Saturday, 31 January 2015

Suramin and the Fragile X (Fmr1 knockout) mouse model (and autism)

Fancy some weekend reading? Well, you could do a lot worse than having a gander through the paper by Jane Naviaux and colleagues [1] (open-access) discussing the results of a whole host of analyses following the use of the antipurinergic agent suramin on a mouse model of Fragile X syndrome.
Overprotective mother, forbidden road trip...

Regular readers might remember some previous discussions about suramin - a pharmaceutic designed to treat African sleeping sickness - and autism which have graced this blog (see here and see here). Following a series of studies which looked at the physiological and behavioural effects of suramin administration on a mouse model trying to recreate conditions of maternal immune activation (MIA (which itself has some autism research history), authors this time turned their attention to a mouse model of Fragile X syndrome, a condition which can in humans manifest with autistic traits (sometimes).

The Naviaux paper is a whopper in terms of data accumulated and results so I'm not going to even try and summarise the findings aside from quoting the authors that their: "results support the novel conclusion that antipurinergic therapy is operating by a mechanism that lies close to the root cause of the core behaviors and development in both the environmental MIA, and the genetic Fragile X models of ASD [autism spectrum disorder]. This mechanism appears to be traceable to mitochondria and regulated by purinergic signaling." Both mitochondrial and purinergic issues have featured in the autism research historical tapestry before (see here and see here respectively).

Just before anyone makes a run on suramin, I might however point out a few things: (a) the current and previous results are based on mouse studies and mice are mice not humans, and (b) suramin, whilst indicated for sleeping sickness, is not without the possibility of some pretty important side-effects (see here).

Still, this latest paper again potentially opens up a number of promising lines of inquiry in need of further investigation. And the added bonus is to see some more metabolomics included in their results!

To close: INXS and Mystify.


[1] Naviaux JC. et al. Antipurinergic therapy corrects the autism-like features in the fragile X (Fmr1 knockout) mouse model. Molecular Autism 2015, 6:1

---------- Jane C Naviaux, Lin Wang, Kefeng Li, A Taylor Bright, William A Alaynick, Kenneth R Williams, Susan B Powell, & Robert K Naviaux (2015). Antipurinergic therapy corrects the autism-like features in the fragile X (Fmr1 knockout) mouse model Molecular Autism : 1186/2040-2392-6-1

Friday, 30 January 2015

Diverse developmental trajectories in early years autism

"Findings confirm the heterogeneous nature of developmental trajectories in ASD [autism spectrum disorder]." That was the bottom line of the study by Peter Szatmari and colleagues [1] (open-access) tracking the developmental trajectory - autistic symptom severity and adaptive functioning - for a sample of "421 newly diagnosed preschool children with ASD 2 to 4 years old." Some accompanying media for the study can be found here.

The Szatmari paper is open-access so it doesn't need any grand details from me... OK, well just a few:

  • "Prospective data collected at 4 points from time of diagnosis to age 6 years were used to track the developmental trajectories of children.
  • Old reliable ADOS (Autism Diagnostic Observation Schedule) was used "to index the developmental trajectories of autistic symptom severity" alongside the VABS (Vineland Adaptive Behavior Scales) which "assesses child adaptive behavior in the communication, socialization, daily living skills, and motor domains." The immediate difference between these schedules outside of looking at autism symptoms and adaptive behaviours is the reliance on observer scores and parent/caregiver report respectively. Just in case you were worried, the timing gaps between ADOS sessions for example, were probably large enough so as not to lead to any so-called practice effects impacting results. Other psychometric tools were also used to gauge 'trajectory prediction and outcome' including the ADI (Autism Diagnostic Interview) among other things.
  • Results: outside of the heterogeneity of symptom presentations, a few key points were noted. So: "Individual children with ASD differ from each other in terms of autistic symptom severity and adaptive functioning from the time of diagnosis in the preschool years, and some of these differences appear to increase by age 6 years." Interesting but not exactly a novel finding as per other discussions in this area (see here).
  • "Moreover, change in one domain is not necessarily associated with change in another." In other words, about 20% of their sample showed changes in "adaptive functioning trajectories" indicative of improvement. But that doesn't necessarily translate into similar changes in autistic presentation which were reported to be "more stable" although in about 10% of cases showing "a decrease in symptom severity from baseline to age 6 years."
  • In all, the authors report two distinct trajectory groups based on autism severity and three groups for adaptive functioning. 
  • Caveats? Well, this was a multi-site study in Canada but following diagnosis, participants were not just left without intervention. The Hanen More Than Words® intervention is mentioned as being offered at one site. Indeed the authors note: "the present analysis did not investigate the possible effect of services or opportunities to learn adaptive functioning skills on the developmental trajectories of children with ASD" so one has to be mindful that the results reported might be affected by this variable. Indeed, one would expect trajectory to be potentially affected by such early intervention...

This is interesting work particularly from the perspective of being a longitudinal study which relied on some of the gold-standard tools available to autism psychometric research. I'm really interested in developmental trajectory and autism in light of this area of research highlighting how autism is perhaps better described as the more plural 'autisms' and the breaking down of some sweeping generalisations and dogma which have pervaded autism understanding. That also one or more trajectory might come under the label of 'optimal outcome' (see here), that is moving outside of the diagnostic boundaries of the clinical description of autism, is another important part of this work. Oh, and just in case you think such ideas are bound to just children, think again (see here).

Gender (sex) is also mentioned in the Szatmari paper and the idea that "sex was the only significant predictor of autistic symptom group trajectory membership." The authors continue: "Boys were more likely to be in the group with more severe symptoms and a stable trajectory than girls, who were more likely to be in the group with less severe symptoms and an improving trajectory (controlling for age at diagnosis, cognitive and language scores, and site)." This is really quite an interesting observation and perhaps ties into the idea of sex differences in the presentation of autism (see here) among other things. I'd be interested to see how the gender splits pan out when it comes to those optimal outcomers too as and when larger participant numbers are eventually meta-analysed by someone.

Finally: "earlier age at diagnosis was more likely associated with membership in a group with higher functioning and improving." Going back to my previous point about a possible role for early intervention in developmental trajectory, the idea that earlier diagnosis can make a difference through the use of earlier intervention also potentially gains ground from such observations. Early diagnosis is a primary endpoint for quite a lot of autism research (see here) although with still quite a bit to do in this area (see here).

The Hurdy Gurdy Man to close from The "B.H. Surfers".


[1] Szatmari P. et al. Developmental Trajectories of Symptom Severity and Adaptive Functioning in an Inception Cohort of Preschool Children With Autism Spectrum Disorder. JAMA Psychiatry. 2015. Jan 28.

---------- Szatmari, P., Georgiades, S., Duku, E., Bennett, T., Bryson, S., Fombonne, E., Mirenda, P., Roberts, W., Smith, I., Vaillancourt, T., Volden, J., Waddell, C., Zwaigenbaum, L., Elsabbagh, M., & Thompson, A. (2015). Developmental Trajectories of Symptom Severity and Adaptive Functioning in an Inception Cohort of Preschool Children With Autism Spectrum Disorder JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.2463

Thursday, 29 January 2015

Autism spectrum symptomatology in individuals with Down syndrome

I was not surprised to read the findings of the paper from Marie Moore Channell and colleagues [1] (open-access) who "identified patterns of ASD [autism spectrum disorder] symptomatology, measured by the SRS [Social Responsiveness Scale], in individuals with DS [Down syndrome] who do not have comorbid ASD."
You're not going Turbo, are you?

Harking back to the paper by Georgina Warner and colleagues [2] discussed not-so-long-ago on this blog (see here), the idea that various autistic traits might also overlap into other conditions including that of Down's syndrome, is gaining some research momentum at the moment. Whether such overlap will yield further clues regarding the aetiology of [some] autism or feed into the various discussions about the changing autism numbers game are discussions to be had in future times.

Channell et al report results for a small group of children/young adults diagnosed with DS. Their participant cohort originally started at 54 individuals with DS who met various study criteria. This was subsequently boiled down to 46 participants given that: "Eight participants scored above our predetermined cutoff" based on scores on the Social Communication Questionnaire (SCQ) "and were determined to be at risk for a comorbid ASD diagnosis, and they were referred for a full diagnostic evaluation." The authors importantly add that: "this number should not be used as a prevalence estimate of ASD risk in DS." Not yet at least.

The SRS was the primary assessment tool, a parent/caregiver reporting schedule "that asks caregivers about their child’s behavior over the past 6 months" specifically looking at reciprocal social behaviours. As part of the autism screening arsenal, the SRS is doing pretty well by all accounts [3]. That being said, it has it limitations as was recently mentioned [4] following it's use in that broccoli sprout - autism trial (see here).

Anyhow, the results: "In general, scores were elevated relative to the available normative data on typically developing children and adolescents, suggesting the need for normative data on the SRS for syndrome-specific samples such as those with DS." Indeed, the authors go on to suggest that as more is done in this area looking at any overlap between autism and DS: "It is likely that some of the currently used diagnostic measures also will require modification for ease of use and interpretation in the DS population." Too true although I would perhaps stress the idea that something like issues with social reciprocity might be something in need of further investigation in some cases of DS.

I've got little more to say on this issue over and above what has already been said. I'd like to think that once science has progressed a little further in this specific area, it might also turn its attention to the preliminary data reported by Worley and colleagues [5] and further testing of the concept of 'Down Syndrome Disintegrative Disorder' (see here) as one among other potential links between DS and the presentation of autism.

Music, music, music to close: Limahl - Never Ending Story. Sing it with passion...


[1] Channell MM. et al. Patterns of autism spectrum symptomatology in individuals with Down
syndrome without comorbid autism spectrum disorder. Journal of Neurodevelopmental Disorders 2015, 7:5.

[2] Warner G. et al. Autism Characteristics and Behavioural Disturbances in ∼ 500 Children with Down's Syndrome in England and Wales. Autism Res. 2014. March 24. 10.1002/aur.1371

[3] Duvekot J. et al. The Screening Accuracy of the Parent and Teacher-Reported Social Responsiveness Scale (SRS): Comparison with the 3Di and ADOS. J Autism Dev Disord. 2014 Nov 28.

[4] Scahill L. Uncommon use of common measures in sulforaphane trial. PNAS. 2015. Jan 13.

[5] 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.

---------- Marie Moore Channell, B Allyson Phillips, Susan J Loveall, Frances A Conners, Paige M Bussanich, & Laura Grofer Klinger (2015). Patterns of autism spectrum symptomatology in individuals with Down syndrome without comorbid autism spectrum disorder Journal of Neurodevelopmental Disorders : 10.1186/1866-1955-7-5

Wednesday, 28 January 2015

Urinary histidine as a marker of 'dioxin-induced' neurodevelopmental issues?

The paper by Muneko Nishijo and colleagues [1] (open-access) caught my eye recently and their continuing investigations into the potential effects of perinatal dioxin exposure on offspring neurodevelopmental outcomes. For a bit of background on this initiative based in Vietnam, I would refer readers to a previous post on this blog (see here).
Your weakness is copper? Y-you're kidding right?

In case you can't be bothered to follow that previous link, the idea was that exposure to TCDD [2,3,7,8-tetrachlorodibenzo-p-dioxin], a particularly hazardous chemical which contaminated the compound known as Agent Orange quite extensively used in Vietnam a few years back, might have some important links to infants exposed to said compound, particularly in relation to the expression of autistic traits. As an aside, I note that dioxin and Agent Orange continues to generate headlines and debate as per news items such as this one suggesting that the legacy of the Vietnam war continues even today.

The latest paper from Nishijo et al sought to look at urinary amino acid profiles of groups (N=26) exposed or not to various combinations of "high total dioxin toxic equivalent (TEQ-PCDDs/Fs)" and/or TCDD. The analytical weapon of choice was gas chromatography-mass spectrometry (GC-MS), and alongside the examination of urine samples, researchers also took into account breast milk concentrations of "PCDD and PCDF congeners (PCDDs/Fs)" as well as variables such as body size, food intake and neurodevelopmental measures based on scores from the "Bayley Scales of Infant and Toddler Development, Ver. 3 (Bayley III)."

Results: "The present study demonstrated that perinatal dioxin exposure to TCDD and TEQ-PCDDs/Fs, as indicated by levels in breast milk, significantly decreased urinary excretion of histidine and tryptophan in 3-year-old Vietnamese children with lower neurodevelopmental scores in dioxin contamination hot spots." As per the title of this post: "urinary levels of histidine were decreased in 3-year-old Vietnamese children who had been exposed to high dioxin levels." Histidine also features quite a bit in the discussion of the study results as per one section labelled: Histidine and brain function.

There is obviously a lot more work to do in this area to further enlighten the research path about the hows, whys and wherefores of dioxin exposure affecting both psychological and biological functions in children. Not least is the need for further prospective study methods to get around the use of breast milk levels of these compounds as a marker of perinatal dioxin exposure. I might also add that decreased levels of urinary histidine have been reported previously with autism in mind [2] (see here for some discussion) so suggesting that dioxin levels might be the only correlate of the group in question might be a step too far at the moment.

With my autism research blogging hat on, I continue to be interested in the chemical exposure link postulated with the expression of 'some' autism and the roads where this might lead autism research. The paper from Peter Stein and colleagues [3] who just featured in that that other paper on urinary histidine among other things [2], suggesting that there may be more to see with regards to Bisphenol-A (BPA) and autism (which I will be blogging about soon) adds to interest in this area, albeit with again the need for further independent verification and more data on the hows and whys.

Music. In memory of Demis... and with the hopes and dreams of Greece and the Greek nation in mind.


[1] Nishijo M. et al. Urinary Amino Acid Alterations in 3-Year-Old Children with Neurodevelopmental Effects due to Perinatal Dioxin Exposure in Vietnam: A Nested Case-Control Study for Neurobiomarker Discovery. PLoS ONE. 2015; 10(1): e0116778.

[2] Ming X. et al. Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res. 2012 Dec 7;11(12):5856-62.

[3] Stein TP. et al. Bisphenol A Exposure in Children With Autism Spectrum Disorders. Autism Research. 2015. Jan 13.

---------- Nishijo M, Tai PT, Anh NT, Nghi TN, Nakagawa H, Van Luong H, Anh TH, Morikawa Y, Waseda T, Kido T, & Nishijo H (2015). Urinary Amino Acid Alterations in 3-Year-Old Children with Neurodevelopmental Effects due to Perinatal Dioxin Exposure in Vietnam: A Nested Case-Control Study for Neurobiomarker Discovery. PloS one, 10 (1) PMID: 25584822

Tuesday, 27 January 2015

Siblings, genetics and the autisms (plural)

The paper by Ryan Yuen and colleagues [1] suggesting that most siblings with autism do not share the same genetic variations thought to contribute to the condition has garnered quite a few media headlines of late (see here and see here).

Applying the concept of whole-genome sequencing whereby the complete genetic blueprint of a person is mapped to provide "the most comprehensive collection of an individual's genetic variation" [2], 340 genomes from 85 families with two children with a diagnosis of autism or autism spectrum disorder (ASD) were analysed. Yuen et al reported that examination of de novo and rare inherited SNPs previously linked to cases of autism were not present in some 70% of their "affected siblings" group. Further, that less than a third of siblings shared the same autism-related gene changes, potentially over-turning the idea that most affected siblings (with the same parentage) share the same genetic issues as being related to their autistic symptoms and label. That all being said, the authors did report that: "Brothers and sisters who shared autism-related mutations displayed more similar symptoms than those who did not".

This is a significant paper in quite a few ways although there are caveats. The results only covered 85 sibling-pairs and the number of autism-related genetic variations inspected was relatively limited. One therefore needs to be a little cautious about sweeping generalisations to the very wide autism spectrum, heterogeneity, comorbidity and all. “The findings suggest that there is significant genetic diversity among people which autism” was one of the commentaries on the Yuen study which I would definitely second (see here). The 'people with autism are like snowflakes' analogy has also been banded around to illustrate that idea of diversity; something that I would also agree with, although perhaps preferring the slightly more scientific idea that 'autism' should perhaps be replaced by the more plural idea: the autisms. Exactly how many 'autisms' there are, remains to be seen as it does in other areas of psychiatry.

Ways forward following the Yuen study? Well, I might suggest that alongside replicating the work in a larger cohort, one might also entertain the idea that structural issues associated with the genome might also be complemented by a little more focus on gene functions and that rising star discipline called epigenetics (see here). The idea for example, that even identical twins might vary in their 'methylomic' profile (see here) is gaining traction in autism research circles to potentially account for some of the missing heritability which has been reported in recent years (see here). I'm not saying that the significant resources ploughed into the genetic roots of autism is all bunk; merely that the idea that genes and environment might synergistically [and variably] act on autism risk should be given a lot more credence, alongside the role that common variants might play in [some] autism (see here). Air pollution is one environmental example perhaps requiring a little more study (see here), although I hasten to stress not the only variable which might need further investigation.

Finally, as part of the Google - Autism Speaks MSSNG initiative (see here), the 'de-identified' data from the Yuen study has been uploaded to the 'cloud' for other researchers to utilise in further investigations. Again, a very good idea for those interested in this branch of autism research but again with the proviso that autism is a very, very heterogeneous condition often including quite a bit of enhanced risk for various comorbidity...


[1] Yuen RKC. et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nature Medicine. 2015. Jan 26.

[2] Ng PC. & Kirkness EF. Whole genome sequencing. Methods Mol Biol. 2010;628:215-26.

---------- Yuen, R., Thiruvahindrapuram, B., Merico, D., Walker, S., Tammimies, K., Hoang, N., Chrysler, C., Nalpathamkalam, T., Pellecchia, G., Liu, Y., Gazzellone, M., D'Abate, L., Deneault, E., Howe, J., Liu, R., Thompson, A., Zarrei, M., Uddin, M., Marshall, C., Ring, R., Zwaigenbaum, L., Ray, P., Weksberg, R., Carter, M., Fernandez, B., Roberts, W., Szatmari, P., & Scherer, S. (2015). Whole-genome sequencing of quartet families with autism spectrum disorder Nature Medicine DOI: 10.1038/nm.3792

Monday, 26 January 2015

What factors are linked to behavioural crises in autism?

The question posed in the title of this post was asked and [partly] answered by the paper by Vincent Guinchat and colleagues [1] based on the analysis of 58 adolescents diagnosed with an autism spectrum disorder (ASD) and "hospitalized for severe challenging behaviors." Challenging behaviours, by the way, refers to a whole spectrum of presentations which doesn't just include aggressive or violent behaviours (see here). Indeed, I recently talked about irritability and autism (see here), which might also fall into this category under certain circumstances.

Guinchat and colleagues "aimed to assess risk factors associated with very acute behavioral crises in adolescents with ASD" by way of collecting various data on participants (both retrospectively and prospectively) including the severity of their presentation, the presence of "comorbid organic conditions" and assessing "predictors of Global Assessment Functioning Scale (GAFS) score and duration of hospitalization at discharge."

Results: well, an inpatient stay did seem to have a positive effect on participants as per the findings that: "During the inpatient stay... patients doubled on average their GAFS scores." A higher score translates as better outcome. Comorbid psychiatric conditions, known and unknown, was the most frequently cited reason for behavioural crises, with depressive episode and schizophrenia representing the known conditions cited most. Organic causes, including epilepsy and "painful medical conditions" followed in frequency, with environmental causes "including lack of treatment... and adjustment disorder" bringing up the rear. The authors also suggest that the severity of autism presentation (I draw back from using the idea of 'functioning') had a negative effect on GAFS scores at discharge. This point may also tie into some recent findings reported by Rattaz and colleagues [2] where symptom severity of autism might be a risk factor for the presence of self-injurious behaviours.

The authors conclude: "Challenging behaviors among adolescents with ASD may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic illness such as epilepsy or acute pain. The management of these behavioral challenges requires a unified, multidisciplinary approach."

I know that some people might look at this data, shrug and say 'what did you expect', but I'm not one of them. Challenging behaviours can occur in relation to autism for all-manner of reasons but as per other discussions on this topic, one should never assume that challenging behaviours are just 'part and parcel' of a diagnosis of autism. They aren't, even if some of the signs and symptoms of autism may make a person more likely to present with such issues at certain times (including puberty).

I've talked before about some of the circumstances around challenging behaviours and autism as per the idea that pain and discomfort for example, might sometimes facilitate the presence of such issues (see here) particularly in the absence of functional language use. Indeed, a lack of communicative abilities (or rather suitable ways or avenues to communicate) can be a real obstacle to health equality more generally when it comes to autism (see here). Epilepsy or seizure-type disorders have also figured on the autism landscape (see here) and potentially contribute as an important factor when it comes to challenging behaviours for some [3]. Ideas on the possibility of overlap between autism and conditions like certain types of depression and/or schizophrenia are gaining traction in recent times (see here and see here respectively) and again, suggest that 'diagnostic vigilance' are the keywords (see here).

To close: Take on Me by Harry Hill (and others)?


[1] Guinchat V. et al. Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement. Research in Developmental Disabilities. 2015; 38: 242-255.

[2] Rattaz C. et al. Symptom severity as a risk factor for self-injurious behaviours in adolescents with autism spectrum disorders. J Intellect Disabil Res. 2015 Jan 12.

[3] Ito M. et al. Subacute postictal aggression in patients with epilepsy. Epilepsy Behav. 2007 Jun;10(4):611-4.

---------- Guinchat V, Cravero C, Diaz L, Périsse D, Xavier J, Amiet C, Gourfinkel-An I, Bodeau N, Wachtel L, Cohen D, & Consoli A (2015). Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement. Research in developmental disabilities, 38C, 242-255 PMID: 25575287

Saturday, 24 January 2015

Hartnup disease in coeliac disease: lessons for 'some' autism?

The paper by Thomas Ciecierega and colleagues [1] (open-access) talking about 'refractory' coeliac disease (CD) - a lack of, or diminished response to a gluten-free diet (the primary management option for CD) - and the subsequent diagnosis of Hartnup disease in a young girl is fodder for today's brief post.
I already had a big bowl of curly-toed weirdo for breakfast.

Describing how authors first diagnosed her with CD but witnessed "only mild clinical and laboratory improvement" following a regime of implementing a gluten-free diet and supplementation with various other nutrients via Total Parenteral Nutrition among other things, further examinations led to a suspicion of a niacin deficiency. The quite remarkable turn-around in clinical fortunes witnessed following the use of "oral niacin (50 mg three times daily)" led to the final diagnosis of Hartnup disease. This was confirmed by some bog-standard chromatography of a urine specimen which "showed increased levels of excreted neutral amino acids (glutamine, valine, phenylalanine, leucine, asparagine, citrulline, isoleucine, threonine, alanine, serine, histidine, tyrosine, tryptophan)." The authors conclude: "Co-occurrence of Hartnup disease and CD is extremely rare." I'd be minded to say, rare yes, but not unheard of in the peer-reviewed domain [2].

This case report stuck out to me for a few reasons. Coeliac disease and the broader spectrum of non-coeliac gluten sensitivity (NCGS) or non-coeliac wheat sensitivity if you wish, are quite a regular feature on this blog; even more so with the news that rates of CD are increasing [3]. Treatment of said 'gluten spectrum conditions' involves the use of a diet devoid of gluten which is found in various cereal products. Said diet also seemingly overlapping with other areas/conditions outside of CD including autism (see here). This is not however, the first time that a gluten-free diet has been talked about as not cutting the mustard in cases of something that initially looked like typical CD (see here).

Hartnup disease is something I came across quite early on in my autism research career. One of the compounds that I had some interest in called trans-indolyl-acryloylglycine (IAG) (see here) was thought to be derived from that ever so versatile aromatic amino acid called tryptophan. Whilst IAG turned out not to be the 'autism biomarker' that we initially thought it might be, one of the other clinical occasions that this compound cropped up in was, yes you guessed it, Hartnup disease. Hartnup disease and tryptophan have an interesting association [4].

Although not wishing to make connections where none may exist, the presentation of Hartnup disease might also manifest in behaviour as well as the more typical skin symptoms which can present [5]. I stumbled across an interesting BBC news article on the condition that mentions Hartnup disease in the same breath as 'the symptoms of autism' which, although rare, is something I've often thought merits further research attention. I'm not necessarily saying that autism = refractory coeliac disease = Hartnup disease - don't be silly - but it strikes me that there may be more to see in connecting some individual cases based on some biological overlap...

So: Paolo Nutini with Candy.


[1] Ciecierega T. et al. Severe persistent unremitting dermatitis, chronic diarrhea and hypoalbuminemia in a child; Hartnup disease in setting of celiac disease. BMC Pediatrics 2014, 14:311 .

[2] Coudray-Lucas C. et al. Association of celiac disease and Hartnup's disease? Value of the tryptophan loading test. Gastroenterol Clin Biol. 1986 Feb;10(2):187-8.

[3] Zingone F. et al. Socioeconomic variation in the incidence of childhood coeliac disease in the UK. Arch Dis Child. 2015. 22 Jan.

[4] Milovanović DD. A clinicobiochemical study of tryptophan and other plasma and urinary amino acids in the family with Hartnup disease. Adv Exp Med Biol. 2003;527:325-35.

[5] Patel AB. & Prabhu AS. Hartnup disease. Indian J Dermatol. 2008 Jan;53(1):31-2.

---------- Ciecierega, T., Dweikat, I., Awar, M., Shahrour, M., Libdeh, B., & Sultan, M. (2014). Severe persistent unremitting dermatitis, chronic diarrhea and hypoalbuminemia in a child; Hartnup disease in setting of celiac disease BMC Pediatrics, 14 (1) DOI: 10.1186/s12887-014-0311-6

Friday, 23 January 2015

NAC + risperidone = decreased irritability in autism?

It's been a while since I talked about NAC - N-acetylcysteine - on this blog with either autism or schizophrenia in mind (see here and see here respectively). Today I'm going to remedy that situation by bringing the paper by Nikoo and colleagues [1] to your attention, and their observation: "N-acetylcysteine can be considered as an adjuvant therapy for ADs [autistic disorders] with beneficial therapeutic outcomes." Adjuvant therapy by the way, refers to a sort of add-on therapy.
We have to call him, Havok. That's his name now.

Just in case you don't know, NAC among other things is the treatment of choice when it comes to paracetamol (acetaminophen) overdose through it's very important role in the formation of the glutathione (the big 'G' as I should start to call it). Glutathione already has something of a research interest when it comes to autism (see here); more recently increased following papers such as the one by Rahbar and colleagues [2] taking about some of the genetics of the glutathione system with [some] autism in mind, touched upon in a recent post.

Nikoo et al reported results based on a gold-standard randomised, double-blind trial whereby one group of children/adolescents with autism received the antipsychotic risperidone plus NAC and another group received risperidone plus placebo over the course of 10 weeks. Risperidone, as I just mentioned is an antipsychotic medicine which has some interesting history when it comes to [some] autism (see here). Irritability was the focus of the study, and what happened to scores on the "Aberrant Behavior Checklist-Community (ABC-C) Irritability subscale" at baseline (start), 5 weeks and 10 weeks. 

The results suggested that NAC may well have some value as an add-on treatment when it came to scores of irritability in cases of autism as per the authors findings: "By week 10, the NAC group showed significantly more reduction in irritability (P = 0.02) and hyperactivity/noncompliance (P = 0.01) subscales scores."

This is not the first time that NAC + risperidone has been mentioned in the peer-reviewed autism research literature. The paper by Ghanizadeh & Moghimi-Sarani [3] (open-access) also reported significant positive effects albeit alongside a few adverse events such as: "constipation (16.1%), increased appetite (16.1%), fatigue (12.9%), nervousness (12.9%), and daytime drowsiness (12.9%)." This follows other research out of Iran looking at NAC + risperidone in relation to some of the negative symptoms of schizophrenia [4]. On all these research occasions, the experimental period of observation was relatively short (8-10 weeks).

Like many others, I'm always a tad reserved when it comes to the use of antipsychotics for cases/behaviours of/associated with autism. As per my recent discussions on weight gain and such pharmaceutics (see here), one always needs to be a little cautious about the use of such medicines and the application of good medicines management including continual health monitoring as a priority when used. The guidance from NICE here in Blighty advising that such medicines should not be used to manage the core symptoms of autism (see here) is testament to the research base on their effectiveness and their limited place in any management plan. That being said, such pharmaceutics do have a role for some people on the autism spectrum [5] even only if as a 'last resort' in the short-term.

I end by harking back to the paper by Hardan and colleagues [6] talked about in a previous post, which suggested that NAC on it's own might have something to add when it comes to irritability in relation to some autism.  I don't necessarily endorse NAC as being a cure-all for irritability in relation to autism - irritability as part of the so-called challenging behaviours is a very multi-faceted thing with lots of potential precursors [7] - but one might give some consideration to NAC as an intervention for some on the autism spectrum. The next question needs to be: how precisely does it work, and does it have any link back to 'the big G' findings with autism in mind?

Music then. Marvin Gaye and Heard it Through The Grapevine (and something funky is going down apparently).


[1] Nikoo M. et al. N-Acetylcysteine as an Adjunctive Therapy to Risperidone for Treatment of Irritability in Autism: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Efficacy and Safety. Clin Neuropharmacol. 2015 Jan 9.

[2] Rahbar MH. et al. Interaction between GSTT1 and GSTP1 allele variants as a risk modulating-factor for autism spectrum disorders. Research in Autism Spectrum Disorders. 2015; 12: 1-9.

[3] Ghanizadeh A. & Moghimi-Sarani E. A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders. BMC Psychiatry. 2013 Jul 25;13:196.

[4] Farokhnia M. et al. N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol. 2013 Nov-Dec;36(6):185-92.

[5] Dinnissen M. et al. Clinical and pharmacokinetic evaluation of risperidone for the management of autism spectrum disorder. Expert Opin Drug Metab Toxicol. 2015 Jan;11(1):111-24.

[6] Hardan AY. et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012 Jun 1;71(11):956-61.

[7] Guinchat V. et al. Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement. Research in Developmental Disabilities. 2015; 38: 242–255.

---------- Nikoo M, Radnia H, Farokhnia M, Mohammadi MR, & Akhondzadeh S (2015). N-Acetylcysteine as an Adjunctive Therapy to Risperidone for Treatment of Irritability in Autism: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Efficacy and Safety. Clinical neuropharmacology PMID: 25580916

Thursday, 22 January 2015

At-risk kids avoiding an autism diagnosis?

The paper from Jonathan Green and colleagues [1] (open-access) discussing results based on a "two-site, two-arm assessor-blinded randomised controlled trial of families with an infant at familial high risk of autism aged 7–10 months, testing the adapted Video Interaction to Promote Positive Parenting (iBASIS-VIPP) versus no intervention" caught quite a few eyes recently. With accompanying media headlines such as 'Parents May Be Able to Lower Kids’ Autism Risk' you can imagine the interest created in such a study. I'll also at this point refer you to a commentary on the study from Cathy Lord [2].

Video interaction to promote positive parenting is by no means a new thing to autism research as per the paper by Poslawsky and colleagues [3]. The adapted - BASIS - program "works with parents using video-feedback to help them to understand and adapt to their infant's individual communication style to promote the best possible social and communicative development." Further: "the therapist makes videotapes of interactions between the parent and child in the home setting and uses video excerpts to work with the parent in a series of sessions that are developmentally sequenced to improve the quality of parent understanding of infant's communication." Treading carefully in this area, the idea that family processes can impact on autism presentation is gaining traction (see here).

Green and colleagues reported results based on 54 families with an infant deemed at high-risk of autism by virtue of having a sibling diagnosed with an autism spectrum disorder (ASD). Twenty eight families were randomly allocated to the intervention group and 26 to a "no intervention" group and participants were monitored and assessed over 5 months. Various measures were used during the trial including the "Manchester Assessment of Caregiver–Infant interaction (MACI)...  to measure infant attentiveness to parent and other interaction variables" and "the Autism Observation Scale for Infants (AOSI)" for the assessment of "early behavioural risk markers for children with ASD."

Results: "point estimates suggest that the intervention increased the primary outcome of infant attentiveness to parent." The authors are rightly careful about this result however because "CIs [confidence intervals] sometimes include the null" across various results. Wide CI's crossing the null are to be viewed with some degree of caution. Likewise other results such as "the intervention reduced autism-risk behaviours" carry the same optimistic yet guarded message.

That all being said, the headline about such intervention potentially 'lowering autism risk' are perhaps a little premature based on the current results. As per some of the media on the study and Prof. Green commenting: "He stressed that the babies have not been tested yet for autism, which will occur when they are around 3 years old, but that the changes he and his team saw strongly suggest that the path to autism may have been interrupted, or at least suppressed in some way." So we wait to see what actually happened to those infants at high-risk and whether intervention actually provided some protection against receipt of a diagnosis of ASD.

I have to say that I was really quite interested in these findings. I am cautious following some of the other findings reported by the authors as per the potential effect of such an intervention on "developmental language measures" and possible "reduced responsiveness to language sounds in the intervention group" but await further results on how this might eventually pan out. Early intervention such as this is a up-coming area in autism research (see here) and the idea that brain and behaviour are plastic and development not potentially as immutable as was once thought. I personally would like to see this area developed further bearing in mind the concept of differing developmental trajectories being associated with autism, and I assume similarly pertinent to high-risk siblings too. I'd also be minded to suggest that a greater focus on the broader autism phenotype (BAP) might be implied in further research (see here) as well as some additional data on the possible genetic/epigenetic/biochemical/neurological correlates which might coincide with the potential efficacy of such early intervention.

Given the previous not-so-effective results of the PACT initiative by some of the authors (see here) I can also imagine the current results were probably received in a more optimistic fashion by the team involved. We wait for further research...


[1] Green J. et al. Parent-mediated intervention versus no intervention for infants at high risk of autism: a parallel, single-blind, randomised trial. Lancet Psychiatry. 2015. Jan 22.

[2] Lord C. Infant autism: parents' role in ameliorating risk? Lancet Psychiatry. Jan 22.

[3] Poslawsky IE. et al. Development of a Video-feedback Intervention to promote Positive Parenting for Children with Autism (VIPP-AUTI). Attach Hum Dev. 2014;16(4):343-55.

---------- Jonathan Green, Tony Charman, Andrew Pickles, Ming W Wan, Mayada Elsabbagh, Vicky Slonims, Carol Taylor, Janet McNally, Rhonda Booth, Teodora Gliga, Emily J H Jones, Clare Harrop, Rachael Bedford, Mark H Johnson, & the BASIS team (2015). Parent-mediated intervention versus no intervention for infants at high risk of autism: a parallel, single-blind, randomised trial The Lancet Psychiatry :

Experts and autism screening triage

Whilst hopefully using the word 'triage' in the right way in the title of this post, I want to briefly talk today about the paper by Terisa Gabrielsen and colleagues [1] (full-text version here) and their observation that when it came to "brief but highly focused observations", a group of psychologists (well, two of them) "with toddler and autism expertise" missed over a third of cases of children who required additional examination/screening for autism or autistic traits.

I am Meredith Vickers, and it is my
job to make sure you do yours.
Some media attention for this study can be found here alongside the quote: "medical professionals can't rely solely on their clinical judgment to detect autism risk." This is a slightly misleading quote given that autism is by definition a behavioural diagnosis with clinical judgement formed on the basis of presented behaviours (and developmental history) in the absence of any biological or genetic test. Perhaps more usefully it should have read that 'some' medical professionals can't rely solely on their clinical judgement to detect 'some' autism risk. Sorry to be so pedantic but it is an important point; that and realising that early detection/diagnosis of autism is still a work in progress.

Gabrielsen and colleagues focused on a small group of infants/children aged between 15-33 months who were screened and assessed to determine their membership of one of three group: autism, speech/language delay and asymptomatic controls. Expert raters were then invited to view video samples of the children and "asked for autism referral impressions based solely on individual 10-minute observations." Unsurprisingly, some children positioned in the autism group were missed, hence the headlines and comments like: "It's often not the pediatrician's fault that referrals are missed".

Another media quote from the study authors is also worthwhile highlighting: "Parents see their children at their very best and very worst... They're the experts for their children. They can be educated about signs and symptoms, and need to help their care providers by speaking up if there's a problem and being involved in referral decisions." I like the idea of passing power back to parents when it comes to autism screening. As per other posts on this blog about parental concerns (see here) and the pre-diagnostic journey (see here), parents are the experts on their own children and medical experts and others alike might perhaps take a little more notice of them when red flags are raised for example.

Oh and whilst we're on the subject of autism screening, remember, remember the work of Dennis Wall and colleagues (see here) on YouTube videos and lay raters among other things...

Music to close, and the exquisite sound of The Shires...


[1] Gabrielsen TP. et al. Identifying Autism in a Brief Observation. Pediatrics. 2015. January 12.

---------- Terisa P. Gabrielsen, Megan Farley, Leslie Speer, Michele Villalobos, Courtney N. Baker, & Judith Miller (2015). Identifying Autism in a Brief Observation Pediatrics : 10.1542/peds.2014-1428

Wednesday, 21 January 2015

Features of autism in childhood epilepsy

"In conclusion, features of ASD [autism spectrum disorder] were common in children with epilepsy regardless of cognitive ability."

Whoa, whoa, whoa! Sorry, Blondie. I don't do backstory
So said Colin Reily and colleagues [1] in their paper examining facets of autism in cases of childhood epilepsy. Suggesting also that the Autism Spectrum Screening Questionnaire (ASSQ) might be "a useful screening instrument in this population, and combining parent and teacher forms was optimal in terms of screening properties", this work adds to other research voices suggesting a possible connection between autism/autistic traits and adult epilepsy too (see here).

I don't want to over-analyse the Reilly results beyond what they found and importantly, their limitations (as in the emphasis on 'features of autism' over and above an actual diagnosis of autism). One might see this research as further evidence of the intimate link between autism and epilepsy / seizure-type disorder(s) potentially intersecting with other issues such as sleep for example [2]. That also various other areas of biological functioning might also be related [3] makes for a potentially interesting future research agenda. Oh and then there is a possible connection with ADHD (attention-deficit hyperactivity disorder) to consider [4] too.

One of the other important issues potentially implied from the Reilly results is whether the possibility of an overlap between autistic traits and epilepsy might also have repercussions in relation to intervention and management. I say this on the basis for example, of the case report (stress: case report) recently described by Philip Bird [5] on the use of low-dose phenytoin - an anticonvulsant medicine - with a man diagnosed with ASD and the implications for various facets of functioning. Appreciating that certain anti-epileptic medications seem to have a rather less positive relationship with autism (see here), it strikes me that there may be more to see and do in this area for certain people...

Music then. I Am The Walrus. Not literally, but The Beatles song.


[1] Reilly C. et al. Features of autism spectrum disorder (ASD) in childhood epilepsy: A population-based study. Epilepsy Behav. 2014 Dec 16;42C:86-92.

[2] Accardo JA. & Malow BA. Sleep, epilepsy, and autism. Epilepsy Behav. 2014 Dec 9. pii: S1525-5050(14)00533-2.

[3] Frye RE. Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum disorder. Epilepsy Behav. 2014 Nov 4. pii: S1525-5050(14)00412-0.

[4] Ettinger AB. et al. Attention-deficit/hyperactivity disorder symptoms in adults with self-reported epilepsy: Results from a national epidemiologic survey of epilepsy. Epilepsia. 2015. 15 Jan.

[5] Bird P. The treatment of autism with low-dose phenytoin: a case report. Journal of Medical Case Reports 2015, 9:8

---------- Reilly C, Atkinson P, Das KB, Chin RF, Aylett SE, Burch V, Gillberg C, Scott RC, & Neville BG (2014). Features of autism spectrum disorder (ASD) in childhood epilepsy: A population-based study. Epilepsy & behavior : E&B, 42C, 86-92 PMID: 25529303

Tuesday, 20 January 2015

Autism and low vitamin D at birth

Discussions about vitamin D (the 'sunshine' vitamin/hormone) and autism are not unfamiliar to this blog. Just last year (2014) I covered research talking about the possibility of a connection between vitamin D and [some] autism at least three times (see here and see here and see here), possibly more.
..but in my game, I'm the bad guy,
and I live in the garbage.

I wouldn't say that I'm an advocate for everything implied by the correlations being made between vitamin D levels and autism given that vitamin D levels have also been linked to everything from depression (see here) to schizophrenia (see here), issues which might also show some passing connection for some people on the autism spectrum (see here for example). But I am interested in how this research area is evolving...

And evolving it is, as yet another study has been published on vitamin D and autism, this time from Elisabeth Fernell and colleagues [1] (open-access) based at the University of Gothenburg in Sweden. Examining 25-hydroxyvitamin D (25(OH)D) levels in dried blood spots "taken in the neonatal period for metabolic screening", researchers concluded that: "low prenatal vitamin D may act as a risk factor for ASD [autism spectrum disorder]."

Aside from some happiness that the fantastic resource which is the neonatal blood spot is being put to good scientific use with autism in mind (see here), I was particularly interested to read about the findings from this research group given their previous foray in this area (see here) based on the paper from Kočovská and colleagues [2] (open-access). On that occasion they concluded that young adults diagnosed with an ASD were, as a group, quite a bit more likely to present with lower vitamin D levels than siblings, parents and an asymptomatic control group.

Back to the Fernell paper, and a few pointers might be in order:

  • "The aim of the present study was to address the emerging hypothesis that low levels of vitamin D at birth increase the risk for ASD." OK.
  • Sibling pairs were used, one child diagnosed with autism, the other "non-ASD affected". Participants were drawn from two samples, a Gothenburg catchment area sample and a "Stockholm Somali group" which have been previously used in a prevalence study of autism in Somali children in Sweden (see here). Those in the know about autism research will perhaps have heard about autism and Somali children a few times before (see here).
  • Participants were coded according to ethnicity into one of three groups: Swedish, Miscellaneous (non-Scandinavian Europe, South America and East Asia) and African/Middle East. This was due to: "well-known ethnic disparity of vitamin D status."
  • Results: "Children to parents of non-Scandinavian ethnicities had lower mean 25(OH)D levels than children to Swedish parents." See the previous point. 
  • "The mean 25(OH)D level was lower in children with ASD... than in their siblings." This trend was significant in "the Swedish and Miscellaneous groups, but not in the African/Middle East group." The authors report that season of birth, a potentially important factor in birth vitamin D levels was likely not the primary variable to account for the ASD - non-ASD sibling differences but there were some disparities noted. I would also draw your attention to another comment from the authors: "Since we studied newborn children before diagnosis, our results are definitely unrelated to lifestyle and diet of the individual, although the mother’s lifestyle and other environmental factors cannot be ruled out."
  • Author conclusion: their findings may support: "the hypothesis that developmental vitamin D deficiency during late pregnancy may carry an increased risk of ASD in the child." Alongside, that is, the requirement for further research with larger numbers of participants.

I would certainly echo the sentiments of the authors for the need for larger-scales studies of any connection between low pregnancy/birth vitamin D levels and risk of autism. This is however not the first time that this issue has been studied as per my commentary on the results from Whitehouse and colleagues [3] (see here) who based on the use of the Autism-Spectrum Quotient (AQ) (itself the topic of some recent inquiry) concluded that: "Maternal 25(OH)-vitamin D concentrations were unrelated to offspring scores on the majority of scales" bearing in mind their focus on mums not offspring when assaying for vitamin D.

A few further points before I let you go about your business.

"In this study we did not examine other possible causes for ASD, such as for instance infections during pregnancy." A very important point indeed if one looks at some of the research literature in this area (see here).

"Autoimmunity is another possible cause for ASD, which was not investigated. However, as low vitamin D is suggested to contribute to the pathogenesis of autoimmunity... our findings could be relevant in this context as well." Again, another potentially important point raised here on the basis of other research which has brought the issue of autoimmunity into the autism-vitamin D frame (see here). More generally, the issue of autoimmunity and autism is of increasing research interest.

Finally, the authors leave us with a tantalising question: "whether or not adequate supplementation of vitamin D to pregnant women might lower the risk for ASD in the offspring"? Before anyone get's ahead of themselves, I think we need quite a bit more discussion and study on this question specific to autism given that more generally vitamin D for pregnant women is seemingly being more frequently indicated.

Just one more thing (to coin a phrase)... although no-one really knows the specific hows, whys and wherefores of any vitamin D connection to autism, I'd be minded to suggest that physiological issues such as gut permeability (yes, it is a real thing) might also register on any future research endeavours given data like that from Assa and colleagues [4] adding to an already interesting area (see here). I'm not saying that this is the only potential factor but one among many.

Music: Do you feel lucky punk?


[1] Fernell E. et al. Autism spectrum disorder and low vitamin D at birth: a sibling control study. Molecular Autism. 2015; 6: 3.

[2] Kočovská E. et al. Vitamin D in the General Population of Young Adults with Autism in the Faroe Islands. J Autism Dev Disord. 2014 Jun 14.

[3] Whitehouse AJ. et al. Maternal vitamin D levels and the autism phenotype among offspring. J Autism Dev Disord. 2013 Jul;43(7):1495-504.

[4] Assa A. et al. Vitamin D Deficiency Predisposes to Adherent-invasive Escherichia coli-induced Barrier Dysfunction and Experimental Colonic Injury. Inflamm Bowel Dis. 2015 Jan 14.

---------- Elisabeth Fernell, Susanne Bejerot, Joakim Westerlund, Carmela Miniscalco, Henry Simila, Darryl Eyles, Christopher Gillberg, & Mats B Humble (2015). Autism spectrum disorder and low vitamin D at birth: a sibling control study. Molecular Autism : 10.1186/2040-2392-6-3