Saturday 29 November 2014

NICE does increasing access to vitamin D supplements

If you happen to live in England or indeed other parts of the UK, you'll no doubt have heard about NICE - the National Institute for Health and Care Excellence - as the body charged with providing us with appropriate evidence-based guidance on all manner of treatments and technologies for all manner of different diagnoses and conditions. I've talked before on this blog about the NICE guidance in relation to the autism spectrum (see here for example).
My name is Elisabeth Shaw,
last survivor of the Prometheus.

Well, after turning it's clinical eye to the sunshine vitamin/hormone (vitamin D), NICE has at last provided some guidance on this matter with a view to increasing access to vitamin D supplements as a means to help tackle some pretty frightening figures with regards to the prevalence of vitamin D deficiency. The full guidance can be seen here and some media coverage can be viewed here.

A quick look over the list of people for whom this guidance might be relevant (children under 5, pregnant and breastfeeding women, people over 65, people who have low or no exposure to the sun, people with darker skin) reveals that quite a large chunk of the population might benefit from supplementation or increased access to supplementation. Certainly, quite a few people living at my latitude - bearing in mind latitude might not the only factor influencing vitamin D production [1] - might benefit from a daily vitamin D supplement, if only at specific times of the year.

I'll freely admit that even with some scientific doubts remaining about vitamin D supplementation impacting on health and wellbeing outside of just preventing rickets, I'm a bit of a fan of further research into the other manifestations potentially linked to vitamin D insufficiency or deficiency. As if to prove a point, below are a few links to previous posts where relationships have been discussed bearing in mind the old adage: correlation is not the same as causation...

I close with a quote from NICE on this issue: "NICE recommends making low cost vitamin D supplements widely available to people at risk of deficiency." I struggle to disagree.

Music to close... and especially for one of my brood: Girlfriend in a Coma. As for my indulgence, the first trailer for Star Wars VII just in case you haven't seen it yet. I have a gut feeling that it's gonna be a bit of classic...


[1] Lucas RM. et al. Vitamin D status: multifactorial contribution of environment, genes and other factors in healthy Australian adults across a latitude gradient. J Steroid Biochem Mol Biol. 2013 Jul;136:300-8.

---------- Lucas RM, Ponsonby AL, Dear K, Valery PC, Taylor B, van der Mei I, McMichael AJ, Pender MP, Chapman C, Coulthard A, Kilpatrick TJ, Stankovich J, Williams D, & Dwyer T (2013). Vitamin D status: multifactorial contribution of environment, genes and other factors in healthy Australian adults across a latitude gradient. The Journal of steroid biochemistry and molecular biology, 136, 300-8 PMID: 23395985

Friday 28 November 2014

The Autism-Spectrum Quotient: overlap between Asperger syndrome and schizophrenia

The paper by Tove Lugnegård and colleagues [1], including mention of one Maria Unenge Hallerbäck who has appeared on this blog previously, is fodder for today's discussions and their finding that a: "significant overlap of AQ [Autism-Spectrum Quotient] scores across the two diagnostic groups clearly reduces the discriminating power of the AQ in the separation of schizophrenia from AS [Asperger syndrome]."
They say you're judged by the strength of your enemies.

As per that link to previous work by Unenge Hallerbäck among others, the idea that the autism spectrum and the schizophrenia spectrum might not be as separate and independent as is commonly thought is gaining some renewed research momentum in recent times (see here). I wouldn't necessarily call it a reunification, as per older sentiments of autism being akin to childhood schizophrenia despite the fact that some of the criteria produced for example, by Mildred Creak and colleagues, contain some potentially pertinent information (see her 9 key features of ‘schizophrenic syndrome in childhood).

Rather however a realisation that (a) autism is nothing like protective against the subsequent development of schizophrenia or related diagnoses particularly with a changing symptom profile moving into adulthood, and (b) in these days of RDoC (see here), common genetic / epigenetic / biological / behavioural ground may be evident across some cases of autism and some cases of schizophrenia including something of familial element [2]. The fact that Prof. Gillberg also makes an appearance on the Lugnegård paper adds to the ESSENCE of overlapping comorbidity (see here) or autism plus [3] if you so wish.

Back to the recent Lugnegård study, and based on quite a bit of work in this area by the authors (see here), they aimed to: "examine the AS-schizophrenia discriminating ability of the AQ." The AQ for those that might not know, represents a series of questions/statements scored on the basis of the presence (or not) of specific cognitive-behavioural traits noted as part of the autism spectrum. It's been talked about a few times on this blog in relation to looking at sensory issues in autism (see here) and rather more uncomfortably, suicide ideation/attempts with parts of the autism spectrum in mind (see here).

The AQ "was completed by 136 individuals: 36 with schizophrenic psychosis, 51 with AS and 49 non-clinical comparison cases." The results: well, as a group, those with AS did score significantly higher than the schizophrenia group, who scored higher than the asymptomatic control group. That being said, there was quite a bit of overlap in the range of AQ scores obtained across the groups and particularly when it came to those with AS and those with schizophrenia. Ergo, using one of the more popular self-report measures for autism, some on the schizophrenia spectrum might also present with a prominent level of autistic traits as part of their symptom profile.

Obviously one has to be slightly cautious with such findings. Self-report is subject to quite a few forms of bias; to some degree complicated by the questions and grading system used by the AQ (take the test here if you wish) which is very subjective in itself (e.g. " I prefer to do things with others rather than on my own" - in what context... going for a drink, taking a bath, etc.). That being said, papers such as the one by Shaun Eack and colleagues [4] (open-access) reporting "considerable similarity in social and non-social cognitive impairment in verbal adults with ASD and outpatients with schizophrenia" under more controlled conditions, offer something of a complementary viewpoint to the Lugnegård and other findings. And before you ask, such overlap in presentation might not just be accounted for by other comorbidity either [5].

Appreciating that diagnostic identity is still an important part of both autism and schizophrenia spectrums for all-manner of different reasons, the idea of compartmentalising when it comes to diagnostic labels is seemingly on less secure ground that it has been for many years. Fuzzy diagnostic boundaries intra-diagnosis - y'know the heterogeneity of the spectrums - has been further complicated by fuzzy diagnostic boundaries inter-diagnosis. And things are only likely going to get even more complicated as per the paper by Song and colleagues [6] for example...

And now for some music... Duck Sauce - Barbra Streisand


[1] Lugnegård T. et al. Asperger syndrome and schizophrenia: Overlap of self-reported autistic traits using the Autism-spectrum Quotient (AQ). Nord J Psychiatry. 2014 Nov 12:1-7.

[2] Sullivan PF. et al. Family History of Schizophrenia and Bipolar Disorder as Risk Factors for Autism. Arch Gen Psychiatry. 2012;69(11):1099-1103.

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

[4] Eack SM. et al. Commonalities in social and non-social cognitive impairments in adults with autism spectrum disorder and schizophrenia. Schizophr Res. 2013 Aug;148(1-3):24-8.

[5] Mealey A. et al. Overlap between autistic and schizotypal personality traits is not accounted for by anxiety and depression. Psychiatry Res. 2014 Oct 30;219(2):380-5.

[6] Song DK. et al. Comparative analysis of autistic traits and behavioral disorders in Prader-Willi syndrome and Asperger disorder. Am J Med Genet A. 2014 Nov 11.

---------- Lugnegård T, Hallerbäck MU, & Gillberg C (2014). Asperger syndrome and schizophrenia: Overlap of self-reported autistic traits using the Autism-spectrum Quotient (AQ). Nordic journal of psychiatry, 1-7 PMID: 25389915

Thursday 27 November 2014

FC is a technique that has no validity

FC, by the way, refers to Facilitated Communication, a controversial technique which as the name suggests relies on a facilitator to support "the hand or arm of a communicatively impaired individual while using a keyboard or other devices with the aim of helping the individual to point and thereby to communicate." The quote for the title of this post comes from the paper by Ralf Schlosser and colleagues [1] who following systematic review, found "unequivocal evidence for facilitator control" and that "messages generated through FC are authored by the facilitators rather than the individuals with disabilities."
It's funny how sometimes the people we remember
the least make the greatest impression on us.

I wouldn't normally be minded to talk about FC if it wasn't something (a) which has appeared alongside the word 'autism' down the years and (b) had not cropped up in various conferences I'd attended, specifically after having watched people such as Dr Andy Grayson talk about the great authorship debate with regards to FC and autism as per some of his publications in this area [2]. I'm by no means an expert on FC and autism and certainly am voicing no opinion beyond that of the peer-reviewed evidence on its usefulness or not.

What does strike me about this area though is the quite large weight of evidence coming down on 'facilitator control' as forming the lion's share of authorship in FC. I remember the paper from Edelson and colleagues [3] (including the late Bernie Rimland on the authorship team) who, quite ingeniously, talked about evaluating a "specially designed hand-support device" as an aid in the "transition from facilitated communication (FC) to independent typing" with autism in mind. They concluded: "Postassessment measures did not reveal any evidence of independent communication with or without the device." Even the American Academy of Pediatrics (AAP) has an opinion on FC with autism in mind [4]: do not use "except within research protocols".

On the basis of this and accounts of where FC can go so terribly wrong, I'd be inclined to follow the recommendations of the Schlosser paper. Even in these times of phones and tablets potentially making FC a whole lot easier, 'consumer beware' is perhaps an appropriate phrase to be derived from the collected research literature in this area...

Music to close: Empire State of Mind.


[1] Schlosser RW. et al. Facilitated Communication and Authorship: A Systematic Review. Augment Altern Commun. 2014 Nov 11:1-10.

[2] Grayson A. et al. Hidden communicative competence: Case study evidence using eye-tracking and video analysis. Autism. 2012; 16: 75-86.

[3] Edelson SM. et al. Evaluation of a mechanical hand-support for facilitated communication. J Autism Dev Disord. 1998 Apr;28(2):153-7.

[4] Committee on Children With Disabilities. Auditory integration training and facilitated communication for autism. American Academy of Pediatrics. Committee on Children with Disabilities. Pediatrics. 1998 Aug;102(2 Pt 1):431-3.

---------- Schlosser RW, Balandin S, Hemsley B, Iacono T, Probst P, & von Tetzchner S (2014). Facilitated Communication and Authorship: A Systematic Review. Augmentative and alternative communication (Baltimore, Md. : 1985), 1-10 PMID: 25384895

Wednesday 26 November 2014

The gut microbiome in Down Syndrome

The recent preliminary findings from Elena Biagi and colleagues [1] (open-access) reporting on the constitution of the gut microbiome - the collected bacteria which reside in the deepest, darkest recesses of our gastrointestinal (GI) tract - in a small number of cases of Down's syndrome caught my eye recently.
It's a funny feeling being taken
under the wing of a dragon

Perhaps a little bit unusually looking at the gut microbiome because of the link between premature ageing in Down's syndrome (DS) and "human aging... associated with a deterioration of the gut microbiota (GM)-host mutualism" researchers set about characterising the gut microbiota (GM) in 17 participants diagnosed with DS. Profiles from DS participants were "compared with the previously published GM profiles of 16 age-matching healthy adultsindeed previously published by some of the authors [2] which itself has been the topic of some discussion.

The results were not exactly spectacular insofar as: "DS persons and healthy adults showed comparable levels of GM diversity and an overall similarity in the composition of the GM community" again bearing in mind the small participant numbers. Indeed their hypothesis about premature ageing of the gut microbiota did not appear to be borne out by their small scale study.

That being said, one particular finding peaked my interest: "DS persons were enriched in Parasporobacterium and Sutterella, and reduced in Veillonellaceae." It is the Sutterella part and the comment: "The increase of Sutterella and the reduction of Veillonellaceae have been described in autistic children with gastrointestinal symptoms" which made me sit up. I've covered Sutterella a few times on this blog with autism in mind (see here and see here for some replication work). Whilst independent work has suggested that Sutterella (Sutterella wadsworthensis) might be nothing more than "a common commensal" [3] based on analyses of samples from "44 treatment naïve de-novo IBD patients and 42 with normal colons", I am still of the opinion that there may be more to see from this bacteria / bacterium.

The fact that Biagi et al also reported that "the abundance of Sutterella in the GM was positively correlated with the ABC [Aberrant Behavior Checklist] total score in DS persons, suggesting a possible link between this microorganism and ASD [autism spectrum disorder] in DS" is to my mind, worthy of some follow-up as a function of some growing links between DS and the autism spectrum (see here). Whether this extends to the recent suggestion of Down Syndrome Disintegrative Disorder [4] is also a question not yet answered.

Bearing in mind the recent revelation that at least some microbiome analyses might be suffering an XMRV moment as per the paper from Susannah Salter and colleagues [5] on reagent and laboratory contamination potentially affecting results (contaminomics as one commentator has put it), there does seem to be quite a bit more to do in this area with DS in mind. If one takes the collected microbiome work with autism in mind (see here also recently added to by the paper by Tomova et al) as a template, and where that might potentially lead in terms of interventions for example, applying similar logic to findings in relation to DS might offer some similarly intriguing opportunities to impact on quality of life.

Next up on the research menu to complete the gut triad: gut permeability and mucosal immunity in DS? What about gluten 'sensitivity' [7] and/or coeliac disease [8]? Too much?

Music, music, music.... Acceptable in the 80's? (shoulder pads etc.)


[1] Biagi E. et al. Gut Microbiome in Down Syndrome. PLoS One. 2014 Nov 11;9(11):e112023.

[2] Schnorr SL. et al. Gut microbiome of the Hadza hunter-gatherers. Nat Commun. 2014 Apr 15;5:3654.

[3] Hansen R. et al. The microaerophilic microbiota of de-novo paediatric inflammatory bowel disease: the BISCUIT study. PLoS One. 2013;8(3):e58825.

[4] Worley G. et al. Down Syndrome Disintegrative Disorder: New-Onset Autistic Regression, Dementia, and Insomnia in Older Children and Adolescents With Down Syndrome. J Child Neurol. 2014 Nov 3. pii: 0883073814554654.

[5] Salter SJ. et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biology 2014, 12:87

[6] Tomova A. et al. Gastrointestinal microbiota in children with autism in Slovakia. Physiology & Behavior. 2014. November 6.

[7] Wolters VM. et al. Intestinal barrier gene variants may not explain the increased levels of antigliadin antibodies, suggesting other mechanisms than altered permeability. Hum Immunol. 2010 Apr;71(4):392-6.

[8] Malt EA. et al. Health and disease in adults with Down syndrome. Tidsskr Nor Laegeforen. 2013 Feb 5;133(3):290-4.

---------- Biagi E, Candela M, Centanni M, Consolandi C, Rampelli S, Turroni S, Severgnini M, Peano C, Ghezzo A, Scurti M, Salvioli S, Franceschi C, & Brigidi P (2014). Gut Microbiome in Down Syndrome. PloS one, 9 (11) PMID: 25386941

Tuesday 25 November 2014

Serotonin - melatonin (and the in-betweeners) linked to autism

The paper by Pagan and colleagues [1] (open-access) looking at "serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD [autism spectrum disorder] and their relatives" set the old grey-pink matter into action recently. Not only because I have some real interest in the starting material for these compounds - the aromatic amino acid known as tryptophan - but because this research group included some quite important analysis of the enzymes involved in the reaction from serotonin to melatonin with autism in mind.

Just before heading into the paper and the details, I'm gonna draw your attention to the picture shown to the right (hand drawn by yours truly) which was originally included in a blog post on something called 5-hydroxytryptophan (5-HTP). As you can see, the source material tryptophan eventually cascades down into various other compounds with serotonin and melatonin in mind. I might add that this is not the only metabolic fate of tryptophan as, for example, per another important compound set: the kynurenine pathway again talked about on this blog.

Serotonin (5-HT) for those who might not know is a neurotransmitter that represents one of the 'S' in the class of medicines called SSRIs hinting at its relationship to mood regulation among other things. Melatonin by contrast has quite an important role in functions like sleep; although, as has been previously mentioned on this blog, melatonin might be quite the molecular handyperson (see here). Both serotonin and melatonin have some history when it comes to autism research and practice (see here for example).

N-acetylserotonin (NAS) is a slightly less well-known compound when it comes to autism. A quick trawl of PubMed using the search term 'N-Acetylserotonin autism' came up with two other entries at the time of writing. Granted both the Anderson-Maes [2] and Carter and colleagues [3] make for interesting reading for different reasons, but there does seem to be a dearth of research on the possibility of a role for NAS for at least some autism.

Now, back to the Pagan paper and a few pointers even though it is open-access:

  • The hypothesis: "that (i) the intermediate NAS might also be altered, (ii) alterations of the serotonin-NAS–melatonin pathway might constitute a possible biomarker for a subgroup of individuals with ASD and that (iii) they would be associated with specific clinical profiles."
  • Whilst avoiding foods high in tryptophan and/or serotonin such as bananas and chocolate, morning blood samples were provided by "278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls" and various parts of the sample assayed for serotonin, melatonin and NAS. The analytical weapons of choice were HPLC (albeit with a rather antiquated method by today's mass spec / NMR standards) and ELISA among other things. A small number of urine samples were also collected and analysed for 6-Sulfatoxymelatonin.
  • Results: on the whole, those with autism presented with "elevated whole-blood serotonin" whilst "Plasma melatonin was significantly decreased in individuals with ASD and their relatives compared with controls." These are not surprising results given the research history in this area. 
  • With slightly more novelty: "the intermediate metabolite NAS, measured in blood platelets, was found to be significantly elevated in individuals with ASD and their relatives compared with controls." Further such elevations in platelet NAS "strongly correlated" with the plasma melatonin findings noted in cases of autism. 
  • There was potentially also something to see when the results were pooled together in terms of discriminating autism from not-autism but I'll leave it up to you to decide how well their biomarkers functioned.
  • Bearing in mind my diagram shown above, the increase in serotonin, increase in NAS but decrease in melatonin might provide some important information about where there may be a metabolic 'block'. In this respect, the authors' analysis of "two enzymes, AANAT [Aralkylamine N-acetyltransferase] and ASMT [N-Acetylserotonin O-methyltransferase] known to form protein complexes with 14-3-3 scaffolding proteins" is also important. Actually, authors looked at 14-3-3 in platelets and reported it/them: "significantly decreased in patients with ASD." Previous work from this group [4] had indicated that ASMT activity to be lower in cases of autism; thus suggesting that problems with this enzyme or the availability of this enzyme converting NAS to melatonin might for example, account for the lower melatonin findings.

I've gone on a little bit in this post but hope that you can see the logic in doing so. Metabolic pathways when it comes to human physiology are pretty complex things affected by all manner of variables including things like enzyme function and the availability of those all-important cofactors (see here for some chatter about BH4 for example). Pagan et al have done a good preliminary job of stitching together some important compounds with autism in mind and particularly their findings in relation to NAS. I personally am looking forward to seeing some independent replication of these findings and perhaps onwards, a little more analysis of some other tryptophan derivatives [5] potentially important to [some] autism...

A little music to close: Mark Ronson - Uptown Funk.


[1] Pagan C. et al. The serotonin-N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders. Translational Psychiatry. 2014. November 11.

[2] Anderson G. & Maes M. Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites, Immuno-inflammation, Autoimmunity and the Amygdala. Curr Neuropharmacol. 2014 Mar;12(2):148-67.

[3] Carter MD. et al. Quantitation of melatonin and n-acetylserotonin in human plasma by nanoflow LC-MS/MS and electrospray LC-MS/MS. J Mass Spectrom. 2012 Mar;47(3):277-85.

[4] Melke J. et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry. 2008 Jan;13(1):90-8.

[5] Anderson RJ. et al. Identification of indolyl-3-acryloylglycine in the urine of people with autism. J Pharm Pharmacol. 2002 Feb;54(2):295-8.

---------- Pagan C, Delorme R, Callebert J, Goubran-Botros H, Amsellem F, Drouot X, Boudebesse C, Le Dudal K, Ngo-Nguyen N, Laouamri H, Gillberg C, Leboyer M, Bourgeron T, & Launay JM (2014). The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders. Translational psychiatry, 4 PMID: 25386956

Monday 24 November 2014

Finland, parental migration and offspring Asperger syndrome

A quote from the paper by Venla Lehti and colleagues [1] to start things off: "The study showed that children whose parents are both immigrants have a significantly lower likelihood of being diagnosed with Asperger's syndrome than those with two Finnish parents."
Can I cook, or can't I?

Based on an analysis of data derived from "the Finnish Hospital Discharge Register" and "the Finnish Medical Birth Register", researchers looked at the records of children with a diagnosis of Asperger syndrome (AS) born between 1987-2005 (n=1783) to ascertain "maternal and paternal immigration" status including mother language spoken. Compared with over 7000 control participants they found that there was indeed something significant to see when it came to parental origins and in particular when mothers and/or fathers were "born in Sub-Saharan Africa".

This is intriguing data. The fact that authors looked at the diagnosis of AS and, by diagnostic criteria, those positioned at a specific point on the autism spectrum with symptoms not normally accompanied by the presence of learning disability (intellectual disability) and fewer issues with spoken language, is important. Previous research by this same group [2] also discussed on this blog (see here) had indicated that "the risk of childhood autism was increased for those whose parents are both immigrants" compared to having two Finnish parents based on the same data registries. The contrast with the more recent data reporting that parental migration status might be protective against receipt of a diagnosis of AS compared with non-immigration status is stark.

That being said, we have seen other hints that when an offspring diagnosis on the autism spectrum is received where parents are immigrants from certain parts of the world to certain other parts of the world, there is a greater tendency towards autism plus learning disability to be present. I've covered it a few times on this blog (see here for example based on data from Sweden). The chatter a while back about the Somali population living in Minneapolis also came to something of a similar conclusion (see here).

The growing idea that autism might be better reflected as a plural condition - 'the autisms' - over and above the singular definition currently being applied to cover some significant heterogeneity across presentation, potentially receives some valuable support from research such as this. Obviously, one has to tread carefully if and when labelling a type of autism potentially linked to something like immigrant status so as not to stereotype or fuel some viewpoints. That being said, there are perhaps quite a few studies to do comparing autism in immigrant children vs. non-immigrant autism presentation which might yet provide some valuable information to autism research in general.

Music then: Taylor Swift - We Are Never Ever Getting Back Together. Although another band did talk about something similar a few years earlier: Beautiful South - A Little Time (and with a much better video).


[1] Lehti V. et al. Parental migration and Asperger's syndrome. Eur Child Adolesc Psychiatry. 2014 Nov 8.

[2] Lehti V. et al. The risk of childhood autism among second-generation migrants in Finland: a case-control study. BMC Pediatr. 2013 Oct 19;13:171.

---------- Lehti V, Cheslack-Postava K, Gissler M, Hinkka-Yli-Salomäki S, Brown AS, & Sourander A (2014). Parental migration and Asperger's syndrome. European child & adolescent psychiatry PMID: 25381114

Saturday 22 November 2014

Children as research participants: assessing competence

I was brought to writing about this topic after reading an interesting post by Virginia Hughes titled: Personhood Week: Do Kids Count? Among the various points raised in that article was some discussion about minors having medical autonomy and how this might impinge on areas outside of just medical decision-making. It also reminded me about something which was raised on more than one occasion when I undertook a stint on a University Ethics committee...

Most people involved in the medical or social care of children in the UK will probably have heard about Gillick competence or the Fraser guidelines. Coupled together under the heading of assessing competency to consent to treatment, these guidance derived from judgements in law offer details on how and when a child under the age of 16 years old is able to consent to his or her own medical treatment without parental input and/or knowledge. Contraception was the test case upon which such guidance was first introduced, but the guidance has subsequently been more widely applied to cover many areas of childhood competence in medicine.
You wouldn't eat your spinach

Gillick competence has also drifted into the arena of research (as members of any University ethics committee might know), alongside questions about whether child participation in research should be similarly governed by such guidance [1].

The recent paper by Irma Hein and colleagues [2] adds to the discussion in this area, specifically with their analysis of the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) and the question of when competency to participate in research studies might actually come about in the paediatric population. I will also direct you to some of the preamble about their study by the same authorship group [3] (open-access).

Hein et al based on data derived from some 160 children aged between 6-18 years of age, concluded that the MacCAT-CR is a pretty good instrument when it comes to its use as a tool for assessing children's competence to consent to clinical research involvement. Perhaps more importantly however based on their results: "[in] children younger than 9.6 years, competence was unlikely (sensitivity, 90%); in those older than 11.2 years, competence was probable (specificity, 90%)". Further that: "The optimal cutoff age was 10.4 years (sensitivity, 81%; specificity, 84%)".

Acknowledging that there is quite a bit more to do in this area, including whether there may geographic variations in the age cut-off described (this was a study conducted in The Netherlands), I found these results to be potentially very important. Not only because "consent may be justified when competence can be demonstrated in individual cases by the MacCAT-CR" suggestive that the MacCAT-CR can be administered to paediatric populations, but also because of the implications for whole disciplines involving children under the age of 16 as research participants.

And on the basis of this being a blog about autism research, the question is: what influence the Hein findings might have on top of previous other ethical issues [4]?

Music to close. Mr Pharmacist by The Fall.


[1] Hunter D. & Pierscionek BK. Children, Gillick competency and consent for involvement in research. J Med Ethics. Nov 2007; 33(11): 659–662.

[2] Hein I. et al. Accuracy of the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) for Measuring Children’s Competence to Consent to Clinical Research. JAMA Pediatrics. 2014. October 13.

[3] Hein IM. et al. Assessing children's competence to consent in research by a standardized tool: a validity study. BMC Pediatr. 2012 Sep 25;12:156.

[4] Hoop JG. et al. Ethical issues in psychiatric research on children and adolescents. Child Adolesc Psychiatr Clin N Am. 2008 Jan;17(1):127-48, x.

---------- Hein IM, Troost PW, Lindeboom R, Benninga MA, Zwaan CM, van Goudoever JB, & Lindauer RJ (2014). Accuracy of the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) for Measuring Children's Competence to Consent to Clinical Research. JAMA pediatrics PMID: 25317644

Friday 21 November 2014

Genomic instability not linked to autism?

An eyebrow was raised upon reading the findings reported by Penelope Main and colleagues [1] concluding that: "it appears unlikely that genomic instability is a feature of the aetiology of autism." Based on results derived in part from "the cytokinesis-block micronucleus cytome (CBMN-cyt) assay" [2] looking at markers of DNA damage, authors reported very little to see in their small cohort of children with autism (n=35) compared with siblings (n=27) and asymptomatic controls (n=25) although with the requirement for: "replication using a larger cohort".
"Nah. I don't need one. I got a Donk".

Of equal interest to this blog was the discovery that there was no significant difference in B vitamins - outside of vitamin B2 - nor homocysteine (the 'big H') levels across the study groups. As regular readers might already know, I've covered homocysteine a few times on this blog with autism in mind (see here for example). Indeed, this authorship group have talked around this topic previously (see here).

Although no expert on the whys and wherefores of the CBMN-cyt assay outside of reading through the Fenech paper [2] and other material around the subject, I gather that this is quite a widely used method for measuring DNA damage covering: "(a) micronuclei (MNi), a biomarker of chromosome breakage and/or whole chromosome loss, (b) nucleoplasmic bridges (NPBs), a biomarker of DNA misrepair and/or telomere end-fusions, and (c) nuclear buds (NBUDs), a biomarker of elimination of amplified DNA and/or DNA repair complexes".

A quick trawl of the other research literature in this area reveals that this is not the first time that members of this group have looked at DNA damage with autism in mind as per another paper by Main and colleagues [3] (including Michael Fenech on the authorship list). On that occasion, lymphoblastoid cell lines (LCLs) from an even smaller group of children with autism and their asymptomatic siblings (N=6 pairs) were analysed for the possible presence of "increased DNA damage events" following artificial challenge to an oxidative stressor (hydrogen peroxide) among other things. They concluded: "(i) that LCLs from children with autism are more sensitive to necrosis under conditions of oxidative and nitrosative stress than their non-autistic siblings and (ii) refutes the hypothesis that children with autistic disorder are abnormally susceptible to DNA damage." The issue of oxidative stress and autism has been discussed quite a bit in the research literature (see here).

I would tend to agree that this is still an area of autism research deserving of further investigations on the basis of that proposed oxidative stress link. I might be further showing my incompetence in this area of endeavour by also referring you back to the paper by Shuvarikov and colleagues [4] and their suggestion that HERV (human endogenous retrovirus) elements may: "mediate other recurrent deletion and duplication events on a genome-wide scale" on the basis of their findings in relation to particular types of de novo deletions including autism as part of the clinical presentation. HERVs are something I've been quite interested in for some time now, with autism (see here), attention-deficit hyperactivity disorder (ADHD) (see here) and myalgic encephalomyelitis (ME) (see here) in mind. Other retrotransposons have also cropped up in more recent times too (see here). The relationship with DNA methylation taps into the rising star discipline that is epigenetics (see here) and potentially back to the reason why homocysteine was included in the most recent Main paper (see here for my lovely hand-drawn picture of the methylation cycle). Certainly with all the recent continued interest in de novo mutations potentially linked to autism [5] it strikes me that further scrutiny of this area is perhaps warranted.

Music then... Emeli Sandé - Next To Me.


[1] Main PA. et al. Lack of Evidence for Genomic Instability in Autistic Children as Measured by the Cytokinesis-Block Micronucleus Cytome Assay. Autism Res. 2014 Nov 4. doi: 10.1002/aur.1428.

[2] Fenech M. Cytokinesis-block micronucleus cytome assay. Nat Protoc. 2007;2(5):1084-104.

[3] Main PA. et al. Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress. Mutagenesis. 2013 Jul;28(4):475-84.

[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] Iossifov I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014 Oct 29. doi: 10.1038/nature13908.

---------- Main PA, Thomas P, Angley MT, Young R, Esterman A, King CE, & Fenech MF (2014). Lack of Evidence for Genomic Instability in Autistic Children as Measured by the Cytokinesis-Block Micronucleus Cytome Assay. Autism research : official journal of the International Society for Autism Research PMID: 25371234

Thursday 20 November 2014

Intestinal permeability: an emerging scientific area (also with autism in mind)

What is the intestinal barrier? What is intestinal permeability? What factors affect the permeability of the intestinal barrier? How do you measure intestinal permeability? How might [altered] intestinal permeability link to health, well-being and various clinical diagnoses?
The new triad @ Bischoff SC et al. 2014

These are some of the questions tackled by the excellent open-access review by Stephan Bischoff and colleagues [1] which I would like to draw your attention to in today's ramblings.

Regular readers of this blog might already know about my borderline obsession with the inner workings of the barrier that separates the contents of our deepest, darkest recesses from the rest of the body. That and the potentially very important triad that is: gut barrier, gut bacteria and gut immune function.

I know the words 'leaky gut' still send shivers down the spines of quite a few people, particularly when mentioned in the context of autism or rather some of 'the autisms'. The NHS Choices website provides a very handy section called: "Why we should be sceptical about 'leaky gut syndrome'" further illustrating the contempt held against this area of science. But peer-reviewed science is peer-reviewed science and leaky gut is beginning to take a foothold in at least some autism research. Indeed, these past few weeks I've also seen quite a lot more positive discussion on the need for more research in this area with autism in mind (see here and see here and see here); real gut-brain science you might say.

There's little more for more to say on this issue outside of perhaps providing you with a few additional selected links to where gut permeability has been discussed on this blog, and perhaps a few areas where quite a bit more autism-related research might be indicated...

Oh, and if you want my peer-reviewed views on this whole gut permeability and autism matter with another, often contentious topic in mind, look no further [2]...

That'll do pig, that'll do. Aside that is, from another barrier [3] which might also require some further investigation with autism in mind...


[1] Bischoff SC. et al. Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterology 2014, 14:189

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

[3] Braniste V. et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014; 6: 263ra158

---------- Bischoff, S., Barbara, G., Buurman, W., Ockhuizen, T., Schulzke, J., Serino, M., Tilg, H., Watson, A., & Wells, J. (2014). Intestinal permeability - a new target for disease prevention and therapy BMC Gastroenterology, 14 (1) DOI: 10.1186/s12876-014-0189-7

Wednesday 19 November 2014

Down Syndrome Disintegrative Disorder

"Down syndrome disintegrative disorder seems an appropriate name for this newly recognized clinical association, which may be due to autoimmunity."
"Hi, everyone. I'm Olaf and I like warm hugs!"

That was the bottom line of the study published by Gordon Worley and colleagues [1] reviewing a small number of cases (N=11) of children diagnosed with Down's syndrome presenting at clinic "with a history of new-onset... or worsening... autistic characteristics" among other things. Based on some potentially important hunches (see here for a summary of the grant proposal for the project), researchers at Duke University and the Duke Down Syndrome Comprehensive Clinic reported results based on various behavioural and biochemical findings including that: "Ten of 11 cases (91%) had elevated ("positive") thyroperoxidase antibody titers compared to only 5 of 21 (23%) age-matched control subjects with Down syndrome".

As preliminary as these findings were, I was really rather interested to read about this study. Not only because of the link established between Down's syndrome (DS) and the presentation of autistic features harking back to some other important work (see here), but also the idea that autoimmunity might potentially be a driving force to such regressive features. Of course we already have something of a template for such a 'disintegrative disorder' in the description of Heller's syndrome, also known as childhood disintegrative disorder (CDD) (see here for some background). Until recently, CDD was included under the category 'Pervasive Developmental Disorder' roughly translating as part of the autism spectrum; although in the DSM update (DSM-5), the diagnosis no longer appears as such (see here). CDD and autism have a somewhat convoluted history intersecting with one and another during various research times and under different circumstances (see here).

Insofar as those anti-thyroid peroxidase (anti-TPO) antibodies being [positively] reported in quite a few cases of Down syndrome disintegrative disorder (DSDD), my interest is maintained. Issues potentially affecting thyroid function in relation to DS are not uncommonly reported in the research literature [2] and so one might not necessarily be surprised to hear that the presence of anti-TPO antibodies have been recorded previously [3]. Whether this finding overlaps with the Worley results in terms of early evidence for DSDD is a question we can't answer at the moment.

Indeed, autoimmunity in general, has something of a relationship with DS as per reviews such as the one by Chistiakov [4] (open-access). The fact that mention is made of coeliac disease (CD) as part of that autoimmune burden is something of particular interest to me; as the paper by Mårild and colleagues [5] noted: "a sixfold increased risk of CD in individuals with DS". These findings are all the more pertinent given that they also include one Jonas Ludvigsson on the authorship list, he of 'gluten issues not quite coeliac disease linked to some autism' (see here).

Going back specifically to the anti-TPO antibodies, I note that with the 'autistic characteristics' in mind, very little peer-reviewed research has been published in this area. It could be that anti-TPO antibodies are not something commonly seen in relation to autism or perhaps because very few people have actually looked at this issue. I will draw your attention to some of the work by Gustavo Román and colleagues [6] (see this post) which reported: "No [autism] risk was found for children of TPO-antibody–positive mothers".

That would have been all I would have said on the matter had the paper from Alan Brown and colleagues [7] not recently emerged indicating that within their cohort: "The odds of autism were increased by nearly 80% among offspring of mothers who were TPO-Ab + [positive for anti-TPO antibodies] during pregnancy (OR = 1.78, 95% CI = 1.16–2.75, p = 0.009), compared to mothers negative for this autoantibody". As interesting as this finding is, it still tells us very little about anti-TPO antibody status for those diagnosed with autism or an autism spectrum disorder (ASD) and how this might overlay with the DSDD description. I might also add that I have talked previously about research suggesting that such autoantibodies might have some link to certain kinds of depression (see here) which also draw in the possibility of comorbidity playing some role [8].

The Worley results, as preliminary as they are, are certainly worthy of further research consideration. It is a revelation to me even having an extended family member with DS, that beyond the classical presentation, there may be quite a bit more medical comorbidity which may require clinical attention. If Worley et al are indeed correct that for those with DSDD autoimmunity plays such an important role, it strikes me that directing efforts to tackle specific symptoms [9] or even autoimmune processes (as per other autoimmune conditions) might yield quite a few benefits for at least some.

Music: The Clash - Rock the Casbah.


[1] Worley G. et al. Down Syndrome Disintegrative Disorder: New-Onset Autistic Regression, Dementia, and Insomnia in Older Children and Adolescents With Down Syndrome. J Child Neurol. 2014 Nov 3. pii: 0883073814554654.

[2] Prasher VP. Down syndrome and thyroid disorders: a review. Downs Syndr Res Pract. 1999 Aug;6(1):25-42.

[3] Chen MH. et al. Thyroid dysfunction in patients with Down syndrome. Acta Paediatr Taiwan. 2007 Jul-Aug;48(4):191-5.

[4] Chistiakov D. Down syndrome and coexistent autoimmune diseases. J Applied Biomed. 2007; 5: 71-76.

[5] Mårild K. et al. Down syndrome is associated with elevated risk of celiac disease: a nationwide case-control study. J Pediatr. 2013 Jul;163(1):237-42.

[6] Román GC. et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol. 2013 Aug 13. doi: 10.1002/ana.23976.

[7] Brown AS. et al. Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2014. 29 October.

[8] Walker JC. et al. Depression in Down syndrome: a review of the literature. Res Dev Disabil. 2011 Sep-Oct;32(5):1432-40.

[9] Hegedüs L. et al. Influence of thyroxine treatment on thyroid size and anti-thyroid peroxidase antibodies in Hashimoto's thyroiditis. Clin Endocrinol (Oxf). 1991 Sep;35(3):235-8.

---------- Worley G, Crissman BG, Cadogan E, Milleson C, Adkins DW, & Kishnani PS (2014). Down Syndrome Disintegrative Disorder: New-Onset Autistic Regression, Dementia, and Insomnia in Older Children and Adolescents With Down Syndrome. Journal of child neurology PMID: 25367918

Tuesday 18 November 2014

Paediatric congenital heart disease and autism risk?

"Children aged 2-17 with CHD [congenital heart disease] were more likely than those without CHD to have had a diagnosis of autism spectrum disorder (crude OR, 4.6; 95% CI, 1.9-11.0) or intellectual disability (Crude OR, 9.1; 95% CI, 5.4-15.4)".
The traveller @ Wikipedia 

That was a key conclusion reported in the study by Hilda Razzaghi and colleagues [1] based on their analysis of data from "the 1997-2011 National Health Interview Survey", a US initiative which aims to provide "information on the health of the U.S. civilian noninstitutionalized population through confidential interviews conducted in households" (see here).

I have to say that I was pretty interested in these findings (even though this is not the first time that neurodevelopmental outcomes have been tied to CHD); a view it seems, that was shared by the authors of the paper, bearing in mind the very wide confidence intervals (CIs) detailed for both conditions and the reliance on second-hand reporting over actual independent screening results. I can't readily offer any one 'smoking gun' explanation for the findings specifically in relation to the autism spectrum but will draw your attention to some discussion about the potential causes of congenital heart disease provided by the NHS Choices websites and how they might tie in.

So: various genetic conditions including Down's syndrome are linked to CHD [2] and the net seems to be closing in on some of the underlying genetics around the association [3]. Although still in need of quite a bit more study, there is a growing appreciation that a diagnosis of autism / autistic traits can coexist alongside a diagnosis of Down's syndrome (see here). As per a recent conversation (thanks Marilyn), one also wonders how this autism - Down's syndrome link might also play out with regards to other areas of the autism research landscape such as dietary effects for example...

Next up is maternal diabetes. As per the NHS Choices entry: "It is estimated that 3 to 6% of women with diabetes who become pregnant will give birth to a baby with a heart defect". Autism and maternal diabetes is an interesting topic which has again cropped up in the autism research literature [4]. If you want my take on the Xu meta-analysis paper and related literature, look no further...

After that is a role for alcohol consumption during pregnancy and mention of the condition called foetal alcohol syndrome (FAS). I have talked about FAS and foetal alcohol spectrum disorder (FASD) before on this blog in the context of autism (see here) but can't readily conclude that the links are overly strong between FAS/FASD and autism presentation.

"A rubella infection can cause multiple birth defects, including congenital heart disease". An interesting association given the history of rubella and autism based to quite a large extent on the work from Stella Chess [5]. I don't know enough about the rate of rubella infection in pregnant women to make any informed statement about how this risk factor might tie into both CHD and autism but the numbers of non-immune women do seem to be quite alarming here in the UK [6].

Influenza during pregnancy? "Women who get flu during the first trimester (three months) of pregnancy are twice as likely to give birth to a baby with congenital heart disease than the general population" according to the NHS Choices website. Regular readers of this blog might already know that I tend to talk quite a bit about how infection - immune system response to infection - during pregnancy seems to have some link to subsequent offspring psychology and development (see here). The link is not altogether straight forward with autism in mind and potentially better related to concepts like fever or fever control [7] but still, there might be more to do here.

The final links - certain medications taken during pregnancy, phenylketonuria (PKU) and exposure to organic solvents during pregnancy - have also, to various extents, been linked to autism (see here and see here for example).

I may very well just be plucking at straws trying to link the causes of CHD with some of the suspected 'causes' of autism (some autism at least) but it strikes me that if one was to further pursue the findings reported by Razzaghi et al those would be the places to start (assuming some shared effect). As per the reports of other physiological findings potentially manifesting alongside a diagnosis of autism (see here), some additional screening of children on the autism spectrum where one or more of the correlates of CHD are suspected might be indicated.

Peter Gabriel and Kate Bush with a beautiful song to close: Don't Give Up.


[1] Razzaghi H. et al. Long Term Outcomes in Children with Congenital Heart Disease: National Health Interview Survey. J Pediatr. 2014 Oct 8. pii: S0022-3476(14)00820-8.

[2] Laursen HB. Congenital heart disease in Down's syndrome. Br Heart J. Jan 1976; 38(1): 32–38.

[3] Ramachandran D. et al. Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genet Med. 2014 Oct 23. doi: 10.1038/gim.2014.144.

[4] Xu G. et al. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. J Autism Dev Disord. 2014 Apr;44(4):766-75.

[5] Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977 Mar;7(1):69-81.

[6] Skidmore S. et al. Is the MMR vaccination programme failing to protect women against rubella infection? Epidemiol Infect. 2014 May;142(5):1114-7.

[7] Zerbo O. et al. Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study. J Autism Dev Disord. 2013 Jan;43(1):25-33.

---------- Razzaghi H, Oster M, & Reefhuis J (2014). Long Term Outcomes in Children with Congenital Heart Disease: National Health Interview Survey. The Journal of pediatrics PMID: 25304924