"There is broad parent interest in a genetic/epigenetic test for ASD"

The quote heading this post - "There is broad parent interest in a genetic/epigenetic test for ASD [autism spectrum disorder]" - comes from the findings reported by Kayla Wagner and colleagues [1]. As per the observation that most parents of those diagnosed with an ASD, or developmental delay (DD) or asymptomatic controls "had positive perceptions toward genetic/epigenetic research in ASD", far from being the 'danger' that it is sometimes portrayed as, the science of genetics seems to have an important standing among many parents.

The Wagner results came about as a result of this research group publishing studies "that demonstrate the utility of RNA sequencing technology (non-coding RNA) to identify children with ASD." They did what few genetic studies have done: asked parents participating in their studies whether what they were doing/finding was of interest to them. This was achieved via the use of a questionnaire which included six themes: "(1) reasons for participating in the epigenetic study; (2) prior knowledge of genetics/epigenetics, and the source of this information; (3) overall interest in genetic/epigenetic testing for ASD; (4) concerns about genetic/epigenetic testing for ASD; (5) preferences about the approach for genetic/epigenetic testing (including age of administration and biofluid of choice); and (6) extent of results to be returned." You'll probably have noted that alongside their use of the term 'genetics' they also talk about a still up-and-coming branch of genetics called epigenetics. I've talked about epigenetics and autism before on this blog (see here and see here) but the description Wager et al use just about says it all: "changes in gene expression, where the changes are not due to modification of the actual DNA sequence, but instead result from modifications that regulate DNA structure and expression." Gene expression seems to be particularly important to the science of epigenetics as per the notion that we don't all walk around with all our genes permanently switched to the 'on' or 'off' position.

Results: quite a few important points emerged from the obtained data. Most parents understood at least a little bit about genetics and some of the processes involved. Epigenetics wasn't as well known about or understood (something which is probably not so surprising). Other points also emerged: "There were no parents (0%, 0/244) concerned about a lack of scientific evidence supporting genetic and epigenetics." But that's not to say that some parents weren't concerned about the implications of genetics and epigenetics, as mention about issues like privacy and insurance status were raised during the Wagner study.

Also: "Nearly all parents (96%, 235/244) indicated that if there were genetic testing for ASD, they were interested in learning results about their child’s risk for ASD." And when it came to results, over three-quarters of all parents expressed a preference for "all epigenetic/genetic results, regardless of whether they were implicated in health and disease" and not just an overview or interpretation of any results. People want data not overviews.

And then to some important but potentially controversial findings: "The majority of parents (71%, 164/231) desired results of a genetic/epigenetic test for ASD when their child was 12 months of age or younger. Over half of parents were interested in receiving results at conception (34%, 78/231) or at birth (37%, 86/231), while fewer requested results at 12 months (17%, 40/231) or at 2 years of age (12%, 27/231)." You can perhaps see where this might be going - particularly 'receiving results at conception' - even if the authors seem to have chosen not to pursue it any further in their discussions.

I'm no bioethicist and so am nowhere near qualified to talk about the ins-and-outs of genetic testing in the context of autism and what implications this could have. I note other commentators have approached this subject previously based on some of the peer-reviewed science in this area (see here) and various points have been raised. One of the important things to bear in mind is that, as it currently stands, there is no single genetic test for all autism. Indeed, allied to the idea that the concept of 'a universal autism gene' is fast becoming a distant memory, genetic studies are serving to further highlight how complex autism actually is.

But there is always the possibility that some day someone will potentially deliver a genetic/epigenetic 'test for some autism'. The question then is how will it be used? What checks and balances will be in place to ensure that it is not misused?

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[1] Wagner KE. et al. Parent Perspectives Towards Genetic and Epigenetic Testing for Autism Spectrum Disorder. Journal of Autism & Developmental Disorders. 2019. March 22.

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A test "that distinguishes ASD fast response constipation from ASD persistent right-sided constipation"?

The quote heading this post - "A test that distinguishes ASD [autism spectrum disorder] fast response constipation from ASD persistent right-sided constipation" - comes from the findings reported by Stephen Walker and colleagues [1]. The Walker results continue a theme from this research group (see here) whereby some important data is being generated on how to treat some fairly prevalent bowel issues that seem to accompany quite a few diagnoses of autism (see here).

Much like other research from this authorship group, the research material examined was biopsy tissue - "ascending colon biopsy tissues" - provided by 35 children diagnosed with an autism spectrum disorder "and chronic constipation on a background of enterocolitis." I know some people don't like the word 'enterocolitis' in the context of autism (see here) but prejudices aside, there is nothing in the current research literature to suggest that a diagnosis of autism is somehow protective against the development of inflammatory bowel disease and/or its symptoms. Nothing.

Anyhow, 20 of those 35 children were categorised as 'slow responders' on the basis of showing "recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis" and 15 were defined as 'fast responders' as a function of experiencing "a sustained state of GI [gastrointestinal] symptomatic remission while on maintenance anti-inflammatory therapy." In effect the group was divided up into those whose bowel symptoms got better (n=15) and those whose bowel symptoms did not (even after multiple attempts) (n=20). Researchers analysed those biopsy samples with the expression of genes in mind as per other research occasions [2].

Results: "Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction)." Apologies for the long quote taken from the Walker paper, but they said it better than I ever could. The translation: gene expression data was different between the fast and slow responder groups.

Obviously more research is needed in this area with larger participant groups and perhaps using samples from other non-autism groups who present (or don't) with various types of bowel issues, whether sensitive to treatment or not. The cluster of genes that were used in the authors' modelling did all right when it came to talk of possible 'biomakers' - "The sensitivity (sensitivity = 0.88), specificity (specificity = 0.89), and kappa (kappa = 0.77) statistics all reflect a good strength of agreement between prediction and actual assignments" - but still need more work before any big claims are made.

There are a couple of other things to mention from the Walker results. So, results suggested that: "predominantly chronic constipation in fast responders is not only related to the inflammatory status of the right colon but is likely a direct consequence of this colonic inflammation." Inflammation perhaps equalling constipation? Interesting. And it not only offers lots more avenues for further study but also some important treatment options.

Next, the amino acid tryptophan was singled out as being potentially "especially significant." I've always been interested in the aromatic amino acids in relation to some autism (see here). Tryptophan is a particularly important aromatic amino acid because it's eventually metabolised into a whole slew of important compounds from serotonin (5-HT) to melatonin and beyond, with some interesting connections to autism (see here). Walker and colleagues mention how: "In the slow responder cluster of patients, there was a significant upregulation of transcripts in each of the metabolic degradation pathways for tryptophan, serotonin, and melatonin, suggesting that TRP [tryptophan] insufficiency (and therefore 5-HT insufficiency) may be an important factor in the sustained hypomotility seen in this patient cohort." There's some much more study that one could do in this area. Particularly when 'gut hypomotility' is a potential issue for quite a few people on the autism spectrum (see here).

There are other things to consider from the Walker paper - "A third relevant theme apparent from the slow response gene expression profile involves a number of pathways that converge in the mitochondria and impact mitochondrial function" - but I'll leave that for now (see here). Suffice to say that there is enough evidence emerging in the peer-reviewed domain to say that (a) pathological bowel problems are more than present alongside a diagnosis of autism, (b) said bowel issues also overlap with functional GI symptoms such as constipation in particular, (c) there are physiological reasons for such bowel issues outside of any psychobabble explanations, and (d) lots more research is required in this area without fear or favour pertinent to improving quality of life...

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[1] Walker SJ. et al. A molecular biomarker for prediction of clinical outcome in children with ASD, constipation, and intestinal inflammation. Sci Rep. 2019 Apr 12;9(1):5987.

[2] Walker SJ. et al. A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis. Sci Rep. 2016 Oct 21;6:35820.

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a "family history of mental and neurological disorders is associated with autism risk"

There's a couple of ways that one could interpret the findings reported by Sherlly Xie and colleagues [1] who concluded that: "family history of mental and neurological disorders is associated with autism risk, and the familial component of autism etiology may differ by presence or absence of co-occurring intellectual disability."

You could 'use' such findings to imply that autism is much more likely expected as and when one or other parent presents with something like "ADHD [attention-deficit hyperactivity disorder], ID [intellectual disability], other childhood disorders, alcohol misuse, drug misuse, NAPD [non-affective psychotic disorder], bipolar disorder, depression, anxiety disorders, OCD [obsessive-compulsive disorder], stress-related disorders, other neurotic disorders, eating disorder, or personality disorder." Indeed, when I tweeted the Xie paper out, I got one (joking) reply saying something along the lines of 'my kids didn't stand a chance' in light of the familial connection being made.

The other way that one could approach the Xie findings is to look at them as part of a bigger picture, where familial genetic, epigenetic and perhaps even non-genetic influences might overlap across an array of different labels. Further, the possibility that if one was able to get to the source(s) of such shared 'risk', one might potentially be able to positively affect a whole range of labels and diagnoses and perhaps mitigate some of their more quality-of-life sapping characteristics associated with them.

I'm an optimist and take the Xie findings with option number 2 in mind. I say that on the basis that whilst some people talk about the 'positives' of something like ADHD or bipolar disorder (perhaps in the context of the movement known as 'neurodiversity') I'm very much more influenced by the peer-reviewed research talking about the heightened risks that come with such diagnoses. Risks that can very much influence important facets of quality of life and sometimes in some pretty extreme ways (see here and see here for examples).

Anyhow, back to the Xie findings and yet another population-based cohort study with participant numbers totalling about half a million. With those sorts of numbers, you probably won't be surprised to hear that this was a study yet again (see here) utilising some of those marvellous Scandinavian registries; this time in Sweden. 'Index people' comprised births where among other things, their medical and other records could be "linked to both biological parents" and beyond (i.e. "Through the eligible index persons, we ascertained their first- to fourth-degree relatives who had resided in Sweden for at least 2 years"). Researchers trawled the records looking for one or more of those psychiatric and/or neurological diagnoses and looked to see if there was an connection to the index cases where autism was diagnosed.

Results: "Having a first-degree relative with ASD [autism spectrum disorder] without ID was associated with a 9-fold increase in odds of ASD without ID in index persons compared with those with unaffected first-degree relatives." Nothing particularly novel about those findings in light of other independent studies reaching similar conclusions (see here and see here).

Then: "Having a first-degree relative with ADHD, ID, other childhood disorders, alcohol misuse, drug misuse, NAPD, bipolar disorder, depression, anxiety disorders, OCD, stress-related disorders, other neurotic disorders, eating disorder, or personality disorder was associated with 1.5- to 4.7-fold increases in odds of the index person having ASD without ID compared with those with first-degree relatives without each of these conditions." Again, alongside other independent results, we are told that: "These associations diminished for more distant family relations."

When it came to autism with intellectual (learning) disability, authors reported some equally important connections: "Having a first-degree relative with ASD with ID was associated with a 14.2-fold increase in odds of the same outcome in index persons compared with those with unaffected first-degree relatives." They also observed some similar connections with regards to first degree relatives (defined as fathers, mothers, and full siblings) with one or more of those psychiatric disorder and the risk of autism and ID as that seen in the risk of autism without ID. In short, the familial presence of various psychiatric and/or neurological diagnoses seemed to up the risk of autism (with or without learning disability).

Oh, and lest I forget, another important detail was mentioned in the Xie paper: "The prevalence of ASD with and without ID was 0.4% and 1.5%, respectively."

I don't think anyone should be particularly surprised by the Xie findings, but that doesn't mean that they aren't important. They're important for the implementation of screening programmes for potentially 'at-risk' populations when it comes to the early diagnosis of autism, bearing in mind that autism can seemingly come about for lots and lots of different reasons (see here and see here) and early diagnosis might not necessarily be relevant to everyone (see here). The findings are also important for future research looking at what 'common mechanisms' might be at work. And, as I've said, they're important because of what it might eventually mean when it comes to intervening in various diagnoses with some potentially shared biology.

Just before I go, there is another angle to mention as a consequence of the Xie results. An angle that I've talked about quite a bit on this blog in two parts: (i) 'autism genes are probably not just genes for autism' (see here) and (ii) 'autistic traits are not just confined to a diagnosis of autism' (see here and see here). It strikes me that the Xie findings provide some quite strong support for both these points...

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[1] Xie S. et al. Family History of Mental and Neurological Disorders and Risk of Autism. JAMA Netw Open. 2019;2(3):e190154.

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Carnitine supplementation and autism: "side-effects and behavioral outcomes"

'Favourable outcomes' is a term mentioned in amongst the various findings reported by Robin Goin-Kochel and colleagues [1] following their examination of "dose compliance, attrition, and potential side effects of short-term, high-dose carnitine supplementation" in a small group of boys diagnosed with an autism spectrum disorder (ASD). Understanding that the Goin-Kochel study was primarily directed at looking at safety, on the basis of 'high-dose' carnitine supplementation, it appears that an elevation of plasma carnitine and related metabolites was not the only effect noted in their small cohort (N=10).

Tracking back slightly, carnitine is an important compound. Not quite an amino acid, carnitine plays an important role in energy production; as per use of the word 'mitochondria' and it's transporting duties of long-chain fatty acids to the cell powerhouse for energy conversion. You probably won't be surprised to hear that carnitine has a *connection* to some autism (see here and see here). Indeed, Goin-Kochel et al mention the findings reported by Patrician Celestino-Soper and colleagues [2] and their identification of a genetic issue that impacts on 'carnitine biosynthesis' in some people diagnosed with ASD. At least one of the authors on the Goin-Kochel paper has some pretty important knowledge about that finding of trimethyllysine hydroxylase epsilon (TMLHE) gene issues in the context of autism...

Alongside looking for reports of any side-effects from the use of carnitine - "oral suspension or tablets of levocarnitine in 3 divided doses, starting at 200 mg/kg/day and increasing to 400 mg/kg/day, with a maximum daily dose of 6 g" - various behavioural schedules were included in the study protocol. Some were objective measures of autism symptomatology; others were parent-report measures. The use of the Clinical Global Impression Scale (CGIS) also provided a helpful 'clinicians' overview' of before and after supplementation in this open-trial.

Results: a few side-effects coinciding with carnitine use were reported. These included: "heavy odor (4 parents), diarrhea (4 parents), and sporadic vomiting (1 parent)." Such reported side-effects meant that three children remained at the lower dose of carnitine over the experimental period (8 weeks).

Alongside, a few other 'favourable outcomes' were also reported: "calmer behavior (2 parents), more energy (2 parents), increased prosocial behaviors (4 parents), greater awareness (2 parents), better eye contact (2 parents), and improved language skills (2 parents)." These parental reports were accompanied by some 'changes' noted on the various schedules included in the study protocol, including those CGIS ratings. The authors used the study results produced by Geier and colleagues [3] as their comparator; highlighting how both studies had picked up "improvements in overall ASD symptoms... and some language ratings." Importantly too, Goin-Kochel et al talk about how none of their cohort were rated as "worse at post treatment."

Where next? More research please. Bigger participant numbers, more methodologically sound study designs and perhaps also, investigation of the potential pros-and-cons of carnitine supplementation over a longer period of time. By all means keep an eye on those side-effects and perhaps look to the biochemistry as to why such side-effects might appear; indeed look to the biochemistry for potential best-responders to this type of intervention too ("One child had documented TMLHE deficiency and 3 had low carnitine levels" in the Goin-Kochel cohort). But more study is definitely indicated...

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[1] Goin-Kochel RP. et al. Side Effects and Behavioral Outcomes Following High-Dose Carnitine Supplementation Among Young Males With Autism Spectrum Disorder: A Pilot Study. Global Pediatric Health. 2019; 6: 1-8.

[2] Celestino-Soper PB. et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A. 2012 May 22;109(21):7974-81.

[3] Geier DA. et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med Sci Monit. 2011 Jun;17(6):PI15-23.

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Zebrafish gut motility, SHANK3 and autism?

I have to admit that I've always been a little bit bewildered by the use of the zebrafish (Danio rerio) in autism research. It's not that I don't understand the [careful] use of 'animal models' for autism research, or that zebrafish make for good research model material [1] from a genetic and biological point of view. It's just that zebrafish seem so far removed from real life autism; it's heterogeneity, complexity and also its 'humanness'.

The findings published by David James and colleagues [2] kinda changed my mind a little bit. Their findings supporting "mutations in SHANK3 as causal for GI [gastrointestinal] transit and motility abnormalities" caught my attention. Even more so when I realised that this was not the first time that I've blogged about SHANK3 disruptions having more than just 'brain effects' (see here), their connection to the gut (intestinal barrier function no less) and what this could mean for some autism.

James et al undertook their study on the basis that: (a) "gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom" alongside many instances of autism (yes it is), and (b) autism research still only has a preliminary idea of why gut issues are over-represented when it comes to autism. Given that zebrafish have been previously used to examine "GI dysfunction in Hirschsprung’s and chronic intestinal pseudo-obstruction diseases" as well as that previous research on gut barrier issues associated with SHANK3 disruptions [3], the research began.

I can't really claim any major expertise in the hows-and-whys of genetically manipulating zebrafish to "generate a zebrafish model of PMS [Phelan-McDermid syndrome]... a condition caused by mutations in the SHANK3 gene" but it was nonetheless achieved. I understand that the technique known as CRISPR/Cas9 was utilised as part of the research strategy and led to the production of mice with "shank3 loss-of-function mutations." Researchers subsequently set about studying their SHANK3 mutant zebrafish specifically focused on "the digestive tract (DT) structure and function." To do this we are told that "videos of gut peristalsis in intact transparent 7-day-old zebrafish larvae after feeding with a chicken egg yolk emulsion" were captured. Peristalsis by the way, refers to the waves generated by muscle movement that, in the gut, keep things moving from top to bottom. Researchers also fed microscopic "fluorescent beads" to mutant and non-mutant (wild type) zebrafish larvae in order to measure digestive tract (DT) transit as a function of that SHANK3 dysregulation. A few other experiments were also carried out and reported on pertinent to their research focus.

"Our studies are the first to establish DT dysmotility as a robust phenotype in any SHANK3 mutant animal model of ASD [autism spectrum disorder]." Hypomobility denoting a reduction in gut motility was found, something that perhaps ties in with other more general autism-related research literature (see here). The magnitude of the reduced gut motility reported by James and colleagues was quite notable: "Comparatively, shank3abΔC +/− larvae took longer than 12 h to begin passing the microspheres and some individuals had not passed the remainder even after 24 h post consumption." Authors talk about 'sloshing' as being potentially important to this increased transit time "where the microspheres would repeatedly move anteriorly and posteriorly between the intestinal bulb and upper-intestine."

Another detail mentioned by James et al relates to their attempt to "rescue the DT dysmotility phenotype" via an injection of "mRNA encoding either the longest human SHANK3 isoform that includes all SHANK3 protein domains (5t, n = 19) or a shorter human SHANK3 isoform that includes only the C-terminal proline-rich and SAM domains (32t, n = 6) into fertilized eggs from shank3abΔC +/− mutants." This 'we can rebuild him' molecular rescue attempt wasn't a complete success, although did partially improve the DT (digestive tract) transit time.

OK, so one needs to remember that this is still work based on the examination of zebrafish. It's work that looked at one particular genetic 'issue' noted in a genetic condition that manifests behaviour(s) that look like autism [3]. There are, as you can see, various issues that perhaps stand in the way of making any sweeping generalisations back to 'all autism'. But in light of the other research in this area similarly linking gut-related parameters back to SHANK3 disruptions, a trend is beginning to appear. A trend that taps into other important concepts in autism research that "brain, gut, and microbiome" represent emerging research areas with respect to autism, that 'autism genes are probably not just genes for autism' in a brain-behaviour sense (see here) and onward that gastrointestinal (GI) issues appearing alongside autism may be much more than just 'comorbidity' for some...

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[1] Sakai C. et al. Zebrafish Models of Neurodevelopmental Disorders: Past, Present, and Future. Front Mol Neurosci. 2018 Aug 29;11:294.

[2] James DM. et al. Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism. Molecular Autism. 2019; 10:3.

[3] Wei SC. et al. SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCε-dependent Pathway. Inflamm Bowel Dis. 2017 Oct;23(10):1730-1740.

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"Further studies are required to understand links between ASD, ADHD, and gender identity..."

The findings reported by Ada Cheung and colleagues [1] provide the blogging fodder today, and specifically the observation that: "depression was prevalent in 55.7%, anxiety in 40.4%, ASD [autism spectrum disorder] in 4.8% and ADHD [attention-deficit hyperactivity disorder] in 4.3%" in an Australian adult transgender cohort.

The aim of the Cheung study was to "assess referral numbers and describe the sociodemographic and clinical characteristics"of their cohort, with specific reference to the prevalence of ADHD and/or ASD (autism). The autism 'connection' (and why I'm blogging about this research) follows quite a bit of other research suggesting that gender identity issues and/or reassignment behaviours *might* be over-represented when it comes to a diagnosis of autism (see here and see here and see here for examples). I stressed the word *might* because, so far, there is still some doubt about whether autism / autistic features is / are the more important variable above other comorbid features or comorbidity (see here). I'll also come to the idea of whether 4.8% is actually 'over-represented' or not when it comes to the autism [prevalence] numbers game shortly...

Based on data for quite a large number of individuals (N=540), researchers arrived at those pretty standout figures for various psychiatric and behavioural comorbidity being present. They use the words 'not surprisingly' when it came to the depression and/or anxiety prevalence stats garnered, and how "discrimination and difficulties accessing gender-affirming treatments" may be a contributory factor. I'd also draw your attention to the finding that: "Despite relatively high levels of education, unemployment rates of 21.3% were high in this relatively young cohort, four-fold higher than the Australian general population unemployment rate of 5–6%" as another possibility to (partly) account for some of those psychiatric features / diagnoses being reported on (see here).

So, 4.8% of the cohort with ASD. Is this a particularly high figure? Well, it depends. The authors rely on data from the Australian Bureau of Statistics (2015) which listed 0.7% as the "Australian population prevalence" of autism or ASD. I've not been able to find much more in the way of published estimates of adult autism specifically in Australia but would perhaps hazard a guess that 0.7% is likely to be an underestimate of the true autism rate on the basis of other population data for example (see here). Bear also in mind that Cheung et al also relied on "consecutive consultations between 1st January 2011 and 31st December 2016" so covered quite a long period of time period over which referral data was collected.

The Cheung study also ventures into some of the possible hows-and-whys of autism (and ADHD) being potentially over-represented among their transgender cohort. I'm not going to head too much into what these might be here because the long-and-short of it is that we don't know about possible overlapping genetics for example (although autism genes aren't necessarily just genes for autism) or even whether non-genetic factors might be at work: "it has been suggested that endocrine disruptors such as prenatal exposure to phthalates or antidepressants may be an explanation for the increase of ADHD and ASD and relationship with gender variance" (authors words not mine). Likewise whether the presence of autism or autistic traits means that someone is more or less likely to be 'socially conforming' is something that cannot be confirmed or denied in relation to gender variance at the present time.

All I will say is that more research is indicated in this area. Preferential screening for a range of developmental / behavioural / psychiatric issues is probably also implied as and when someone clinically presents for gender-related issues, in order to ensure that the care they receive is tailored specifically to them.

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[1] Cheung AS. et al. Sociodemographic and Clinical Characteristics of Transgender Adults in Australia. Transgend Health. 2018 Dec 26;3(1):229-238.

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"The neurodiversity movement is, arguably, still in its infancy"

The quote heading this post - "The neurodiversity movement is, arguably, still in its infancy" - comes from the paper published by Jacquiline den Houting [1] discussing the idea / concept / movement known as neurodiversity as applied to autism.

I wanted to talk about this article because it's fair to say that neurodiversity, with specific reference to the label / diagnosis / condition that is autism, has been a source of quite a bit of discussion down the years (see here for example) and probably will continue to be so for a while yet. Even by posting on this topic and perhaps offering something just a little bit critical of some facets of neurodiversity, one runs the risk that someone, somewhere will take offence, such is the strength of feeling about this topic. But being "still in it's infancy" perhaps means that the idea of neurodiversity is still being properly formulated and adapted. And respectful [critical] dialogue is an important part of that development process.

Although there are lots of different interpretations of what neurodiversity [currently] is and what it includes, I would probably suggest that the ideas that (a) all brains (and bodies) are different and (b) diagnostic labels such as autism "are the result of normal, natural variation in the human genome" are key to any description. It's also worth pointing out that under neurodiversity "autism is conceptualised using the social model of disability" as an alternative to the medical model. The difference between the models lies in 'where disability comes from'. The medical model focuses on the individual; the social model focuses on society at large.

den Houting set out "to debunk some of the misunderstandings of the neurodiversity movement" in her writings. The three areas that she focuses on are: "that the neurodiversity paradigm frames autism as a difference and a cultural identity, but not a disability... that the neurodiversity paradigm can only be appropriately applied to autistic people with lower support needs... that framing autism through the neurodiversity paradigm implies that autistic people do not require support, as neurodiversity would supposedly have us believe that autism is ‘just a natural variation’." She provides some important responses to those 'misunderstandings' which are truly refreshing to see. These include the ideas that "the social model of disability is not a panacea for all disabilities" and some additional commentary on the problematic use of functioning labels applied to autism (see here for other discussions on this topic). Throughout, the focus is on how "the insiders’ perspective on the neurodiversity paradigm" is important, and needs to be more readily incorporated into autism research and practice (see here and see here), also perhaps added to other important voices (see here).

Without trying to ruffle any feathers and importantly, accepting that people are entitled to their own viewpoints about autism, particularly those who are themselves autistic, I still have further questions to ask about the neurodiversity paradigm and some possible limitations of the current version of it in the context of autism.

So first, the social model of disability is important. As per one example I found about how society still does create barriers to disabled people (wheelchair users and stairs is the classic example), there is merit in saying that society is not always as inclusive as it should be. Society needs to do a lot more, particularly where disability might not be so obviously present. I am however always struck by the neurodiversity idea that the social model of disability should serve as a total replacement of the medical model of disability. Can the two models not seemingly co-exist? Is it not possible for example, that someone can be both disabled by autism, or facets of autism, and also be disabled by the way that society 'responds' to an autistic person / person with autism? If I take the wheelchair user example again and apply it to this 'shared' model, would it not be sensible to suggest that if there are the means to empower a person not to have to use a wheelchair all the time, they could be utilised alongside also providing a ramp access if and when it is needed? Or should an important intervention that could potentially help someone to walk unaided for example, be discarded just to fit a sociological narrative? Now apply similar sentiments to autism and say someone who has crushing anxiety as a prominent feature (see here) where there may be options worth considering for some (see here). And just before you say anxiety is not a core feature of autism, I'd be minded to suggest that it may very well be intricately connected to core autistic features (see here and see here)...

Related to that last thread are the discussions about autism and natural genetic variation and how this plays out in relation to support and intervention, particularly when: "Conflict between critics and neurodiversity advocates in the debate over support and interventions tends to centre on the end goal of such interventions." den Houting uses some pretty sweeping language when concluding that: "Critics often (either explicitly or implicitly) promote reducing or eliminating autistic traits as a key priority of intervention." Such a line of thought ties into the idea of autistic identity that has followed neurodiversity; highlighting how autism is often seen as something 'central' to a person and perhaps impacts on how that person wants to be perceived by the world at large (see here). The logical notion is that any intervention to try and *change* autism represents an attempt to try and change something fundamental about a person.

Although I can't speak for every person who has ever or continues to involve themselves in autism research, particularly autism research geared toward intervention, I've often thought of the idea of 'eliminating autistic traits' as a rather sweeping generalisation. Most researchers understand that (a) there is no behaviour seen in autism that is not potentially seen in some measure in the 'not-autism' population at some point during a lifetime, and (b) the diagnosis of autism relies on the fact that autistic behaviours are present to an extent that they "cause clinically significant impairment in social, occupational, or other important areas of current functioning." I might add that point (a) is NOT in any way supporting throwaway phrases like 'we're all a little but autistic'. If aspects of autism are however so 'clinically significantly' impairing, I don't see why the choice to potentially reduce or alleviate certain issues shouldn't be offered if and when a suitable - safe and effective - intervention becomes available. Not to do so would perhaps constitute discrimination and represent a further inequality. Bear also in mind that a diagnosis of autism rarely exists in some sort of diagnostic vacuum (see here). As I've already mentioned, the presentation of certain 'comorbid' conditions may very well be intricately *related* to certain core facets of autism (see here and see here) as per what has been noted in the peer-reviewed literature on rare genetic conditions manifesting autism plus other issues (see here for one example). With increasing recognition of these points, the discussions about the ethics of 'reducing autistic traits' turn out to be a little more complicated than one might originally think. I might also add at this point that neurodiversity doesn't seem to much like the ideas that not all autism is wholly genetic (see here) and/or present from birth or before (see here).

I'd suggest that the authors call for "services aimed at improving subjective quality of life and well-being while respecting and preserving autistic ways of being" is also not at odds with other research and practice aims and objectives. It's perfectly acceptable to look at how autistic traits and features might positively impact on a person and try and disentangle them from other traits that might be rather more disabling and could perhaps be amenable to some sort of intervention if wanted/required. Indeed, with initiatives such as the development of the ICF cores sets for autism, there is already a potential plan of action under such a heading (see here). And yes, the words "provided at the request and with the consent of the autistic person in question" are absolutely to be respected.

I have to say that in all I've read about neurodiversity and autism down the years, the key themes that jump out to me about why this idea is so readily acceptable to so many are the concepts of respect and belonging. Respect as in ensuring that a person is valued as a person and not some sort of clinical entity or diagnosis to be 'researched' and belonging insofar as neurodiversity offering an identity and perhaps even kinship for many people with many different 'medicalised' labels. It's impossible to know the personal histories and circumstances of everyone who subscribes to the concept of neurodiversity (whatever they see this as), but after hearing many challenging stories of childhood and early adulthood adversities faced by those on the autism spectrum, finding some sort of 'belonging' would seem to be an important part of the draw of neurodiversity (and probably why neurodivesity flourishes on social media platforms). Indeed as the author herself once said in an interview: 'Find your tribe'. From those points of view, neurodiversity does offer something valid to autism and beyond.

I can't however brush over certain aspects of neurodiversity including the wholly social model view of disability that it strives to adopt. It's quite evident that the obstacles posed by society do impact people, but probably not with any less of an effect on some autistic people as their autistic features do. I speak particularly of those who present with significant difficulties that mean a life of constant care and supervision; something perhaps described as level 3 in the latest DSM-5 criteria for autism (see here). Indeed, one could argue that where autism for example, means a lifetime of parental guardianship and/or residential care and support, society is generally at its most 'ableing' in providing such services and support. Not always, and improvements are always required (see here), but generally speaking society is not the universally disabling monster that some would have it labelled as.

Finally I can't mention neurodiversity without also mentioning an unfortunate word: 'neurotypical' also known as NT. As I've said before, the misnomer known as 'neurotypical' (see here), thankfully only mentioned twice in the den Houting paper, is something that seems to be synonymous with neurodiversity, despite being a tad counter-intuitive [2] (typicality in diversity?). If neurodiversity wants to perhaps evolve further, distancing itself from the nonsense that there is such a thing as 'neurotypical' within the vast ever-changing individual complexity of the brain and central nervous system (CNS) is perhaps as a good a first step as any to take.

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[1] den Houting J. Neurodiversity: An insider’s perspective. Autism. 2018. Dec 17.

[2] Armstrong T. The myth of the normal brain: embracing neurodiversity. AMA J Ethics. 2015 Apr 1;17(4):348-52.

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Project TENDR and chemical exposures part 2: organophosphate pesticides aren't great for child health

So, without striking too many chords on the old 'we've been here before' piano, consider this post an extension of some other discussions a while back suggesting that exposure to some classes of 'chemicals' might not be particularly great for child health (see here).

The findings reported by Irva Hertz-Picciotto and colleagues [1] continue the Project TENDR theme with their assertion that there is "compelling evidence" that prenatal exposure to organophosphate (OP) pesticides "is putting children at risk for cognitive and behavioral deficits and for neurodevelopmental disorders." Their observations have also been picked up by the lay media with some striking headlines like 'Ban entire pesticide class to protect children's health, experts say' complete with the required stock photo of crops being sprayed from the air.

Organophosphate (OP) compounds such as OP pesticides have a very mixed history. As well as being the insecticide of choice in many countries as a result of their excellent pest control profile, the organophosphate chemistry has also been utilised for less desirable purposes as per its classification as a component of nerve agents. Remember all the quite recent chatter about a nerve agent called Novichok? Well, the chemistry behind Novichok apparently has a very distinctive OP "structural backbone" [2]. That's not to say that every OP pesticide is Novichok. But rather that the activity of OPs specifically targeting the action of acetylcholinesterase (AChE) enzymes, important enzymes that are required for proper nerve function, is also an important biological action of various nerve agents. This in itself would suggest caution in the use of OPs.

The Hertz-Picciotto paper (policy forum) is pretty data heavy in terms of how much OP pesticides are used across the globe, the slew of mostly observational research studies that have looked at pesticide exposure and various neurodevelopmental variables and the concerns voiced at both high and low levels of OP pesticide exposure. They make a few recommendations: better training for health professionals on the potential risks attached to OP pesticide exposure, greater moves to switching to "nontoxic approaches to pest control" and perhaps most controversially: "Governments phase out chlorpyrifos and other OP pesticides."

The caveats? Well I might mention a few, minus any charges of me somehow 'standing up for OPs'. First, I don't think it's unreasonable to suggest that children in particular, do need to be more strongly protected against pesticides that are (chemically-speaking) not a million miles away from nerve agents. As the authors mention, there is quite a bit of evidence in the peer-reviewed literature to suggest a possible *association* between pesticide exposure and diagnoses such as autism (see here and see here) or beyond (see here). The thing is that like many other non-genetic environmental factors (e.g. air pollution) *linked* to a heightened risk of autism or other neurodevelopmental labels, it's more about environment + genetics when it comes to risk (see here) rather than environment just working on its own. We need for example, to know more about the ways and means that OPs are metabolised in the body and whether there could be some interesting biochemistry potentially linked to labels like autism (see here).

Second, some thought needs to go into the possible replacements if OP pesticides were to be banned outright. Thinking back to a post not-so-long-ago talking about DDT exposure and offspring autism (see here) I was struck by how short some memories are in terms of why such products were developed in the first place. I don't think anyone would seriously contemplate that the development of OP pesticides was anything more than to stop pests attacking crops and to maintain yields that can feed the population. These compounds were developed with good intentions. Obviously, as the research literature has grown, we have come to realise that such products are not side-effect free and more stringent controls have been put into place regarding safety. But to ban them outright is not something that can be done overnight. What do we replace them with? Do we just accept that crop yields will be lower and less food will be produced? Do we instead start thinking about other ways to make crops more resistant to the pests that blight them? That last question has already had its own 'issues'.

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[1] Hertz-Picciotto I. et al. Organophosphate exposures during pregnancy and child neurodevelopment: Recommendations for essential policy reforms. PLoS Med 15(10): e1002671.

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Childhood ADHD and vitamin D meta-analysed again

Consider this short post about the findings reported by Evangelia Kotsi and colleagues [1] an extension of some previous discussions on the topic of vitamin D levels and attention-deficit hyperactivity disorder (ADHD) (see here and see here).

The conclusion reached by Kotsi et al - "The systematic review and meta-analysis of observational studies demonstrated an inverse association between serum 25(OH)D and young patients with ADHD" - was not entirely unexpected given the results of other independent meta-analyses [2]. They do however reiterate that in amongst the tons of research linking vitamin D deficiency / insufficiency to various labels (see here and see here for other examples), ADHD should perhaps be part of any future research strategy. Specifically, as the authors mention, the question is: "whether vitamin D-deficient infants are more likely to develop ADHD in the future?" (Perhaps.)

A couple of next research steps should also include: (a) a focus on the reason(s) for vitamin D deficiency / insufficiency in relation to ADHD (including the genetics angle) and (b) whether supplementation *might* be something that 'affects' the behavioural presentation of ADHD [3] as well as just physiological levels of the sunshine vitamin/hormone and hence should be considered an intervention? We'll see what happens.

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[1] Kotsi E. et al. Vitamin D levels in children and adolescents with attention-deficit hyperactivity disorder (ADHD): a meta-analysis. Atten Defic Hyperact Disord. 2018 Oct 26.

[2] Khoshbakht Y. et al. Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies. Adv Nutr. 2018 Jan 1;9(1):9-20.

[3] Dehbokri N. et al. Effect of vitamin D treatment in children with attention-deficit hyperactivity disorder. World J Pediatr. 2018 Nov 19.

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Vitamin D supplementation and autism: more work needed on the biochemistry of vitamin D metabolism

The findings reported by Conor Kerley and colleagues [1] provide the brief blogging fodder today. Researchers, who are no stranger to the research area that is vitamin D and autism (see here), decided to conduct a 'post-hoc analysis' of data from two controlled trials where vitamin D supplementation was experimentally tested for children with autism and children with asthma. They were specifically looking at the "serum response to vitamin D supplementation" rather that the amount of vitamin D supplemented as potentially being important to the clinical results obtained. They concluded that "children with ASD [autism spectrum disorder] had a lower increase in 25(OH)D levels with supplementation." Further: "Potential mechanisms include altered absorption/metabolism as well as well genetic factors."

Bearing in mind the relatively small participant group numbers used and comparisons between kids with autism and kids with asthma without any other 'asymptomatic' group involvement, I was really rather interested in the Kerley findings. This was a research group who previously concluded that vitamin D supplementation did little for their cohort of autistic children under experimental conditions [2]. Now they're perhaps suggesting that there may have been valid biological reasons behind such results with respect to the biochemistry/metabolism behind vitamin D with such issues potentially affecting how much vitamin D supplementation is required to suitably raise vitamin D levels.

Of course this is not necessarily a new finding. Science has already started to look at the genetics/biology of vitamin D metabolism in relation to autism (see here and see here) and continues to do so [3]. It also converges with the idea that a deficiency/insufficiency of vitamin D is an important clinical finding but does not necessarily mean that a universal dose of vitamin D supplementation will 'fix anything' (see here for another example in another label).

"Clinical and research work relating to vitamin D is ASD should measure 25(OHO)D response to supplementation to assess therapeutic doses." I can't argue with such sentiments on the basis of the results observed. Working back from sayings such as 'the dose makes the poison', it appears that for some on the autism spectrum, that dose may not be the same as everyone else...

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[1] Kerley CP. et al. Blunted serum 25(OH)D response to vitamin D3 supplementation in children with autism. Nutr Neurosci. 2018 Oct 10:1-6.

[2] Kerley CP. et al. Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT. Arch Dis Child. 2017 Nov;102(11):1030-1036.

[3] Biswas S. et al. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018 Aug 29;10(8):e3228.

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On autism symptom trajectories and diagnosing autism late...

It's another one of my mash-up posts today, as two paper are brought to the blogging table. The first paper is from So Hyun Kim and colleagues [1] and looked at the rather interesting topic of differing symptom trajectories in the context of diagnosing autism. The second paper by Sally Ozonoff and colleagues [2] follows in a similar vein in terms of their analysis of children "who had undergone multiple comprehensive assessments in preschool and were determined to be ASD [autism spectrum disorder]-negative, only to meet criteria for ASD when tested in middle childhood."

Both these paper originate from well-respected autism research groups and appear in the same respected journal (Journal of the American Academy of Child & Adolescent Psychiatry). The common theme between them is that within the significant heterogeneity seen under the label of 'autism', there are various different developmental and presented symptoms trajectories, some of which (a) are not as stable as one might imagine, and (b) do not seemingly follow the oft-used assertion that 'autism is present and manifests from birth'. Indeed, on that last point, the implications are that autism is sometimes very much associated with regression (see here) and onward, that genetic and/or non-genetic post-natal factors may very well influence some children reaching clinical cut-off thresholds for a diagnosis of autism (see here for example).

So, to the Kim paper first: authors looked at over 900 "observations of the Autism Diagnostic Observation Schedule (ADOS)" from nearly 150 young children. They were specifically looking at symptoms trajectories based on those ADOS scores and whether or not 'clusters' of similar symptom trajectories were evident. The answer: yes, yes there were some different clusters of symptom trajectories noted. Not six developmental trajectories as per other research (see here) but four clusters: "Nonspectrum ∼25%; Worsening ∼27%; Moderately-Improving ∼25%; Severe-Persistent ∼23%)." Authors also report how: "Trajectory clusters varied significantly in the proportions of confirmatory ASD diagnosis, the level of baseline and final verbal/nonverbal abilities, and symptom severity."

Then to the Ozonoff paper: "Fourteen children met inclusion criteria for the Late Diagnosed group and were compared to a large sample of high- and low-risk siblings from the same sites who had ASD or typical development (TD) outcomes at age 3." Authors focused in on these 14 children and concluded that: "Seven showed very little evidence of ASD in preschool, while seven demonstrated subtle, subthreshold symptomatology." They also suggest that their results identifying a small but important group of children who seemingly first present with 'typical' behaviour but then 'grow into' the presentation of autism "shed light on reasons why the mean age of ASD diagnosis remains over 4 years." Indeed (see here).

I don't really need to say much more than I have already on these studies. Aside that is, from reiterating that the autism spectrum is truly wide and heterogeneous in both symptom presentation and also it seems, with regards to symptom onset and stability too. Alongside other research (see here) talking about how the presentation of autistic signs and symptoms wax and wane for some, I'm wondering when autism research is going to start looking beyond just presented behaviour, at whether for example, genetic and biological 'changes' might accompany such fluidity in behaviour and 'cluster' differences. Y'know, the same way that another group seemingly heading in the opposite direction - those who 'lose their diagnosis' (see here and see here) - also need to be closely investigated from a biological point of view too. It's only when we have such biological data that we can then start meaningfully probing the possible hows-and-whys...

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[1] Kim SH. et al. Variability in Autism Symptom Trajectories Using Repeated Observations from 14 to 36 Months of Age. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 5.

[2] Ozonoff S. et al. Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy. Journal of the American Academy of Child & Adolescent Psychiatry. 2018. Sept 3.

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Headline fail: "Autism traits could be 'edited' out genetic trial suggests"

The Telegraph June 25 2018

"Autism traits could be 'edited' out genetic trial suggests" was one of the headlines that accompanied the publication of the findings by Bumwhee Lee and colleagues [1].

The Lee article details some interesting science following the use of something called CRISPR-Cas9 gene editing (see here) or more precisely the use of a new-ish development to this technique - "CRISPR–Gold, a nonviral delivery vehicle for the CRISPR–Cas9 ribonucleoprotein." CRISPR is one of the hottest things in science at the moment, as the words 'find, cut and paste' move to a genetic level (see here) and promises so much. In the Lee study, the target was the metabotropic glutamate receptor 5 (mGluR5) gene as a move to "efficiently reduce local mGluR5 levels in the striatum."

Oh, did I also mention that this research was done using mice? Indeed, this was a study of mice engineered to display some of the molecular and behavioural characteristics of a condition called Fragile X syndrome (FXS). As such, authors reported that the use of CRISPR-Gold injections into the striatum of said FXS mice correlated with a reduction in certain behaviours such as obsessive digging and leaping into the air. The authors opine that such behaviours 'overlap' with those noted in autism (FXS has a 'connection' to autism) and voilà, a link to autism is made.

Aside from that brief overview of the findings from Lee et al just mentioned, I'm not going to go too much into the nitty-gritty of the actual results. A cobbler should stick to his last and all that, and others have done a far better job than I ever could in discussing the science (see here). I do however want to make a case that the 'autism traits could be edited out' headline represents a fail when covering the Lee findings.

I say 'headline fail' in the title of this post because well, it is. Not only does it assume that obsessive digging and sporadic leaping into the air made by mice are singularly autistic traits, it takes a few sentences before the word 'mice' is even mentioned in the coverage. I've talked before about the caution(s) needed when translating animal findings to real people (see here) and how autism in particular, seems to be a label ripe for mass sweeping generalisations from 'autistic animals' to autistic people. I'm not saying that some of the features of autism are uniquely human (see here) but rather that is it premature to even imply that the traits of autism can be 'edited out' on the basis of a single mouse or other animal genetic study.

I've already mentioned about a 'connection' between FXS and autism but it is perhaps also important to realise that there seem to be many routes that bring someone to a diagnosis of autism. FXS is one condition that manifests autistic traits but it is not the only one and certainly science does not yet know everything there is to know about the genetics of autism and FXS. And just before anyone starts talking about autism being universally 'in-born' and 'genetic' as it is [assumed] in FXS, well, the peer-reviewed research evidence might just disagree with you (see here for one example)...

Finally there's another aspect to this work that requires sensitive media handling: the ethics of 'editing out' autistic traits. I know this is a 'hot potato' area, as an increasingly vocal - certainly on social media - group of people on the autism spectrum talk about their strengths as well as their disabilities. Much of this discussion is framed around the notion that autism is not something separate from who they are but rather a fundamental part of who they are. If one takes this viewpoint, it is logical to assume that 'editing out' autistic traits might mean something rather ominous to some people...

The point I'm trying to get across is that the Lee paper is seemingly good science. It faithfully reported the results of an exciting new technology that holds promise for many different labels, conditions and diseases (see here). The issue however, is that the reporting of such research needs to be accurate and responsible. Headlines in particular, need to mention the word 'mouse' if it was a mouse study. They need to avoid sweeping generalisations that infer that digging and leaping behaviour in animals are generalisable as autistic traits (certainly the latest ICD-11 schedule says nothing about such behaviours), and they need to be sensitive to the fact that 'editing out' may very well provoke significant anxiety among some people on the autism spectrum. All for the sake of an attention-grabbing headline...

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[1] Lee B. et al. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nature Biomedical Engineering. 2018. June 25.

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"children with ASD who experience GI symptoms have an imbalance in their immune response"

The findings reported by Destanie Rose and colleagues [1] piqued my interest recently for a variety of reasons. Not only was there an emphasis on gastrointestinal (GI) issues in relation to autism (see here) but mention of the words 'microbiota composition' and 'impaired gut barrier function' make an important reference to something of a new triad in relation to [some] autism (see here).

First things first, as well as being another welcome research publication from the MIND Institute, the name Destanie Rose has appeared before on this blog with reference to maternal immune activation (MIA) and 'Old World monkeys' (see here). This work illustrated how infection during pregnancy can, under certain circumstances and at critical times, have a bearing on offspring development and behaviour; keeping in mind, that is, the possibility of logical fallacies (see here) when it comes to extrapolating from animal studies.

This latest time around, and including other notable names on the authorship list including Alessio Fasano (zonulin man) and Paul Ashwood (gut and immune system man), the focus shifted to immune function in the context of real life autism with the aim to "determine whether there are biological signatures in terms of immune dysfunction and microbiota composition in children with ASD with GI symptoms."

Four groups of children diagnosed with an autism spectrum disorder (ASD) participated in the study, including those with and without a diagnosis of ASD and with and without "current or previous GI symptoms." Both blood and stool samples were donated by study participants and subject to various analyses pertinent to assessing 'cytokine production' (cytokines are chemical signallers of the immune system) and ahem, the 'microbial composition' of poo(p) samples.

Results: those in the ASD + GI symptoms group showed "increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17" under "Toll-Like receptor (TLR)-4 stimulation" compared with those diagnosed with autism but with no bowel symptoms. TLR-4 is a protein that, as one of its duties, "plays a fundamental role in pathogen recognition and activation of innate immunity." Artificial stimulation of TLR-4 kinda mimics what would happen in real life as and when the body comes across a pathogen such as bacteria and needs to activate those immune defences.

Alongside other findings suggestive of "differences in microbiome composition between ASD and TD [typically developing] children with GI symptoms", authors also observed some interesting findings pertinent to impaired gut barrier function too. So: "The ASDGI also showed an over-representation of the gene encoding zonulin, a molecule regulating gut permeability, compared to the other groups." The gene in question is something called HP or Haptoglobin, and specifically HP2 which refers to a "common polymorphism consisting of two structural alleles: HP1 and HP2" [2]. As per the Vanuytsel paper [2], the HP2 allele is described as a risk allele for things like inflammatory bowel disease (IBD).

Bearing in mind that symptoms such as functional bowel issues (such as constipation and diarrhoea) are not necessarily the same as pathological bowel conditions such as the IBDs, I was interested in one of the figures included in the Vanuytsel paper on how HP2 links into gut permeability issues. In particular how "it is not unlikely that carriers of the zonulin gene (i.e., individuals with genotype HP21 or HP22) could possibly have an increased risk to develop IBD, because of the permeating effect of zonulin on the intestinal barrier." Zonulin has been something else of interest to this blog in the context of autism and so-called 'leaky gut' (see here) hence the interest in "a propensity to impaired gut barrier function which may contribute to their [gastrointestinal] symptoms and clinical outcome."

From what I gather, there was an over-representation of the HP2 allele (HP22 genotype) and under-representation of the HP1 allele in the ASDGI group examined in the Rose study, but things were not [statistically] completely cut-and-dried. This however, has to be set in the context of a seemingly increased risk of IBD as and when autism is diagnosed (see here).

What are the take-away messages from the Rose findings? Well bowel symptoms - functional bowel symptoms - occurring alongside autism probably have quite a complicated series of genetic and biological processes going on behind them. Both the mucosal immune system and the wider immune system are probably going to show 'some kind of relationship' to such chronic symptoms and, unsurprisingly, those trillions of wee beasties known as the gut microbiota are also probably involved/affected. The "propensity to impaired gut barrier function" associated with autism + bowel issues is also mentioned by Rose, and offers further testable hypotheses regarding the possibility of a gut-brain axis in relation to [some] autism (see here) and indeed, what measures might ease the pressures of such bowel issues. Also, whether bowel symptoms *might* show a connection to certain presented behaviour (see here) is another important area of further investigation...

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[1] Rose DR. et al. Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain, Behavior, and Immunity. 2018. March 20.

[2] Vanuytsel T. et al. The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease. Tissue Barriers. 2013;1(5):e27321.

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Effects of pregnancy vitamin D deficiency on social behaviours of offspring rats

I note the findings reported by Nathanael Yates and colleagues [1] have garnered a few lay and science media headlines recently (see here) as authors concluded that "early life levels of vitamin D are an important consideration for maternal behavioural adaptations as well as offspring neuropsychiatry." Further coverage of their findings is provided in a helpful article for The Conversation (see here), where some authors - including the autism research powerhouse that is Andrew Whitehouse - provide a little more interpretation of their findings. I might also add that Whitehouse is no stranger to the vitamin D - autism research story (see here).

So, what's all the current discussion about?

Well, vitamin D - the 'sunshine' vitamin/hormone - is front and centre of this latest research, and some investigation into "how early life vitamin D deficiency during rat pregnancy and lactation alters maternal care and influences neurodevelopment and affective, cognitive and social behaviours in male adult offspring." This is set within the context that vitamin D seems to be doing a lot more than just contributing to bone health (see here). You'll of course note the use of the word 'rat' in the above text, and in particular what happened to offspring baby rats in terms of "offspring neurodevelopmental markers, ultrasonic vocalisations and adult behavioural outcomes including social, cognitive and affective-like behaviours" when mummy rat diets are loaded up with enough vitamin D as opposed to those mummy rats who were provided with a vitamin D deficient diet. The theory behind those vitamin D loaded vs. vitamin D deficient mummy rat diets is that: "In both humans and rats, a baby developing in the womb is completely reliant on the mother’s vitamin D stores." Probably something to do with the lack of sunlight exposure in the womb(!)...

Results: there did seem to be some difference across various 'test a rat / test an offspring rat' measures as a function of vitamin D status, looking across behaviour, brain scans (yes, rats did meet some MRI equipment) and also "plasma corticosterone levels and neural expression of genes associated with language, dopamine and glucocorticoid exposure." So for example, authors describe how "males that had been exposed to vitamin D deficiency in early life exhibited decreased social behaviour, impaired learning and memory outcomes and increased grooming behaviour, but unaltered affective behaviours." It's not difficult to see the 'decreased social behaviour' links that *could* be made with a condition / label / diagnosis like autism; particularly when vitamin D has quite the peer-reviewed research history with autism in mind (see here).

Interestingly too, but not made too much of in the chatter about this study for obvious reasons, were the observations made around maternal care as a function of vitamin D status, bearing in mind that vitamin D deficiency will probably impact both mummy rat and baby rat. So: "the quality of maternal care was decreased in dams consuming a vitamin D-deficient diet." Mmm...

Whilst this is important work, and adds to our understanding that appropriate nutrition throughout the lifespan is important to various aspects of functioning, I'll reiterate that this was research using rats. Rats not humans. It is perhaps timely that at around the same time that the Yates paper was published, I also chanced upon some discussion over at Spectrum on how we all need to be a little bit careful when talking about modelling autism in various animals (see here) and their relevance to real, often much more complicated, people (see here) and their [multiple] labels (see here).

I note that in their piece for the The Conversation, authors caution that their findings don't mean everyone who is pregnant (or could become pregnant) should rush out and load up on vitamin D so as to potentially influence offspring developmental course. I would second that view; but would also direct your attention to some Government advice quite recently (at least here in Blighty) that we should perhaps all be thinking about vitamin D supplementation (see here) and the many and varied ways that this vitamin/hormone *might* impact on our physiology and beyond (see here).

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[1] Yates NJ. et al. Vitamin D is crucial for maternal care and offspring social behaviour in rats. J Endocrinol. 2018 May;237(2):73-85.

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