Monday, 20 October 2014

Reasons for visiting ER by those with autism

ER - Emergency Room - or as we call it here in Blighty Accident & Emergency (A & E), is never a particularly desirable place to visit given the emphasis on illness or injury of yourself or loved one. That being said, staff there do a sterling job sometimes under very stressful circumstances, responding to all-manner of complaints, some of which are life-threatening.

The paper by Dorothea Iannuzzi and colleagues [1] sought to identify some of the medical reasons why ER visits were made by people on the autism spectrum. They concluded that, depending on age, epilepsy or seizure-type disorders and "psychiatric conditions" were well represented in cases of autism based on data derived from the US 2010 National Emergency Department database.

Realising that epilepsy / seizure-type disorders seem to have more than a passing connection to quite a few cases of autism (see here) and can, in some cases, lead to that most extreme of outcomes (see here), I'm not going to focus any further on this part of the Iannuzzi findings. Rather the finding that: "Psychiatric conditions were primary among ASD individuals aged 12-15 years, accounting for more than 11 % of all visits" merits some further analysis.

The findings reported by Kalb and colleagues [2] documenting that: "Thirteen percent of visits among children with ASD [autism spectrum disorder] were due to a psychiatric problem, as compared with 2% of all visits by youths without ASD" provides further evidence for the extent of the Iannuzzi finding. Whilst treading carefully in this area of autism research, one detail stuck out from the Kalb report, whereby ER visits due to psychotic disorders seemed to be increased in likelihood compared to visits by asymptomatic children/youths. This seemed to tie in well with my recent discussions on the observations of Maibing and colleagues [3] and the risk/onset of schizophrenia spectrum disorders following a previous child or adolescent psychiatric diagnosis.

Unfortunately, my discussions on the research literature on ER visits and autism do not get any happier as I turn to the body of work looking at suicide attempts and autism, and as per the conclusion from Kato and colleagues [4], "ASDs should always be a consideration when dealing with suicide attempts in adults at the emergency room". Again, I've covered the very sensitive topic of suicide (ideation and attempts) and autism previously on this blog (see here and see here) and as we speak further research has emerged pertinent to this topic [5]. Though sometimes quite uncomfortable to discuss, this collected work emphasises how we all really need to be talking a lot more about this issue and what can be done to divert people away from this most extreme type of behaviour. Admission to the ER - which will often be the first point of contact after such behaviour - could be a good place to start having those discussions.

In amongst the literature talking about the ER and autism, there are other details which provide a rather more positive discussion about this topic. Take for example, the paper by Giarelli and colleagues [5] looking at the ways and means ER might be made more comfortable to [some of] those on the autism spectrum. Similarly, the guidance supplied by McGonigle and colleagues [6] talking about ways of managing agitation in the ER for those on the autism spectrum might also be better referenced in this clinical setting. Oh, and a bit more knowledge about medical comorbidities potentially affecting people with autism would probably not go amiss more generally.

I should conclude that whilst I've focused on some of the more frequently reported reasons why people with autism might present to the ER, one shouldn't forget that all the other reasons why the general population go to the ER are similarly as pertinent to those on the spectrum. That being said, I very much doubt that "help with removing false nails" would feature on most people's reasons to attend hospital...

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[1] Iannuzzi DA. et al. Brief Report: Emergency Department Utilization by Individuals with Autism. J Autism Dev Disord. 2014 Sep 27.

[2] Kalb LG. et al. Psychiatric-related emergency department visits among children with an autism spectrum disorder. Pediatr Emerg Care. 2012 Dec;28(12):1269-76.

[3] Maibing CF. et al. Risk of Schizophrenia Increases After All Child and Adolescent Psychiatric Disorders: A Nationwide Study. Schizophr Bull. 2014 Sep 5. pii: sbu119.

[4] Kato K. et al. Clinical features of suicide attempts in adults with autism spectrum disorders. Gen Hosp Psychiatry. 2013 Jan-Feb;35(1):50-3.

[5] Takar K. & Kondo T. Comorbid atypical autistic traits as a potential risk factor for suicide attempts among adult depressed patients: a case–control study. Annals of General Psychiatry 2014, 13:33.

[6] Giarelli E. et al. Sensory stimuli as obstacles to emergency care for children with autism spectrum disorder. Adv Emerg Nurs J. 2014 Apr-Jun;36(2):145-63.

[7] McGonigle JJ. et al. Management of agitation in individuals with autism spectrum disorders in the emergency department. Child Adolesc Psychiatr Clin N Am. 2014 Jan;23(1):83-95.

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ResearchBlogging.org Iannuzzi DA, Cheng ER, Broder-Fingert S, & Bauman ML (2014). Brief Report: Emergency Department Utilization by Individuals with Autism. Journal of autism and developmental disorders PMID: 25261249

Saturday, 18 October 2014

More epigenetics, EN-2 and autism... the plot thickens

I don't mind admitting that I was to some extent 'winging it' with my previous post on epigenetics and Engrailed-2 (EN-2) as a consequence of the findings reported by Jill James and colleagues [1] with autism in mind. Although an avid follower of the science of epigenetics when (cautiously) applied to autism, I am by no means any authority on the subject matter particularly when it comes to the nitty-gritty details. You can probably therefore expect similar things in my latest discussions on yet more work from this research group which appeared recently [2].
I have only one rule. Everybody fights, no one quits.

And so, with that pinch of salt at the ready...

The final conclusion made in the most recent James article boils down to the suggestion that "persistent postnatal overexpression of EN-2 suggests that the closing of this programed developmental window may have been missed in some individuals with autism because of epigenetic abnormalities". That being said I think we have quite a way to come before we can substantiate this finding particularly when the main protagonist in the latest article is something called 5-hydroxymethylcytosine (5-hmC) and results which show "that elevated 5-hmC in the EN-2 promoter is associated with a significant decrease in repressive MeCP2 and histone H3K27me3 that appear to over-ride 5-mC hypermethylation". The H3K27me3 bit comes from their previous findings by the way.

To most readers that probably sounds as complicated as it first did to me so I will try and explain more.

EN-2 as I've talked about in that post on the previous James work, has been linked to cases of autism as per the example of the study by Wang and colleagues [3] linking mutations in this gene to cases of autism. The idea being that mice bred without the gene (the homeobox domain of EN2) show some of the [mouse] signs and symptoms of autism alongside issues with the cerebellum and a reduction in the number of Purkinje cells which have been previously noted in cases of autism [4]. The previous James results in this area reported on hypermethylation of the EN-2 promoter region which would normally equate as gene silencing in epigenetic terms, in line with the more structural genomic issues seen in autism that I've just talked about. But, and it is an important point, when they looked at EN-2 expression and protein levels - function and products of the gene - they actually found that levels were increased in their autism samples despite the methylation mark and its 'stop talking' properties. They noted on that occasion that "transcriptional upregulation by other epigenetic mechanisms predominated over the repressive tendencies of DNA cytosine methylation".

Their latest foray into this area sought to further clarify just what might be going on specifically with EN-2 gene-specific DNA hypermethylation previously reported. To do this they focused on both measuring 5-hmC and also 5-methylcytosine (5-mC) among other things based on the same tissue samples (post-mortem cerebellum samples) detailed in their previous study. 5-hmC is apparently an oxidation product of 5-mC mediated via something called TETs.

What they found, far from answering the question of a discrepancy between epigenetic gene silencing of EN-2 but increased gene function and products, actually makes the whole thing a lot more complicated. So they observed "a significant increase in both 5-mC and 5-hmC in the autism cerebellum relative to the control samples". Further that there was "a significant increase in 5-hmC content within the upstream EN-2 promoter region" and "a highly significant positive correlation... was found between 5-hmC content and EN-2 gene expression in the 5’ promoter CpG island in autism but not in control samples". They note that: "that 5-hmC accumulation is mechanistically related to gene upregulation" something which I think ties into other work hinting at the demethylating role for 5-hmC [5].

Insofar as my mention of MeCP2 and histone H3K27me3 from the latest and previous James reports, I can't really say too much more aside from noting again: "reduced MeCP2-mediated gene repression may have contributed to persistent EN-2 gene overexpression in the autism samples". Actually the authors speculate that MeCP2 binding and histone H3K27 trimethylation might work together in a "repressive" manner but when reduced as they were "may contribute to aberrant overexpression of EN-2 in the autism cerebellum" as per their findings.

I have to say that I struggled with getting my head around these findings and I'd quite understand if readers also struggled with my interpretation of them ("If you can't explain something to a six-year-old/granny, you really don't understand it yourself"). I understand that we don't all walk around with our genes stuck in the 'on' or 'off' position and that particularly during foetal and the early post-natal periods, genes are being switched on and off at a surprising rate for many, many different important reasons. I also understand that DNA methylation is an important part of the whole genes switched on or off thing but not the only way that this process can happen as per the authors mention of chromatin and some previous text in this area [6]. With my very limited knowledge of this area, I am however not yet convinced that we have the full story here; specifically in terms of why the original finding of hypermethylation of the EN-2 promotor region (gene silencing) yet increased expression and protein levels were reported. I wonder if indeed we might be able to learn more from a two-hit approach whereby hypermethylation of only one gene allele leaves the other still working?

Just before I finish I'd like to also draw your attention to another paper which has started to ask similar questions about 5-hmC and might be contrasted with the recent James paper. Zhubi and colleagues [7] (open-access here) looked at 5-hmC with a couple of other potentially important genes linked to cases of autism (RELN and GAD1) in mind. They reported: "a significant increase in TET1 expression and an enrichment in the level of 5-hmC... at the promoters of GAD1 and RELN in ASD when compared with CON [controls]". Further that their data are: "consistent with the hypothesis that an increase of 5-hmC (relative to 5-mC) at specific gene domains enhances the binding of MeCP2 to 5-hmC and reduces expression of the corresponding target genes in ASD [autism spectrum disorder] cerebella".

The plot thickens...

So then to some music... Hey Jude.

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[1] James SJ. et al. Complex epigenetic regulation of Engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Translational Psychiatry. 2013; 3: e232.

[2] James SJ. et al. Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum. Translational Psychiatry. 2014. 7 October.

[3] Wang L. et al. Association of the ENGRAILED 2 (EN2) gene with autism in Chinese Han population. Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):434-8.

[4] Fatemi SH. et al. Purkinje cell size is reduced in cerebellum of patients with autism. Cell Mol Neurobiol. 2002 Apr;22(2):171-5.

[5] Dahl C. et al. Advances in DNA methylation: 5-hydroxymethylcytosine revisited. Clin Chim Acta. 2011 May 12;412(11-12):831-6.

[6] Lasalle JM. et al. Autism genes keep turning up chromatin. OA Autism. 2013 Jun 19;1(2):14.

[7] Zhubi A. et al. Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum. Transl Psychiatry. 2014 Jan 21;4:e349.

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ResearchBlogging.org James SJ, Shpyleva S, Melnyk S, Pavliv O, & Pogribny IP (2014). Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum. Translational psychiatry, 4 PMID: 25290267

Friday, 17 October 2014

Altered ghrelin levels in boys with autism

"Honey, it's the '90s, remember?"
Saudi Arabia and autism research? It must be at least one author from the research tag-team that is Mostafa and Al-Ayadhi.

Indeed, in today's post it is Laila Al-Ayadhi featured on the paper by Felwah S. Al-Zaid and colleagues [1] (open-access) who concluded on: "a potential role for the hormone ghrelin in the pathogenesis of autism".

Ghrelin, by the way, is often called the 'hunger hormone' as a result of its effects in relation to energy homoeostasis. Alongside another hormone called leptin (which has also been implicated in cases of autism) the long-and-short of food intake regulation seem to be covered by these hormones [2].

The Al-Zaid paper is open-access but I'll direct you to a few important points...

  • A case-control study, authors looked at various measures for 31 boys diagnosed with autism compared with 28 age- and sex-matched controls.
  • Alongside various anthropometric measures, plasma and serum levels of "acyl ghrelin (AG), des-acyl ghrelin (DG), total testosterone (TT), free testosterone (FT), leptin and growth hormone (GH)" were measured. These were single spot measures with samples taken "after an overnight fast". 
  • Results: the autism group were on average heavier than controls but aside from that, no other physical measure was significantly different (mean height was greater in the autism group but just escaped significance). Both acyl ghrelin and des-acyl ghrelin levels were significantly lower in the autism group. By contrast, leptin levels were higher in the autism group (as per other independent findings) and free and total testosterone levels were significantly elevated compared to controls. Taking into account the effect of weight and it's link to adiposity, authors also showed that an analysis of a smaller subgroup (autism, n=27; controls, n=28) where mean weight was controlled for, found a similar trend in hormone levels (see this link to Table 3 of the paper) bearing in mind how body fat can influence the parameters.
  • Various correlational analyses were completed on the data but given the relatively small participant groups and the use of spot samples I'm not particularly minded to read too much into these findings at this time.
  • The authors conclude that their study: "contributes significantly to the understanding of hormonal dysregulation in the pathophysiology of autism, as it provides baseline data regarding hormonal profiles in autism and substantiates potential clinical interventions".

Small participants numbers and a "lack of female subjects with autism" kinda prohibit me from reading too much into these findings as they stand. I've already made mention of the research trend when it comes to elevated leptin levels and autism (see the paper from Rodrigues and colleagues [3] as one example). Likewise, testosterone levels and autism have received quite a bit of autism research attention down the years (see here). Indeed, elevations in testosterone levels not described in-utero with some potential relationship to foetal programming, has been the stuff of controversy in autism research circles [4].

Going back to the primary ghrelin findings and the observations of lower levels detected in their autism group, the authors speculate on some of the hows and whys of their findings. Gastrointestinal (GI) issues get a call-out and how some of the variety of GI issues noted in cases of autism "could affect the gastric mucosa and interfere with the normal function of ghrelin-secreting cells". although no particulars about GI issues are included in their descriptions of their cohort. One additional issue that I would perhaps add to the whole inflammation, dysbiosis et al discussions would be how ghrelin seems to play some role in GI motility [5] too. That being said, 'wide-ranging' is perhaps the best way to describe what biological processes ghrelin might impact on [6].

I was a touch surprised that the more usual role for ghrelin in terms of hunger and energy homoeostasis was not given more prominence in the Al-Zaid article on autism. Food and feeding patterns are important topics when it comes to autism as per discussions on the extremes sometimes noted in cases of autism (see here) and the increasingly important issue of weight (see here) (which also seemed to be picked up in the authors' findings). One might speculate that hunger and signals linked to hunger might be similarly tied into at least some of the feeding issues reported in autism?

As I seem to do in many discussions these days, I'll reiterate that there is quite a bit more to see and do in research terms on the relationship between ghrelin and related hormones and autism. The additional suggestion from Ghanizadeh [7] about the ghrelin being a "promising therapeutic target for co-occurring autism and epilepsy" might also be worthy of greater inspection.

Music to close. Iggy Pop and Lust for Life.

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[1] Al-Zaid FS. et al. Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation. Sci Rep. 2014 Sep 26;4:6478.

[2] Klok MD. et al. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007 Jan;8(1):21-34.

[3] Rodrigues DH. et al. Changes in Adipokine Levels in Autism Spectrum Disorders. Neuropsychobiology 2014;69:6-10

[4] Geier DA. & Geier MR. A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies. Neuro Endocrinol Lett. 2007 Oct;28(5):565-73.

[5] Greenwood-Van Meerveld B. et al. Ghrelin as a target for gastrointestinal motility disorders. Peptides. 2011 Nov;32(11):2352-6.

[6] Delporte C. Structure and physiological actions of ghrelin. Scientifica (Cairo). 2013;2013:518909.

[7] Ghanizadeh A. Ghrelin as a promising therapeutic target for co-occurring autism and epilepsy. Epilepsy Behav. 2011 Feb;20(2):420-1.

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ResearchBlogging.org Al-Zaid FS, Alhader AA, & Al-Ayadhi LY (2014). Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation. Scientific reports, 4 PMID: 25257829

Thursday, 16 October 2014

MicroRNAs and Chronic Fatigue Syndrome

"No one User wrote me! I'm worth
millions of their man-years!"
Not so long ago I posted an entry talking about microRNAs and autism (see here). As well as including some rather interesting, if preliminary findings, that particular piece of work also served to introduce yet another layer of complexity to our genome and its expression: microRNAs.

I was therefore always going to be more than a little intrigued by the results published by Ekua Brenu and colleagues [1] and their observations on circulating microRNAs (miRNAs) in a small participant group diagnosed with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Indeed their conclusion that "three differentially expressed circulating miRNAs in CFS/ME patients" might have potential biomarker qualities invites quite a bit of further study in this area.

The Brenu paper is open-access but a few details are worthwhile reiterating:

  • The name of the game was "high-throughput sequencing (HTS) to globally profile circulating miRNA expression" in a small participant group diagnosed with CFS/ME (n=20) compared with non-fatigue controls (n=20). "This was followed by confirmative reverse transcription-quantitative PCR (RT-qPCR) to determine differential miRNA expression in CFS/ME".
  • Actually, when it came down to it: "The six CFS/ME patients and six non-fatigued controls with the highest abundance of small RNA were used for HTS".
  • Results: 19 miRNAs were reported as being significantly 'dysregulated' in CFS/ME compared to controls. Sixteen of these were subsequently dropped from the analysis as a result of being considered "low in abundance" from a detection point of view.
  • Three miRNAs were left - hsa-miR127-3p, hsa-miR-142-5p and hsa-miR-143-3p - and were confirmed by RT-qPCR. All were up-regulated in CFS/ME cases and considered: "potential plasma biomarkers for CFS/ME diagnosis".

Obviously there is a long, long way to go before these findings translate into anything like a biomarker for CFS/ME. As per the authors' discussions, there are quite a few other conditions / biological processes which are seemingly impacted by these miRNAs; as one example: "Over-expression of miR-142-5p has been observed in most cancer-related and immunological disorders". So exclusivity to CFS/ME is unlikely to be seen. That and the fact that like quite a few conditions described these days, CFS/ME is likely not to just be one unified condition...

I note also that this is not the first time that this research group have ventured into the whole "microRNAs as prospective biomarkers" of CFS/ME as per some work a few years earlier [2]. On that particular occasions, drawing on an equally small participant group, the authors reported findings implicating other miRNAs. Specifically: "There was a significant reduction in the expression levels of miR-21, in both the NK [Natural Killer] and CD8(+)T cells in the CFS/ME sufferers". The immune system link with CFS/ME is interesting but again there's a lot more work needed in this area.

Music, music, music... D.I.Y from Heaton & Abbott.

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[1] Brenu EW. et al. High-Throughput Sequencing of Plasma MicroRNA in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PLoS One. 2014 Sep 19;9(9):e102783.

[2] Brenu EW. et al. Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Affect Disord. 2012 Dec 10;141(2-3):261-9.

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ResearchBlogging.org Brenu EW, Ashton KJ, Batovska J, Staines DR, & Marshall-Gradisnik SM (2014). High-Throughput Sequencing of Plasma MicroRNA in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PloS one, 9 (9) PMID: 25238588

Wednesday, 15 October 2014

Hookworm infection and microchallenge for coeliac disease?

I'm getting rather baffled by some of the literature appearing with the autoimmune condition coeliac (celiac) disease in mind. The paper by Kalliokoski and colleagues [1] started the bafflement ball rolling with their suggestion that: "administration of IgA-deficient celiac disease patient serum or total IgG induces both deterioration of the intestinal mucosa and clinical features of celiac disease in mice". Then came the paper from Namatovu and colleagues [2] who concluded that: "Neighborhood composition influences CD [coeliac disease] risk". Such discussions were based on a condition which science seemed to be getting a handle on in terms of the genetic and biological processes involved... or maybe not.
"Klaatu Barada N... Necktie... Neckturn... Nickel"

Enter also the findings reported by John Croese and colleages [3] observing that: "Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD [coeliac disease] subjects" and the bafflement ball starts to roll away yet faster and further.

A few points from the Croese paper are worth noting:

  • This was a year long study looking at a small number of adults with "diet-managed" CD (N=12). In case you might not know, the diet in question is a gluten-free diet.
  • Said participants were "inoculated" with 20 hookworm larvae (see here for a picture if you really wish) and subsequently fed increasing doses of gluten - consumed as pasta - ranging from micrograms to grams over the course of some weeks. 
  • "Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined".
  • Results: Not all the participants went the distance with the gluten challenge; two of which were labelled 'gluten intolerant' (which is a little odd because intolerance of gluten is I presume a hallmark of all CD). That being said, there were some interesting findings observed such as: "the mean IgA-tissue transglutaminase titers declined". I'm not an expert on CD but elevated IgA-tissue transglutaminase is closely associated with CD and I believe levels should fall when a person adopts a gluten-free diet [4]. The fact that levels declined when a gluten challenge (ingesting gluten) was in place was, in the words of the authors, "contrary to the predicted rise".
  • Researchers also described how: "Intestinal T cells expressing IFNγ were reduced following hookworm infection". Again with my non-expert hat on, these are some interesting results. The interferons have been previously discussed on this blog with autism in mind (see here) but with CD in focus, are thought to be part of the destructive immune system processes which describe the condition (see here). The suggestion that hookworm infection might be somehow placating such immune processes is intriguing.

Obviously, there is a lot more to do in this area before anyone decides that hookworm infection is a panacea for CD. I've already mentioned the small participant number and attrition rate but given also that CD is usually described as a lifelong condition, one year of experimental study is not nearly enough to discuss any long-term effects. That other studies from the authors have reported less eventful results [5] is also worth mentioning.

But, I'm also minded to discuss another paper from this research group [6] which was covered on a sister blog (see here). On that occasion, authors talked about how hookworm infection seemed to influence production of the TH-17 cytokine, IL-17A too: "Hookworm infection suppressed basal production of the inflammatory cytokines IFN-γ and IL-17A". I've become quite interested in IL-17 over the years, again with the autism research connection in mind (see here) and a possible link with autoimmunity. The fact that IL-17 might also represent one way of distinguishing subgroups with CD [7] is likewise intriguing and offer something in the way of a variable on response to such helminthic therapy...

Music to close. How about some bluegrass... The Grascals and Bugle Call Rag?

And since, I have your attention, here's a link to my latest paper [8] on the potential use of gluten and casein-free diets for autism (shameless self-publicity I know).

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[1] Kalliokoski S. et al. Injection of celiac disease patient sera or immunoglobulins to mice reproduces a condition mimicking early developing celiac disease. J Mol Med (Berl). 2014 Sep 12.

[2] Namatovu F. et al. Neighborhood conditions and celiac disease risk among children in Sweden. Scand J Public Health. 2014 Sep 23. pii: 1403494814550173.

[3] Croese J. et al. Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. J Allergy Clin Immunol. 2014 Aug 29. pii: S0091-6749(14)01010-0.

[4] Dahele AV. et al. Serum IgA tissue transglutaminase antibodies in coeliac disease and other gastrointestinal diseases. QJM. 2001 Apr;94(4):195-205.

[5] Daveson AJ. et al. Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial. PLoS One. 2011 Mar 8;6(3):e17366.

[6] McSorley HJ. et al. Suppression of inflammatory immune responses in celiac disease by experimental hookworm infection. PLoS One. 2011;6(9):e24092.

[7] Sapone A. et al. Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol. 2010;152(1):75-80.

[8] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2014 Oct 14:1-6.

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ResearchBlogging.org Croese J, Giacomin P, Navarro S, Clouston A, McCann L, Dougall A, Ferreira I, Susianto A, O'Rourke P, Howlett M, McCarthy J, Engwerda C, Jones D, & Loukas A (2014). Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. The Journal of allergy and clinical immunology PMID: 25248819

Tuesday, 14 October 2014

Prenatal genetic testing and autism: a delicate subject

I realise that the paper by Lei-Shih Chen and colleagues [1] covers a most sensitive topic when it comes to the autism spectrum, exploring: "the attitudes toward PGT [prenatal genetic testingand termination decisions of 42 parents of children with ASD [autism spectrum disorder]". Indeed, this is not the first time that this research group has looked at this area of autism research [2] and it seems like they will be talking about it further too (see here).

I chose to discuss the most recent paper on this blog because (a) the Chen paper is peer-reviewed science, (b) the likelihood of PGT being 'applied to autism' at some point in the future is growing (if not here in some parts of the world?), and (c) similar to the screening tests available for conditions like Down's syndrome (see here), there are going to be conversations to be had about the decisions and choices potentially offered to parents on the basis of any screening results. Charities here in the UK such as Antenatal Results and Choices (ARC) are probably going to figure in those conversations which, in some quarters, have already begun to happen (see here). I write this blog from a cold, scientific perspective so please don't get offended by some of the discussions.

The Chen paper describes the results of a qualitative study where parents of children with ASD were given "a hypothetical scenario" regarding PGT and asked their hypothetical response to using PGT and their hypothetical response to a positive test response. "Of the 31 parents who were either willing or unsure about undergoing the PGT, approximately three-fourths would continue their hypothetical affected pregnancies".

A few things struck me about the Chen paper. First is a line introducing the abstract which reads: "In the United States, prenatal genetic testing (PGT) for Autism Spectrum Disorders (ASD) is currently available via clinical genetic services". I was quite taken aback by this sentence. As far as I was aware science was still feeling around as to the underlying genetics of autism (that is, if you consider autism to be a unitary concept rather than a more plural condition and to be solely driven by structural genetics over and above environmental factors or epigenetic changes). If someone is suggesting otherwise, please do point me towards the peer-reviewed science for that prenatal genetic test outside of something like just screening for Fragile X syndrome [3] or the preliminary results reported by Wapner and colleagues [4] mentioned with autism in mind...

The next thing that caught my eye was the high number of parents who, if faced with the hypothetical PGT situation, said they would continue with their pregnancy. I'm not so surprised at this, given that researchers were asking parents who already had a child with autism and so perhaps knew a little bit about both the good and not-so-good times which go with raising a child with a developmental disability. I also emphasise the word 'child' there before their condition/label. If the questions were put to parents with no personal experience of autism, one wonders whether similar outcomes would have been reported. Likewise if parents were for example, offered differing scenarios under such experimental conditions with other conditions outside of autism, such as Down's syndrome, the question remains about what results might have shown also bearing in mind the literature in this area [5].

Finally, and I again tread very carefully with this, was the observation that: "Parents who reported they would terminate the affected pregnancy in this hypothetical situation were primarily Asians". I go to great lengths on this blog not to over-generalise autism research such that not every finding has to apply to every single person with autism. In this instance I'd also point out that the sample size for the Chen results was very small and outside of cultural differences and representations [6], one similarly cannot assume that every person/parent of Asian origin is going to report like this. Neither however should judgement be passed on those parents who did choose this hypothetical option and the road(s) which might have led them to this hypothetical decision. This might however suggest that as per other examples, autism is looked at in very different ways according to factors such geography and culture.

As I mentioned at the top of this post, prenatal testing (genetic or otherwise) is always going to be a sensitive subject when applied to autism and will inevitably stir up considerable emotions for many people, not least those who are themselves on the autism spectrum. I'm going to leave you with some more discussion about this area from Prof. Andrew Whitehouse - he of the 'Is autism one or multiple disorders?' paper - and a very sensible post he wrote (see here) which covers most of the important issues well.

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[1] Chen LS. et al. Autism Spectrum Disorders: A Qualitative Study of Attitudes toward Prenatal Genetic Testing and Termination Decisions of Affected Pregnancies. Clin Genet. 2014 Sep 24.

[2] Chen LS. et al. Autism genetic testing: a qualitative study of awareness, attitudes, and experiences among parents of children with autism spectrum disorders. Genet Med. 2013 Apr;15(4):274-81.

[3] Gutiérrez JF. et al. Prenatal screening for fragile x: carriers, controversies, and counseling. Rev Obstet Gynecol. 2013;6(1):e1-7.

[4] Wapner RJ. et al. Chromosomal Microarray versus Karyotyping for Prenatal Diagnosis. NEJM. 2012; 367: 2175-2184.

[5] Scott CJ. et al. Prenatal diagnosis and termination of pregnancy: perspectives of South African parents of children with Down syndrome. J Community Genet. 2013 Jan;4(1):87-97.

[6] Bie B. & Tang L. Representation of Autism in Leading Newspapers in China: A Content Analysis. Health Commun. 2014 Jul 29:1-10.

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ResearchBlogging.org Chen LS, Xu L, Dhar SU, Li M, Talwar D, & Jung E (2014). Autism Spectrum Disorders: A Qualitative Study of Attitudes toward Prenatal Genetic Testing and Termination Decisions of Affected Pregnancies. Clinical genetics PMID: 25251361

Monday, 13 October 2014

Yes folks... broccoli chemical impacts on autism presentation

Please do not adjust your set. Broccoli, or least a chemical found in broccoli called sulforaphane has, under placebo-controlled, double-blind experimental conditions, been reported to impact on the presentation of autism according to the paper by Kanwaljit Singh and colleagues [1] (open-access).
Eat your greens @ Fir0002/Flagstaffotos

I had to do a bit of a double-take myself when I first read about these results (see here). Indeed, even the authors themselves seemed to be a little taken aback by their own findings if other media on this study is to be believed (see here). Still peer-reviewed science is peer-reviewed science and that goes just as much for this study as any other.

The paper is open-access but a few details might be useful:

  • The study was previously registered in the US ClinicalTrials.gov database (see here). It involved comparing "capsules of sulforaphane-rich broccoli sprout extracts" with "indistinguishable placebo capsules" containing microcrystalline cellulose (wood pulp) in a small group of young men (aged 13-27 years) diagnosed with an autism spectrum disorder (ASD) administered daily over 18 weeks. As I mentioned, the study was also double-blind.
  • Various measures - behavioural and physiological - were recorded at baseline (prior to study start) and at choice points during the 18 week study period. The results of the behavioural measures including the Aberrant Behaviour Checklist (ABC) and Social Responsiveness Scale (SRS) completed by parents/caregivers and the Clinical Global Impression Severity (CGI-S) and the Clinical Global Impression Improvement (CGI-I) scales completed by "study physicians" are included in the main paper results and conclusions.
  • Results: well, first and foremost there were a few adverse events reported during the trial. The authors note that: "Sulforaphane treatment effectively improved core aberrant behaviors of ASD, and was safe and well-tolerated". But... "the sulforaphane group gained significantly more weight over the 18-wk period, compared with placebo" and there was mention of "single unprovoked seizures" occurring in two participants taking the active treatment. These seizures may well be unconnected to the sulforaphane capsules but one cannot rule out the possibility that they were connected.
  • Forty participants completed the trial, or at least "part of the outcome measure evaluations" boiling down to "14 placebo and 26 sulforaphane". The statistical evaluation undertaken involved looking at "the differences between scores of individuals at 4, 10, 18, and 22 wk from their respective average pretreatment values". But the authors also undertook a separate intention-to-treat analysis that "included all 44 participants".
  • The headlines: "many of the participants who were treated with sulforaphane in this study had statistically significant and clinically meaningful improvements during treatment with sulforaphane". With all due respect to parent/caregiver reports, I was particularly drawn to the fact that study physicians although blinded to who was on active treatment and who was taking a placebo were able to rate "13 of the 40 participants" as showing noticeable improvements in behaviour and sociability and "all were receiving sulforaphane". That's quite a feat by any study's standard.
  • The authors conclude: "The substantial improvements of individual ASD patients’ trajectories were conspicuous and suggest that further investigation of sulforaphane in ASD is promising".

These are interesting results crying out for further independent [longer term] replication. The fact also that this was a trial of adolescents and adults with autism also fills a gap in the autism research market alluded to in previous posts on this blog (see here). 

Mechanism of effect? Well, there does seem to be quite a bit more to do in this area. The authors note that sulforaphane "was selected because it upregulates genes that protect aerobic cells against oxidative stress, inflammation, and DNA-damage, all of which are prominent and possibly mechanistic characteristics of ASD". Oxidative stress does indeed appear on the research radar when it comes to autism, at least some autism (see here) and sulforaphane fits the bill in terms of its potential 'protective' effects [2]. I've also talked about such mechanisms with another source of sulforaphane in mind (see here). That all being said, I don't doubt that there may be other biological processes at work.

So, in conclusion 'eat your greens' might very well be an important phrase for some on the autism spectrum. Whether eating the source material carries the same effect or will be equally well received as taking a daily pill is another matter...

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[1] Singh K. et al. Sulforaphane treatment of autism spectrum disorder (ASD). PNAS. 2014. October 13.

[2] Guerrero-Beltrán CE. et al. Protective effect of sulforaphane against oxidative stress: recent advances. Exp Toxicol Pathol. 2012 Jul;64(5):503-8.

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ResearchBlogging.org Kanwaljit Singh, Susan L. Connors, Eric A. Macklin, Kirby D. Smith, Jed W. Fahey, Paul Talalay, & Andrew W. Zimmerman (2014). Sulforaphane treatment of autism spectrum disorder (ASD) PNAS : 10.1073/pnas.1416940111