Generalised joint hypermobility: not so generalised in the non-clinical general population

"Although GJH [generalised joint hypermobility] is overrepresented in clinical cases with neurodevelopmental disorders, such an association seems absent in a normal population."

'A normal population' is not exactly the term that I would use to denote a non-clinical population (hands up if you're 'normal') but I was interested in the findings reported by Martin Glans and colleagues [1] (open-access) talking about how GJH does seem to be over-represented in cases of autism (see here), attention-deficit hyperactivity disorder (ADHD) and other ESSENCE-type overlaps (see here) but does not seem to be frequently present in a non-clinical population. To quote: "... in a non-clinical, adult Swedish population comparing individuals endorsing or not endorsing GJH traits (broadly defined), we found no difference in self-reported symptoms of ADHD or ASD, nor self-reported childhood clumsiness."

The suggestion of a link between joint hypermobility disorders and psychiatry has been around for a while now (see here). Joint hypermobility describes an "ability to extend several synovial joints beyond their normal limits" and is a frequent feature of several connective tissue disorders including Ehlers-Danlos syndrome (EDS). There's still quite a bit of debate about hows-and-whys of joint hypermobility rates being elevated in particular neurodevelopmental conditions but I've speculated that other somatic presentations of GJH such as those affecting the bowel [2] might eventually provide some clues for some groups (see here for example) in the context of a proposed gut-brain axis [3].

This time around Glans et al set about asking nearly 900 people about both their GJH symptoms via the 5PQ (Five-Part Hakim-Grahame Questionnaire) and presentations around diagnoses such as autism and ADHD. The AQ-10 was the autism-symptoms measure used, which, as regular readers might know, I've always been a little hesitant about when it comes to it's ability to separate out autism from other potential diagnoses (see here). No mind, after excluding "thirty-two individuals (3.6%) [who] endorsed being diagnosed with ADHD or ASD [autism spectrum disorder] or did not respond to this question" researchers reported that around a third of their sample "endorsed two or more items on the 5PQ, suggesting GJH in accordance with our criteria." When also examining responses pertinent to autism or ADHD, researchers reported no outstanding results linked to the presentation of GJH symptoms. They did observe something of a *possible* link between "extraordinary hypermobile women" and their ADHD symptoms measure for example, but this was based on a very small sample number indeed.

"Contrary to our hypothesis, we did not find any relationship between GJH and neurodevelopmental traits, nor between GJH and clumsiness in our primary analyses." The authors seem to be quite surprised by their findings. Bearing in mind the fact that researchers were exclusively basing their findings on the results of self-report questionnaires (including GJH symptoms) and the like, the observations made are interesting and potentially suggest that "GJH is not a dimensional trait associated with neurodevelopmental symptoms in the general population" but something perhaps more integral to clinically-relevant signs and symptoms. Further, independent replication might shed some more light on this potentially important topic.

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[1] Glans M. et al. Generalised joint hypermobility and neurodevelopmental traits in a non-clinical adult population. British Journal of Psychiatry Open. 2017; 3: 236-242.

[2] Beckers AB. et al. Gastrointestinal disorders in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: A review for the gastroenterologist. Neurogastroenterol Motil. 2017 Aug;29(8).

[3] Whiteley P. Food and the gut: relevance to some of the autisms. Proc Nutr Soc. 2017 Sep 26:1-6.

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Low muscle tone and autistic traits

"This large study showed a prospective association of infant muscle tone with autistic traits in childhood."

So said the findings reported by Fadila Serdarevic and colleagues [1] who, looking at nearly 3000 children, were able to assess early motor development and muscle tone "between ages 2 and 5 months" and later parental ratings of autistic traits in children at 6 years of age. Said autistic traits were surveyed using the "the Social Responsiveness Scale (SRS) and the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist." Authors concluded that there was something of a connection between low muscle tone and autistic traits: "Low muscle tone in infancy predicted autistic traits measured by SRS... and PDP" and further: "early detection of low muscle tone might be a gateway to improve early diagnosis of ASD [autism spectrum disorder]."

Just before anyone gets ahead of themselves with this data, it is worth pointing out that despite the large participant group included for study and the prospective nature of the study design, this was a study only really looking at two sets of variables across quite a long time-frame. It's not beyond the realms of possibility that other factors might influence the presentation of [parent-reported] autistic traits outside of just early measures of muscle tone or anything related...

But let's set this research in some context. Muscle tone in a broader sense had been noted to be potentially 'linked' to autism in some of the earliest texts on the topic (see here). More recent discussions on how motor skill in the context of gait for example, might be something important to at least some autism (see here) add to the relevance. One might also look to the some of the typical reasons why low muscle tone (hypotonia) may present to see whether there are areas that could inform autism research too. I note for example, mention of Ehlers-Danlos syndrome (EDS) in some of the texts and this would perhaps appeal to further investigation on any overlap between EDS (or other connective tissues disorders) and autism (see here). Serious infections such as encephalitis and meningitis have also been mentioned in the context of hypotonia, and again, might be indicated in relation to hypotonia and some autism (see here). There is also a possibility that hypotonia could (in some cases) be tied into mitochondrial disease; something else that could be relevant to at least some 'types' of autism (see here). All of these areas are worthy of further research inspection added to the idea that muscle tone might be rather more core to autism than many people might appreciate.

'And the best picture goes to'...

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[1] Serdarevic F. et al. Infant muscle tone and childhood autistic traits: A longitudinal study in the general population. Autism Res. 2017 Feb 9.

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Serdarevic F, Ghassabian A, van Batenburg-Eddes T, White T, Blanken LM, Jaddoe VW, Verhulst FC, & Tiemeier H (2017). Infant muscle tone and childhood autistic traits: A longitudinal study in the general population. Autism research : official journal of the International Society for Autism Research PMID: 28181411

ESSENCE meets connective tissue disorders?

ESSENCE referred to in the title of this post concerns 'Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations', a concept championed by the ever-intrepid Prof. Christopher Gillberg and colleagues. Combined with some rather important discussions about the research validity of the concept of a singular 'autism' (see here) [part of the ESSENCE issues described] I'm drawn to quite a few of the proposals put forward by this research group it has to be said.

It is with ESSENCE in mind, that I'm rather interested in the paper by Carolina Baeza-Velasco and colleagues [1] and the observation that following a review of the pertinent research literature, there is some support for a possible connection between ESSENCE issues and another favourite topic on this blog: Joint Hypermobility Syndrome (JHS) and the spectrum of connective tissue disorders (see here for example). JHS and connective tissue disorders refer to a group of conditions where various connective tissues are 'weaker' than they should typically be, with various knock-on effects and symptoms.

"The clinical picture of EDS-HT/JHS [EDS = Ehlers-Danlos syndrome] is poorly known by the medical community, as is the presence of "ESSENCE" (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) problems in affected children" was the starting point for this review paper of the various research literature on this topic. Authors searched, surveyed and concluded that: "Children with EDS-HT/JHS present ESSENCE problems that often coexist and tend to be recognized before the HDCT [hereditary disorder of the connective tissue]." Further: "Awareness of these interconnected clinical problems might help improve early referral, diagnosis and treatment of EDS-HT/JHS."

In a previous blog post on the issue of 'joint hypermobility, gait and autism' (see here), discussions turned to how there may be some important 'intersection' going on with regards to the presentation of motor and gait issues in autism and connective tissues disorders present in some people. I don't want to make sweeping generalisations nor move too far away from the current thinking linking specific brain functions and motor issues [2] but there is some sound logic in how neurodevelopmental issues might go hand-in-hand with connective tissue disorders. If for example, we turn to some of the other manifestations of something like JHS - functional bowel issues such as constipation and/or irritable bowel syndrome (IBS) - there are other potential overlapping features that might also prove to be just as important (see here).

There is a need for quite a bit more research in this area before any grand, sweeping generalisations are made. That and the idea that yet another level of screening might be implied for those with ESSENCE issues or conversely, those diagnosed with connective tissue disorders...

Music to close: The JCB song. For the next time you're stuck behind one....

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[1] Baeza-Velasco C. et al. A connective tissue disorder may underlie ESSENCE problems in childhood. Res Dev Disabil. 2016 Oct 29. pii: S0891-4222(16)30240-2.

[2] Gillberg C. et al. Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations. The Scientific World Journal. 2013;2013:710570.

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Baeza-Velasco C, Grahame R, & Bravo JF (2016). A connective tissue disorder may underlie ESSENCE problems in childhood. Research in developmental disabilities PMID: 27802895

Ehlers-Danlos syndrome (EDS) associated with autism?

Ehlers-Danlos syndrome (EDS) refers to a collection of conditions also headed under the label of connective tissue disorder. EDS affects the 'cellular glue' that basically gives biological tissues their shape and stability such as cartilage. There are various types of EDS and symptoms can vary from person-to-person but one of the most frequent characteristics of the syndrome is joint hypermobility.

I've speculated a few times on this blog about the possibility that EDS and/or joint hypermobility might be yet another comorbidity (albeit rare) to look for when it comes to at least some autism (see here). My reasoning was based on the suggestion that joint hypermobility might not be uncommon for some people on the autism spectrum [1] set against a backdrop of various behavioural/psychiatric diagnoses perhaps being over-represented among cases of such connective tissue disorder (see here).

The findings reported by Martin Cederlöf and colleagues [2] (open-access) add to the scientific interest in this area with their observation that: "Individuals with EDS and hypermobility syndrome are at increased risks of being diagnosed with psychiatric disorders." Autism or rather autism spectrum disorder (ASD) figures in their various conditions screened for among those with EDS and hypermobility syndrome; said data coming once again from one of those very useful Scandinavian population registries ("the Swedish Patient Registry"). With one Jonas F. Ludvigsson on the authorship list - he of 'not quite coeliac disease but something else gluten-related potentially linked to some autism' and quite a lot more besides - researchers looked at some 1700 individual diagnosed with EDS compared to 17,000 asymptomatic controls to calculate any risk of "autism spectrum disorder (ASD), bipolar disorder, attention deficit hyperactivity disorder (ADHD), depression, attempted suicide, suicide and schizophrenia." They additionally report data on "10,019 individuals with hypermobility syndrome (67 % females) and 11,082 hypermobility syndrome siblings."

Results: well, those with EDS did seem to be at some advanced risk of most of the behavioural/psychiatric conditions screened for particularly autism (ASD) and attention-deficit hyperactivity disorder (ADHD) compared with controls. This risk also seemed to extend to those diagnosed with hypermobility syndrome compared with matched controls (+100,000 participants); ADHD particularly standing out in that cohort (RR 5.8, 95 % CI 5.0–6.7). Interestingly the advanced risk of behavioural or psychiatric diagnosis occurring alongside also seemed to extend to siblings of those with EDS in terms of ADHD and labels such as depression and extreme events such as suicide (completion). In short, there appears to be quite a bit to see when it comes to the behavioural and/or psychiatric correlates of EDS and hypermobility syndrome. I might however again reiterate that the absolute numbers of people with co-occurring EDS and autism (52/1771 = 2.9%) or hypermobility syndrome and autism (161/10019  =1.6%) for example, indicate that such issues are not exactly widespread among the population.

I know some people might be getting a little tired of hearing me go on and on about how a diagnosis of autism seems to be protective of nothing in terms of comorbid conditions/states and how screening for the various comorbidity potentially present should perhaps be preferentially offered. Yes, resources are stretched, money is getting tighter all the time and the rates of autism (for whatever reason) seem to be only going one way... up. But, entertaining the idea that comorbidity might in some cases be actually pretty disabling to those on the autism spectrum (think anxiety for example) and that the label of autism does seem to result in some significant health inequalities, the onus really should be on setting up some sort of 'screening checklist' as and when an autism diagnosis is handed out. Indeed, I might just end up doing that myself one day...

Although Cederlöf et al don't do much speculating about why behavioural/psychiatric comorbidity might be linked to EDS or hypermobility syndrome, there is a pressing need to establish any shared pathways. In these days of plural autisms (see here) and specifically the idea that particular genetic conditions might manifest autism+ (see here) it wouldn't be difficult to devise further research looking at possible common genetic threads where autism and EDS for example, represent one possible phenotype. Beyond just genetics however, I'm also minded to bring in another possible example where connective tissue disorder might overlap with autism: the concept of a hyper-permeable intestinal barrier (yes, the so-called leaky gut). I know, I know, for some people the 'dread' that is leaky gut brings about furrowed brows and rolling eyes, but the scientific reality is that for some on the autism spectrum, this may be an important concept (see here) growing, as it is, in other circles of medicine too (see here). Could intestinal hyperpermeability be a feature of EDS/joint hypermobility syndrome in cases of autism? Well, I'd really like to see questions like this further explored in light of what it known about gastrointestinal issues accompanying joint hypermobility syndrome [3] and indeed, whether there may be other interventions to consider (see here) as a result [4]...

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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] Cederlöf M. et al. Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers–Danlos syndrome or hypermobility syndrome and their siblings. BMC Psychiatry. 2016; 16: 207.

[3] Fikree A. et al. A prospective evaluation of undiagnosed joint hypermobility syndrome in patients with gastrointestinal symptoms. Clin Gastroenterol Hepatol. 2014 Oct;12(10):1680-87.e2.

[4] Hong Y. et al. Salutary effects of melatonin combined with treadmill exercise on cartilage damage. J Pineal Res. 2014 Aug;57(1):53-66.

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Cederlöf, M., Larsson, H., Lichtenstein, P., Almqvist, C., Serlachius, E., & Ludvigsson, J. (2016). Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers–Danlos syndrome or hypermobility syndrome and their siblings BMC Psychiatry, 16 (1) DOI: 10.1186/s12888-016-0922-6

Joint hypermobility and links to psychiatry

"The relationship between JH/HDCT [joint hypermobility / heritable disorders of connective tissue] and mental disorders merits further attention in order to improve current knowledge and clarify a possible common etiology."

There is nothing in the desert and no man needs nothing.

That was the conclusion reached in the paper by Carolina Baeza-Velasco and colleagues [1] looking at the possibility of some interesting connections, outside of just physical presentation, when it comes to the range of conditions headed under the label 'disorders of connective tissue'. The list of diagnoses potentially 'associated' with JH/HDCT by Baeza-Velasco et al is pretty long: "anxiety disorders, depression, schizophrenia, neurodevelopmental disorders (autism, attention deficit/hyperactivity disorder [2], and developmental coordination disorder), eating disorders, personality disorders and substance use/misuse."

From the point-of-view of this blog, mention of the word 'autism' is perhaps the most important suggested link, harking back to some previous discussion of joint hypermobility and gait with the autism spectrum in mind (see here). I'm still pretty interested in seeing this issue followed up in the autism research arena bearing in mind the possible influence of comorbidity as per findings related to the presence of anxiety and joint hypermobility [3] and the question of which comes first: autism or hypermobility?

Music: Glow by Ella Henderson.

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[1] Baeza-Velasco C. et al. Joint hypermobility and the heritable disorders of connective tissue: clinical and empirical evidence of links with psychiatry. Gen Hosp Psychiatry. 2014 Oct 16. pii: S0163-8343(14)00264-3.

[2] Baeza-Velasco C. et al. Connective tissue problems and attention deficit and hyperactivity. ADHD Attention Deficit and Hyperactivity Disorders. 2014. 1866-6647

[3] Sanches SB. et al. Anxiety and joint hypermobility association: a systematic review. Rev Bras Psiquiatr. 2012 Jun;34 Suppl 1:S53-60.

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Baeza-Velasco C, Pailhez G, Bulbena A, & Baghdadli A (2014). Joint hypermobility and the heritable disorders of connective tissue: clinical and empirical evidence of links with psychiatry. General hospital psychiatry PMID: 25459977

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