Is the word 'comorbid' accurate when describing emotional and behavioural issues occurring alongside autism?

The findings reported by Per Normann Andersen and colleagues [1] observing that: "The amount of autism symptoms and degree of attention problems at baseline significantly predicted EBP [emotional and behavioral problems] at follow-up" potentially taps into a wider discussion in the context of autism.

EBP refers to feeling "anxious/depressed, withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior, and aggressive behavior." The wider discussion is framed around a question on whether use of the term 'comorbid' - comorbid EBP for example - is accurate when it comes to such 'issues' appearing alongside the core features of autism? Should instead we be thinking and talking about comorbid issues/symptoms such as depression and anxiety as being something rather more central to at least 'some' autism? Y'know, is there a lot more than just the the triad/dyad of core features for some at least?

It's a discussion that has emerged before on this blog (see here and see here) and continues in the peer-reviewed science arena [2]. It has some potentially profound implications for things like autistic identity, the distinction between autism as a developmental condition as opposed to a psychiatric disorder, talk about the 'disabling aspects' of autism (and 'where they potentially come from') and the often polarised topic of intervention specifically 'for autism'...

Andersen et al report results based on analysis of children and adolescent diagnosed with autism - 'high-functioning' autism (HFA) (their term not mine) - where "levels of EBP, autism symptoms, inattention problems, and verbal IQ" were assessed at baseline and 2 years later.  The aim was to see whether symptoms such as autism "can predict EBP 2 years later."

Interestingly, the authors opted for the use of the Autism Spectrum Screening Questionnaire (ASSQ) as one of their study instruments, [partly] devised by a researcher who I have a lot of time for on this blog (see here) and his equally pertinent concept of ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations). This was complemented by "the Schedule for Affective Disorders and Schizophrenia for School Age Children/Present and Lifetime version-2009 (K-SADS-PL)" covering questions on possible "affective disorders, psychotic disorders, anxiety disorders, behavioral disorders (ADHD), substance abuse disorders, eating disorders, tic disorders and ASD [autism spectrum disorder]" and the ADHD rating scale IV among others research tools.

Results: "the level of autism symptoms at baseline were the best predictor of EBP in our group of children with HFA." The authors also observed that "attention problems had an independent impact on EBP" but noted that whilst autism and attention issues correlated at baseline, the role of attentional issues on EBP was "considerably less compared to the level of autism symptoms." Authors also stated that verbal IQ did not seemingly predict EBP, which is perhaps at odds with other independent research on a similar topic (see here). They conclude by suggesting that "interventions aimed at improving ASD symptoms may positively affect the prevalence of EBP in children with HFA."

Of course the Andersen study was not perfect and one has to be careful not to extrapolate too much. As the authors note, their study: "focused on symptoms of autism and attention, and we cannot generalize these findings to those with ASD and clinical diagnoses of ADHD" representing one important limitation. They add that their focus on those with an IQ above 70 and their investigating a very 'male-orientated' sample group also limited the generalisability of their findings to the entire autism spectrum; particularly some of the 'under-studied' people of the autism spectrum (see here). And before you mention it, yes, IQ still needs quite a bit more research work done on it when it comes to autism...

Nevertheless, I believe that these findings do add to an increasingly vocal peer-reviewed research evidence base suggesting that the term 'comorbidity' might not be the most 'useful' description when it comes to chatter about a range of labels/conditions/symptoms that are seemingly over-represented in relation to autism. Indeed, as per more historical mentions - yes, Mildred Creak yet again - set within the context of the plural 'autisms' (see here), many issues described today as 'comorbid' may eventually turn out to be rather more central to [some] autism...

The idea also discussed by Andersen et al about 'intervening' in/on the traditional 'core symptoms' of autism as potentially 'offsetting' some of the effects of those EBP is, no doubt, going to be a bit of a hot potato. We do have a few other examples showing how a reduction/dissipation of core autism symptoms does seem to impact on 'comorbid' signs and symptoms as per some of the discussions on the term 'optimal outcome' (see here). In the example recorded by Gillberg et al [3] observing that "The minority of the AS [Asperger syndrome] group who no longer met criteria for a full diagnosis of an autism spectrum disorder were usually free of current psychiatric comorbidity", we see how there could be quite a bit more to a diagnosis of autism (AS) than has traditionally been recognised. Other research from Andersen and colleagues [4] talking about the same cohort as being discussed today with depression and autism presentation again in mind likewise adds to such 'intervening' sentiments.

I have one final point to make just in case the idea of intervening does not sit well with some: if one assumes that something like depression is in fact, a core part of some autism and could be 'modified' by intervention(s) targeting core autism symptoms, there is a potentially important impact to be made on one of the primary issues affecting the autistic population: risk of suicide. I say that on the basis that depression or related psychiatric disorder (see here) is an all-too-frequent companion when it comes to suicidal behaviour(s) and therefore represents a potentially modifiable variable. Exactly how and where intervention on core autism symptoms is done is another question for another day; also bearing in mind that 'current' core autism symptoms themselves, might be an important risk factors when it comes to suicidal thoughts/behaviours (see here).

Lots more research is indicated, minus hype and minus too much politics...

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[1] Andersen PN. et al. Severity of Autism Symptoms and Degree of Attentional Difficulties Predicts Emotional and Behavioral Problems in Children with High-Functioning Autism; a Two-Year Follow-up Study. Frontiers in Psychology. 2017; 8: 2004.

[2] Nah Y-H. et al. Brief Report: Screening Adults with Autism Spectrum Disorder for Anxiety and Depression. J Autism Dev Disord. 2017. Dec 2.

[3] Gillberg IC. et al. Boys with Asperger Syndrome Grow Up: Psychiatric and Neurodevelopmental Disorders 20 Years After Initial Diagnosis. J Autism Dev Disord. 2016 Jan;46(1):74-82.

[4] Andersen PN. et al. Associations Among Symptoms of Autism, Symptoms of Depression and Executive Functions in Children with High-Functioning Autism: A 2 Year Follow-Up Study. J Autism Dev Disord. 2015 Aug;45(8):2497-507.

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On the under-studied populations within the autism spectrum

I don't typically post on a Sunday, but given that today - 2nd April - is World Autism Awareness Day I've decided to make an exception. The theme of today's post is based around the notion that the autism spectrum is truly wide and heterogeneous, and although this is fairly universally acknowledged, the current peer-reviewed research literature on autism is perhaps not yet so accepting. So...

Consistent with the idea that scientific research seems to go through cycles of themes/interests, the commentary paper by Bhismadev Chakrabarti [1] (open-access) continues an important theme talking about the representativeness of autism research (see here). Specifically how: "Research on the autistic phenotype has focused mostly on higher functioning individuals on the spectrum, neglecting those on the lower end."

OK, first things first. The idea of 'functioning' in relation to the autism spectrum is something that some people (including myself) find a little problematic. Yes, I know what it is trying to describe in terms of ability levels, adaptive skills and the level of support seemingly required as examples. But like many things when it comes to the autism spectrum, the [sweeping] generalisation that high-functioning autism automatically means 'can function' autism and low-functioning autism conversely means 'can't' doesn't really do justice to the complexity underneath such categorisations. I say all that acknowledging that no simple, viable alternative currently exists to replace 'functioning' at the present time.

Chakrabarti takes the reader through the issues of research representativeness based on the findings reported by Jack & Pelphrey [2] and their research review of neuroimaging studies in relation to autism. They concluded that: "There is a paucity of neuroimaging research on ASD [autism spectrum disorder] + ID [intellectual disability], ASD + MV [minimally verbal], and ASD + R [developmental regression], and what findings do exist are often contradictory, or so sparse as to be ungeneralizable."

I'm gonna pull out a couple of key points raised by Chakrabarti that are worthy of lots more research and clinical inspection.

First: "Should we be thinking of these different populations (MV, R and ID) as distinct subgroups within ASD?" Set within the context of 'the plural autisms' (see here) and how autism as a singular label seems to have very little usefulness as a research starting point (see here), it strikes me that Chakrabarti's suggestion of 'phenotypic dimensions' is quite a good one. The fact that developmental regression gets a look-in is also quite important (see here and see here) (no, not every single case of autism was present before or at birth/early infancy).

Second, on the question of 'neuroimaging phenotypes' akin to some of the parameters set out in the RDoC alternative to DSM (see here) I think we have to wait and see. From what we already know about neuroimaging results when it comes to the autism spectrum as a whole, there is no one 'brain area' seemingly linked to all diagnoses of autism (see here) as things currently stand, bearing in mind the limitations of the technology currently used. I don't doubt however that specific groups of people on the autism spectrum might be more likely to show definite collective brain pathology (see here) particularly where certain over-represented comorbidity might complete the clinical picture. The current state of findings in this area also has implications for the use of problematic terms such as 'neurotypical' to denote not-autism (I personally have no idea what neurotypical looks like on a brain scan nor in terms of development, behaviour, maturation or comorbidity).

I'm hoping that papers/commentaries such as the one from Chakrabarti are a call to action when it comes to making autism research 'work' for everyone on the autism spectrum. That and acknowledging that the existing - skewed - research base might be missing some important details when it comes to the very wide and very heterogeneous autisms...

To close and without getting too political, I want to link to a piece that was published in the Huffington Post this week (see here) discussing the idea of 'celebrating' world autism awareness day. It's something that I've seen quite a lot of these past years. Reiterating that the autism spectrum is indeed wide and heterogeneous, I found the article to very moving particularly the writer's notion that: "What I will do is celebrate my son for who he is... But I won’t celebrate the struggles we call autism." Appreciating that autism as a label is 'identity' for some on the spectrum, such sentiments reaffirm the requirement to ensure that all voices on the autism spectrum are heard, and that 'celebration' is reserved for people and their achievements, not their labels...

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[1] Chakrabarti B. Commentary: Critical considerations for studying low-functioning autism. J Child Psychol Psychiatry. 2017 Apr;58(4):436-438.

[2] Jack A. & A Pelphrey K. Annual Research Review: Understudied populations within the autism spectrum - current trends and future directions in neuroimaging research. J Child Psychol Psychiatry. 2017 Apr;58(4):411-435.

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Chakrabarti B (2017). Commentary: Critical considerations for studying low-functioning autism. Journal of child psychology and psychiatry, and allied disciplines, 58 (4), 436-438 PMID: 28346760

"Are we expecting too much from the extreme male brain theory of autism?"

The title of this post reflects the commentary published by Andrew Whitehouse [1] (open-access) discussing the meaning of the findings reported by Kung and colleagues [2] who quite categorically stated that there was: "No relationship between prenatal androgen exposure and autistic traits" in their study.

OK, androgen exposure and psychology basically refers to the extreme male brain theory and autism which suggests that the so-called over-representation of autism in males is potentially down to hormone exposure (testosterone). The theory implies that androgen exposure at critical points in early development are skewing brain development towards a more 'male brain'. The definition of a male brain: well, apparently men are better systemisers than empathisers (better engineers that priests, I assume). The extreme male brain (EMB) hypothesis is an extension of the 'Theory of Mind' (ToM) stuff, which quite a few years back suggested that those diagnosed as being on the autism spectrum have greater difficulties in decoding mental states such as intents and desires. Grand psychological theories at their very finest you might say.

The problem is that whilst ToM and the EMB theory made great psychological textbook reading (certainly in their heyday between the mid-1980s up to the late 1990s) and have spawned a whole industry around testing and teaching ToM for example, the scientific evidence for these concepts being exclusively and universally attributable to the great heterogeneity that is autism is not actually all that great. A shocker I know; and don't even ask about how comorbidity around autism might also be pretty important to such psychological concepts (see here and see here for example).

Whitehouse - who himself has done some research in this area - talks quite a bit about the hows and whys of quite a few negative findings when it comes to the EMB theory (yes, there are quite a few) and what perhaps needs to be done to "advance beyond this stalemate" in relation to the EMB theory and autism.  His suggestion: "future research must first understand how the prenatal hormone environment relates to individual behavioural dimensions, and then incorporate this knowledge into the investigation of links with the more aetiologically and phenotypically complex profile of ASD [autism spectrum disorder]."

These are wise words indeed but I'd suggest this perhaps applies to any 'theory' in relation to autism, psychological, biological or genetic. Indeed, I believe that other authors (see here) have already staked their claim on how using the word 'autism' as a starting point for anything other than a descriptive label probably isn't going to move autism research along any time soon; autisms people, autisms. The challenge is also one of moving away from generalisations; so talking about male and female brains is probably about as useful as talking about left and right-sided brains. Indeed, I'll refer you to some discussions about 'gender brains' between the main proponent of the EMB theory and a psychologist a few years back (see here and see here) that kicked up some scientific dust.

I personally do think there is something in the findings looking at androgen levels and cognitive styles in the same way that there is something in most (replicated) peer-reviewed research when it comes to autism. But as Prof. Whitehouse indicates, it's probably going to be more relevant to some on the autism spectrum than others, and even then, disentangling the 'cognitive' structure of autism is going to be important [3]. The days of grand over-arching psychological theories about autism do seem to be riding off into the scientific sunset as the huge diversity and 'burden' of over-represented comorbidity start to come into plain sight. And certainly I don't think it's too rude to end with the words 'about time too'.

To close, I hark back to simpler days or should that be to a simpler future when Buck Rogers showed the 25th Century how to boogie. Tell him what you think Twiki.

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[1] Whitehouse AJO. Commentary: Are we expecting too much from the extreme male brain theory of autism? A reflection on Kung et al. (2016). J Child Psychol Psychiatry. 2016 Dec;57(12):1463-1464.

[2] Kung KT. et al. No relationship between prenatal androgen exposure and autistic traits: convergent evidence from studies of children with congenital adrenal hyperplasia and of amniotic testosterone concentrations in typically developing children. J Child Psychol Psychiatry. 2016 Dec;57(12):1455-1462.

[3] Happé F. et al. Time to give up on a single explanation for autism. Nat Neurosci. 2006 Oct;9(10):1218-20.

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Whitehouse AJ (2016). Commentary: Are we expecting too much from the extreme male brain theory of autism? A reflection on Kung et al. (2016). Journal of child psychology and psychiatry, and allied disciplines, 57 (12), 1463-1464 PMID: 27859346

On autism spectrum disorder [research] validity

Today I'm directing your reading attention to a really, really interesting paper by Lynn Waterhouse and colleagues [1] (open-access) whose review findings suggest that: "the ASD [autism spectrum disorder] diagnosis lacks biological and construct validity."

The paper is a bit of a long read but most definitely worth it as the quite complicated subject of exactly what goal the label of autism actually serves is discussed. The results of various questions posed by the authors suggest: "No unitary ASD brain impairment or replicated unitary model of ASD brain impairment exists. ASD core diagnostic symptoms are not uniquely linked and are only very rarely expressed without nondiagnostic symptoms. ASD has no reliable early predictor, no unitary developmental course, no unitary life outcome, no unitary recurrence risk, no unitary pattern of BAP [broader autism phenotype] features, and no standard homogeneous subgroups." They conclude that from a research perspective at least, disbanding the label of autism as it currently stands is the next logical step. Said disbanding "is likely to be reductive and uncomfortable" particularly when it comes to all those grand [sweeping] theories of autism put forward down the years. Feathers would not doubt be ruffled.

The authors do make reference to two important concepts when it comes how we might want to rethink autism: the Research Domain Criteria framework (RDoC) and Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations (ESSENCE). One is an attempt to move away from simple psychiatric labels as somehow denoting homogeneity, the other is the recognition that labels rarely appear in some sort of diagnostic vacuum. Both are in some way the future of autism research and indeed, the future is already now.

I'm impressed with the paper from Waterhouse et al. The authors have done a good job of basically saying that as things stand, one single label covering such a diverse and heterogeneous group is not fit for purpose. To see real progress in autism research, science needs to think more about those 'autisms' (see here) and stop using the label of autism as the starting point for research (see here). I struggle to disagree with both those sentiments and other authors appear to have reached similar conclusions [2]. Exactly what that means for the autism in the future - from both a research and clinical perspective - is still a little up in the air but the label has weathered change before and no doubt will continue to do so.

And if that isn't enough reading material for you, how about the latest instalment from the British Psychological Society here in Blighty when it comes to autism? Perhaps this will need a revision or two as the Waterhouse suggestions start to percolate through the research community?

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[1] Waterhouse L. et al. ASD validity. Review Journal of Autism and Developmental Disorders. 2016. Aug 10.

[2] Geier DA. et al. Examining genotypic variation in autism spectrum disorder and its relationship to parental age and phenotype. Appl Clin Genet. 2016 Jul 28;9:121-9.

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Waterhouse, L., London, E., & Gillberg, C. (2016). ASD Validity Review Journal of Autism and Developmental Disorders DOI: 10.1007/s40489-016-0085-x

Epilepsy begets autism?

"Individuals with epilepsy are at increased risk of ASD [autism spectrum disorder], especially if epilepsy appears in childhood. Further, ASD is more common in the siblings and offspring of individuals with epilepsy, suggesting shared etiology."

That was the research bottom-line from Heléne Sundelin and colleagues [1] reporting results based on examination of the "Swedish Patient Register" with regards to the "risk of autism spectrum disorder (ASD) in individuals with epilepsy and in their first-degree relatives." Including one Jonas F. Ludvigsson, PhD on the authorship list (yes, he of 'gluten and autism: probably not coeliac disease but...' fame), researchers identified some 85,000 individuals diagnosed with epilepsy "as well as all their siblings (n = 80,511) and offspring (n = 98,534)." With some nifty statistical analysis including matching cases 5:1 with control participant data, they were able to conclude that around 1.6% of those with epilepsy were diagnosed with an ASD compared with 0.2% of controls. Those percentages are seemingly quite small both in real terms and also in differences between the groups but given the huge participant numbers included for study came out with a hazard ratio (HR) around 10.49 "confidence interval [CI] 9.55–11.53)." To put that HR of 10.49 in context, other work by Ludvigsson on epilepsy coinciding with coeliac disease for example, with a participant number in the tens of thousands came out with a HR of 1.42.

When also looking at what happened to siblings and offspring of those diagnosed with epilepsy, the authors also observed something of a potentially increased risk of autism being also diagnosed, although quite a bit less than risk to those themselves diagnosed with epilepsy. The results did however suggest that: "The risk in the offspring was particularly high in mothers with epilepsy." And just for good measure, the Sundelin results also noted that risk of epilepsy was "also associated with a prior diagnosis of ASD" confirming what many others have reported over the years (see here).

Although making some headlines I wasn't particularly shocked by the bi-directional associations reported by Sundelin and colleagues. Quite a few times on this blog I've talked about autistic features being potentially over-represented in cases of epilepsy (see here and see here) so to see some of those features crossing diagnostic thresholds into an actual autism diagnosis is perhaps not unsurprising. Continuing that line of thought I do wonder what might happen if the broader autism phenotype (BAP) was also analysed with epilepsy in mind (even the new DSM-5 categorisation of social communication disorder?)

Insofar as the hows and whys of the association between epilepsy and autism, well, we're still in guessing mode at the current time. I've talked about some of the various genetic syndromes that tend to include autism and epilepsy together as a diagnostic package (see here) as evidence for the more plural 'autisms'. Such syndromes suggest that mechanisms linking the two conditions are likely to be multiple and not necessarily the same for everyone. The issue of GABA and autism might also show some connection in some cases as per what is starting to be known about this neurotransmitter (see here) and where it might fit with some autism (see here) on top of epilepsy. Assuming also that epilepsy in pregnant mothers for example is being managed by medication, it is also not outside of the realms of possibility that certain preparations could also exert an effect on offspring autism risk (see here). I say this with no scaremongering intended.

I might also (speculatively) advance the idea that another research area might also be a connecting feature for some autism and some epilepsy: diet. Don't just click away yet as I will first bring your attention to the increasing peer-reviewed literature talking about the use of a ketogenic diet and autism (see here); said dietary intervention more typically indicated in 'some' cases of epilepsy. It's still early days but it strikes me that quite a bit more research is required in this area. Allied to the use of a ketogenic diet (see here) and also perhaps linking back to that other important research area frequently examined by Dr Ludvigsson (coeliac disease) I'm also inclined to ask whether some autism and some epilepsy might show a more specific connection to dietary gluten too. No, I'm not saying that a gluten-free diet nor a ketogenic diet is some sort of 'cure-all' for autism and epilepsy (please don't mess with epilepsy) but rather there may be overlapping genetics or biology potentially linked to facets of gluten metabolism that might be important for some on the autism spectrum with epilepsy. Certainly much more research on this and other less-traditional areas is indicated [2].

There are many questions that remain unanswered in this area of research. With regards to the here and now, well, the Sundelin and other data perhaps suggest that as and when epilepsy is diagnosed, preferential screening for autism could and should be offered particularly in infancy; and perhaps even offered family wide.

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[1] Sundelin HEK. et al. Autism and epilepsy: A population-based nationwide cohort study. Neurology. 2016. June 15.

[2] Frye RE. et al. A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel. Front Public Health. 2013 Sep 13;1:31.

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Sundelin, H., Larsson, H., Lichtenstein, P., Almqvist, C., Hultman, C., Tomson, T., & Ludvigsson, J. (2016). Autism and epilepsy Neurology DOI: 10.1212/WNL.0000000000002836

The 'disrupted connectivity hypothesis of autism': where next?

'The disrupted connectivity hypothesis of autism spectrum disorders: Time for the next phase in research' went the title of the paper by Roma Vasa and colleagues [1].

Disrupted connectivity by the way, refers to the idea that "deficiencies in the way the brain coordinates and synchronizes activity amongst different regions may account for the clinical symptoms of ASD [autism spectrum disorders]." Picture if you will, the brain as a serious of telephone wires all connecting different parts of itself and transmitting information down multiple phone lines. The idea that certain areas might be talking too little or too much to each other kinda simplistically sums up what this theory is all about [2].

I'm not going to spend a lot of time on the Vasa paper because (a) it is an area well outside of my comfort zone (a cobbler should stick to his last and all that) and (b) the sizeable peer-reviewed literature on this topic (see here) is still a little confusing as to which areas are 'under-connected' and which areas are 'over-connected'. If one also takes into account added 'issues' such as the growing moves towards pluralising autism ('the autisms) and the fact that a diagnosis of autism rarely exists in some sort of diagnostic vacuum, the best advice I can give about the 'where next for disrupted connectivity and autism' is to cut out any sweeping generalisations. Y'know, learn from past theories trying to describe/explain autism (see here) and maybe focus in one or more individuals or subgroups, but please don't over-hype the theory. Oh, and bear in mind that whilst it is important to focus on the brain and central nervous system, the body also houses another important 'second brain' where connectivity might likewise be 'disrupted'.

Said connectivity issues might not be static also (for various reasons) which opens up the associated question of 'what can be done' [3] about disrupted connectivity in the 'first brain' as and when identified. Indeed, one wonders whether reports on the promise of transcranial magnetic stimulation (TMS) for example [4] might require quite a bit more controlled investigation with at least some autism in mind with reference to connectivity. But keep in mind that intervention like TMS might not always work out the way you might want it to...

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[1] Vasa RA. et al. The disrupted connectivity hypothesis of autism spectrum disorders: Time for the next phase in research. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2016. March 2.

[2] Wass S. Distortions and disconnections: disrupted brain connectivity in autism. Brain Cogn. 2011 Feb;75(1):18-28.

[3] Fox MD. et al. Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS). Neuroimage. 2012 Oct 1;62(4):2232-43.

[4] Oberman LM. et al. Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research. Autism Res. 2016 Feb;9(2):184-203.

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Vasa, R., Mostofsky, S., & Ewen, J. (2016). The disrupted connectivity hypothesis of autism spectrum disorders: Time for the next phase in research Biological Psychiatry: Cognitive Neuroscience and Neuroimaging DOI: 10.1016/j.bpsc.2016.02.003

Mitochondrial response to BCKDK-deficiency and 'some' autism

I'll admit to being pretty fascinated by the Branched Chain α-Keto acid Dehydrogenase Kinase (BCKDK) gene. As per previous blog entries about this gene (see here and see here) and the important biological step it plays in the metabolism of the branched-chain amino acids (BCAAs), at least one 'form' of autism might be particularly sensitive to issues with it [1]. I take it you've heard of the idea that the autisms (plural) might be a better description of autism? If you haven't, here is a peer-reviewed take on it [2]...

I'm happy to report that science continues to study this gene; its biology and it's associations with "a novel dietary-treatable form of autism" as per the findings reported by Oyarzabal and colleagues [3]. The focus of the Oyarzabal paper was to study the "mitochondrial response to the BCKDK-deficiency" potentially brought about for example, when there are issues with the BCKDK gene given its links to the mitochondria matrix. This work also takes on particular relevance given the idea that mitochondrial issues - mitochondria: the powerhouse of cells - might not be something entirely new to at least some autism (see here for example).

Anyhow, fibroblasts were the starting material and the measurement of "bioenergetics, ultra-structural and dynamics parameters" of fibroblasts from those who had BCKDK-deficiency. Although not totally au-fait with all the science included in the paper, the authors report results on: "a general bioenergetics depletion that could affect the mitochondrial dynamics and cell fate." They even reported complementary findings following a: "Knockdown of BCKDK gene in control fibroblasts" and mention of some findings relevant to maple syrup urine disease (MSUD) in light of the involvement of the BCAAs there. In short: "All these data gives us a clue to understand the positive dietary response to an overload of branched-chain amino acids."

This is an exciting area of autism research pertinent to the idea that (a) there may be various types of autism characterised by various different genetic and biological factors being involved, and (b) the possibility that at least some autism might stem from one or more inborn errors of metabolism is gaining ground (see here) and hence might be potentially 'treatable'. For that last point I'm minded to take you back to a recent post on phenylketonuria and autism (see here) and some more recent [peer-reviewed] research talking about 'Succinic Semialdehyde Dehydrogenase Deficiency Presenting as Autism Spectrum Disorder' [4]. Dare I even present the idea of carnitine issues falling into this area?

Screening for such inborn errors of metabolism seems to be the important conclusion; screening not assuming nor guessing nor making grand generalisations. Just screening.

Music: the glorious music accompanying the film Interstellar has to be the one for today in light of new discoveries in recent days...

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[1] Novarino G. et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012 Oct 19;338(6105):394-7.

[2] Poot M. Towards identification of individual etiologies by resolving genomic and biological conundrums in patients with autism spectrum disorders. Mol Syndromol. 2013 Jun;4(5):213-26.

[3] Oyarzabal A. et al. Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochim Biophys Acta. 2016 Jan 22. pii: S0925-4439(16)30003-5.

[4] Gogou M. et al. Succinic Semialdehyde Dehydrogenase Deficiency Presenting as Autism Spectrum Disorder. Indian J Pediatr. 2016 Jan 25.

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Oyarzabal A, Bravo-Alonso I, Sánchez-Aragó M, Rejas MT, Merinero B, García-Cazorla A, Artuch R, Ugarte M, & Rodríguez-Pombo P (2016). Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochimica et biophysica acta PMID: 26809120

Pregnancy paracetamol use and the 'hyperactive behavioral phenotype' of autism

"Prenatal use of acetaminophen was associated with an increased risk of ASD [autism spectrum disorder] accompanied by hyperkinetic symptoms..., but not with other ASD cases."

I was rather interested to read that conclusion presented in the study by Zeyan Liew and colleagues [1] talking about how acetaminophen (or paracetamol as it is known here in Blighty) use during pregnancy might have some rather important connections to offspring outcomes specifically with autism and hyperkinetic symptoms in mind.

Interested not only because I've discussed other research talking about how we might need to be a little more cautious about how OTC pain relief such as paracetamol is used in certain circumstances with potential offspring outcomes in mind (see here and see here) but also because it makes reference to a quite specific effect to the "hyperactive behavioral phenotype" of autism. That hyperkinetic behavioural phenotype by the way, plugs into a growing body of peer-reviewed evidence talking about the over-representation of ADHD (attention-deficit hyperactivity disorder) symptoms in relation to [some] autism (see here).

Liew et al "followed 64,322 children and mothers enrolled in the Danish National Birth Cohort (DNBC; 1996–2002) for average 12.7 years to investigate whether acetaminophen use in pregnancy is associated with increased risk of ASD in the offspring." Details about paracetamol use during pregnancy were "collected prospectively from three computer-assisted telephone interviews" and offspring outcomes with labels like autism were compared. This follows a similar methodological template from some of this research team (see here).

Some 1.6% of children included in the analysis were eventually diagnosed with as ASD. Roughly a third of that 1.6% of children were also diagnosed with hyperkinetic disorders (which seems to tally with other independent data analysis [2]). Perhaps unsurprisingly, paracetamol use during pregnancy was pretty widespread in the cohort (~50%) but, despite this, authors detailed something of a potentially important relationship between pregnancy paracetamol use and offspring "ASD accompanied by hyperkinetic symptoms." That there also appeared to be a relationship between length of use of paracetamol and risk of offspring autism with hyperkinetic symptoms, seems to strengthen details of a possible association.

Accepting that this was a study plotting pregnancy medication use and offspring outcomes and hence findings need to be treated with a degree of caution (as with other studies on other medicines), set within the other research talking about paracetamol use during pregnancy I'm coming around the idea that more investigation is required in this area [3]. I could, once again, start talking about how pregnancy paracetamol use might link into childhood asthma symptoms [4] (albeit with some cautions attached [5]) and what that might mean for the behavioural 'associations' noted in some cases of asthma (see here) as a possible angle for future research. I would however temper such musings within the context of autism (see here); although the preliminary suggestion that prenatal exposure to certain drugs used to treat asthma might also affect risk of offspring autism is also interesting [6].

I do like that Liew and colleagues talked about the idea of a specific behavioural phenotype potentially linked to pregnancy paracetamol exposure as providing a guide for more targeted investigation and perhaps to some degree bypassing the need for the sweeping generalisations about 'all autism' (we've had enough of those down the years). I believe there is quite a bit of research traction in this area with the notion of the autisms (see here) in mind.

Music: Elvis Presley - If I Can Dream.

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[1] Liew Z. et al. Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood. Autism Research. 2015. Dec 21.

[2] Berenguer-Forner C. et al. Comorbidity of autism spectrum disorder and attention deficit with hyperactivity. A review study. Rev Neurol. 2015 Feb 25;60 Suppl 1:S37-43.

[3] de Fays L. et al. Use of paracetamol during pregnancy and child neurological development. Dev Med Child Neurol. 2015 Aug;57(8):718-24.

[4] Eyers S. et al. Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis. Clin Exp Allergy. 2011 Apr;41(4):482-9.

[5] Cheelo M. et al. Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis. Arch Dis Child. 2015 Jan;100(1):81-9.

[6] Gidaya NB. et al. In utero Exposure to β-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders. Pediatrics. 2016. 6 Jan.

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Liew Z, Ritz B, Virk J, & Olsen J (2015). Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study. Autism research : official journal of the International Society for Autism Research PMID: 26688372

Immune endophenotypes in paediatric autism

Today I'm serving up the paper by Milo Careaga and colleagues [1] for your blogging delight, who concluded that: "Children with ASD [autism spectrum disorder] may be phenotypically characterized based upon their immune profile." Further that there may be: "several possible immune subphenotypes within the ASD population that correlate with more severe behavioral impairments."

With many thanks to Natasa for the paper, participants - 50 boys with a median age of 3.2 years diagnosed with an ASD and enrolled "through the Autism Phenome Project (APP) study" and who were free of any "major immune modifying medications" - provided a blood sample. A similar process was employed for a smaller group of typically developing (asymptomatic) control group (n=16). Said blood sample went through various processes to harvest peripheral blood mononuclear cells (PBMC) which were then 'stimulated' to provoke an immune reaction via "either lipopolysaccharide (LPS) or phytohaemagglutinin (PHA)." Various cytokines were then assayed for in the stimulated PBMC and results analysed according to immune responses and behavioural outcomes.

Results: as per the opening paragraph, there was potentially something to see in the findings added to a more general role for cytokines in relation to autism [2]. Those children with ASD who presented with a more 'pro-inflammatory' cytokine profile in their stimulated blood results "showed more impaired developmental and behavioral scores, as well as increased problems with sleep and aggression." That pro-inflammatory cluster by the way (n=22) tended to show significantly increased production of cytokines such as IL-6 for example, than those children with autism (n=28) "who displayed a less robust response to LPS." Ergo, perhaps more to see and certainly more investigations required in these days of plural autisms.

I was taken by one particular sentence included in the conclusion of the Careaga paper: "Although immune abnormalities were first described in ASD over forty years ago, no consensus has been reached as to what constitutes clinically significant immune dysfunction in ASD." As per quite a bit of autism research, sweeping generalisations about this, that or t'other 'causing' autism or being part and parcel of autism have been a big contributor to the noticeable lack of progress on knowledge about autism and where required and wanted, what can be done to ameliorate the more disabling aspects including that related to comorbidity (see here). Realisation that 'autism' is probably better described as providing an umbrella term for various different conditions on a genetic and molecular level is making some headway these days (see here) including that linked to immune function (see here for example). This might have important implications for intervention (see here) as per other recent results that I'll be musing over soon.

As part of a broader realisation that immune function and psychiatry probably show a lot more connections than many people first realised (see here), I think we are seeing a shift in knowledge here. As per the Careaga results, the idea that there may be distinct clusters within the presentation of autism linked to immune function, opens up a whole new world of more 'targeted' inspection and intervention which, added to other similar phenotype work (see here), is probably an important direction for autism research...

Music: Duran Duran - Pressure Off feat. Janelle Monáe and Nile Rodgers.

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[1] Careaga M. et al. Immune endophenotypes in children with autism spectrum disorder. Biological Psychiatry. 2015. 10 Sept.

[2] Krakowiak P. et al. Neonatal Cytokine Profiles Associated with Autism Spectrum Disorder. Biol Psychiatry. 2015 Aug 14. pii: S0006-3223(15)00655-1.

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Milo Careaga, Sally Rogers, Robin L. Hansen, David G. Amaral, Judy Van de Water, & Paul Ashwood (2015). Immune endophenotypes in children with autism spectrum disorder Biological Psychiatry : 10.1016/j.biopsych.2015.08.036

HERVs as a mechanism of genetic deletion formation: relevance to some autism?

My stark lack of knowledge in the area of genetics and specifically that linked to the human endogenous retroviruses (HERVs) that litter the genome is likely to shine through in this post so be ready with that pinch of salt.

The starting point for today's post is the paper by Ines Quintela and colleagues [1] detailing a case report of "a 9-year-old female patient with autistic disorder, total absence of language, intellectual disability, anxiety disorder and disruptive, and compulsive eating behaviors." Following some genetic analysis of this young girl researchers reported on "the identification of a de novo recurrent 3q13.2-q13.31 deletion encompassing 25 genes." This in itself is interesting and adds to a growing tide of research suggesting that there may be lots of different genetic influences acting in different cases of autism; all pertinent to a more plural view of the label: the autisms.

One sentence however took my specific interest in this paper insofar as: "a 3.4 Mb recurrently altered region at 3q13.2-q13.31 has been recently described and non-allelic homologous recombination (NAHR) mediated by flanking human endogenous retrovirus (HERV-H) elements has been suggested as the mechanism of deletion formation."

As I indicated at the start of this post, the finer details of genetics are not really my forte so be warned. I was however really interested in the suggestion that the process of NAHR - when "highly similar portions of the genome wrongly recombine, deleting and sometimes duplicating a portion of the genome that lies between them" - might be linked to the presence of all/some of those fossil viruses that make us who we are [2].

The long-and-short of it is the idea that some of those little variants that we ALL have in our genome might not be all due to just chance if described as de novo (as in not inherited from mum or dad). Take CNVs (copy number variants), small alterations to the genome characterised by gains and losses in segments of DNA (I think!), as the starting point. The idea is that the location of said CNVs in relation to HERVs and other transposable elements means that there may be some kind of relationship between the two. Preliminary research has suggested that HERVs flanking particular parts of the genome might be involved in the formation of CNVs [3]. Other research has noted this process as potentially being relevant in other case reports [4] similar to that described by Quintela and colleagues where behaviour and autism have been mentioned.

Just to make the whole process even more complicated (and interesting) is the idea that CNVs when talked about with autism in mind might tend to be concentrated in 'hypomethylated' regions of the genome [5]. This brings in the potentially important process of DNA methylation (yes, epigenetics yet again) into proceedings, made further interesting by suggestions that hypomethylation of DNA = more genomic instability [6] and that certain HERVs might also to some degree be 'kept in check' by methylation means [7]. Add in some evidence of methylation issues associated with some autism (see here) and preliminary evidence of certain HERVs expression correlating with autism (see here) and comorbidity (see here), and there is the making of some potentially important hypotheses ripe for further testing.

But please, don't take my word for it.

Music: Purple Rain - Prince.

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[1] Quintela I. et al. Female patient with autistic disorder, intellectual disability, and co-morbid anxiety disorder: Expanding the phenotype associated with the recurrent 3q13.2-q13.31 microdeletion. Am J Med Genet A. 2015 Aug 29.

[2] Nelson PN. et al. Demystified . . . Human endogenous retroviruses. Molecular Pathology. 2003;56(1):11-18.

[3] Campbell IM. et al. Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination. BMC Biol. 2014 Sep 23;12:74.

[4] Shuvarikov A. et al. Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays. Hum Mutat. 2013 Oct;34(10):1415-23.

[5] Li J. et al. Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome. PLoS Genetics. 2012: 8: e1002692.

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

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

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Quintela I, Gomez-Guerrero L, Fernandez-Prieto M, Resches M, Barros F, & Carracedo A (2015). Female patient with autistic disorder, intellectual disability, and co-morbid anxiety disorder: Expanding the phenotype associated with the recurrent 3q13.2-q13.31 microdeletion. American journal of medical genetics. Part A PMID: 26332054

The autisms, case reports and two 'intervention' options

I'm looking at two papers today which I'd like to think cover the title of this post pretty well dealing with the plurality of autism - the autisms - and the idea that intervention or management-wise, there is no 'one size fits all' when it comes to the autisms.

First up are the findings reported by Ziats and colleagues [1] who presented results for a child - "A 4-year-old male with autism and two episodes of neurodevelopmental regression" - who was also found to have a "mutation in the TMLHE gene, which encodes the first enzyme in the carnitine biosynthesis pathway, and concurrent carnitine deficiency." Supplementation with carnitine (see here) seemed to lead to some interesting changes in the developmental profile for this boy such that: "the patient's regression ended, and the boy started gaining developmental milestones."

Accepting that this was another example of the N=1 and autism (see here) I was rather interested in these results having previously blogged about issues with the TMLHE (trimethyllysine hydroxylase) gene in relation to autism (see here). The source of that previous post was the paper from Patricia Celestino-Soper and colleagues [2] (open-access) who concluded that: "TMLHE deficiency is a risk factor for autism" and quite a bit more should be done to screen for such issues. I wouldn't disagree with those sentiments (see here).

Next up are the results reported by Serret and colleagues [3] (open-access) who presented findings based on two participants "diagnosed with autism spectrum disorders in childhood and presented regression with catatonia features and behavioural disorders after a stressful event during adolescence." Further: "both patients presented mutation/microdeletion of the SHANK3 gene, inducing a premature stop codon in exon 21." Issues with SHANK3 have been reported in relation to autism previously.

Authors reported that: "lithium therapy reversed clinical regression, stabilized behavioural symptoms and allowed patients to recover their pre-catatonia level of functioning, without significant side effects." Further: "These cases support the hypothesis of a specific SHANK3 phenotype" and that lithium might hold some favour in improving clinical presentation in those cases.

Again, I was interested in the Serret findings with the caveat about their also using the case study approach in their paper. Lithium is an interesting compound that has graced this blog a few times in relation to its potential 'anti-suicide' correlating properties (see here) and as a possible management tool when it comes to the presentation of mood disorders comorbid to a diagnosis of autism (see here). Accepting that lithium has its own potential side-effects profile, the idea that cost-benefits might be calculated and if so deemed more benefit and less cost subsequently applied to 'some' autism, is an interesting prospect.

Reiterating my opening paragraph, what the Ziats and Serret papers serve to tell us is that within 'the autisms' there may be many different roads to a diagnosis of autism and that under the diagnostic label of 'autism', genetics, biochemistry and subsequent intervention/management strategies may vary from person to person. As I've said before, receipt of a diagnosis of autism (when it is eventually received) should be a starting point for further inquiry not the 'finishing line'.

That comorbidity - if I can still call it that - might also be a 'target' for analysis and investigation is also an important point raised and further asks more questions about the value of intervening on said comorbidity and the possible knock-on effects on the presentation of more core autism symptoms (see here). Y'know something like what is emerging in the body of research looking at anxiety and autism (see here).

With the body of work linking this, that and t'other to autism I'm starting to think that some further resources might be needed to pull all the available peer-reviewed information together in terms of what factors have been linked to those 'autisms'. I've always been very partial to autism research looking at inborn errors of metabolism (IEMs) as a starting point for investigations (see here) given both the data on overlap and even the idea that some of the various interventions for specific IEMs might hold promise for 'some' autism (see here). Analysis of things like rare genetic variations also being linked to the appearance of autism (see here) ties into the IEM investigations and perhaps represents the next tier of evaluation, bearing in mind the reduced costs of things like whole genome sequencing these days set within the perspective of personalised medicine (see here). Environment, bearing in mind the range of factors this might cover, should also be included in any diagnostic work-up based on the evolving science connecting something like infection to autism onset for some (see here and see here). There are various tests that could be performed covering a whole slew of potential infective agents (see here).

This is just a rough-and-ready idea of where autism research and practice could go with this but much like the pathways to diagnosing and managing bowel issues when comorbid to autism for example (see here), a general diagnostic roadmap is perhaps indicated...

Music: Years & Years - King.

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[1] Ziats MN. et al. Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. Am J Med Genet A. 2015 May 5.

[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] Serret S. et al. Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports. BMC Psychiatry 2015, 15:107.

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Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, & Schaaf CP (2015). Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. American journal of medical genetics. Part A PMID: 25943046




Serret, S., Thümmler, S., Dor, E., Vesperini, S., Santos, A., & Askenazy, F. (2015). Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports BMC Psychiatry, 15 (1) DOI: 10.1186/s12888-015-0490-1

Healthcare experiences and autism

In today's brief post I want to highlight the important findings reported by Christina Nicolaidis and colleagues [1] who suggested that quite a bit more could be done to improve the success of "healthcare interactions" when it comes to the autism spectrum.

Based on the experiences of 39 adults with autism and "16 people who had experience supporting autistic adults in healthcare settings" researchers came up with a few "patient- and provider-level factors" that might impact on said healthcare interactions and thus the quality of service received by this group. Quite small changes such as improving healthcare provider's knowledge of autism - specifically adult autism - including a realisation that factors such as "verbal communication skills, sensory sensitivities, [and] challenges with body awareness" might impact on the quality of healthcare received are detailed. The idea that 'if you've met one person with autism, you've met one person with autism' might also be a useful phrase for healthcare providers to keep in mind given the significant heterogeneity and heightened risk of comorbidity normally attached to the 'autisms' (plural) label.

I've always been rather interested in the disparities in healthcare quality and provision attached to behavioural and/or psychiatric labels derived from books such as ICD and DSM. Having previously covered some of the extremes of "catastrophic illnesses [that] were misdiagnosed due, at least partially, to their autism" (see here) on this blog, I have a flavour for just how bad things can get when healthcare provider knowledge of autism is poor and phrases like 'it's just part of their autism' are used willy-nilly.

"Further efforts are needed to empower patients, adequately train providers, increase the accessibility of the healthcare system, and decrease discrimination." I don't think many people would disagree with the conclusions from Nicolaidis et al although the precise ways and means that such changes can be practically made still requires some flesh on the bones. As per another article from this research group [2] "the recognition of associated conditions" potentially comorbid to a diagnosis on the autism spectrum might also help healthcare providers plan for what they might expect, bearing in mind the considerable number of conditions/labels that might follow such a diagnosis (see here) and the idea that a label of autism is seemingly protective of nothing in healthcare and other terms [3]. But let's start with the simple things...

Music: The White Stripes - Fell In Love With A Girl (video pre-Lego movie). And assuming you are 'falling in love with a girl [or boy]' you might want to see how she/he might see you with the new Microsoft 'How old do I look' tool. After analysing a few mugshots of mine I'm not afraid to say that I might be visiting Boots the Chemists quite soon...

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[1] Nicolaidis C. et al. “Respect the way I need to communicate with you”: Healthcare experiences of adults on the autism spectrum. Autism. 2015. 16 April.

[2] Nicolaidis C. et al. Primary care for adults on the autism spectrum. Med Clin North Am. 2014 Sep;98(5):1169-91.

[3] Croen LA. et al. The health status of adults on the autism spectrum. Autism. 2015 Apr 24. pii: 1362361315577517.

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Nicolaidis, C., Raymaker, D., Ashkenazy, E., McDonald, K., Dern, S., Baggs, A., Kapp, S., Weiner, M., & Boisclair, W. (2015). "Respect the way I need to communicate with you": Healthcare experiences of adults on the autism spectrum Autism DOI: 10.1177/1362361315576221