Are early "movement and sensory differences" prodromal signs of autism?

"These results highlight the importance of early surveillance of children who are at elevated risk for ASD [autism spectrum disorder], and early initiatives should focus on early signs of the phenotype, including both movement and sensory differences (prodromal signs) prior to the emergence of diagnostic characteristics."

It was that sentence from the findings reported by Lori-Ann Sacrey and colleagues [1] (open-access available here) that caught my eye, and the idea, once again, that movement 'issues' should perhaps be considered a core feature of autism (see here) or at least more of a core feature than they currently are. I might add that I've covered other important findings from Sacrey et al on this blog previously (see here).

Although open-access, a few details might be useful: "Infants were selected at random to comprise three groups of equal size: (1) 10 non-sibling controls (LR [low risk]-control; 7 boys); (2) 10 HR [high-risk] siblings without an ASD diagnosis (i.e., with an older sibling with ASD but did not receive an ASD diagnosis themselves at 36 months; HR-N; 3 boys); and (3) 10 HR siblings with an ASD diagnosis (i.e., with an older sibling with ASD and also received an ASD diagnosis at 36 months; HR-ASD; 6 boys)." As you can see the participant numbers were fairly small but to balance this, authors did report results based on testing "for differences in reaching-to-grasp" across quite a long period (6-36 months) and utilised quite an array of psychometric testing tools pertinent to their population and study aims.

Researchers found that: "Children who were later diagnosed with ASD showed higher (worse) total scores on the reach-to-grasp movement, as well as higher scores on the components of Orient, Lift, and Pronate compared to children in the LR and HR-N groups." They concluded that: "results suggest that such movement mechanics are relevant to monitoring motor development in children at risk for or diagnosed with ASD." Ergo, there may be quite a bit to see when it comes to early surveillance for autism in respect of movement and/or sensory differences.

Just before you leave I'll also bring the findings reported by Emilia Biffi and colleagues [2] to your attention. Theirs wasn't so much a study of the possible early 'prodromal' signs of autism with a focus on movement patterns but rather another finding suggesting that such movement issues may be persistent in relation to autism and can be readily tested for. Utilising some pretty nifty movement capture technology - "an immersive virtual environment using a 3-D motion analysis system with a dual-belt, instrumented treadmill" - Biffi et al reported that their findings "depicted gait peculiarities in children with ASD, including both kinetic and kinematic features." Movement and gait issues it seems, may very well be a vitally important part of autism...

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[1] Sacrey LR. et al. The reach-to-grasp movement in infants later diagnosed with autism spectrum disorder: a high-risk sibling cohort study. J Neurodev Disord. 2018 Dec 27;10(1):41.

[2] Biffi E. et al. Gait Pattern and Motor Performance During Discrete Gait Perturbation in Children With Autism Spectrum Disorders. Front Psychol. 2018;9:2530.

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Physical conditions accompanying intellectual disabilities

By linking to some media discussing the inquest findings for Richard Handley (see here) I don't want to trivialise his death or use it as some kind of 'I told you so' example. Here was a man who died as a result of "gross failures" in his care as someone with Down's syndrome who also had a history of bowel issues. His death, linked to chronic constipation and "as a result of choking on his own vomit having inhaled gastric contents following complications with surgery", represents failures on many different levels. Not least is a seeming lack of appreciation of how bowel issues can very much be part of the clinical profile of many conditions / labels / diagnoses considered within the spectrum of intellectual or learning disabilities. Said issues require both regular monitoring and appropriate and timely intervention.

It is perhaps notable then that the paper by Deborah Kinnear and colleagues [1] is published these days, highlighting how various physical conditions are over-represented alongside diagnoses characterised by intellectual (learning) disability. The authors reported that: "The five most prevalent were visual impairment, obesity, epilepsy, constipation and ataxic/gait disorders."

Based on the examination of data for "people with intellectual disabilities living within the geographical area of Greater Glasgow Health Board, Scotland" between 2002 and 2004, researchers reviewed case records and "completed a comprehensive semi-structured health interview and targeted physical examination and followed a phlebotomy protocol, with the person with intellectual disabilities and their carer." This was time consuming affair - the "complete assessment process took about 4 hours per participant" - covering over 1000 people.

Alongside the reporting of those 'top five most prevalent conditions', researchers also observed several other important details. Namely that nearly all of their cohort had a least one co-existing health condition. The average number of comorbid conditions was 11. Yes, that's 11. And some people had over 25 comorbid physical conditions. When also taking into account the presence or not of Down's syndrome, not much changed in relation to the detected physical comorbidity. Similarly, when age and sex/gender were examined, the authors concluded that there only minor differences noted in terms of comorbidity profiles for example.

Relevant to the case of Richard Handley are some discussions in the Kinnear paper about constipation and learning disability. So: "Constipation was the fourth most prevalent physical health condition." Further, they note in another study [2]: "Eight people with chronic constipation had serious side effects (rectal prolapse, diverticula of colon, intestinal obstruction, megacolon and haemorrhoids) and four eventually died of intestinal obstruction... Thus, as well as being painful, constipation may remain undetected for a long time and can cause death due to missed clinical symptoms." Constipation can cause death. It shouldn't in this day and age, but it still does...

In relation to the implications of their findings, the authors make some additional comments. So: "Medical education is also focused on assessment and management of single conditions, yet management of multimorbidity is far more complex." This is important. It implies that outside of the view of one [primary] diagnosis being present per patient, clinicians and others need to have a more plural view, particularly when it comes to something like learning disability. The focus also on 'physical' comorbidities is also important insofar as how various developmental / behavioural / psychiatric conditions can very much manifest other non-developmental / behavioural / psychiatric conditions. This kinda mirrors what has been discussed with autism in mind (see here and see here for examples) and, alongside, the barriers that need to be overcome when it comes to appropriate diagnoses being made in such contexts (see here).

Set within other data indicating that premature mortality is very much over-represented when it comes to learning disability (see here), and that much of that early mortality is due to the presence of physical health conditions, the Kinnear findings should serve as a wake-up call to many sectors of the professional and other communities. Screening, diagnosing and implementing timely and appropriate intervention(s) are key recommendations; with a specific focus on the person as a whole rather than just being the sum of individual somethings like the diagnosis of learning disability. Bear in mind also that guidance on the management of something like constipation in the context of learning disability does exist in the peer-reviewed domain [3].

And finally, just in case you think that today's discussions aren't directly relevant to autism, constipation has also been mentioned in the death of another young person (see here)...

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[1] Kinnear D. et al. Prevalence of physical conditions and multimorbidity in a cohort of adults with intellectual disabilities with and without Down syndrome: cross-sectional study. BMJ Open. 2018; 8: e018292.

[2] Evenhuis HM. Medical aspects of ageing in a population with intellectual disability: III. Mobility, internal conditions and cancer. J Intellect Disabil Res. 1997 Feb;41 ( Pt 1):8-18.

[3] Robertson J. et al. Constipation management in people with intellectual disability: A systematic review. J Appl Res Intellect Disabil. 2017 Nov 23.

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"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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From limp to scurvy in the context of autism

"A panel of nutritional markers was sent, and a presumptive diagnosis of scurvy was made."

So said the case report detailed by Adam Yan and colleagues [1] as, yet again (see here and see here), the topic of scurvy in the context of autism appears in the peer-reviewed science literature. Scurvy, a condition affecting various tissues of the body, comes about as a result of a lack of adequate vitamin C in the diet. It's thought of as a rare disease nowadays, following on from some 'limey' historical observations (see here).

I say that scurvy is a rare disease, but as per the other blogging occasions when it's received attention, for those diagnosed on the autism spectrum it's not as rare as it should be. Indeed, even Yan et al note that "scurvy is increasingly identified in children with ASD [autism spectrum disorder] and developmental delay who consume restrictive diets, often lacking in fruits and vegetables." Their case report highlights how clinicians need to be observant...

The subject of the Yan case report was a young boy diagnosed with autism who was described as non-verbal. He came to clinical attention following "a 2-week history of limp and oral mucosal bleeding." Unfortunately, his first contact with medical professionals resulted in less-than-revealing typical test results that meant he was discharged with "a referral to dentistry to address the oral mucosal changes." Things did not improve. He presented again to hospital, this time "with new onset of fevers for 1 week, ongoing limp that had progressed to complete refusal to weight bear, and persistent bleeding from his oral mucosa." This second time a few more investigations were ordered and a very (VERY) low level of vitamin C (ascorbic acid) was detected: "The low ascorbic acid level confirmed the diagnosis of scurvy with a concomitant diagnosis of anemia." Treatment in the form of vitamin C and an iron supplement (alongside a multivitamin) did the trick in terms of the limp/leg problem and bleeding gums.

What are the lessons from this case report? Well, yet again, the realisation that issues such as those related to feeding problems present quite widely in relation to autism (see here) and can very much impact on health is paramount. Indeed, it should really be part of standard medical care to monitor and keep monitoring children in particular, with a diagnosis of autism to ensure that their nutritional needs are being met in many areas (see here). If they're not, supplement (under appropriate medical guidance) and don't be afraid to do so, keeping in mind that each person/child is different (see here).

I'm also minded to mention that when medical and other allied healthcare practitioners are faced with a child/adult with autism that is non-verbal and presenting with 'symptoms', the onus really should be on medicine to turn investigator to find out 'hows-and-whys' rather than discharging with a 'we don't know' sentiment. I say this in the context that a diagnosis of autism is seemingly not protective against any other condition/label/disease occurring, and noting other, more catastrophic, examples where this has happened (see here). And minus any sweeping generalisations, a few correctly framed questions can sometimes be enlightening [2] for all-manner of different issues pertinent to autism...

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[1] Yan A. et al. Limp in a Child With Autism Spectrum Disorder. Global Pediatric Health. 2017. Nov 30.

[2] Cohen S. et al. Sleep patterns predictive of daytime challenging behavior in individuals with low-functioning autism. Autism Res. 2017 Dec 1.

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Joint hypermobility, gait and autism

I have already made mention of the paper by Maya Shetreat-Klein and colleagues [1] on this blog as part of a post on the potential usefulness of kata training for at least some people on the autism spectrum (see here). Based on an analysis of 38 children diagnosed with autism spectrum disorder (ASD) and a similar number of asymptomatic controls (all medication free), researchers set about recording "the characteristics of gait and prevalence of toe walking, the range of passive joint mobility, and age at walking" for their groups. They concluded that: "Children with ASDs had significantly greater joint mobility... more gait abnormalities... and on average walked 1.6 months later than their non-autistic peers". Ergo, much greater research focus should be directed to motor issues in cases of autism.

The cliff walk @ Wikipedia 

A few further details from the study might be useful:

• The analysis of movement such as gait and mobility is a science which I won't even pretend to understand. You get terms like goniometer fulcrum which probably makes a lot of sense to those in the know, but to me just sounds like a character from Game of Thrones. Suffice to say however that various measures were used to ascertain passive joint mobility - that is suppleness - across fingers, wrist, elbow and ankle. Gait was also analysed based on participants being "videotaped while walking and running barefoot up and down a hallway in the physician's office for 1-2 min".
• Results: as a group, participants with autism showed significantly greater values for maximum passive joint mobility angles across nearly all measured joints than controls. Taking one example, finger extension (or should that be 'finger metacarpo-phalangeal joint extension angle'), the authors present the very stark differences in angles obtained in histogram form between ASD and control participants. The majority of those with autism able to extend 110 degrees or over; such a feat only noted in 1 of the control participants. I might direct you to a post I wrote a while back on joint hypermobility (see here) which I'll talk about it moment.
• When it came to gait, the authors observed: "toe-walking was significantly more prevalent in children with autism" than controls (33% vs 3% observed on video only). I've talked about toe walking and autism in a previous post (see here) and what it may or may not mean for autism when present. Several other features of gait were also observed; 33% of children with autism were described as apraxic (an inability to execute learned purposeful movements) and 20% were described as clumsy. Both of these issues were not noted in any of the control group participants.

I found the Shetreat-Klein paper to be quite an intriguing read. Not only for the results obtained but because nestled in the paper introduction was reference to some of the original descriptions of autism by Leo Kanner, and how he "commented on the motor deficits in many of his patients". I've talked previously on this blog about how the seminal 1943 paper from Kanner [2] contained so much more than just descriptions of the triad (now dyad) of behaviours which make up the clinical diagnosis of the condition (see here). Aspects which we have perhaps ignored for too long...

The word 'hypotonia' - roughly translated as decreased or low muscle tone - is also a discussion point in the paper: "Our findings that passive joint mobility is on average increased in autism corroborates other studies that report a significantly increased proportion of clinically hypotonic children among those with ASD". Once again, I can't profess to be able to offer any great insight into this issue aside from some light reading around this concept and other uses in the research texts with autism in mind. Hypotonia seems to crop up quite a bit in various case reports detailing often rare genetic conditions with autism as part of presentation. Take for example the paper by Belengeanu and colleagues [3] reporting on a young child presenting with developmental delay and among other things, hypotonia. The paper by Shuvarikov and colleagues [4] talking about a potential HERV (human endogenous retrovirus) mediated genetic deletion with hypotonic features is another example; HERVs are another favourite talking point on this blog (see here).

That all being said, I'd also like to go back to the previous mention of joint hypermobility. Shetreat-Klein et al do talk about whether the descriptions of hyptonia in cases of ASD, or at least "joints with ligamentous laxity", might suggest "a disorder of elastin or collagen". Collagen issues immediately brought my mind back to the condition called Ehlers-Danlos syndrome (EDS), a heritable disorder of connective tissue. One of the primary features of EDS - accepting that there are various different presentations - is hyper-flexible joints. The literature looking at any overlap between autism and EDS is currently sparse, very sparse. I did happen upon the paper by Takei and colleagues [5] (open-access here) detailing a single case where "autistic disorder and EDS were diagnosed" concurrently. Takei et al describe a family history of EDS and as they note: "We speculate that associations exist between connective tissue diseases and autistic disorders, and that connective tissue abnormalities may contribute to autistic symptoms". I do wonder whether this might be an area requiring a little more scientific inspection.

The take home message from this post is that joint mobility and gait issues do seem to be quite apparent across the autism spectrum. Alongside other research in this area, one might start asking further questions about the hows and whys of such findings and whether it may offer further insight into some of the underlying issues potentially associated with at least some of the autisms?

To close, football (soccer). Now knowing that Germany are the 2014 World Cup Champions and this is the first lifting of the Jules Rimet trophy in a reunified Germany, I'm sure David Hasselhoff might have something to say...

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[1] Shetreat-Klein M. et al. Abnormalities of joint mobility and gait in children with autism spectrum disorders. Brain Dev. 2014 Feb;36(2):91-6.

[2] Kanner L. Autistic disturbances of affective contact. Nervous Child. 1943; 2: 217-250.

[3] Belengeanu V. et al. A de novo 2.3 Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl. Gene. 2014 Apr 10;539(1):168-72.

[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] Takei A. et al. High-functioning autistic disorder with Ehlers-Danlos syndrome. Psychiatry Clin Neurosci. 2011 Oct;65(6):605-6.

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Shetreat-Klein M, Shinnar S, & Rapin I (2014). Abnormalities of joint mobility and gait in children with autism spectrum disorders. Brain & development, 36 (2), 91-6 PMID: 22401670

Toe walking and autism

Whilst grazing, as one does, on the plains of the Internet savanna, I stumbled across an interesting article by Williams and colleagues* (open-access) describing a protocol for a study looking at toe walking. As what normally happens with me, memories of autism research times gone by started to flood back, culminating with the question: what ever happened to research looking at toe walking in cases of autism?

En Pointe @ Wikipedia  

Going back quite a few years now, I remembered one occasion when I had research reasons to be in contact with the family of a young girl diagnosed with autism. I quite vividly remember this youngster because of her almost ballet-like gait, hoisting her body weight (which it has to be said was only a very slender frame) on the front portion of her feet; her heels almost never touching the ground for the duration of my visit. The parents I recall, described how she would spend literally hours toe walking; her gait intertwined with various stereotypies depending on her mood and disposition at the time.

Most people will know about the links suggested between autism and issues with gait as per studies like the one from Fournier and colleagues** and the one from Green and colleagues***. Indeed just flicking through an old copy of the ADI (Autism Diagnostic Interview) which I have to hand, I note that in the general behaviours section there is an entry under gait and the words 'up on toes' and 'toe-walking' detailed as part and parcel of the schedule, even if not part of the diagnostic algorithm.

So what evidence is there for toe walking being linked to cases of autism?

• I was actually quite taken aback as to how few references there were for toe walking research in relation to autism as listed in PubMed. One the more important studies seems to be this one from Barrow and colleagues**** which was also discussed on a SFARI entry (see here). Barrow et al suggested that toe walking might be a facet of quite a few cases of autism - during childhood - and raised "the possibility of a secondary orthopedic deformity" to be present. Barrow also reported a disparity in results between the autisms (autism vs. Asperger syndrome) which might also tie into the various research looking at toe walking from a language point of view (see here) or the possibility of a cognitive developmental issue (see here).
• The possibility that toe walking might be a 'red flag' for the presentation of autism had been previously discussed as exemplified by the paper from Mandell and colleagues***** (open-access). As a parcel of behavioural presentations including 'hand flapping' and 'sustained odd play', they suggested that toe walking was associated with a decrease in the age of diagnosis. Someone it seems, has been taking its presence quite seriously.
• The paper by McDougle and colleagues****** (who is talking about some very interesting concepts these days) on tryptophan depletion in cases of autism offers some interesting links between everyone's favourite aromatic amino acid and behaviours such as toe walking. Their results, based on the very complicated area of tryptophan and serotonin chemistry in relation to autism, might have some connection back to more recent mouse model results (see here).

Of course there are other papers looking at toe walking and autism (even with a potential mitochondrial slant to them) but I'm not going to bore you with all the details. Obviously one has to keep in mind that toe walking is not an exclusively autism-linked trait and that some children can present with such a behaviour without presenting with other features linked to a diagnosis of autism or anything else.

I do wonder about a few things based on this collected work: whether we should, following Barrow's suggestion, be screening for orthopaedic issues where sustained toe walking presents in cases of autism, and indeed whether this heralds any link (or not) to things like joint hypermobility (see this post). Whether also toe walking might correlate with other signs and symptoms around either comorbidity (such as cerebral palsy) or even other slightly less well-defined motor-related behaviours are important questions too. That also, for the most part, examination of toe walking in cases of autism has tended to concentrate on the early years of childhood, leaves quite a wide gap into how far maturity acts on such behaviours, and indeed the extent to which toe walking persists into adulthood in cases of autism.

To close, I don't do advice on this blog. But if you really want some life advice, then how about listening to this chap and starting with wearing sunscreen.... (dancing is also a good idea).

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* Williams CM. et al. Do external stimuli impact the gait of children with idiopathic toe walking? A study protocol for a within-subject randomised control trial. BMJ Open. 2013; 3: e002389.

** Fournier KA. et al. Motor coordination in autism spectrum disorders: a synthesis and meta-analysis. J Autism Dev Disord. 2010; 40: 1227-1240.

*** Green D. et al. The severity and nature of motor impairment in Asperger's syndrome: a comparison with specific developmental disorder of motor function. J Child Psychol Psychiatry. 2002; 43: 655-668.

**** Barrow WJ. et al. Persistent toe walking in autism. J Child Neurol. 2011; 26: 619-621.

***** Mandell DS. et al. Factors associated with age of diagnosis among children with autism spectrum disorders. Pediatrics. 2005; 116: 1480–1486.

****** McDougle CJ. et al. Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry. 1996; 53: 993-1000.

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Barrow WJ, Jaworski M, & Accardo PJ (2011). Persistent toe walking in autism. Journal of child neurology, 26 (5), 619-21 PMID: 21285033