"Minor physical anomalies" and autism: hypermobility very much included

'Minor physical anomalies' (MPAs) are defined as "subtle, abnormal morphological features, such as deviations in morphology of the head, eyes, ears, mouth, hands, and feet." I appreciate that such a term is probably not going to everyone's cup of tea, but given the embryological links between organs such as the brain and skin, it's assumed that "MPAs may mirror altered brain development."

That was the starting point for the study results published by Lynnea Myers and colleagues [1] looking for the presence of MPAs in a cohort of over 110 twins, around half of whom had received a concordant or discordant neurodevelopmental disorder diagnosis such as "intellectual disability (ID), communication disorders, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), specific learning disorders, and motor disorders." Alongside various behavioural and diagnostic assessments, researchers also used a special MPA checklist "containing a total of 179 anomalies for males (24 body regions) and 171 for females (23 body regions)" with their cohort. This checklist also included various other 'issues' that are "commonly assessed for in physical exams."

Various results were produced bearing in mind the quite complicated participant mix included for study (i.e. presence or not of a neurodevelopmental disorder, concordance among twins, zygosity, specific neurodevelopmental diagnosis, etc). Autism was the only neurodevelopmental diagnosis that was "significantly associated with the extent of MPAs." If twins were concordant for autism or autism spectrum disorder (ASD), researchers observed that they "had descriptively the highest median (Md) number of MPAs." Where twins were discordant - one had autism, the other not - researchers still observed MPAs, albeit to a slightly lesser degree (number). Further: "The most common MPAs in participants with ASD included overweight (39%), hypermobility (36%), pes planus (29%), straight eyebrows (29%), vision impairment (25%; 29% of these with corrective lenses), arachnodactyly/long toes (25%), long eyelashes (21%), and microtia (21%)."

Putting to one side the important findings that almost 40% of those with ASD were described as overweight (see here) or that vision issues were present in a quarter (see here), I was drawn to the suggestion that quite a percentage of those with autism (36%) were described as having hypermobility. Hypermobility, where joints are more flexible than usual, in the context of autism is something of an interest of mine (see here and see here). Not least because it is an area of the autism research landscape crying out for a lot more investigation, both as part of a wider 'psychiatric picture' (see here) and also in the 'ESSENCE' context that autism rarely exists in some sort of diagnostic vacuum (see here).

Minus any sweeping generalisations, there are a few potentially important implications either linked to or arising from hypermobility in the context of autism. Poor balance and/or coordination is one possible outcome from hypermobility that would perhaps tie into what has been discussed in the autism research literature for years and years now [2] (even Kanner mentioned it). The observation that functional gastrointestinal (GI) issues such as constipation and diarrhoea also seem to be over-represented in relation to hypermobility [3] also potentially accords with findings pertinent to quite a lot of autism (see here) (bearing in mind that I'm not saying that all bowel issues noted in autism are necessarily hypermobility-connected). If however one was to stretch things further, one might be looking at something like joint hypermobility in the context of connective tissue disorder and what that could mean for something like intestinal permeability issues associated with 'some' autism (see here). I know this is speculative, but at least it provides a research plan of action to include in future investigations in this area.

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[1] Myers L. et al. Minor physical anomalies in neurodevelopmental disorders: a twin study. Child and Adolescent Psychiatry and Mental Health. 2017; 11: 57.

[2] Cassidy S. et al. Dyspraxia and autistic traits in adults with and without autism spectrum conditions. Mol Autism. 2016 Nov 25;7:48.

[3] Fikree A. et al. Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case-control study. Neurogastroenterol Motil. 2015 Apr;27(4):569-79.

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Features of dyspraxia in childhood epilepsy

Developmental coordination disorder (DCD) or dyspraxia is a condition affecting 'planning of movements and coordination'. No-one really knows exactly how and why DCD comes about but various risk factors are associated with the condition (see here) including the possibility of acquired problems through head injury or a stroke for example.

I was recently interested to read the paper published by Colin Reilly and colleagues [1] and their findings that: "Parent-reported symptoms of DCD are very common in childhood epilepsy." This follows other work from this group looking at various other potential comorbidities accompanying epilepsy including autism [2] (covered in a previous post), attention deficit hyperactivity disorder (ADHD) [3] and pathological demand avoidance (PDA) [4] or Newson's syndrome as I believe it should be called (see here).

It's probably no coincidence that included in the authorship of the various papers by Reilly et al describing epilepsy plus (+) we find the name Gillberg, as in Christopher Gillberg. This is one and the same person who has, alongside other researchers, brought the concept of ESSENCE - early symptomatic syndromes eliciting neurodevelopmental clinical examinations - to autism research (see here) and the idea of autism plus [2]. It looks to me that they are working on similar principles when it comes to epilepsy too.

Insofar as their recent study results, Reilly et al base their findings on a parent report questionnaire - the DCD Questionnaire (DCD-Q). They further noted: "Significant predictors of higher scores on the DCD-Q included the presence of autism spectrum disorder, CP [cerebral palsy], and early seizure onset" indicating how complicated the clinical picture might be when it comes to the presentation of dyspraxia in cases of epilepsy. Their relatively small participant number (n=85) means that further replication of their results is warranted.

There's little more for me to say about this topic over and above what has already been mentioned. Using the label of autism as an example, more and more the research base is suggesting that behavioural / psychiatric / neurological issues rarely appear on their own and should perhaps reflect a move away from just talking about comorbidity towards the labelling of lots and lots of different individual conditions variably manifesting symptoms crossing multiple labels. Yes, this is a daunting prospective given the potential number of permutations (ordered combinations) potentially present, but at least then there is the possibility of focusing on the important factors linked to the presence of such symptoms in individuals or smaller cohorts...

Music: Pixies - Monkey Gone To Heaven.

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[1] Reilly C. et al. Features of developmental coordination disorder in active childhood epilepsy: a population-based study. Dev Med Child Neurol. 2015 Apr 16.

[2] Gillberg C. & Fernell E. Autism plus versus autism pure. J Autism Dev Disord. 2014 Dec;44(12):3274-6.

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Reilly C, Atkinson P, Das KB, Chin RF, Aylett SE, Burch V, Gillberg C, Scott RC, & Neville BG (2015). Features of developmental coordination disorder in active childhood epilepsy: a population-based study. Developmental medicine and child neurology PMID: 25882788

Antiepileptic exposure and offspring autism risk

The great autism research spotlight continues to focus its gazerbeam on the very earliest days of being for any clues governing why some children might go on to develop autism. I've kinda lost count of how many times I've talked about maternal exposure for this or that having been linked to an elevated risk of offspring autism; ranging from maternal inflammation to parental occupational exposure to the possibility that maternal medication history during pregnancy might singularly or cumulatively exert some potential effect on risk.

Baby @ Wikipedia  

Indeed this last factor on medication during pregnancy has once again been the source of some speculation following the publication of a paper by Bromley and colleagues* suggesting an increased risk of offspring autism in cases of exposure to various antiepileptic drugs in-utero.

A quick search of PubMed reveals that Dr Bromley has some history in looking at foetal antiepileptic exposure on developmental outcomes as per papers like this one and this one (open-access). There were a few clues in these papers that autism and other developmental disorders might well have been next on the list for investigation for this research group.

Press attention for the current study? Er, yes, it goes without saying particularly in light of headlines like: Epilepsy drug linked to tenfold increase in autism (complete with picture of pregnant mums holding their tummy) and Epilepsy drug link to brain damage in 17,500 babies. Aside from thinking that there is probably lots of money to be made in stock photos of pregnant women and their bumps, if I were a pregnant mum with epilepsy taking such meds, I would probably be straight on the phone to my doctor/midwife to ask about these findings.

So what did Bromley et al actually find and report:

• Based on an analysis of children born to 528 pregnant mums based here in Blighty, physical and cognitive abilities were assessed at various point during early infancy and childhood.
• Of the total cohort, data across various testing points were available for 415 children; of which 19 had been diagnosed with a "neurodevelopmental disorder" by the age of 6 years.
• Some of these neurodevelopmental disorders included autism (n=12); others had diagnoses of conditions like ADHD and dyspraxia (developmental coordination disorder, DCD).
• Looking through the kind of meds being taken by mum's during pregnancy, the authors reported a connection between greater offspring neurodevelopmental issues in those mothers who were taking anti-epileptic medication compared to those who weren't (7.4% vs. 1.8% respectively) as per the rate of epilepsy in mums-to-be (243/528; 46%).
• Sodium valproate was in particular singled out as part of the study as per the text: "children exposed to valproate alone in the womb were six times more likely to be diagnosed with a neurodevelopmental disorder". Indeed an even greater risk if a cocktail of other meds were also used during pregnancy.

As one would expect, the authors have cautioned that pregnant women with epilepsy taking these medications does not automatically translate into offspring autism and on no account should pregnant women just stop taking the drug without appropriate medical advice. Risk, as I have discussed before, is risk not certainty and epilepsy can be a life-threatening condition.

Valproate has already some history with regards to its possible effects on the developing infant as per the description of foetal valproate syndrome** (open-access) highlighting its potential teratogenicity. With autism in mind, this is also not the first time that valproate has appeared in the research texts. I note for example papers like this one from Bristot Silvestrin and colleagues*** which talked about an "animal model of autism induced by prenatal exposure to valproate", also bringing in words like 'glutamate' which has also seen its fair share of scientific inquiry in recent times (see this post). There are several other papers I could cite with a valproate-autism connection but I don't want to bore you.

Valproate is also a compound I've become quite interested in recently as a result of being part of some very brief forays into the science writing domain and in particular on the topic of epigenetics (see here but now for PJ members only). Since doing a little bit of research in that area I've for example, read quite a bit on how valproate is now considered to be quite a potent HDAC inhibitor**** (open-access) with some potentially useful effects in cancer therapy. This HDAC inhibition quality - leading on to histone hyperacetylation - has also been questioned as a possible route towards some of the autism-like findings. To quote from the paper by Kataoka and colleagues***** "findings suggest that VPA-induced histone hyperacetylation plays a key role in cortical pathology and abnormal autism-like behaviours in mice". Bearing in mind mice are mice and not humans.

The Bromley paper is an interesting paper and certainly invites a lot more study into how prenatal valproate exposure *might* show some connection to offspring risk of autism and other developmental conditions. Not trying to be anti-medication or anything, the study also highlights how little we actually know about the medicines we take and in particular their potential for things like trans-generational effects...

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* Bromley RL. et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry. January 2013.

** Kini U. Fetal valproate syndrome: a review. Pediatric & Perinatal Drug Therapy. 2006; 7: 123-130.

*** Bristot Silvestrin R. et al. Animal model of autism induced by prenatal exposure to valproate: Altered glutamate metabolism in the hippocampus. Brain Res. 2013; 1495: 52-60.

**** Göttlicher M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969–6978.

***** Kataoka S. et al. Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol. 2013; 16: 91-103.

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Bromley, R., Mawer, G., Briggs, M., Cheyne, C., Clayton-Smith, J., Garcia-Finana, M., Kneen, R., Lucas, S., Shallcross, R., Baker, G., & , . (2013). The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs Journal of Neurology, Neurosurgery & Psychiatry DOI: 10.1136/jnnp-2012-304270