Saturday, 3 December 2016

Parent-mediated interventions for young children with autism meta-analysed

Do not mess with  Lois.
Today I'm posting on the topic of the paper by Rose Nevill and colleagues [1] concluding: "that while most outcome domains of parent-delivered intervention are associated with small effects, the quality of research is improving."

Parent-mediated interventions in relation to autism have been covered on this blog quite recently (see here) accompanied by that 'super-parenting' headline fail. Such approaches work on the idea that helping parents to "develop strategies for interaction and management of behaviour" [2] might be one route of early intervention when it comes to autism. The research road has however not been smooth when it comes to this class of intervention (see here) and despite some positives (see here) has perhaps not been the overwhelming success that many had hoped for.

Nevill and colleagues reviewed 19 trials of parent-mediated interventions for autism ("randomized clinical trials") looking at various outcomes in relation to core symptoms of autism and aspects such as communication and cognitive functions. The results kinda reiterate what we already know that so far, parent-mediated interventions aren't really cutting the statistical mustard when it comes to outcomes and important statistics related to effect sizes. Indeed, the [weighted] Hedge's g statistics produced by the authors on the cumulative data in this area can, at best, be described as 'modest' (and I mean at best). As a comparison, have a look at the Hedge's g stats produced by a meta-analysis of the placebo response when it came to autism [3]: "a moderate effect size for overall placebo response (Hedges' g=0.45, 95% confidence interval (0.34-0.56), P<0.001)" (based on "25 data sets (1315 participants)"). This bearing in mind that the parent-mediated intervention trials don't usually include a placebo condition (and indeed, typically don't even blind - how could you?)

I don't want to poo-poo all of this area of autism science because it may still be pretty important. A few things do however worry me about the attention here based on the ideas that parent-child interactions are somehow the be-all-and-end-all of autism (also harking back to the bad 'ole days) and that in these times of continued cost-savings and austerity, parents are being expected to carry out the same services as other professionals. On that first point focused on parent-child interactions, I've always been a little cautious about what this means. Certainly in light of the primary focus on this blog, looking at genetics, epigenetics and biochemistry when it comes to autism, parent-mediated interventions are to be seen as a reactive strategy attempting to deal with 'symptoms' not necessarily causes. Yes, I know 'symptoms' are what parents and other family members see and deal with day in day out, but I'm wondering how successful parent-mediated intervention would be if used in the context of autism secondary to an inborn error of metabolism for example? Surely it makes more sense to spend a little more time ruling out some of the potential reasons why autism or particular autistic features might come about (i.e. screening - see here and see here for some other examples) rather than universally providing a parent-mediated intervention manual and hoping for the best? I might also add that a greater recognition that among 'the autisms' (see here) there may be some important waxing and waning of presentation(s) (see here) potentially influenced by things like the presence of comorbidity too reiterates that every person is an individual and set manuals on parent-child interactions don't necessarily cover all that heterogeneity. And there's also the suggestion that some parent-mediated intervention options are also seemingly failing when it comes to important comorbidities such as anxiety (knowing how disabling these can be) as being something else that needs to be kept in mind.

We'll have to see how this area develops further but for now, I don't think anyone can seriously say the existing research on this topic has shown anything like the successes that everyone hoped for. And whilst we should celebrate the fact that "the quality of research is improving" I'm not sure one can blame the limited success of such an approach on previous poor quality research.

To close, today is a really, really big day for some of my brood who have their 1st Dan black belt grading. After several years of training, hard work and effort pertinent to their voyages through Shotokan karate it all comes down to examination this evening. Thanks and credit need to go to their Sensei for all their efforts in getting them this far, as well as a certain practitioner who is Shotokan YouTube royalty. Whoever you are, thank you.

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[1] Nevill RE. et al. Meta-analysis of parent-mediated interventions for young children with autism spectrum disorder. Autism. 2016. Nov 14.

[2] Oono IP. et al. Parent-mediated early intervention for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2013 Apr 30;(4):CD009774.

[3] Masi A. et al. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2015 Sep 22;5:e640.

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ResearchBlogging.org Nevill, R., Lecavalier, L., & Stratis, E. (2016). Meta-analysis of parent-mediated interventions for young children with autism spectrum disorder Autism DOI: 10.1177/1362361316677838

Friday, 2 December 2016

The prebiotic galactooligosaccharide (B-GOS) and autism: just add to poo(p)

Yes, it is childish but...
With all the continued chatter on a possible role for the collected gut microbiota - those wee beasties that inhabit our deepest, darkest recesses - in relation to some autism (see here for example), the paper by Roberta Grimaldi and colleagues [1] (open-access available here) provides yet more potentially important information.

So, poo(p) samples were the starring material in the paper - "obtained from three non-autistic children and three autistic child donors"- and specifically what happened when something called B-GOS "a prebiotic galactooligosaccharide" was added to samples following their journey through a "Three stage continuous culture gut model system" otherwise known as an artificial gut. Said gut model based at Reading University has already been the topic of other news (see here).

As well as looking at the initial bacterial profile of those stool samples, researchers plotted the changes to the stool's inhabitants (or what was left of the stool) over the course of B-GOS addition, as well as looking at things like the "production of SCFAs [short-chain fatty acids] in the fermentations" and other metabolites via the gold-standard chemical analytical technique called 1H-NMR (see here for more details).

Results: "Consistent with previous studies, the microbiota of ASD [autism spectrum disorder] children contained a higher number of Clostridium spp. and a lower number of bifidobacteria compared to non-autistic children." With the addition of B-GOS to the 'mixture', researchers reported on a significant increase in bifidobacterial populations at the different stages of their gut model and in samples from both those with autism and those without autism. Such "bifidogenic properties of B-GOS" are not unheard of.

As to the metabolites of those bacteria present in the poo(p) samples, there were some interesting knock-on effects noted in both raw and B-GOS supplemented samples. "Our data show a lower concentration of butyrate and propionate in autistic models, compared to non-autistic models, but no
differences in acetate before adding B-GOS into the system." Propionic acid (propionate) has some research history with autism in mind (see here). Butyric acid (butyrate) is something of a rising star in quite a few domains, having also been mentioned in the context of autism too (see here). Indeed it's interesting to note that B-GOS administration "mediated significant production of... butyrate... simulating the transverse and distal colon respectively. There was no effect on propionate." The findings of lower starting levels of butyrate in samples from children with autism were also substantiated by the NMR analyses undertaken. Increases in butyrate and changes to various other metabolites ("increasing ethanol, lactate, acetate and butyrate and decreasing propionate and trimethylamine") were also noted via this analytical method for this group.

A long quote coming up: "This in vitro study showed promising and positive results in that supplementing the microbiota of ASD children with 65%B-GOS may manipulate the gut bacterial population and alter metabolic activity towards a configuration that might represent a health benefit to the host. However, further work will be required to assess such changes in an in vivo human intervention study."

Just before anyone makes a run on B-GOS or any similar product however, I do need to stress a few important points. First, this was a study of poo(p) samples from 3 autistic children compared with samples from 3 non-autistic children. Aside from the small participant numbers, we don't know anything about participants' various comorbidities (although we know they were "free of any metabolic and gastrointestinal diseases") and only limited information on their dietary habits and medication history. Second, poo(p) was the target material included for analysis and what happened when B-GOS was supplemented during the journey through the artificial gut model. This study said nothing about what happens when real people with autism take B-GOS orally for example, and how it might affect gut bacterial populations and metabolites as it progresses down a real gastrointestinal (GI) tract. This also includes a lack of information on any potential side-effects in a real-world situation. We are also assuming that any supplement survives the stomach. There is quite a bit more to do in this area.

But for now, I stick to the idea that the Grimaldi paper provides some potentially important information and certainly, some new routes/methods for further study of the link between prebiotics, probiotics and synbiotics in the context of the gut microbiota and autism...

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[1] Grimaldi R. et al. In vitro fermentation of B-GOS: Impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children. FEMS Microbiol Ecol. 2016 Nov 16. pii: fiw233.

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ResearchBlogging.org Grimaldi R, Cela D, Swann JR, Vulevic J, Gibson GR, Tzortzis G, & Costabile A (2016). In vitro fermentation of B-GOS: Impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children. FEMS microbiology ecology PMID: 27856622

Thursday, 1 December 2016

Dietary fibre deficiency and gut barrier integrity

"Dietary fiber deprivation, together with a fiber-deprived, mucus-eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen, Citrobacter rodentium."

So said the findings reported by Mahesh Desai and colleagues [1] meriting an editorial in the publishing journal [2] as the sentiments of 'eating your greens' applies to some rather interesting [mouse] findings.

Fibre (UK spelling) comes in various different forms typically categorised as soluble and insoluble depending on their relationship with water. Using a "gnotobiotic mouse model" - where mice were "colonized with a synthetic human gut microbiota composed of fully sequenced commensal bacteria" - Desai et al reported on the effects of different diets with different fibre content. Their results make for important reading as a fibre-deprived gut was associated with the rise of some rather potent bacteria that seemed to enjoy dining out on the "colonic mucus barrier, which serves as a primary defense against enteric pathogens." Yes, mice gut barriers - or some of their components at least - were being eaten by the very bacteria they contain. Enjoy your lunch.

I'm not dwelling too much on the Desai findings, bearing in mind their focus on mice not humans, but I do want to raise a couple of potentially relevant points. First is the focus on the intestinal barrier and how that so-called 'leaky gut' seems to show a connection to dietary fibre intake. Yet more research bringing this woo-like term in from the scientific cold (see here). Next is the idea that if the Desai results are transferable from mouse to humans, they could be relevant to quite a lot of people who perhaps don't enjoy as much dietary fibre as they should. Further, there may be particular groups of people who might be particularly prone to a poor diet [3] (see here too) where the already discussed term 'leaky gut' is also relevant (see here); also bringing in the idea of a role for those trillions of wee beasties (the gut microbiota) that call us home.

I'll be watching for how this research area pans out...

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[1] Desai MS. et al. A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell. 2016 Nov 17;167(5):1339-1353.e21.

[2] Gazzaniga FS. & Kasper DL. Veggies and Intact Grains a Day Keep the Pathogens Away. Cell. 2016 Nov 17;167(5):1161-1162.

[3] Bandini LG. et al. Changes in Food Selectivity in Children with Autism Spectrum Disorder. J Autism Dev Disord. 2016 Nov 19.

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ResearchBlogging.org Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, Pudlo NA, Kitamoto S, Terrapon N, Muller A, Young VB, Henrissat B, Wilmes P, Stappenbeck TS, Núñez G, & Martens EC (2016). A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell, 167 (5), 1339-2147483647 PMID: 27863247

Wednesday, 30 November 2016

Restless leg syndrome in parents of children with autism

The findings reported by Maureen Russell and colleagues [1] provide some blogging fodder today and the observation that: "Biological caregivers of children with ASD [autism spectrum disorder] demonstrated a high prevalence of RLS [Restless Legs Syndrome] symptoms and poorer mental health."

OK, I know some people might be asking 'just what is Restless Legs Syndrome'? It is a recognised condition complete with 'disease' title (Willis-Ekbom disease). Symptoms, as the name suggests, centre on 'an overwhelming, irresistible urge to move the legs'. But things might not just stop at 'jittery legs' when it comes to this condition, as various other parts of the body can also be involved and indeed, affect important functions such as sleep.

Russell et al surveyed 50 biological caregivers (parents) of children diagnosed with an autism spectrum disorder (ASD) with regards to sleep habits "that included RLS as determined by four questions." They also "compared the sleep quality and daytime behaviors of children with ASD in caregivers with and without symptoms of RLS."

They observed that just over a fifth of their caregiver cohort "fit the criteria for RLS symptomatology." They also reported that those 'biological caregivers' who reported RLS symptoms also reported "poorer mental health" based on responses to the "Medical Outcomes Survey (MOS) 12-Item Short Form (SF-12)." When it came to offspring parameters, authors reported that: "Caregivers with RLS described more night waking and greater internalized behavior problems in their children with ASD than the caregivers without RLS." They interpret this 'association' in the context that there is a degree of heritability attached to RLS and some of those sleeping issues noted in offspring could mean that the symptoms of RLS are also present in children diagnosed with ASD too.

Noting the relatively small scale of the Russell study in participant number terms, the very preliminary method of reporting on mental health and the fact that there isn't a single test for RLS, these are interesting findings. I note the lead author has her PhD online (see here) showing how this research fits into a larger scheme of work on sleep and quality of life in caregivers of children with autism.

Looking at the Russell findings in the context of 'hows and whys' there are some potentially important correlations that might be noteworthy. RLS has been linked with the presentation of attention-deficit hyperactivity disorder (ADHD), a not insignificant comorbidity noted in quite a bit of autism (see here). I don't want to make any connections where none might exist but it is reasonable to assume that an over-represented occurrence of ADHD in autism could be important. Insofar as the heritability of ADHD specifically across families, there is more to do in this area but it's not unheard of for ADHD symptoms to be present in other family members including parents. This could impact on the results reported by Russell et al.

Although certain medicines have been associated with the symptoms of RLS, there is also a body of peer-reviewed science suggesting that a deficiency in iron might also be important [2]. There is still a degree of debate specifically as to how iron deficiency might 'cause' RLS but one of the primary lines of thinking revolves around how iron is an important co-factor for the biological reactions that turn the amino acid tyrosine [eventually] into the neurotransmitter dopamine. Again, minus any 'I know all the answers' sentiments, iron levels in relation to autism have been a source of some investigation down the years (see here). Some researchers have also talked about maternal iron intake potentially affecting the 'risk' of offspring autism too (see here) (with appropriate caveats).

Whatever the reason(s) to account for the Russell findings, there is a requirement for further research in this area, for a start to assess just how prevalent RLS might be in both people diagnosed on the autism spectrum and their significant others. Knowing how much comorbidity seems to follow a diagnosis of autism (see here) I wouldn't be surprised to see yet another connection; this one however, might provide some rather important clues as to overlapping genetics and biology...

Music, and Gotye still has an amazing song...

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[1] Russell M. et al. Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders. J Clin Sleep Med. 2016 Oct 28. pii: jc-00043-16.

[2] Li X. et al. Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla. Sleep Med. 2016 Jun;22:75-82.

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ResearchBlogging.org Russell M, Baldwin C, McClain D, Matthews N, Smith C, & Quan SF (2016). Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine PMID: 27855729

Tuesday, 29 November 2016

Publication bias and autism research

The title of the paper by Konstantin Mechler and colleagues - "Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis" [1] - provides some discussion today. Drawing on the ideas that publication bias and/or the so-called 'file-drawer problem' - terms that refer to the non-publication of study results potentially skewing the collected scientific opinion in a particular area - might also extend into autism research too, Mechler et al detail results according to their analysis of a particular trial registration database called: ClinicalTrials.gov.

ClinicalTrials.gov is one of the premier 'tell everyone about your trial' databases designed to provide a bit of transparency to science. The idea is that you register (pre-register hopefully) your research study, register what you are going to do and how, and importantly, provide some details about what your are going to be assessing (outcomes). Some of the research that I've been involved with has a mention in this database (see here) with more to come in future times. Once your entry is in ClinicalTrials.gov it kinda stops you from making any major 'alterations' to your study potentially based on the results you get, whilst at the same time also getting quite a few prods to post things like your raw study results for everyone to see and analyse as they wish. And believe me, they are quite a persistent bunch over at ClinicalTrials.gov!

So Mechler and colleagues "searched for all completed randomized controlled clinical trials investigating interventions in ASD [autism spectrum disorder] and their results made public." They looked at how many trials had been submitted and how many reported results. Where no results were available on ClinicalTrials.gov or on other 'scientific databases' or after "enquiries of the responsible parties or sponsors listed", the authors listed the trial as 'not published'.

The good news: 60% of trials (n=30) were published in the peer-reviewed domain. The not-so-good news was that reported in the opening sentence of this post as some 40% of trials (n=20) fell into that not published category. Authors also mention that some 1600 participants were included in those not published trials, inferring that data on quite a few people diagnosed with an ASD and agreeing (themselves or by proxy) to participate in research remain 'missing' in a research sense.

"The results emphasize the serious issue of publication bias. The large proportion of unpublished results precludes valuable information and has the potential to distort evidence for treatment approaches in ASD." This an important point in any area of science but perhaps more so when you have a label like autism and a whole host of 'unknowns' about the aetiology, nature and course of presentation. I would like to think that there were some rational reasons why so many trials were missing results (studies having to be halted/stopped, collaborations breaking down, resources being exhausted, etc) but there is always going to suspicion around the non-publication of such results particularly the idea that 'researchers or funders did not get the results they hoped for'. Other discussions on this topic outside of autism (see here) point to the failure to publish being tantamount to an ethical breach. Strong words indeed.

Although Mechler et al focused on data from the ClinicalTrials.gov initiative I'd perhaps suggest that the issues they discuss probably go a lot deeper as a function of there being quite a few other databases where such trial information is held and listed. Perhaps also just as concerning is the fact that many other pieces of research are not listed anywhere when it comes to trial registration and therefore have even less 'motivation' to publish results or are perhaps more likely to be subject to 'alteration' in terms of methodology or outcome(s). All of which contributes to the possible tarnishing of science and the reporting of said science and paves the way for criticism.

Music, it's not Mother's Day or anything like that but do give her a call from time-to-time and treat your mother right...

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[1] Mechler K. et al. Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis. International Journal of Methods in Psychiatric Research. 2016. Nov 9.

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ResearchBlogging.org Mechler K, Hoffmann GF, Dittmann RW, & Ries M (2016). Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis. International journal of methods in psychiatric research PMID: 27862603

Monday, 28 November 2016

On moving off the autism spectrum

The paper by Nahit Motavalli Mukaddes and colleagues [1] provides some important, if small-scale, information when it comes to that still controversial term - optimal outcome - with the diagnosis of autism in mind. Optimal outcome basically refers to a particular 'type' of autism whereby following a definite diagnosis of autism or autism spectrum disorder (ASD), a later re-evaluation of signs and symptoms reveals that diagnostic thresholds are subsequently not reached and/or exceeded and hence, the criteria for autism are not fulfilled.

I say this is a controversial term because it is. Still after quite a bit of peer-reviewed published research saying 'yes, it exists' (and alongside quite a few manifestations of autism) coupled with quite a bit of research talking about different developmental trajectories accompanying different 'types' of autism (see here) the old 'they weren't really autistic' phrase still comes out time and time again. And with it, children/adults who were diagnosed with autism are doubted to have been actually autistic. The skills of the professionals who made the diagnosis are doubted. The parents and significant others who most likely initiated the screening and diagnosis of autism are doubted. All of this seemingly to uphold the 'lifelong' tag that accompanies quite a bit of discussion about autism. Not a great state of affairs eh?

Work by Mukaddes et al has previously made an appearance on this blog (see here) talking about possible predictors of optimal outcome. This time around they aimed to "assess the autism symptoms and other psychiatric disorders in a group of children with a past history of autism." Their group, comprised of 26 who "lost the diagnosis of autism two to eight years previously", were assessed for autism - DSM-5 autism no less - together with various other psychometric/behavioural schedules.

Results: "None of the participants met criteria for an autism diagnosis." What this means is that for their cohort, 'loss' of a diagnosis of autism was not some short-term thing. But be careful here, as I remind you that DSM-5 criteria "were used for [a] diagnosis of ASD" for autism and the emerging data suggesting that DSM-5 is already likely to move quite a few people off the autism spectrum compared with previous diagnostic schedules (see here). Indeed, I wonder how many of their cohort might be labelled with SCD instead?

When it came however to looking at other psychiatric/behavioural labels, being an optimal outcomer with autism in mind did not necessarily mean symptom-free: "81% had a present psychiatric disorder based on the K-SADS. ADHD [attention-deficit hyperactivity disorder], specific phobia and Obsessive Compulsive Disorder (OCD) were the most common disorders." This finding is interesting. Interesting because it does not necessarily tally with other work on this topic (see here) but at the same time, reiterates that a diagnosis of autism rarely exists in a diagnostic vacuum (see here) (and that includes past diagnoses of autism). That ADHD in particular, is a label of growing importance to quite a few cases of autism should also be mentioned (see here) as should be the 'effects' that such a label has been linked with (see here).

"It is crucial to maintain psychiatric follow up of children who move-off ASD." Wise words from Mukaddes and colleagues but given the state of things here in Blighty, with continued austerity and long, long wait lists for assessments (see here), I don't really have a great deal of confidence that removal from the autism spectrum is going to prompt much in the way of follow-up. Indeed, going back to the question of whether optimal outcomers might nevertheless hit SCD - 'autism lite' -  diagnostic thresholds, I'm not even sure that those fitting into the SCD description are going to receive anything like the services and support they will still no doubt require. I do hope that I am wrong but...

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[1] Mukaddes NH. et al. What Happens to Children Who Move off the Autism Spectrum? A Clinical Follow-Up Study. Pediatrics Int. 2016. Nov 12.

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ResearchBlogging.org Motavalli Mukaddes, N., Mutluer, T., Ayik, B., & Umut, A. (2016). What Happens to Children Who Move off the Autism Spectrum? A Clinical Follow-Up Study Pediatrics International DOI: 10.1111/ped.13202

Saturday, 26 November 2016

Acetylation focus over methylation in autism epigenetics?

The paper by Wenjie Sun and colleagues [1] (open-access) provides the blogging fodder for today's post and although based on the science of epigenetics, the usual suspect - DNA methylation - gives way to another concept: histone acetylation with autism in mind. Before heading into the paper myself, I'll draw your attention to some other write-ups of the study including a hat-tip to Jeff Craig and his piece on the topic (see here).

So histone acetylation... I've covered the subject before on this blog (see here) but basically DNA, the stuff that carries the genetic blueprint, complexes with histones to form something called nucleosomes. It's a combination likened to thread wrapped around a spool. Continuing that thread wrapped around a spool analogy, protruding threads called histone tails can be modified in a chemical sense (via processes such as acetylation where an acetyl group is added or deacetylation where one is removed) which can subsequently affect genetic transcription.

Still with me? Good. Sun and colleagues set out to look at histone acetylation in the context of autism; specifically in post-mortem brain samples donated from those deceased who were diagnosed with autism and whether they might show some important changes based on the use of "a histone acetylome-wide association study (HAWAS)."

Specific areas of the brain were assessed using the HAWAS approach - "prefrontal cortex (PFC), temporal cortex (TC), and cerebellum (CB)" - and researchers were looking for a specific type of acetylation mark called H3K27ac linked to gene activation. Based on brain samples from 94 participants ("45 ASD [autism spectrum disorder], 49 control"), a few details emerged:

  • Despite the expected heterogeneity across the presentation of autism in terms of whether the diagnosis of autism was syndromic (secondary to an existing condition) or non-syndromic (idiopathic), the authors reported that approaching 70% of the autism cases "shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex." In other words, a not uncommon molecular signature in relation to histone acetylation seemed to be present in quite a few of the participant samples included for study.
  • Although one needs to be a little cautious about making grand, sweeping claims about how such an 'acetylome signature' comes about, the authors reported "that ASD-specific differential acetylation is driven mostly by.. factors such as environmental influences, SNPs in trans (at a different locus), indels, and larger chromosomal variants." Note the term 'environmental influences' (something I'll come back to shortly).
  • When it came to what types of genes were potentially being 'affected' by acetylation, the authors report on quite a diverse spread "involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity." Epilepsy and autism is a recurrent theme in the research and clinical literature (see here for example) so there are no great surprise there. 'Immunity' and autism is something else that keeps cropping time and time and time again (see here).
  • I appreciate that the authors also acknowledge that whilst autism was the focus on the current work, they do also mention: "By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases." This opens up the idea that various different psychiatric/behavioural labels might show 'overlap' when it comes to the histone acetylome too.

Interesting stuff by all accounts. I do like the idea that autism research is continuing to look at other areas of gene expression outside of just structural issues to the genome being linked to the condition (or should that be plural). Aside from the fact that people don't walk around with their genes permanently stuck in the 'on or off position' in every tissue all the time, the whole epigenetics field is a welcome complement to more traditional genomics. The focus on gene expression being potentially 'modifiable' might also reunite genetics and environment too (see here).

Criticisms of the Sun study? Well, brain samples from the deceased are a precious resource but not without complications when it comes their use for science (see here). I appreciate that we don't have the technology to look at histone acetylation in real-time or real-life yet with the brain in mind but one has to be cautious about the results from the brains of the deceased who may have passed away for many different reasons. There is also the temptation to move the whole epigenetics 'thing' towards acetylation on the basis of such research, but the methylome still remains potentially important (see here) and probably for more than one reason (see here). Perhaps soon we'll see a study looking at more than one epigenetic factor with autism in mind?

Going back to the concept of 'environmental influences' mentioned in the Sun paper, there are some potentially important repercussions from study results such as these. As with the concept of DNA methylation, one of the important concepts linked to the science of epigenetics is that such chemical alterations affecting the expression of DNA are potentially modifiable. This could mean that particular environmental factors working at critical periods might affect acetylation and methylation patterns and onward the expression of certain genes pertinent to the presentation of something like autism or at least facets of autism. The other scenario is that certain 'conditions' or 'interventions' might 'reverse such changes. On that last point, I might bring in some previous discussions on this blog in relation to something called HDAC (histone deacetylase) inhibitors (see here) that, as their name suggests, have the ability to inhibit the action of histone deacetylases (they remove acetyl groups). Various classes of medicines are classed at HDAC inhibitors including something called valproic acid which has some autism research history (see here for example). It's not therefore beyond the realms of possibility that the actions of certain medicines or other non-genetic factors with an influence on acetylation could be a source for further research in this area.

Independent replication is the next stage in the research process here. Alongside marrying acetylation trends with methylation trends, I do also wonder whether more functional analysis of other tissue(s) outside of just the brain might also be revealing too. I might add that traditional structural genomic issues (all those SNPs and CNVs that are talked about) can still play a role and indeed, might show some association with epigenetic issues too (see here).

And with all this talk of epigenetics and the like, due credit needs to be given to those who've been talking about this for quite a while in the peer-reviewed domain [2]...

To close, we have one final look at Rogue One before touchdown...

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[1] Sun W. et al. Histone Acetylome-wide Association Study of Autism Spectrum Disorder. Cell. 2016. Nov 17.

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

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ResearchBlogging.org Sun, W., Poschmann, J., Cruz-Herrera del Rosario, R., Parikshak, N., Hajan, H., Kumar, V., Ramasamy, R., Belgard, T., Elanggovan, B., Wong, C., Mill, J., Geschwind, D., & Prabhakar, S. (2016). Histone Acetylome-wide Association Study of Autism Spectrum Disorder Cell, 167 (5), 1385-2147483647 DOI: 10.1016/j.cell.2016.10.031