism also seems to include an element of regression for quite few on the spectrum, means that the holy grail that is very early red flags hinting at the earliest manifestation(s) of autism is going to be a difficult universal concept to find. Also complicated by various other factors including ethnicity, issues around the possible stability of symptoms in the early years and the possibility of plural autisms. Oh and healthcare providers can, on occasion, be barriers themselves too (see here).

Two papers recently caught my eye on this topic, coming to quite different conclusions.

The first paper by Samango-Sprouse and colleagues* based on an impressive participant number (N=1024) reported that their "study demonstrates an efficient means to identify infants at risk for autism spectrum disorder by 9 months of age and serves to alert primary care providers of infants who are vulnerable for autism spectrum disorder before symptoms are discernible by clinical judgment of primary care providers, parental concerns, or by screening questionnaires". They arrived at this conclusion on the basis of "abrupt head circumference acceleration and the absence of head tilt reflex by 9 months were used to identify infants at risk for autism spectrum disorder". So, with some more work to do, looking at head size and the head tilt reflex might be something to watch for in subsequent publications.

The second paper by Stenberg and colleagues** including an authorship list of the great and good of autism research (including Drs Hornig and Lipkin) came to a rather different conclusion based on the behavioural identification of children aged 18 months as likely having autism: "results imply that it might not be possible to detect all children with ASD at this age". Their participant size was even more impressive.

Of course I am kinda looking at apples and pears in comparing these two findings. The Samango-Sprouse study looking at something rather more physiological than behavioural, as compared to the Stenberg findings which was putting the M-CHAT (Modified Checklist for Autism in Toddlers) screening tool through it's paces based to a large part on the MoBa cohort. Again, with ear to the autism research ground, some people might remember that M-CHAT (itself a revision of the CHAT) has gone through even more adaptation fairly recently with the Diana Robins paper*** talking about M-CHAT-R/F (see here for more details). One therefore wonders if the Stenberg findings are already out-of-date even before they were published?

Insofar as the issue of rapid head circumference acceleration being potentially linked to the development of autism, well, we know the topic of head size and autism is a complicated one (see this previous post). I'm also thinking back to the work that came out the MIND Institute a couple of years back, which suggested that brain enlargement in relation to autism might show some link to the issue of regression (see here) at least for some types of autism. Quite how this data (if reproduced) would impact on the Samango-Sprouse findings is still unclear.

Don't get me wrong, the issue of early red flags potentially pointing to autism is a very, very important area of autism research. Every once in a while one hears about some ground-breaking research that a new marker for autism is on the horizon - see Jon Brock's post one example of this a few months back - but more often than not, nothing further comes of such research. What perhaps I would like to see more of in this area are a few things:

• some better appreciation for 'the autisms' over the singular concept of autism (and different developmental profiles / red flags potentially being present across different sub-groups?),
• greater amalgamation of various sources of information, behavioural and physiological, to see if looking at overt signs and symptoms together with something like head growth charts, might actually yield more real-world effects in combination. Although seemingly forgotten, the issue of airway anatomy and autism (no, really) might also be something to include here alongside other early markers that have been previously suggested.

Oh, and remember that at least one of the diagnostic schedules to denote autism or not has recently gone through a bit of a change, so one waits to see how this might affect all this early identification talk too.

Music to close. Having seen the Lego Movie not-so-long ago with some of my brood, I can very much recommend it for all ages. And just remember: everything is awesome...

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* Samango-Sprouse CA. et al. Identification of infants at risk for autism spectrum disorder and developmental language delay prior to 12 months. Autism. 2014 Feb 18.

** Stenberg N. et al. Identifying Children with Autism Spectrum Disorder at 18 Months in a General Population Sample. Paediatr Perinat Epidemiol. 2014 Feb 18.

*** Robins DL. et al. Validation of the modified checklist for Autism in toddlers, revised with follow-up (M-CHAT-R/F). Pediatrics. 2014 Jan;133(1):37-45.

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Samango-Sprouse CA, Stapleton EJ, Aliabadi F, Graw R, Vickers R, Haskell K, Sadeghin T, Jameson R, Parmele CL, & Gropman AL (2014). Identification of infants at risk for autism spectrum disorder and developmental language delay prior to 12 months. Autism : the international journal of research and practice PMID: 24550549



Stenberg N, Bresnahan M, Gunnes N, Hirtz D, Hornig M, Lie KK, Lipkin WI, Lord C, Magnus P, Reichborn-Kjennerud T, Schjølberg S, Surén P, Susser E, Svendsen BK, von Tetzchner S, Oyen AS, & Stoltenberg C. (2014). Identifying Children with Autism Spectrum Disorder at 18 Months in a General Population Sample Paediatr Perinat Epidemiol. DOI: 10.1111/ppe.12114

Paediatric autoimmune enteropathy: I did not know that

Consider this post one of my 'other musings' entries on this blog and also a slightly more descriptive post than usual.

The source paper today is by Singhi and colleagues* discussing the pretty rare condition paediatric autoimmune enteropathy (AIE), which I have to say was a bit of an eye-opener for me. Associated with protracted diarrhoea (sorry if your eating at the moment), weight loss and gut mucosa damage, the crux of the paper by Singhi et al seemed to be that the gut or gastrointestinal tract is a central organ affected by AIE - hence the enteropathy bit of the condition description - but also that "autoimmune enteropathy in children is a heterogeneous disease with protean clinical and pathologic findings". Protean by the way, means readily assuming different forms or characters (yes, I had to look it up).

I say that this is another one of my other musings post, but one of the first people to describe this condition was one Prof. John Walker-Smith** who some people might know from the still quite contentious area of gut physiology and autism*** (see a related post here). Mention of the gluten-free (GF) diet in amongst the AIE literature also piqued my attention, allowing for the fact that such dietary intervention does not seem to help in many cases of AIE**** as it does more frequently in coeliac (celiac) disease.

With my non-expert hat very firmly in place when it comes to AIE and my caveat about not giving medical or clinical advice on this blog, I was rather interested in the condition and so set about looking at some of the related literature around it to share with you. Here goes:

• AIE is a serious condition primarily reported in very young infants. I say serious because in quite a few of the experimental reports of AIE, mortality is, unfortunately, mentioned (see here for an example). 
• Whilst quite a lot of the research literature is focused on AIE in children as a function of the increased likelihood of occurring infancy, there is a body of research suggesting that adults can also present with the condition*****. In some quarters, that adult presentation has been linked to refractory sprue. 
• Boys are over-represented in AIE. 
• Gut epithelial cell antibodies - that is an immune response to the cells lining the gut - characterise this disease. In particular, anti-enterocyte antibodies are reported to be an important part of AIE as per the link with autoimmunity. That being said, anti-goblet (the mucus producing cells) and anti-Paneth (important defender cells of the gut) cell antibodies have also been reported in cases. 
• The autoimmunity link is certainly strong when it comes to AIE as per the varied comorbidity and other autoantibodies tied into presentation******. T-cells, and in particular Th-17 cells, which have been linked on more than one occasion to autoimmune conditions (see here), have been a focal point for the pathology of AIE*******. Indeed to quote the article by Ruemmele et al "Anti-enterocyte autoantibodies .... seem to be of a secondary nature and can no more be considered as directly disease causing".
• Going back to the Singhi paper, the autoimmune element to AIE has very much informed the therapeutic response to AIE and the use of various immuno-suppressing medicines. So starting with things like steroids, treatment can also include cyclosporin (see here********), tacrolimus and cyclophosphamide. Other therapeutic interventions also include anti-lymphocyte immunoglobulin and eventually in some cases, a bone marrow transplant (see here too). I did wonder, in light of the recent-ish news that alefacept - another immuno-suppressive medicine - might impact on the presentation of another autoimmune conditions, type 1 diabetes (see here), whether there may be other treatment options waiting in the wings too.

I'm gonna stop at that with this very descriptive post. AIE is a complicated condition which is both heterogeneous and potentially carrying quite a bit of other autoimmune related baggage. I do get the impression from quite a few sources that in almost 30 years since formal description, some progress has been made on discovering how AIE is expressed and indeed, in treating the condition. One might say that the advent of immuno-suppressive therapeutic options being applied to AIE, has been nothing short of remarkable in terms of long-term prognosis.

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* Singhi AD. et al. Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders. Mod Pathol. 2013 Sep 20. doi: 10.1038/modpathol.2013.150.

** Unsworth DJ. & Walker-Smith JA. Autoimmunity in diarrhoeal disease. J Pediatr Gastroenterol Nutr. 1985 Jun;4(3):375-80.

*** Ashwood P. et al. Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin Immunol. 2003 Nov;23(6):504-17.

**** Walker-Smith JA. Coeliac Disease and Autoimmune Enteropathy. Developments in Gastroenterology. 1991; 13: 131-136.

***** Freeman HJ. Adult autoimmune enteropathy. World J Gastroenterol. 2008. 14(8): 1156–1158.

****** Akram S. et al. Adult autoimmune enteropathy: Mayo Clinic Rochester experience. Clin Gastroenterol Hepatol. 2007 Nov;5(11):1282-90.

******* Ruemmele FM. et al. Autoimmune enteropathy: molecular concepts. Curr Opin Gastroenterol. 2004 Nov;20(6):587-91.

******** Sanderson IR. et al. Response to autoimmune enteropathy to cyclosporin A therapy. Gut. 1991 Nov;32(11):1421-5.

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Singhi AD, Goyal A, Davison JM, Regueiro MD, Roche RL, & Ranganathan S (2013). Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc PMID: 24051695

BCKDK mutations and autism continued?

February 19th 2014 (yesterday). Questioning Answers celebrates 3 years of life as a blog. Happy birthday. To quote from one website: "Congratulations, you have survived the "terrible two's!"'. Maybe I should start claiming some free early education for it too?

You are 3 @ Paul Whiteley

Anyhow...

Cast your mind back to September 2012 and the publication of a paper by Gaia Novarino and colleagues* which I posted about (see here) discussing some interesting observations with respect to a potentially treatable form of autism.

The main point of the Novarino research was how genetic mutations upset a delicate biochemical balance. Various 'inactivating' genetic mutations in respect of the BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) gene have knock-on implications for the production or rather non-production of BCKDK protein. Lower levels of this protein/enzyme left another important group of enzymes, the branched-chain keto-acid dehydrogenase complex (BCKD) to run unchecked which has implications for the metabolism and over-zealous degradation of branched-chain amino acids. The resulting lower levels of these branched-chain amino acids (BCAAs) seemed to correlate with presence of epilepsy and behavioural issues not a million miles away from those which characterise autism. Supplementation with BCAAs seemed to have a positive restorative effect on said behavioural issues. And rest.

Both then and now I consider these findings to be extremely interesting. As indicated on my post at the time, they hint at both some interesting roles for various amino acids in cases of autism (see here) and provided some exquisite evidence for the plurality of autism: the autisms (see here). That they also follow a pattern of inborn errors of metabolism being potentially linked to autism was also an important point.

Enter then another paper on BCKDK mutations by García-Cazorla and colleagues** found in two children presenting with "developmental delay, microcephaly and neurobehavioral abnormalities" also demonstrating the potential power of the BCAAs in affecting symptom presentation.

A few details about the latest study:

• It was a small study looking at two children who presented with "two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, [that] were identified at the homozygous state". Homozygous refers to the issue of genetic zygosity which, as the results go on to report, very much impacted on the function of BCKDK: "Mutation p.L389P showed total loss of kinase activity".
• Authors also confirmed how detrimental the mutations were based on analysis of "patient-derived fibroblasts" and how undetectable or barely detectable levels of BCKDK protein (the product of the BCKDK gene) resulted "in increased BCKD activity and the very rapid BCAA catabolism".
• They conclude that for one of the children who presented with undetectable levels of the BCKDK protein, use of a BCAA supplement "normalized plasma BCAA levels and improved growth, developmental and behavioral variables".

Obviously one has to be a little careful in extrapolating these results to the wider population of autism. This is a report of specific identified cases where genetic mutations of the BCKDK gene were found and the resultant biological effect of mutation confirmed. They don't imply that supplementing willy-nilly with BCAAs will impact on all cases of autism and neither am I suggesting they will. Autisms not autism...

That being said, there is another message to come from this paper on the value of keeping an open mind when it comes to look at the potential underlying genetics and biochemistry of autism. Not so long ago for example, I talked about the paper by Spilioti and colleagues (see here) on the presence of inborn errors of metabolism in their participant group diagnosed with autism. The message there was if you don't look, don't expect to find anything. Indeed, if you need some further evidence for this message I would also direct you to the work by Celestino-Soper and colleagues (see here) on another compound, carnitine, and their analysis of the gene Trimethyllysine Hydroxylase, Epsilon (TMLHE) in relation to carnitine and autism. Again, you've got to look to find or not find. And the papers keep coming***...

I'm going to keep my eye out for any further information on BCKDK mutations...

To close, no music link today but rather following some rather interesting conversations with my brood about winners and losers across the previous 6 films of the Star Wars saga, I vote for Darth Sidious as being the real winner... "unlimited power" and all that.

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* Novarino G. et al. Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy. Science. 2012; 338: 394-397.

** García-Cazorla A. et al. Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients. Hum Mutat. 2014 Jan 21. doi: 10.1002/humu.22513.

*** Helsmoortel C. et al. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nature Genetics. 2014. 16 Feb.

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García-Cazorla A, Oyarzabal A, Fort J, Robles C, Castejón E, Ruiz-Sala P, Bodoy S, Merinero B, Lopez-Sala A, Dopazo J, Nunes V, Ugarte M, Artuch R, Palacín M, Rodríguez-Pombo P, & Working Group (2014). Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients. Human mutation PMID: 24449431

HLA alleles and specific language impairment

I've talked about the [almighty] major histocompatibility complex (MHC) before on this blog (see here). The important duties that this biological system performs in relation to identification and communication insofar as antigen presentation and importantly, the process of differentiation between 'self' and 'non-self' from an immunological perspective, are not to be sniffed at.

Harold? @ Wikipedia

I've found myself quite interested in all things MHC (also referring to the human leukocyte antigen, HLA, genes) from quite a few different perspectives. Be it with reference to the genetics of coeliac (celiac) disease (see here) or the very preliminary work being discussed on HERVs [human endogenous retroviruses], or rather HERV proteins, as being possible superantigens in relation to a condition such as myalgic encephalomyelitis (ME) (see here), there's lots to think about when it comes to the MHC.

So when I stumbled across the paper by Ron Nudel and colleagues [1] (open-access here) talking about "a possible role for HLA loci in language disorders" my attention was piqued. Before progressing into some of the details behind the Nudel paper, it's important to note the authorship team involved in this research paper. Alongside some quite well-known names attached to autism research (see here and see here for example), I was also interested to see Gillie Baird as one of the research team. Prof. Baird has impressed me in recent times; not only with her research involvement looking into the whole functional bowel issues in autism research (see here) but also with that recent 'leaky gut' paper with autism in mind (see here) which despite some methodological 'issues' gave me cause to smile that this area was at last starting to be taken seriously in more orthodox circles. Who knows, one day even the NICE guidance might recognise it as a potentially important comorbidity?

No mind, a few details from the Nudel paper are noteworthy, accepting that the paper is open-access:

• This was a multi-centre study looking at "the possible involvement of HLA loci in SLI [specific language impairment]". Loci by the way, is the plural of locus, and with genes in mind, refers to specific locations on a gene, DNA sequence or chromosome; a sort of area or postcode if you will. Participants were mostly derived from the SLIC (SLI consortium) groups with additional families included. All were assessed as having a SLI; all did not have autism, but some had comorbid features of ADHD and/or dyslexia. A control group was also included for some of the analyses.
• OK here's where is starts to get a little bit complicated. I found quite a nice website talking about the ways and means that HLA genes are indexed in terms of nomenclature. The complexity of the HLA genes and their molecules derives from the fact that HLA genes are highly polymorphic (see here). Regular readers might have heard me talk about SNPs (Single Nucleotide Polymorphisms) before reflecting single changes to the genetic alphabet. In the case of HLA genes it gets a little more complex (see here) and, as such, specific terminology has been introduced. I'll also draw your attention the description of an allele too (see here). 
• So, first researchers went looking for SNPs "across the HLA [genetic] region". Further, they then imputed HLA type from the SNP data to see if there was any connection between HLA type(s) and SLI or the specific parts of SLI from a psychometric point of view.
• Results: The HLA-A locus seemed to show a possible connection for "susceptibility to SLI". The A1 allele (HLA-A A1) in particular came out as the "most highly positively correlated allele". When it came to looking at SLI cases vs. controls, the "DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls". There are some other findings reported in terms of parental inheritance patterns but I'm going to leave those for now.
• The authors conclude that their preliminary data requires further study but: "provide an intriguing link to those described by previous studies of other neurodevelopmental disorders suggesting a possible role for HLA loci in language disorders".

I'm sure you can see why I was so interested in this paper. The bigger picture of the HLA (MHC if you prefer) being potentially implicated in something other than just immune function and all those 'self' and 'non-self' duties, opens up a whole new world of research. Given also my increasing interest in all things autoimmunity with an autism research slant, I'm minded to suggest that this may go some much further than anyone ever suspected [2]. That being said I would direct readers to the graphs showing the frequencies of alleles across the different HLA genes to see how aside from the HLA-DRB1 DR10 allele, this is more of a 'shades of grey' over and above 'there or not' pattern of findings when comparing SLI and non-SLI groups.

Looking back at some of the quite limited autism research in this area, I did find some clues that HLA involvement in SLI should perhaps not be totally unexpected as a function of the potential overlap between autism and SLI [3]. I say this acknowledging the debates are still on-going about the links or not between the two conditions and also that Nudel and colleagues ruled out autism as a diagnosis in their particular cohort. As an aside, readers might also find a recent post by Dorothy Bishop of interest, and in particular her model C for language development.

HLA alleles and autism? Well, you might say this is an emerging area in light of results like those from Mostafa and colleagues [4]. I dare say there may be other HLA overlap with other findings from autism research (see the open-access review from Torres and colleagues [5] for further reading). More recently I also stumbled across the paper by Al-Hakbany and colleagues [6] (open-access) which continued discussions about overlapping alleles (I'll probably formulate a separate post on that research soon).

The late Reed Warren also talked about the null allele of C4B [7] (see here for some more explanation on this) quite a few years back now, and as intimated in a past blog entry on his later work, reading disorders and ADHD actually turned up as being more relevant to the null allele than autism did (67%, 56% and 48% respectively). OK SLI is not necessarily reading disorder or ADHD, but as Nudel and colleagues noted there is a "high degree of co-occurrence for SLI and ADHD or dyslexia".

I think it's also important to recognise that those HLA types talked about in the Nudel study aren't just limited to behavioural or psychiatric conditions. I'm not going to go through the myriad of conditions and clinical findings related to the HLA alleles identified, but suffice to say that we perhaps need to look at a bigger picture when interpreting this data. This includes whether there may be other comorbidity present in those SLI cases - including somatic comorbidity - which might link into HLA genotype as per previous work looking at coeliac disease and ADHD for example (see here). SLI like autism like every other behavioural, developmental or psychiatric condition does not just exist in a diagnostic vacuum.

Still, I'll say again that this is a potentially very important paper which potentially opens up a whole new world of research...

Music. The life and times of Nelson Mandela will always remain in the public consciousness. I always fondly remember the Special AKA tribute to the great man.

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[1] Nudel R. et al. Associations of HLA alleles with specific language impairment. J Neurodev Disord. 2014 Jan 17;6(1):1.

[2] Choudhury N. & Benasich AA. A family aggregation study: the influence of family history and other risk factors on language development. J Speech Lang Hear Res. 2003 Apr;46(2):261-72.

[3] Bishop DV. Autism and specific language impairment: categorical distinction or continuum? Novartis Found Symp. 2003;251:213-26

[4] Mostafa GA. et al. The link between some alleles on human leukocyte antigen system and autism in children. J Neuroimmunol. 2013 Feb 15;255(1-2):70-4.

[5] Torres AR. et al. HLA Immune Function Genes in Autism. Autism Res Treat. 2012;2012:959073.

[6] Al-Hakbany M. et al. The Relationship of HLA Class I and II Alleles and Haplotypes with Autism: A Case Control Study. Autism Res Treat. 2014; 2014: 242048

[7] Warren RP. et al. Increased frequency of the null allele at the complement C4b locus in autism. Clin Exp Immunol. 1991 Mar;83(3):438-40.

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Nudel R, Simpson NH, Baird G, O Hare A, Conti-Ramsden G, Bolton PF, Hennessy ER, Monaco AP, Knight JC, Winney B, Fisher SE, & Newbury DF (2014). Associations of HLA alleles with specific language impairment. Journal of neurodevelopmental disorders, 6 (1) PMID: 24433325

Does not support an association...

I want to briefly draw your attention to the paper by Fernando Navarro and colleagues* which concluded: "Our study although underpowered to show small differences does not support an association between dietary gluten/milk, IP [intestinal permeability], and behavioral changes in subjects with ASD". At the moment, I'm only blogging based on the study abstract so I'm gonna keep things quite brief and will post again when I have the full-text. BTW we had heard that this study was coming as far back as 2008 (see here for some media).

Anyone who knows me and my interest in all-things autism spectrum conditions would probably understand my degree of disappointment in the above statement from the study. Whilst having great faith in the principles of science and the scientific method, it's always a little bit difficult to digest results which cast doubt on something which you've put quite a few weeks/months/years examining (see here) particularly when published in the same journal that you have (see here and see here). But I do feel it's important to blog about the Navarro findings so as to remain impartial and objective and show that there are two sides to every science story.

The Novarro study, utilising the gold-standard randomised double-blind placebo controlled study design, looked at two elements which have cropped up with some frequency over the past few years when it comes to autism: (1) that removal of foods containing gluten and/or casein may impact on the presentation of some cases of autism (see here) and (2) leaky gut or rather intestinal hyperpermeability may be one reason why said dietary components seem to show some effect on cases of autism (see here).

Based on quite a short study duration (4 weeks) it appears that: "Neither the L/M ratio [lactoluse:mannitol ratio] nor behavioral scores were different between groups exposed to gluten/dairy or placebo. The changes observed were noted to be small and not clinically significant". I could start savaging the short study duration or what I think was the relatively small participant group included or the reliance on "the Aberrant Behavior Checklist and Conners Parent Rating [Scale]" but sour grapes don't make for good science. Indeed, I need to reiterate that this was a gold-standard trial in terms of methodology... This is also not the first time that the gluten- and casein-free (GFCF) diet for autism has fallen at the experimental stage as per the results reported by Elder and colleagues** under similar experimental conditions.

I'm not going to say much more than what I have already at this stage. I'm sure various opinions will be voiced about this study depending to some degree, on one's perspective on dietary intervention for autism and well, that's fair enough.

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* Navarro F. et al. Are ‘leaky gut’ and behavior associated with gluten and dairy containing diet in children with autism spectrum disorders? Nutr Neurosci [Advance Article] DOI: 10.1179/1476830514Y.0000000110

** Whiteley P. et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010 Apr;13(2):87-100.

*** Pedersen L. et al. Data mining the ScanBrit study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders: Behavioural and psychometric measures of dietary response. Nutr Neurosci. 2013 Sep 7. [Epub ahead of print]

**** Elder JH. et al. The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord. 2006 Apr;36(3):413-20.

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Fernando Navarro, Deborah A Pearson, Nicole Fatheree, Rosleen Mansour, S Shahrukh Hashmi, & J Marc Rhoads (2014). Are ‘leaky gut’ and behavior associated with gluten and dairy containing diet in children with autism spectrum disorders? Nutritional Neuroscience DOI: 10.1179/1476830514Y.0000000110

Gluten-free diet, immune response and autism?

I was heartened to see the publication of the paper by Giacomo Caio and colleagues* (open-access version available here) discussing how the use of a gluten-free diet has a pretty obvious effect on the presence of IgG anti-gliadin antibodies in cases of non-coeliac gluten sensitivity (NCGS). To quote from the Caio paper: "Anti-gliadin antibodies [AGA] of the IgG class disappear in patients with non-celiac gluten sensitivity reflecting a strict compliance to the gluten-free diet and a good clinical response to gluten withdrawal". NCGS is a real interest of mine and for any UK pharmacists out there, you can access an article I helped write about it not so long ago (see here).

For those who might need a little background, antibodies to something like gliadin (part of the protein gluten derived from various cereal produce) represent the ever-vigilant immune system labelling gluten as 'foreign' and taking appropriate biological action. You might say, well gluten is foreign (as opposed to self i.e. the body) and so should be immune labelled in such a way. But if this were the case then everyone would be mounting an immune response to gluten and well, then we probably wouldn't be consuming it in the first place.

Also have a think about it... how does the immune system come into contact with something like gliadin in the first place? We eat foods containing gluten and after some chopping up by various enzymes in that long dark corridor we call the gastrointestinal (GI) tract, we are supposed to derive nutrition from such feasts. Gluten and other proteins/peptides should in the most part be confined to the GI tract and hence not meeting immune function aside from the odd brush with the various mucus membranes in the GI tract. So, why does the immune system start to recognise said proteins and mount a response to them via the production of antibodies in some people? I'll come back to this question shortly.

Anyhow, extrapolating the Caio results to instances where IgG antibodies to gliadin have been reported in the scientific literature, we end up with some intriguing suggestions when it comes to cases of autism. Indeed, we also arrive at some interesting work in other behaviourally defined conditions including schizophrenia (see here) but I'm gonna leave that side of things for now.

The finding by Caio that "AGA IgG persisted positive only in 3 (6.8 %) out of the 44 NCGS patients tested after 6 months of gluten withdrawal" to me suggests something really rather important when one takes on board the AGA findings reported in cases of autism by Lau and colleagues** and de Magistris and colleagues***. Not only does it suggest that some cases of autism might fall into that NCGS category but also that there is appropriate justification to implement a gluten-free diet in order to reduce that immunological load towards gliadin. That is, if one is to ensure that a label of autism does not equate to health inequality in this area...

There is another interesting detail within the Caio paper with regards to their comparisons to participants who presented with the more classical gluten-related condition, coeliac (celiac) disease insofar as those with NCGS and their intestinal presentation. Another quote: "Small intestinal biopsy, tested in all of them on a gluten-containing diet, showed either a normal mucosa (Marsh 0) (n = 26) (58 %) or mild abnormalities (n = 18) (42 %), with an increased number of intra-epithelial lymphocytes (Marsh 1)". If you click on the link above to a mega-post I wrote on 'what is coeliac disease' you'll get a flavour for what the Marsh criteria are. What the Caio results suggest is that the characteristic mucosal findings normally related to a diagnosis of coeliac disease were not present in the NCGS group, which interestingly enough was also similar to the findings from Ludvigsson and colleagues**** in cases of autism which I talked about in a previous post (see here). Perhaps even more evidence that some autism might fit into that NCGS category?

Going back to that question of what makes the immune system react to gliadin in some people and not others, well, again I'm leaning towards some possible effect from issues like gut hyperpermeability (the so-called leaky gut) as being one possible mechanism. I'll direct readers back to another of my mega-posts on all-things leaky gut and autism for some further details about this (see here) but as yet, I can't for sure provide you with details of a specific biological mechanism of effect outside of the present generalisations.

Still, I'll reiterate that the Caio findings are potentially very important to research examining the link between some cases of autism and dietary components like gluten (or gliadin) and certainly add to the speculation that NCGS may be a valid clinical entity for some on the spectrum.

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* Caio G. et al. Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity. BMC Gastroenterol. 2014 Feb 13;14(1):26.

** Lau NM. et al. Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS One. 2013 Jun 18;8(6):e66155.

*** de Magistris L. et al. Antibodies against food antigens in patients with autistic spectrum disorders. Biomed Res Int. 2013;2013:729349.

**** Ludvigsson JF. et al. A nationwide study of the association between celiac disease and the risk of autistic spectrum disorders. JAMA Psychiatry. 2013 Nov;70(11):1224-30.

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Caio G, Volta U, Tovoli F, & De Giorgio R (2014). Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity. BMC gastroenterology, 14 (1) PMID: 24524388

Vitamin-mineral mix for ADHD?

The BBC quite recently ran with the headline: "Vitamins ‘effective in treating ADHD symptoms’" discussing an interesting paper by Julia Rucklidge and colleagues* reporting results from a controlled trial of a vitamin-mineral mix on 80 adults diagnosed with Attention-Deficit Hyperactivity Disorder (ADHD). The trial entry can be seen here and NHS Choices have also given the trial the research once-over.

Food n' medicine? @ Wikipedia 

The paper, by someone who is not an unfamiliar name to this blog based on some previous work looking at micronutrients for stress after earthquake (see here and see here), utilised the gold-standard of experimental design (double-blind randomised placebo-controlled trial). The authorship team looked at an all-in-one supplement containing things like "vitamin D, vitamin B12, folate, magnesium, ferritin, iron, calcium, zinc and copper" and compared use of it for 8 weeks against a placebo or dummy pill (see here). Their results, based on a protocol of intention-to-treat, "showed significant between-group differences favouring active treatment on self- and observer- but not clinician-ADHD rating scales". The authors conclude that their study "provides preliminary evidence of efficacy for micronutrients in the treatment of ADHD symptoms in adults, with a reassuring safety profile". I think we might have already seen a taster of these results in a publication** from late last year (2013) too.

Given my interest in Prof. Rucklidge's previous research and the potential effectiveness and ease of use of a simple vitamin-mineral supplement on anxiety and stress after a major natural disaster such as an earthquake, I was always going to be drawn to this paper. Indeed, with the current weather that we are enduring here in Blighty, I dare say that there may be some further applications from the previous Rucklidge results. That also similar findings, based on an equally rigorous methodological design, have been reported in cases of autism (see here) and the growing realisation of an overlap between autism and ADHD (see here) just adds to the interest. Dare I even mention the suggested link of food and nutrition between the two conditions too (see here)?

That's not to say that there isn't more to do in this area, particularly in light of the important issue of scientific replication. As Prof. Rucklidge talked about in another review paper*** preliminary support is all well and good****, but further well-controlled investigations are still required.  There is also the question of 'why'... why did supplementation with vitamins and minerals seem to 'work' on the presentation of ADHD? I can't offer a definitive answer on this, but as per some of the additional commentary on the BBC website about this work, the suggestion "that vitamins and minerals improved brain metabolism" is a front-runner explanation. Indeed, based on the study talking about treatment response** one finds a few potential starting points based on statements like: "higher baseline ferritin and lower baseline copper and vitamin D levels were associated with a better response to treatment for some but not all outcomes". Regular readers might already know about my interest in all things vitamin D, but one does wonder whether correcting this deficiency might have some interesting physiological effects not just directly related to the brain (see here) indeed harking back to that solar intensity - ADHD link posited not so long ago (see here). Indeed, other research has also turned up vitamin D deficiency as potentially being more frequent in [pediatric] ADHD***** too. I might add that I'm under no delusion that any effect is probably going to be synergistic across the various micronutrients and a lot more complicated that just a single effect on one physiological process.

Still the Rucklidge results offer some really interesting insights into both ADHD, or at least some types of ADHD (the ADHDs!) and how one might go about potentially improving quality of life for those diagnosed with the condition. That cases of adult ADHD seem to be increasing****** and as the authors noted about the issue of comorbidity - "[for] those with moderate/severe depression at baseline, there was a greater change in mood favouring active treatment over placebo" - one wonders whether a cheap and cost-effective nutritional supplement may indeed have an important role to play for at least some diagnosed with ADHD, bearing in mind my blogging caveat: no medical or clinical advice given or intended. Oh and such results might indeed be timely if the recent Nature news piece on the over-selling of medication strategies for ADHD is to be believed.

And to finish, treat your vitamin supplements as pharmaceutics...

Now something short and loud for your listening pleasure (and for all you lovers, er, rock lovers, out there).

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* Rucklidge JJ. et al. Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial. Br J Psychiatr. 2014: 30 Jan.

** Rucklidge JJ. et al. Moderators of treatment response in adults with ADHD treated with a vitamin-mineral supplement. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Dec 26;50C:163-171.

*** Rucklidge JJ. & Kaplan BJ. Broad-spectrum micronutrient formulas for the treatment of psychiatric symptoms: a systematic review. Expert Rev Neurother. 2013 Jan;13(1):49-73.

**** Rucklidge JJ. et al. Can micronutrients improve neurocognitive functioning in adults with ADHD and severe mood dysregulation? A pilot study. J Altern Complement Med. 2011 Dec;17(12):1125-31.

***** Goksugur SB. et al. Vitamin D Status in Children with Attention Deficit Hyperactivity Disorder. Pediatr Int. 2014 Jan 13. doi: 10.1111/ped.12286.

****** Montejano L. et al. Adult ADHD: prevalence of diagnosis in a US population with employer health insurance. Curr Med Res Opin. 2011;27 Suppl 2:5-11.

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Julia J. Rucklidge, Chris M. Frampton, Brigette Gorman, & Anna Boggis (2014). Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial British Journal of Psychiatry Other: 10.1192/bjp.bp.113.132126

Environmental toxicants and autism reviewed

So: "The findings of this review suggest that the etiology of ASD [autism spectrum disorder] may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD".

That's the conclusion reached by a huge review paper by Dan Rossignol and colleagues* (open-access). I'm going to say no more aside from inviting readers to put half an hour aside, read and digest the significant work that has gone into this paper. Oh, and aside from including the autism research tag-team that is Rossignol and Frye (see here and see here and see here), a certain S Genuis also appears on the authorship list (see here and see here).

Toodle pip.

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* Rossignol DA. et al. Environmental toxicants and autism spectrum disorders: a systematic review. Translational Psychiatry. 2014; 4: e360; doi:10.1038/tp.2014.4

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D A Rossignol, S J Genuis, & R E Frye (2014). Environmental toxicants and autism spectrum disorders: a systematic review Translational Psychiatry DOI: 10.1038/tp.2014.4

Optimal outcome (and autism) by any other name

In my annual review of all things autism research covered on this blog, the accolade of paper of the year for 2013 went to [drum roll maestro]... that optimal outcome paper by Deborah Fein and colleagues* (see here and here for more information). Detailing the experiences of well-defined group of children previously diagnosed with an autism spectrum disorder (ASD) who no longer met the diagnostic criteria, the notions that (a) there may be differences in the developmental trajectories of children on the autism spectrum (a shocker, I know), and (b) at least one of those trajectories might include moving out of the autism spectrum, was nothing short of ground-breaking.

The daily ship jam @ Wikipedia 

Whilst discussions still continue about the Fein findings and indeed, whether for example, moving outside of the diagnostic domains of an autism diagnosis actually translates as a better shot at real-world issues such as gaining meaningful (and financially rewarding) employment or living an independent life relatively free of medication or ill-health, the notion of optimal outcomes really stoked the autism research fire. The paper by Deborah Anderson and colleagues** (including Cathy Lord on the authorship list) treads in similar footsteps with their suggestion that: "some cognitively able children with ASD who participate in early intervention have very positive outcomes". The paper capitalising on the question of what variables and factors might influence positive outcomes and indeed, optimal outcome. I will also direct you to some views on this paper over at the SFARI blog too.

As I do so many times on this blog, I have to thank Natasa from providing the full-text version of the Anderson paper for discussion here. Reading through the Anderson paper, I dare say we might have a contender for the paper of the year 2014 as per their study which spanned 17 years, prospectively following a group of children diagnosed with autism. Just before I go on I should point out that I think we've already seen earlier data from the Anderson group on this cohort as per this 2007 publication*** and this 2009 publication**** (see here for open-access).

A few details from their latest:

• From a starting sample number of some 213 children initially referred for "possible autism" or with "non-ASD developmental delays" all under 37 months of age, 142 now young adults were in contact with researchers at 19 years of age including 85 youths who were diagnosed with ASD in early childhood.
• An important quote: "A battery of diagnostic and psychometric instruments was administered in person when children were 2, 3, 5... 9 and 19 years, free of charge". This battery included the ADI-R, the ADOS (PL-ADOS), the Mullen Scales of Early Learning (MSEL), VABS and quite a bit more. That and the fact that logs were kept noting things like medication and "educational and intervention treatments" among participants.
• Based on the division of participants diagnosed with autism into two groups as a function of (verbal) IQ at aged 19 (a) IQ less than 70 denoting 'Cognitively less able' (n=53) and (b) IQ equal or more than 70 ('Cognitively able' n=32), the authors reported that: "Intellectual disability at 19 was accurately predicted by age 2 about 85% of the time from IQ scores alone". Further that: "lower cognitive and adaptive abilities, along with more ASD-related symptoms at 2, predict membership in the VIQ <70 group [the 'Cognitively less able' group] 17 years later". That cognitive abilities may be predictive of future outcome is something which was also touched upon in the review paper by Magiati and colleagues*****.
• When it came to those members of the 'Cognitively able' group', well: "Of the 32 VIQ ≥70 youths, eight no longer retained a clinical diagnosis of ASD at age 19". These 'optimal outcomers' were described as a 'Very Positive Outcome' (VPO) group. Indeed, it also seems that alongside 'losing' their diagnosis of autism, this VPO group also seemed not to be affected by issues such as depression: "Twenty-nine percent (n=7) of the VIQ ≥70-ASD youths had scores suggesting possible depression while none of the VPO youths had elevated scores" and also did not present with clinically elevated scores in areas of irritability or hyperactivity neither.
• Perhaps more importantly than just scores and test results, the authors note that: "There was a strong trend toward higher rates of employment among VPO youths" added to their increased rates of independent living (away from the family home). Oh and no reports of having to take psychotropic medications. That being said the authors note that even when VPO was not 'achieved' at least some of the 'Cognitively able' group were: "doing very well in several areas" with many being "quite independent within their social contexts".

There is the promise of more data to come from this group insofar as the "stability of very positive outcomes", which with all the talk about diagnostic stability (see here) is an interesting prospect. What we can take from the current data from Anderson is that similar to the Fein results and other recent results, there may be multiple trajectories in autism when looked at longitudinally, and for some at least, a diagnosis of autism is not necessarily a lifelong event. I keep going on about it, but surely this must be another string to the bow for the concept of the autisms?

What else would I like to see from the Anderson data in publications to come? Well, maybe a few more details about the types of interventions that were reported over the course of children growing up might be a good place to start over above just "early treatment.. defined as at least 20 hr (once per week parent-training for 6 months)" in relation to the VPO group. At least then we'd be able to gauge what their relative contribution might or might not have been to youth outcome. Oh and I'm not just talking about educational and behavioural intervention either (see the recent paper by RogerAkins and colleagues***** which was covered in a recent post). I'd also like to know whether comorbidity played it's part in terms of outcome; y'know whether the onset of epilepsy or seizure disorder for example, affected later presentation.

These and lots of other questions which I'm hoping we'll see answered (or at least discussed) in future papers from this group. Watch this space...

I'll leave you with some Bob Marley and Stir it up.

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

** Anderson DK. et al. Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. J Child Psychol Psychiatry. 2013 Dec 9. doi: 10.1111/jcpp.12178.

*** Anderson DK. et al. Patterns of growth in verbal abilities among children with autism spectrum disorder. J Consult Clin Psychol. 2007 Aug;75(4):594-604.

**** Anderson DK. et al. Patterns of growth in adaptive social abilities among children with autism spectrum disorders. J Abnorm Child Psychol. 2009 Oct;37(7):1019-34.

***** Magiati I. et al. Cognitive, language, social and behavioural outcomes in adults with autism spectrum disorders: A systematic review of longitudinal follow-up studies in adulthood. Clinical Psych Rev. 2014; 34: 73-86.

****** Akins RS. et al. Utilization Patterns of Conventional and Complementary/Alternative Treatments in Children with Autism Spectrum Disorders and Developmental Disabilities in a Population-Based Study. J Dev Behav Ped. 2014; 35: 1-10.

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Anderson DK, Liang JW, & Lord C (2013). Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. Journal of child psychology and psychiatry, and allied disciplines PMID: 24313878