Atopic disease and adolescent psychotic experiences

I was intrigued to read the paper by Khandaker and colleagues [1] (open-access here) reporting results based on a longitudinal study that suggested: "Childhood atopic disorders increase the risk of psychotic experiences in adolescence".

Bish, bash, Bosch @ Wikipedia 

I've talked about the issue of atopic disease and it's potential overlap with something like neurodevelopment before on this blog (see here) based on the possibility of a neuro-immune interaction (i.e. that our immune system might be involved in many more processes than just fighting infection as per the microglia work) as suggested by Meldrum and colleagues [2]. The recent paper from Chang and colleagues [3] reporting a possible connection between allergic disease and behavioural issues in preschoolers adds to that debate. I very much consider the Khandaker findings to be of a similar ilk in terms of potential mechanisms of effect (accepting though that correlation does not necessarily mean causation).

In brief, Khandaker et al followed several thousand children over the course of their trial (data from the ALSPAC cohort which has just received some good news), detailing the presence of atopic diseases such as asthma and eczema of participants at age 10 and any subsequent psychotic experiences at age 13. Various markers linked to inflammation (C-reactive protein and IL-6) were also assessed at age 9. It was then a case of comparing those with atopic disease, whether present singularly or combinatorially, with those without atopic disease on whether the risk of a psychotic episode (PE) was more or less likely. And it was more likely in the atopic group; although strangely enough those markers of inflammatory processes did not seem to "mediate association between atopy and PEs" bearing in mind that inflammatory markers were not seemingly assessed at the time of the PE.

As per the authors findings, I'm not yet able to provide a specific hypothesis to explain the Khandaker findings. I do hark back to my previous chatter about the 'skin-brain axis' for example (see here) as potentially being important although not specifically related to the psychosis findings. The accompanying literature on psychocutaneous disorders [4] "conditions that are characterized by psychiatric and skin manifestations" may very well be something of a research focus to account for at least the proposed eczema - PE link.

With regards to asthma, well there is the suggestion from Moreno and colleagues [5] that asthma was one of a number of conditions "more frequent in individuals with psychotic symptoms but no psychosis diagnosis" but again, comparatively little to suggest a mechanism of connection outside of individual case reports on steroid medication for example (used for some cases of asthma) being linked to the presence of psychotic episodes [6]. I could be really speculative and talk about physiological mechanisms other than atopy potentially linked to such somatic and psychiatric symptoms such as that encompassed by the body of work looking at dietary elements [7] (and this paper by Faith Dickerson and colleagues [8]) but don't want to get ahead of myself given the lack of testing for such parameters in the Khandaker paper.

What however we can take from the Khandaker results is that a possible connection between somatic and psychiatric symptoms should remain an important area of research particularly with regards to shared genetics, epigenetics or biological markers. Perhaps also that more emphasis should be placed on screening for psychotic episodes and related conditions in cases where atopy is present. The tantalising question of whether treating somatic symptoms might have a potential knock-on effect on psychiatric symptoms or vice-versa also remains, as for example, per the recent update on the use of anti-inflammatory agents for schizophrenia by Sommer and colleagues [9]. There doesn't at the moment appear to be an awful lot of research on the potential usefulness of antihistamines (H1-receptor antagonists) commonly used to treat allergic disorders, in cases of psychosis or conditions manifesting psychosis. When however it comes to H2-receptor antagonists and accepting that these medicines are not generally viewed as antihistamines, I am drawn to the chatter about famotidine and schizophrenia [10] for example, something which I think was also mentioned with regards to autism at one point [11] and seemingly never heard of again. So, with no medical advice given or intended, there's still quite a bit more research to do in this area.

To close, having watched the recent BBC4 documentary about The Doors and really appreciating the musical talent they were, a classic: Riders on the Storm... sit back and enjoy.

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[1] Khandaker GM. et al. A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence. Schizophr Res. 2013 Nov 21. pii: S0920-9964(13)00520-3. doi: 10.1016/j.schres.2013.09.021.

[2] Meldrum SJ. et al. Allergic disease in the first year of life is associated with differences in subsequent neurodevelopment and behaviour. Early Hum Dev. 2012 Jul;88(7):567-73. doi: 10.1016/j.earlhumdev.2011.12.032.

[3] Chang HY. et al. Allergic diseases in preschoolers are associated with psychological and behavioural problems. Allergy Asthma Immunol Res. 2013 Sep;5(5):315-21.

[4] Al Hawsawi K. & Pope E. Pediatric psychocutaneous disorders: a review of primary psychiatric disorders with dermatologic manifestations. Am J Clin Dermatol. 2011 Aug 1;12(4):247-57.

[5] Moreno C. et al. Psychotic symptoms are associated with physical health problems independently of a mental disorder diagnosis: results from the WHO World Health Survey. World Psychiatry. 2013 Oct;12(3):251-7.

[6] Lee KM. et al. Steroid-induced acute psychosis in a child with asthma: report of one case. Acta Paediatr Taiwan. 2001 May-Jun;42(3):169-71.

[7] Karlsson H. et al. Maternal antibodies to dietary antigens and risk for nonaffective psychosis in offspring. Am J Psychiatry. 2012 Jun;169(6):625-32.

[8] Dickerson F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry. 2010 Jul 1;68(1):100-4.

[9] Sommer IE. et al. Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update. Schizophr Bull 2014; 40: 181-191.

[10] Martinez MC. Famotidine in the management of schizophrenia. Ann Pharmacother. 1999 Jun;33(6):742-7.

[11] Linday LA. et al. Famotidine treatment of children with autistic spectrum disorders: pilot research using single subject research design. J Neural Transm. 2001;108(5):593-611.

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Khandaker GM, Zammit S, Lewis G, & Jones PB (2013). A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence. Schizophrenia research PMID: 24268471

The gut microbiome and autism... so far

A micropost if you will, to provide readers with a link to the paper by Xinyi Cao and colleagues* (open-access) reviewing where autism research is up to when it comes to those trillions of beasties - the various gut bacteria - which call our deepest, darkest recesses home.

Regular readers probably already know about my borderline obsession with the gastrointestinal tract (gut) and its inner workings when it comes to at least some cases of the autisms and how the gut microbiome represents a potentially valuable new research frontier for lots of different states and conditions.

The paper by Cao et al lists just about everything, research-wise, related to the analysis of gut bacteria pertinent to autism up to October 2013, with all the big players so far included - from Williams (see here) to Wang (see here) and lots in-between. The final conclusions are a familiar one: more research needed and a requirement to ensure that "confounding variables" are controlled for as best they can be. Of course, as is common in research, one might argue that the Cao paper is already out of date given for example, the replication of that Sutterella finding by Wang and colleagues (see here). And slightly outside of studies of looking at gut bacteria in real people, there is the emerging evidence from mouse models too (see here) which sparked talk about probiotics and the feasibility of trying to alter gut bacterial arrangements**. I'm not yet entirely convinced about this probiotic method in the longer-term but alongside other suggestions (see here) will be keeping my research eyes open for any trial results.

A final quote to leave you with: "There does, however, appear to be a ‘signal’ suggesting significant differences in the GI microbiome between ASD [autism spectrum disorder] children and children without ASD, so there would be value in continuing this line of research". I can't argue with that.

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* Cao X. et al. Characteristics of the gastrointestinal microbiome in children with autism spectrum disorder: a systematic review. Shanghai Archives of Psychiatry. 2013; 25: 342-353.

** Critchfield JW. et al. The potential role of probiotics in the management of childhood autism spectrum disorders. Gastroenterol Res Pract. 2011;2011:161358.

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Xinyi CAO, Ping LIN, Ping JIANG, & Chunbo LI (2013). Characteristics of the gastrointestinal microbiome in children with autism spectrum disorder: a systematic review Shanghai Archives of Psychiatry Other: http://www.saponline.org/upload/2013/1231/342.pdf

Autism, gastrointestinal disorders and comorbidity clusters

I start this post with a few important observations. Please feel free to disagree with me (as long as you can provide peer-reviewed evidence for your alternate viewpoint).

Bunting @ Wikipedia 

(1) Comorbidity can, and quite frequently does, surround a diagnosis of autism.

(2) Gastrointestinal (GI) issues form an important part of that comorbidity spectrum.

(3) The relationship between autism and comorbidity is, at present, poorly understood insofar as which influences the appearance of which and how the two are related.

So, with those statements in mind, I offer some discussion today on two potentially very important papers which variably reference the above points.

The first paper is from Brittany Peters and colleagues* (with many, many thanks to Natasa for the paper) which suggests that there indeed may be an important relationship between GI issues and rigid-compulsive behaviours noted in cases of autism. The second paper is from Finale Doshi-Velez and colleagues** (again, with thanks to Natasa) who looked at 'comorbidity clusters' when it comes to the autism spectrum.

Both these papers come from groups who have some 'research form' in their respective areas. For the Peters paper it comes in the guise of the valuable research contribution from Gorrindo and colleagues*** which basically said that yes, parents might know when their children with autism present with bowel issues: "parents were sensitive to the existence, although not necessarily the nature, of GID [gastrointestinal dysfunction]". For the Doshi-Velez paper I'll link back to the paper by Kohane and colleagues**** (covered in this post) and their notion of 'significantly over-represented' when it comes to the comorbidity burden with autism in mind.

The more recent papers make for interesting reading. Starting with the Peters paper:

• The authors start with a hypothesis: "a possible association between rigid-compulsive behaviors and GI symptoms" based on their clinical experience of the autism spectrum conditions.
• They tested their hypothesis on data from participants (N=5076) in the Autism Treatment Network (ATN) and various measures collected from the ATN database. Alongside including diagnostic data, the database also contains data from a GI symptom questionnaire; both of which were used to collect information for their study analysis.
• Results: Nearly half of the total cohort (43.5%) "had at least one GI symptom". In light of other quite recent reports (see here and here) this finding is not totally unexpected.
• Based on data from children (aged 2-17 years) - nearly 3000 of which were in the 'no GI symptoms' group (n=2957) and 806 in the 'constipation plus diarrhea or underwear staining' - several other details emerged from the data. The latter GI symptoms group were "more likely to have a parental report of repetitive behavior.... or compulsive behavior... and OCD [obsessive compulsive disorder] diagnosis". Ritualistic behaviours were also picked up more frequently in the GI group by clinician report (ADOS) over the no GI symptoms group.
• A few other research nuggets: children in GI symptoms group were "more likely to have a family history of anxiety or OCD" and also more likely to have received "treatment with an atypical antipsychotic".
• The authors conclude that, allowing for potential issues with the use of the ATN database and missing values, "all five primary measures of rigid-compulsive behavior were significantly associated with constipation and diarrhea or underwear staining". 

And then we have the Doshi-Velez paper:

• This was a study looking at "patterns of co-occurence of medical comorbidities in ASDs".
• Electronic medical records or rather electronic health records (EHR) were the source material for the paper and in particular, the ICD-9 codes relevant to particular conditions derived from the i2b2 National Center for Biomedical Computing (N=13,740). This sounds to me like a similar job to that of SHRINE (used in the previous Kohane paper).
• "Key patterns" identified from this rather large participant group were then tested on a smaller, independent cohort comprising 496 participants from Wake Forest University Health Sciences.
• With the application of some technical and statistical wizardry, various subgroups were identified within the cases examined based on the clustering of comorbidity alongside the diagnosis of autism.
• Results: "Four subgroups were identified" based on medical comorbidity and the paper offers quite a bit of detail about the hows and whens certain comorbidity tend to present.
• Group 1. That old comorbidity nemesis seizures (I assume to indicate some kind of epilepsy) was the focus for the first group with a prevalence of 77% within this group. 
• Group 2. Then came in "multisystem disorders" to form group 2 which included GI disorders (distinct from just functional GI issues). That being said "early ear infections" seemed to stand head and shoulders above other comorbidities for this group particularly with preschool presentation. 
• Group 3. Next for comorbidity was group 3 "characterised by psychiatric disorders" (33%). This group "had the highest rate of individuals with Asperger syndrome and the lowest rate of intellectual disability" and included some familiar conditions including anxiety (see here). That being said (again!), "Hyperkinetic syndrome of childhood" also prominently featured in the group 3 comorbidity profile. 
• Group 4. Finally, there was a 'not' resolved group. Not much more to say there really.
• Buried in the text is the quite alarming suggestion that: "All of these subgroups had higher levels of cardiac disorders" which, similar to the example of schizophrenia (see here), implies that health screening should be high on any physician's list when someone presents with autism save any charges of health inequality being levelled.
• The authors conclude that the identification of these comorbidity subgroups centred on the autism spectrum may very well indicate "distinct etiologies with different genetic and environmental contributions". I'm minded to say that we have another possible piece of evidence pertinent to the plural concept of 'the autisms'.

Combined, both these papers offer some really quite important information about the autisms and their very complicated presentation including comorbidity. I would hasten to point out that there is still quite a bit of 'fuzziness' about these results as for example, seen in a quote from the Doshi-Velelz paper: "The 3 subgroups from our original clustering analysis consisted of <10% [less than 10%] of the overall sample". In short, it's complicated. But don't let that take anything away from these results...

Oh and since we're on the topic of 'the autisms' and comorbidity, I note from the recent-ish findings from Giardino and colleagues***** that GI comorbidity has been reported in cases of 22q11.2 deletion syndrome (22q11DS). Autism or autistic behaviours if you like, show more than a passing connection****** to 22q11DS... perhaps research fodder for another blogging day? (Er, yes, watch this space).

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* Peters B. et al. Rigid-Compulsive Behaviors are Associated with Mixed Bowel Symptoms in Autism Spectrum Disorder. J Autism Dev Disord. 2013 Nov 29. [Epub ahead of print]

** Doshi-Velelz F. et al. Comorbidity Clusters in Autism Spectrum Disorders: An Electronic Health Record Time-Series Analysis. Pediatrics. 2013. Dec 9.

*** Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8. doi: 10.1002/aur.237.

**** Kohane IS. et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One. 2012;7(4):e33224.

***** Giardino G. et al. Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. Scand J Gastroenterol. 2013 Dec 18.

****** Vorstman JA. et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J Am Acad Child Adolesc Psychiatry. 2006 Sep;45(9):1104-13.

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Peters B, Williams KC, Gorrindo P, Rosenberg D, Lee EB, Levitt P, & Veenstra-Vanderweele J (2013). Rigid-Compulsive Behaviors are Associated with Mixed Bowel Symptoms in Autism Spectrum Disorder. Journal of autism and developmental disorders PMID: 24293040

Finale Doshi-Velez, Yaorong Ge, & Isaac Kohane (2013). Comorbidity Clusters in Autism Spectrum Disorders: An Electronic Health Record Time-Series Analysis Pediatrics DOI: 10.1542/peds.2013-0819d

How many steps a day should I be walking?

Granted, this entry is a slight departure from the usual material to be found on this blog, but I'm going to post it nevertheless. I'm a big fan of walking. I know that probably sounds a little bit obvious, but I'm actually referring to the use of walking as a tool to keeping in shape rather than just getting from A to B.

Tudor-Locke C. et al (2011) Int J Behav Nutr Phys Act.

Here in the UK (and perhaps beyond) there is quite a lot of chatter about the '10,000 steps a day' challenge (see here) and how walking seems to confer quite a lot of physical (and potentially psychological) benefits.

I know it might seem a little arbitrary to say that we should all be working towards 10,000 steps (as many of our health standards seem to be) but there is some evidence emerging that the magic number of 10,000 might be an important standard*.

Anyhow, I stumbled across the paper by Catrine Tudor-Locke and colleagues** (open-access here) who seems to be quite an important name in the area of 10,000 steps. The paper as you'll see talks about how various ages and genders seem to vary in their daily step count and onwards produce some kind of population normative standards.

It's an interesting review but what particularly took my attention in these days of infographics was the picture attached (which can be found here that I've reproduced with all rights reserved to the authors and publishing journal).

There's not too much more for me to say about it aside from 10,000 steps is a nice universal number to aim for but bear in mind this figure might not reflect the daily goal for everyone. It's also interesting that as we age so our step count goes down, which to me at least, suggests that we should all be living life a little more like when we were children (from a walking perspective).

So, with my blogging caveats of not giving medical or clinical advice in full working order, don't be afraid to put on a comfy pair of walking shoes or trainers and go and enjoy the fresh air with a pedometer if you choose or with the knowledge that 10 minutes of fairly brisk walking is equivalent to about 1000 steps...

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* Tudor-Locke C. & Bassett DR Jr. How many steps/day are enough? Preliminary pedometer indices for public health. Sports Med. 2004;34(1):1-8.

** Tudor-Locke C. et al. How many steps/day are enough? for children and adolescents. Int J Behav Nutr Phys Act. 2011 Jul 28;8:78.

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Tudor-Locke C, Craig CL, Beets MW, Belton S, Cardon GM, Duncan S, Hatano Y, Lubans DR, Olds TS, Raustorp A, Rowe DA, Spence JC, Tanaka S, & Blair SN (2011). How many steps/day are enough? for children and adolescents. The international journal of behavioral nutrition and physical activity, 8 PMID: 21798014

HERVs and ADHD

HERVs. Human endogenous retroviruses. The remnants of our evolutionary struggle with the viruses of the times of our distant ancestors, now part and parcel of our modern-day genome. Yes, genetically, we are all part virus to various extents [so embrace your viral self].

HMS Beagle @ Wikipedia

I've talked HERVs on a few occasions on this blog, in relation both to the autism spectrum conditions (see here) and myalgic encephalomyelitis (ME) (see here).

Without getting too technical, the crux of those posts was to suggest that although those bits of virus in our genomes are not necessarily 'active viruses' (i.e. not able to produce infectious virus or replicate) they may have implications for things like autoimmunity given that HERV proteins are supposedly recognised as 'self' by the almighty MHC [1] and seem to be able to provoke autoimmunity (in mice) [2]. That and the fact that the expression of HERVs may be kept in check by epigenetic means (methylation) [3] and 'hypomethylation [of DNA] = more genomic instability' [4] so, theoretically under certain circumstances could mean HERVs get a chance to start expressing (something). Or that's the theory (I think)...

With all that in mind, I move to the paper by Balestrieri and colleagues [5] (yes, the same group who completed the HERV paper with autism in mind) who discussed some very preliminary data on the expression of certain families of HERVs. Indeed, they reported: "The expression levels of HERV-H are significantly higher in patients with ADHD [attention-deficit hyperactivity disorder] compared to healthy controls".

I can't pretend to know all the ins-and-outs of how one goes about assaying for the expression of HERVs - "expression of retroviral mRNAs from the three HERV families was evaluated in peripheral blood mononuclear cells (PBMCs)" apparently. It was however interesting to see that HERV-H 'over-expression' was "significantly higher in patients with ADHD compared to healthy controls". HERV-H was also the same family reported to be 'more abundantly expressed' in cases of autism.

A search of some of the literature covering HERV-H reveals that it is a gamma-retrovirus (yes, similar to those letters X-M-R-V and that de-discovery issue). In terms of associations and roles, it "contributes to pluripotency in human cells" according to the paper by Santoni and colleagues [6] and their finding of high levels of HERV-H RNA in human embryonic stem cells. The HERV-H family have also been suggested to have immunosuppressive properties [7].

HERV-H has been linked to conditions such as multiple sclerosis as per papers like this one by Christensen [8] which also hinted at how other viruses may 'interact' with HERVs; in that paper concluding that: "retroviruses and herpes viruses have complex interactions". That being said, not all results have arrived at the same conclusion.

I was also particularly interested to read the paper by Shuvarikov and colleagues [9] who seemed to suggest "HERV-H elements as a mechanism of deletion formation", as in genetic deletions. I might be making mountains out of molehills but their case report that HERV-H elements seemed to flank "recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31" could potentially lead down some very important paths as intimated in a previous post. The fact that they mention autism as being part and parcel of some of their participant group description is likewise intriguing.  As I've indicated in other posts on this blog where the term 'de novo' has been used, the uncertainty or chance finding of de novo now, might not be so in X numbers of years time. And the future may already be here [10] with schizophrenia in mind.

I'm going to stop there with this quite heavy going post and the chatter about HERVs and ADHD (or autism or anything else). Science is to quite a large extent still feeling it's way around the HERVs and their role - if any - in health and wellbeing. The reported link between the expression of HERVs and a condition as complicated as ADHD needs a lot more work on it before anyone can arrive at any firm conclusions. That being said, I find this to be a fascinating area of science which really does add a new layer of complexity to the whole genetics-environment relationship.

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[1] Lavie L. et al. CpG Methylation Directly Regulates Transcriptional Activity of the Human Endogenous Retrovirus Family HERV-K(HML-2). J. Virol. 2005; 79: 876-883

[2] Perron H. et al. Human Endogenous Retrovirus Protein Activates Innate Immunity and Promotes Experimental Allergic Encephalomyelitis in Mice. PLoS ONE 8(12): e80128. doi:10.1371/journal.pone.0080128

[3] Wilson AS. et al. DNA hypomethylation and human diseases. Biochimica et Biophysica Acta. 2007; 1775: 138–162.

[4] Tugnet N. et al. Human Endogenous Retroviruses (HERVs) and Autoimmune Rheumatic Disease: Is There a Link? Open Rheumatol J. 2013; 7: 13–21.

[5] Balestrieri E. et al. Human endogenous retroviruses and ADHD. World J Biol Psychiatry. 2013 Nov 28. [Epub ahead of print]

[6] Santoni FA. et al. HERV-H RNA is abundant in human embryonic stem cells and a precise marker for pluripotency. Retrovirology. 2012; 9: 111.

[7] Mangeney M. et al. The full-length envelope of an HERV-H human endogenous retrovirus has immunosuppressive properties. J General Virology. 2001; 82: 2515-2518.

[8] Christensen T. Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses. Rev Med Virol. 2005 May-Jun;15(3):179-211.

[9] 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.

[10] Bundo M. et al. Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia. Neuron. 2014. 2 Jan.

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Balestrieri E, Pitzianti M, Matteucci C, D'Agati E, Sorrentino R, Baratta A, Caterina R, Zenobi R, Curatolo P, Garaci E, Sinibaldi-Vallebona P, & Pasini A (2013). Human endogenous retroviruses and ADHD. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry PMID: 24286278

Treatable inborn errors of metabolism in cases of autism

Happy New Year! Καλή Χρονιά (in Greek).

Welcome back to Questioning Answers in 2014. Let's continue our journey across the autism research landscape.

Party time, excellent @ Wikipedia 

Holidays. Whilst never regretting the opportunity to go on holiday/vacation, I am the type of person who has a strong desire to stay connected to the (research) world. I wouldn't necessarily say that I'm a product of the age of social media, more of late convert who ran enthusiastically towards the light.

A few months back however, I missed something important. It was the chance to peer review the paper by Martha Spilioti and colleagues* (open-access here) and some very interesting information following the screening of 187 children presenting with an autism spectrum disorder (ASD) for the signs and symptoms of various inborn errors of metabolism.

Actually it wasn't all my fault that I didn't accept this review. Granted I didn't access my email on holiday as often as I do when working, but more than that, the publishing journal seemed to expect quite a prompt reply on whether or not I was willing to review. I didn't reply in time, so I missed out. That's what happens in August, the holiday month, the time the kids are off school, y'know, the summer (at least here in my part of the World). No mind, I am happy to see that the Spilioti paper has seen the light of scientific day and hence become fodder for this blog.

Anyhow, inborn errors of metabolism. I've talked about them before in relation to autism (see here and here) and how at least some of them might actually be pretty revealing when it comes to at least some autism (as per those interesting findings in relation to the branched-chain amino acids). More recently I've been reading the paper by Stockler-Ipsiroglu and colleagues** talking about outcomes with regards to a diagnosis of guanidinoacetate methyltransferase (GAMT) deficiency which included some chatter on autistic behaviours (or should that just be autism?) as being involved.

The Spilioti paper evaluated 187 Greek children diagnosed with an autism spectrum condition on the basis of quite a few parameters. We're told that alongside taking quite a bit of information about family history and dietary habits, quite a few laboratory investigations were initiated, too numerous to all mention here. I have to say I was particularly impressed by the authors talking about a glucose loading test (with mitochondrial issues in mind) alongside serum and urine amino and organic acid screens; even looking at carnitine levels. The Greeks seem to be taking a lead in this 'look-see' approach when it comes to the autisms.

Their results: well, only a small proportion of their cohort turned up an inborn error of metabolism. Two participants with Lesch-Nyhan syndrome linked to the overproduction of uric acid (see here for a post of impulsivity and uric acid). Two further participants were identified with succinic semialdehyde dehydrogenase (SSADH) deficiency (which is a very, very rare condition indeed). One child was also diagnosed with PKU (see here).

Perhaps of more interest were the findings related to that glucose loading test and the suggestion that there was an increase in serum beta hydroxybutyrate (β-OH-b) in around 8% of participants. Although not an expert on this particular metabolite, I understand that elevations can indicate one or several possible scenarios (see here). The authors elaborate that some of those with elevations in β-OH-b also "manifested exacerbation of symptoms during high carbohydrate intake" which brings in an interesting dietary element. Indeed, further when a ketogenic diet (high fat, low carbohydrate intake) was initiated in [some of] those with increased β-OH-b, some interesting behavioural changes were reported; one participant was reported to show "remarkable improvement" in his CARS scores, which was followed by a cessation of medication and attendance at a "public elementary school without clinical problems". Yes, I know this was a case series (an optimal outcomer?) and not a controlled trial of the ketogenic diet where increased serum β-OH-b levels have been identified. Perhaps this is the next experimental step?

Other interesting findings. Well, yes. Around 7% of participants also showed elevated levels of urinary 3-hydroxyisovaleric acid (3-OH-IVA). Assuming that these child participants were not smokers (see here***) we are also told that none of these 7% were also "undergoing valproate intervention" which is another potential way of elevating 3-OH-IVA (see here****). And when it came to intervening with biotin as a function of the connection between 3-OH-IVA and biotin*****, authors again reported some interesting outcomes leading to "clear therapeutic benefit" noted in CARS scores for some. Please note I'm not suggesting anything based on these findings as per my caveat about no medical or clinical advice given or intended.

There is a lot more, data-wise, in the Spilioti paper which I've not been able to include in this post. As per the growing literature on autism perhaps being better defined as the 'autisms' I would echo the sentiments of Spilioti and colleagues when they say: "further consideration be given to the selected analysis of IEM [inborn errors of metabolism] in ASD". That dietary and nutritional supplementation might also be a road to improvement in the presentation of symptoms for some on the spectrum with identified metabolic parameters is also a very important consideration too.

Some music to close, and for those of who watched the New Year festivities from the comfort of your own home like I did to the tune of offspring chatter of 'can I stay up late please?', Alfie and Gary sing a classic...

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* Spilioti M. et al. Evidence for Treatable Inborn Errors of Metabolism in a Cohort of 187 Greek Patients with Autism Spectrum Disorder (ASD). Front. Hum. Neurosci. 2013; 7:858. doi: 10.3389/fnhum.2013.00858

** Stockler-Ipsiroglu S. et al. Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 2013 Nov 7. pii: S1096-7192(13)00366-1. doi: 10.1016/j.ymgme.2013.10.018.

*** Sealey WM. et al. Smoking accelerates biotin catabolism in women. Am J Clin Nutr. 2004 Oct;80(4):932-5.

**** Mock DM. et al. Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroenterol Nutr. 1998 Mar;26(3):245-50.

***** Mock NI. et al. Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased biotin status in experimental biotin deficiency. Am J Clin Nutr. 1997; 65: 951-958.

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Martha Spilioti, Athanasios Evangeliou, Despoina Tramma, Zoe Theodoridou, Spyridon Metaxas, Eleni Michailidi, Eleni Bonti, Helen Frysira, Katerina Haidopoulou, Despoina Asprangathou, Aggelos Tsalkidis, Panagiotis Kardaras, Ron Wevers, Cornelis Jakobs, & Michael Gibson (2013). Evidence for Treatable Inborn Errors of Metabolism in a Cohort of 187 Greek Patients with Autism Spectrum Disorder (ASD) Front. Hum. Neurosci.