Sunday, 28 December 2014

Pre-eclampsia exposure and autism

A few weeks back, the paper from Cheryl Walker and colleagues [1] reporting that: "Children with ASD [autism spectrum disorder] were twice as likely to have been exposed in utero to preeclampsia as controls with TD [typical development]" provided some column inches in certain media quarters.
How dare you insult Hero's Duty, you little guttersnipe!

Although not the first time that pre-eclampsia - a hypertensive state characterised by proteinuria occurring during pregnancy and potentially affected by/affecting the placenta - has been mentioned in the autism research literature [2] (open-access), the value-added bit to the Walker paper was the use of participants/data included in the CHARGE study. As an aside, CHARGE has been mentioned a few times on this blog (see here for example).

The Walker study looked at maternal self-reports and details "abstracted from medical records" of "Preeclampsia and placental insufficiency" in their cohort comprising some 500 children diagnosed with an ASD and nearly 200 diagnosed with developmental delay (DD) compared against 350 asymptomatic controls. Compared against those TD children, those with autism were more frequently reported to have been exposed to pre-eclampsia during gestation. Further, some relationship between pre-eclampsia severity and autism risk was also observed. The authors also noted: "Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia."

Whilst appreciating that not nearly a week goes by without scientific research linking something or other to a higher risk of autism and the subsequent possibility of 'correlation burnout', these are interesting results. Pregnancy hypertension - high blood pressure - as part of pre-eclampsia is an important factor driving various adverse effects/events which can impact on both developing foetus and mother (e.g. placental abruption). Maternal hypertension as part of the condition called metabolic syndrome has previously been linked to an increased risk of offspring autism [3] (see here for my take on the study) as well as being a potential stand-alone factor [4].

The link between pre-eclampsia and placental insufficiency (where the placenta does not deliver the optimal amount of oxygen or nutrients to the baby) is also a potentially intriguing point with autism in mind. Regular readers might remember some of my previous discussions on the Barker (foetal programming) hypothesis proposed by the late David Barker, and the idea that nutrition in-utero might have some pretty profound consequences for offspring later life health. Although hesitant to say that issues mediated by placental function are directly linked to autism, there is a growing appreciation that the placenta may be a further point of inquiry when it comes to offspring neurodevelopmental functions. Take for example other work by Walker and colleagues related to trophoblast inclusions in relation to autism [5] (see here for my previous discussion on this research) as one example. Perhaps more speculatively is the suggestion that a short interpregnancy interval (IPI) might also increase the risk of offspring autism [6] and what this could also mean from a 'depletion of micronutrients' point of view potentially similar to a placental insufficiency scenario.

What is becoming clearer from this and other research on the 'nine months that made us' in relation to autism or other neurodevelopmental diagnoses, is that further efforts are required to tease apart various factors. So:

(a) What are the process by which adverse pregnancy conditions impact on offspring outcomes? Do we already have research precedents as per the paper by van Gelder and colleagues [7] talking about "physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the aetiology of major birth defects, including congenital heart defects and hypospadias". Both congential heart defects and hypospadias have been previously mentioned in the autism research literature (see here and see here respectively).

 and

(b) Linked to the previous question(s), who is more likely to be at risk of such issues, and what intervention(s) might mean for offspring and mother alike?

Music: Dolly sings Jolene at Glastonbury 2014.

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[1] Walker CK. et al. Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay. JAMA Pediatrics. 2014. 8 December.

[2] Gardener H. et al. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009 Jul;195(1):7-14.

[3] Krakowiak P. et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012 May;129(5):e1121-8.

[4] Polo-Kantola P. et al. Obstetric risk factors and autism spectrum disorders in Finland. J Pediatr. 2014 Feb;164(2):358-65.

[5] Walker CK. et al. Trophoblast Inclusions Are Significantly Increased in the Placentas of Children in Families at Risk for Autism. Biological Psychiatry. 2013; 74: 204-211.

[6] Gunnes N. et al. Interpregnancy interval and risk of autistic disorder. Epidemiology. 2013 Nov;24(6):906-12.

[7] van Gelder M. et al. Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case-control study. BJOG. 2014 Nov 14. doi: 10.1111/1471-0528.13138.

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ResearchBlogging.org Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, & Hertz-Picciotto I (2014). Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay. JAMA pediatrics PMID: 25485869

Saturday, 27 December 2014

Late/moderately preterm kids at risk for a positive autism screen

If you're sick of the sight of tinsel and/or turkey (delete as appropriate), I promise no more mention of them in this post. Just a brief introduction to the the paper by Alexa Guy and colleagues [1] (open-access) who concluded that: "LMPT [late and moderately preterm] infants are at significantly increased risk for positive autistic screen."
Megamind, incredibly handsome criminal
genius and master of all villainy!

Based on the [final] analysis of data from some 600 LMPT infant and 760 term-born infants taking part in a study initiative here in the UK, researchers looked at M-CHAT (Modified Checklist for Autism in Toddlers) scores derived from parental questioning when the child was 2 years old. They found: "LMPT infants were at significantly increased risk for a positive M-CHAT questionnaire screen compared with term-born infants, and this remained significant after application of the follow-up interview and exclusion of infants with neurosensory impairments." Further that their findings: "provide empirical evidence that screening for ASD is especially confounded in preterm populations" as a function of the the high false-positive rate found compared against the term-born controls.

M-CHAT has cropped up a few times on this blog (see here for example). In recent times, the schedule has undergone a bit of (further) revision, evolving into the M-CHAT-R/F [2] (see here for further details) to further improve on its sensitivity statistics when it comes to assessing risk of an autism spectrum disorder (ASD). Indeed, as per the Guy quote: "An M-CHAT follow-up interview is essential as screening for autism spectrum disorders is especially confounded in preterm populations" one can perhaps see where M-CHAT R/F might be particularly handy for further study of this important group.

These results add to an already sizeable volume of peer-reviewed research literature hinting that the timing of our very earliest introduction into the world might influence risk of neurodevelopmental issues such as autism and/or a positive screen for potential autism. That being said, the various factors linked to time in-utero such as birth weight as potentially impacting on development illustrate how complex an issue this might be. How we screen for autism in among the various complexities of preterm births (and lower birth weight) remains a question on many people's minds, including the possibility of using more than one instrument [3].

Music to close: Norwegian Wood.

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[1] Guy A. et al. Infants Born Late/Moderately Preterm Are at Increased Risk for a Positive
Autism Screen at 2 Years of Age. J Pediatrics. 2014. 5 December.

[2] Robins DL. et al. Validation of the modified checklist for Autism in toddlers, revised with follow-up (M-CHAT-R/F). Pediatrics. 2014 Jan;133(1):37-45.

[3] Dudova I. et al. Comparison of three screening tests for autism in preterm children with birth weights less than 1,500 grams. Neuropsychiatr Dis Treat. 2014 Nov 17;10:2201-2208.

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ResearchBlogging.org Guy, A., Seaton, S., Boyle, E., Draper, E., Field, D., Manktelow, B., Marlow, N., Smith, L., & Johnson, S. (2014). Infants Born Late/Moderately Preterm Are at Increased Risk for a Positive Autism Screen at 2 Years of Age The Journal of Pediatrics DOI: 10.1016/j.jpeds.2014.10.053

Wednesday, 24 December 2014

Gluten-free diet affecting EEG findings?

Acknowledging that a certain 'jolly' person with a beard wearing a red suit will be visiting a few homes across the globe quite soon (the only time of the year that most people would let a stranger enter their home via a chimney) I want to briefly direct your attention to the paper by Parisi and colleagues [1] talking about how in "the presence of unexplained EEG abnormalities and/or other neurological disorders/SDB [sleep disordered breathing] an atypical or silent CD [coeliac disease] should also be taken into account."
Merry Christmas.

One sentence in particular took my attention: "After 6 months of GFD [gluten-free diet] headache disappeared in 72% of children and EEG abnormalities in 78%" based on examination of a small participant group (N=19) "with a new biopsy-proven celiac disease (CD) diagnosis."

Coeliac disease (CD), gluten and EEG abnormalities is something I'm actually quite interested in. As per my previous musings, I'm not expert on the dark art that is EEG (see here) but I am interested in how EEG findings might relate to CD and in particular, the suggestion that CD might also have a neurological effect for some (see here). The idea that embarking on a gluten-free diet (the primary intervention for CD) might 'correct' unusual EEG patterns and/or their clinical signs is by no means a new one as per studies such as the one from Diaconu and colleagues [2] talking about the use of the diet and a 'favourable course' when it came to migraine and epilepsy.

Hopefully without too much speculation or controversy, the possibility that a gluten-free diet might impact on EEG issues and/or epilepsy outside of CD has also cropped up in my own research. My dabbling in the science of gluten-free diets for cases of autism (stress on 'cases' [3]) has led me to hear some individual instances where the diet seemed to accompany positive changes to the presentation of seizures in cases of autism [4]. I've talked about individual cases documented in the research literature where a gluten-free diet might have been part and parcel of seizure control in relation to autism (see here), also as a segment of the regime known as a ketogenic diet (see here). One of the studies which I think is missing from the body of research looking at dietary intervention in autism (some autism, perhaps some autism falling into that non-coeliac gluten sensitivity category) is whether impacting on 'unusual' EEG patterns might be something to look at when it comes to gluten removal...

Merry Christmas! And the usual 'best seasonal song ever' link... The Pogues and Kirsty MacColl.

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[1] Parisi P. et al. Role of the gluten-free diet on neurological-EEG findings and sleep disordered breathing in children with celiac disease. Seizure. 2014 Oct 6. pii: S1059-1311(14)00267-2.

[2] Diaconu G. et al. Celiac disease with neurologic manifestations in children. Rev Med Chir Soc Med Nat Iasi. 2013 Jan-Mar;117(1):88-94.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2014 Oct 14:1-6.

[4] Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2013 Jan 4;6:344.

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ResearchBlogging.org Parisi P, Pietropaoli N, Ferretti A, Nenna R, Mastrogiorgio G, Del Pozzo M, Principessa L, Bonamico M, & Villa MP (2014). Role of the gluten-free diet on neurological-EEG findings and sleep disordered breathing in children with celiac disease. Seizure PMID: 25457448

Tuesday, 23 December 2014

The bipolar - schizoaffective - schizophrenia spectrum?

"This pattern of results is consistent with the conceptualisation of a spectrum of disorders, ranging from BDP [bipolar disorder] at one end, to SAD [schizoaffective disorder] in the middle, and SCZ [schizophrenia] at the other end." So concluded the paper by Serafino Mancuso and colleagues [1] examining clinical data derived from the Australian Survey of High Impact Psychosis (SHIP).
The thing about perfection is that it's unknowable.

I'm not going to dwell too long on this paper aside from suggesting that such results add to a growing trend in psychiatry asking whether our current compartmentalising way of diagnosing mental health issues is actually fit for purpose à la RDoC (Research Domain Criteria). A few weeks back Virginia Hughes talked about 'Category Fail' based to a large extent on the paper by London [2] who suggested that: "The use of autism as a diagnostic category guiding translational research is fraught with so many problems that the validity of research conclusions is suspect." Sentiments which have been rumbling on for quite a few years now.

The Mancuso results are complemented by quite a few other findings suggestive of fuzzy boundaries when it comes to giving psychiatric labels and their associated qualities. Plucking randomly from the peer-reviewed literature, the paper from Silver & Bilker [3] for example, talking about people with schizophrenia showing "impairments in [the] recognition of identity and emotional facial clues" as part of social cognition carries hints of what has been described in cases of autism for example. The findings reported by Langdon and colleagues [4] talking about a specific Theory of Mind (ToM) impairment in their cohort with early psychosis provides further evidence for the non-exclusivity of this concept when similarly talked about with autism in mind (see here). I might add that I'm not a great fan of the link between ToM and autism anyway.

Of course, one might also see the concept of a spectrum of psychiatric conditions to be itself rather too simplified when it comes to describing and categorising behaviours and actions. The growing pluralisation of autism - 'the autisms' - and schizophrenia - 'the schizophrenias' - perhaps implies that 'tapestry' might be a better way to define presented symptoms, bearing in mind the potential number of permutations of displayed symptoms and underlying genetic/biological issues that may be evident. It might also cover the evidence talking about overlapping spectrums also.

It's all getting rather complicated...

Music: Chase & Status - Lost & Not Found.

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[1] Mancuso SG. et al. A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: Results from the Second Australian national psychosis survey. J Affect Disord. 2014 Sep 30;172C:30-37.

[2] London EB. Categorical diagnosis: a fatal flaw for autism research? Trends Neurosci. 2014 Nov 14;37(12):683-686.

[3] Silver H. & Bilker WB. Social cognition in schizophrenia and healthy aging: Differences and similarities. Schizophr Res. 2014 Nov 15;160(1-3):157-162.

[4] Langdon R. et al. Theory of mind and neurocognition in early psychosis: a quasi-experimental study. BMC Psychiatry 2014, 14:316

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ResearchBlogging.org Mancuso SG, Morgan VA, Mitchell PB, Berk M, Young A, & Castle DJ (2014). A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: Results from the Second Australian national psychosis survey. Journal of affective disorders, 172C, 30-37 PMID: 25451392

Monday, 22 December 2014

Cytokines activating the kynurenine pathway in schizophrenia?

I'm a bit of a fan of tryptophan biochemistry on this blog. This quite remarkable aromatic amino acid and it's off-shoot metabolites, which appear to have no end of biological uses, have taken quite a bit of my blogging time down the years. Most recently was the suggestion that a metabolite slotting in between serotonin (5-HT) and melatonin might require quite a bit more investigation when it comes to at least some cases of autism (see here).
See ya later, President Fartfeathers.

The findings reported by Lilly Schwieler and colleagues [1] (open-access here) add to the scientific interest and their assertion that: "IL-6 [interleukin-6] induces the KYN [kynurenine] pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA [kynurenic acid] in patients with schizophrenia." IL-6 by the way, is a cytokine (chemical messenger of the immune system) which is normally taken to be a pro-inflammatory cytokine (see here). Kynurenine and it's metabolic relations, are yet another set of compounds derived from tryptophan. The kynurenic hypothesis of schizophrenia (see here) hints at some of the research history this compound (and metabolites) has with the condition.

The Schwieler paper is open-access but a few pointers might be in order:

  • Looking at a "well-characterized cohort of olanzapine-treated patients with chronic schizophrenia" researchers set about looking at cerebrospinal fluid (CSF) levels of various cytokines compared to a small participant group of asymptomatic controls "free from current signs of psychiatric morbidity or difficulties in social adjustment at the time of sampling".
  • Previously measured levels of "tryptophan metabolites of the KYN pathway" were also included in the study bundle. Researchers also looked at a possible 'interplay' between IL-6 and kynurenic acid in human astrocyte cultures. This involved stimulation of said cultures with IL-6 and measuring KYNA using triple quadrupole mass spectrometry.
  • Results: "The CSF IL-6 concentration was elevated in patients with chronic schizophrenia compared with controls." No real surprises there considering what has been reported previously in this area of schizophrenia research [2] and the growing idea of inflammation and psychiatry being linked
  • CSF levels of kynurenine and kynurenic acid were also elevated in the schizophrenia group compared to controls, but no significant differences were noted in the starting material (tryptophan) between the groups. Authors also confirmed that IL-6 did indeed significantly raise levels of kynurenic acid (KYNA) in astrocyte cultures.
  • They conclude that "The increased production of KYNA in fetal human astrocytes following exposure of IL-6 shows that this cytokine is able to induce the activity of the KYN pathway." This process may also pertain to schizophrenia.

Aside from the limitations already pointed out by the authors in terms of some analytical issues and the spot sampling methodology employed, I might also point out that whilst participants with schizophrenia were all taking olanzapine (and other meds in some cases), the asymptomatic controls were "free from medication for at least 1 month". Granted olanzapine is not generally thought to directly impact on levels of IL-6 for example [3] but one can't discount that other, more indirect effects might come into play. Indeed, I'm going to be talking about olanzapine, gut bacteria and weight gain (see here) early in the New Year.

I'd like to introduce the paper by Johansson and colleagues [4] at this point, and their observations related to kynurenic acid and related metabolites in "cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals." Looking at cells specifically from participants (with all their biological heterogeneity), they similarly concluded that there was an "increase in ratio between neurotoxic 3-HK [3-hydroxykynurenine] and neuroinhibitory/neuroprotective KYNA following exposure to cytokines" in the bipolar and schizophrenia groups compared to controls. The 3-HK finding might be of even greater interest to schizophrenia given the suggestion of a link with redox modulation [5] and the idea that oxidative stress might be a factor to the condition [6].

What's more to say on this topic? Well, not much more aside from the fact that there may be a complicated relationship between immune function - immune signalling - and amino acid biochemistry which may very well impinge on presented behaviour. Such links also offer some interesting prospects for potential intervention too...

And to some music: Lower Than Atlantis - Here We Go.

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[1] Schwieler L. et al. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. J Psychiatry Neurosci. 2014 Dec 2;39(6):140126.

[2] Kunz M. et al. Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr. 2011 Sep;33(3):268-74.

[3] Hori H. et al. Effects of olanzapine on plasma levels of catecholamine metabolites, cytokines, and brain-derived neurotrophic factor in schizophrenic patients. Int Clin Psychopharmacol. 2007 Jan;22(1):21-7.

[4] Johansson AS. et al. Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine. J Psychiatr Res. 2013 Nov;47(11):1815-23.

[5] Colín-González AL. et al. The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum. Brain Res. 2014 Nov 17;1589:1-14.

[6] Flatow J. et al. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013 Sep 15;74(6):400-9.

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ResearchBlogging.org Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, Finn A, Bhat M, Samuelsson M, Lundberg K, Dahl ML, Sellgren C, Schuppe-Koistinen I, Svensson C, Erhardt S, & Engberg G (2014). Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. Journal of psychiatry & neuroscience : JPN, 39 (6) PMID: 25455350

Sunday, 21 December 2014

Vitamin D for autism... a double-take?

Yes, I know. Another post on the 'day of rest' but I promise you that this will not become a habit. The reason: the paper by Feiyong Jia and colleagues [1] published in the premier journal Pediatrics. The authors describe a case report of a young child with autism who is observed to have shown improvement in some of the core symptoms of autism following supplementation with the [sunshine] vitamin/hormone of the hour: vitamin D. Further reporting on the paper can be seen here.

Although the paper is interesting - "stressing the importance of clinical assessment of vitamin D3 deficiency and the need for vitamin D3 supplementation in case of deficiency" - and fits in well with my borderline obsession with vitamin D, my interest was piqued because we have actually seen something similar from this research group before [2]. On this and that occasion, 'possibly' reporting on the same "32-month-old boy with ASD [autism spectrum disorder] and vitamin D3 deficiency". I've also discussed the previous Jia paper on this blog before (see here).

I'm gonna say little more on this topic aside from reiterating my reiteration(?) on that previous post about Jia et al talking about their description of a single case report and how one has to be very careful about generalising to the very wide and very heterogeneous autism (or autisms). Yes, there may indeed be issues with vitamin D levels / availability when it comes to some people on the autism spectrum [3] (see here for example) but science is still feeling it's way around this topic and where such a finding might link into the grand scheme of things with a diagnosis of autism spectrum disorder in mind.

I'm also minded to bring to your attention two other papers also appearing in the same journal and reporting with vitamin D in mind: Hart and colleagues [4] detailing more results from the Raine study on what maternal vitamin D levels might mean for offspring outcomes, and McNally and colleagues [5] (who has some research history with vitamin D in mind) talking about how to correct any deficiency. That all being said bearing in mind my prime [blogging] directive: no medical or clinical advice given or intended.

Now, about that Sunday lunch...

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[1] Jia F. et al. Core Symptoms of Autism Improved After Vitamin D Supplementation. Pediatrics. 2014. December 15.

[2] Jia F. et al. Vitamin D Supplementation Improves Autistic Symptoms in a Child with Autism
Spectrum Disorder. Asian Case Reports in Pediatrics. 2014; 2: 21-24.

[3] Pioggia G. et al. Autism and lack of D3 vitamin: A systematic review. Research in Autism Spectrum Disorders. 2014; 8: 1685-1698.

[4] Hart PH. et al. Vitamin D in Fetal Development: Findings From a Birth Cohort Study. Pediatrics. 2014. December 15.

[5] McNally JD. et al. Rapid Normalization of Vitamin D Levels: A Meta-Analysis. Pediatrics. 2014. December 15.

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ResearchBlogging.org Feiyong Jia, Bing Wang, Ling Shan, Zhida Xu, Wouter G. Staal, & Lin Du (2014). Core Symptoms of Autism Improved After Vitamin D Supplementation Pediatrics : doi: 10.1542/peds.2014-2121

Saturday, 20 December 2014

Joint hypermobility and links to psychiatry

"The relationship between JH/HDCT [joint hypermobilityheritable 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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ResearchBlogging.org 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