Inborn errors of creatine metabolism and autism

I might have said it before but inborn errors of metabolism represent a particularly interesting group of conditions relevant to this blog. I have tended to focus on one particular metabolic condition, phenylketonuria (PKU), simply because it represents the archetypal 'diet-can-affect-behaviour-and-cognition' condition. That and the fact that PKU has been known to overlap with certain cases of autism.

In this post I turn my attention to another group of metabolic disorders related to creatine and its biosynthesis and metabolism. The papers that brought me to this post are this one from Chilosi and colleagues* (full-text) and this one from Kurosawa and colleagues** (full-text).

In brief, Chilosi et al describe how supplementation with the amino acid L-arginine (one of the precursor compounds used in the formation of creatine) might be able to positively affect some of the symptoms associated with creatine transporter deficiency. Kurosawa et al reported results following supplementation with cyclocreatine (CincY) in a mouse model of creatine transporter deficiency. I might add that I am not endorsing these or any other course of action without the proper medical advice, merely describing what was published.

Reversing a little, creatine (not to be confused with a relation, creatinine, something else that has cropped up on this blog - here and here) is probably best described as an energy supplier. A fusion of the amino acids L-arginine and glycine form guanidinoacetate which then goes on to creatine. Creatine continues onwards on to prop up production of ATP. It's obviously a little more complicated than just that but I'm not here to deliver a biochemistry lesson.

Inborn errors of creatine metabolism normally fall into one of a few categories best described here. You'll note that one of the conditions is something called X-linked SLC6A8 creatine-transporter deficiency.  Just keep that in mind for now; that and the words 'autistic-like' with reference to the behavioural presentation.

So what about with autism in mind:

• Well, let just say that inborn errors of creatine metabolism are probably not going to be very common in autism as per this review by Schiff and colleagues*** (full-text) and this paper by a familiar name, Wang and colleagues**** (of SCFAs fame). That being said, I don't know if screening for creatine metabolism issues in cases of autism is widespread or not.
• Bearing in mind the important energy function of creatine, in turns out that getting creatine into cells via the SLC6A8 gene is quite prevalent in certain areas of the body particularly the brain. Indeed there is some suggestion that moving from monkeys to humans might have had a lot to do with this and another gene and their transporting ability as per this study by Pfefferle and colleagues***** (full-text). With all this creatine floating around the grey stuff (well, the pink-red stuff), it is perhaps not surprising that a few imaging studies have looked at brain creatine distribution in cases of autism. Very much like the use of creatinine as a ratio marker for quantifying urinary metabolites, so creatine levels serve a similar function when it comes to the use of 1H magnetic resonance (MR) spectroscopy to quantify various brain metabolites. Much also like the suggestion of issues with the use of the ratio marker creatinine (see here) in autism so brain creatine levels also seem to be suggestive of certain 'findings' in various brain areas (see here, here and here).
• Remember SLC6A8 and the 'X-linked' issue? Well, there has been some interesting research done there too with autism in mind (here, here and here). X-linked refers to the chromosomal make-up of boys and girls, such that girls have two X chromosomes (XX) and boys have two distinct chromosomes (XY). I should also make mention other conditions such as Klinefelter's syndrome where an extra X chromosome is present. The male bias noted in autism has led some people to speculate on some role for the X chromosome in relation to the condition, as detailed in this paper by Marco & Skuse****** (full-text). 

There are some interesting points to take from this collected research on creatine in relation to autism. Probably first and foremost is the further evidence for autism being a very complicated condition with seemingly lots of paths to the presentation of behaviours gathered under the autism label. I know many people won't find any new revelations in this statement but issues with creatine metabolism is a good example.

Second is a reiteration of the importance of the inborn errors of metabolism to concepts like autism. OK so these conditions are likely not going to be universal to all people with autism (as far as we know); but for a minority they might be, and as per the PKU connection and recent Chilosi / Kurosawa findings, there may very well be interventions which might impact upon behavioural presentation.

Finally, screening. I could be here all day reciting what screening 'could' be undertaken when a diagnosis of autism is received. I won't aside from mentioning things related to SPAD, PFIES, coeliac disease, inflammatory markers, antioxidant markers, iron levels, zinc levels, etc, etc. Assuming learning disability is also present alongside the presentation of autism, screening for errors in creatine metabolism might also be a possible addition to that list.

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* Chilosi A. et al. Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency. Orphanet Journal of Rare Diseases. June 2012.
DOI: 10.1186/1750-1172-7-43

** Kurosawa Y. et al. Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency. The Journal of Clinical Investigation. July 2012.
DOI: 10.1172/JCI59373

*** Schiff M. et al. Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders? PLoS ONE. 2011; 6: e21932.

**** Wang L. et al. Is there a role for routinely screening children with autism spectrum disorder for creatine deficiency syndrome? Autism Research. 2010; 3: 268-272.

***** Pfefferle AD. et al. Comparative expression analysis of the phosphocreatine circuit in extant primates: Implications for human brain evolution. Journal of Human Evolution. 2011; 60: 205-212.

****** Marco EJ. & Skuse DH. Autism-lessons from the X chromosome. Social Cognitive & Affective Neuroscience. 2006; 1: 183-193.

IL-17A elevated in cases of autism

"The converging evidence strongly argues that neurodevelopmental immune insults and genetic background critically interact and result in increased risk for either autism or schizophrenia". So say Max Michel and colleagues* in their recent paper reviewing the often intricate findings in this area of investigation. Personally, I have to say that I agree with their sentiments, after having read through quite a lot of the literature on this topic over the years. I hasten to add that both the genetic and environmental effects acting on the immune system, or any other system in cases of autism, is likely to be variable and not uniform across the condition. As far as we know...

Yet more evidence for a potential role for the immune system and certain cytokines in cases of autism has emerged from two very familiar names, Laila Yousef Al-Ayadhi & Gehan Ahmed Mostafa in this paper** (full-text) looking at levels of the proinflammatory cytokine IL-17A. I say that these are familiar names because this research tag-team have been pretty prolific in recent years as per their publication entries on autism (here) and various immune-related findings. I would perhaps also plug a few previous blog posts about their work (here, here and here).

Let's start with a description. I'm sure quite a few people who follow the immune system research in relation to autism will have heard about Th1 and Th2 (type 1 and 2 helper T-cells). As per their name, helper T-cells help; more specifically they are involved in the orchestra that this is the immune response and in particular, cytokines and their expression, different types of cytokines, depending on the type of helper T-cell. Balance seems to be quite an important concept when it comes to Th1 and Th2 as per this article by Berger*** (full-text).

For quite a long time, the concepts of Th1 and Th2 predominated. That is until another kind of helper T-cell came onto the scene: Th17 - T helper 17 cells. Th17 produces the IL-17 family of cytokines which play a role in host defence and inflammation. Th17 has also been tied to quite a few 'autoimmune' conditions such as psoriasis (here) and inflammatory bowel disease (here) among others. There is of course quite a lot of biochemistry behind Th17 cells and the counterbalance, Treg(s) (including an old friend, IL-6) but I have neither the will nor expertise to go too far into all that now.

After that very brief overview, let's go through what Al-Ayadhi & Mostafa did and found:

• A sample of 45 children diagnosed with DSM-IV autism (mean age: 8.4 years) were included for study and compared with 40 age- and sex-matched 'apparently healthy' asymptomatic children. No comorbid autoimmune conditions were recorded in participants as far as the authors could tell.
• Participants with autism were also 'graded' on the severity of their autism presentation by way of the CARS; most fell into the severe category (n=28); the others (n=17) were described as having mild to moderate autism.
• Blood samples were drawn from all participants and serum levels of IL-17A determined by ELISA. Importantly, from an analytical perspective, all samples were run twice in independent experiments to confirm the results and rule out cross-reactivity (see here for a description).
• Results: as a group, the children with autism presented with significant elevations in IL-17A compared to controls. Individually, almost half of the children with autism presented with elevated IL-17A levels based on results on or above the 95th percentile of serum IL-17A noted in the control group.
• Severity of autistic symptoms seemed also to show some relationship with serum IL-17A levels in that the more severe presentation was associated with greater serum levels than those with a more moderate presentation. Age and gender did not seem to show effects.

There are a few things that can be taken from this study. IL-17 and inflammation. IL-17 and autism. Inflammation and autism. Need I say anything else? The association between Th17 and autoimmune disorders is something to bear in mind. I've talked before about autism and both features of autoimmunity seemingly present in some cases (here) or overlap with autoimmune comorbidity (here). The current results seem to suggest that there maybe something which might, at a biochemical level, relate autism and autoimmunity in at least some cases of autism; indeed quite a few cases judging by this latest paper. The question is: are IL-17A levels a core feature of autism or merely describing some hidden autoimmune comorbidity?

This is not the first time that a relationship between Th17 and autism has been suggested. Suzuki and colleagues**** (full-text) reported elevations in IL-17 and various other cytokines in their study of young adolescent boys with autism compared with control. Indeed the current authors also cited a potential role for IL-17 in other findings, specifically related to elevations in osteopontin levels previously discussed with parallel features according to things like symptom severity affecting results.

I suppose the final question should be: what can be done about elevated levels of IL-17? Reiterating my position about not giving medical advice or anything that could be construed as medical advice, the research literature contains a few options for further investigation. The therapeutic application of monoclonal antibodies against human IL-17A has already been mentioned in other areas of investigation. Leonardi and colleagues***** reported some initial success on the use of ixekizumab for a specific type of psoriasis, plaque psoriasis and improvement in clinical symptoms. Similar preliminary findings were also reported by Hueber and colleagues****** based the use of on another IL-17A human monoclonal antibody, AIN457 (secukinumab). Other compounds also seem to have the potential to affect IL-17 levels or production too. Lanzilli and colleagues******* for example, discussed the potential of resveratrol to affect IL-17 levels (at least in vitro).  Again, I reiterate the need for a lot more efficacy and safety research before these and other potential compounds go anywhere near people with autism.

There seems to be a rising tide of research coming through suggestive of links between at least some cases of autism and issues with the immune system and more precisely autoimmunity. Bearing in mind the 'correlation does not equal causation' motif, I think back to the post on Dr Kevin Becker's paper and the other work that has been done in this area and wonder whether we really should be making moves to more generalised screening for autoimmune markers and comorbidity where an autism diagnosis is given, if only to establish how deep the rabbit hole really goes?

To finish, and to coincide with the news about "detecting a particle consistent with the Higgs boson", the Galaxy song by Monty Python. Makes me feel quite insignificant really.

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* Michel M. et al. Immune system gene dysregulation in autism & schizophrenia. Developmental Neurobiology. June 2012.

** Al-Ayadhi LY. & Mostafa GA. Elevated serum levels of interleukin-17A in children with autism. Journal of Neuroinflammation. 2012; 9: 158.
DOI: 10.1186/1742-2094-9-158

*** Berger A. Th1 and Th2 responses: what are they? BMJ. 2000; 321: 424.1.

**** Suzuki K. et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS ONE. 2011; 6: e20470.

***** Leonardi C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. NEJM. 2012; 366: 1190-1199.

****** Heuber W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Science Translational Medicine. 2010; 2: 52ra72.

******* Lanzilli G. et al. Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation. 2012; 35: 240-248.

The DOGMA of dysbiosis

I think it's been time enough for the initial excitement of first results from the Human Microbiome Project (HMP) to have subsided and questions like 'where next?' to be asked. Although the research possibilities are almost endless and have the potential to re-write some biochemistry textbooks, I admit that I raised a smile when seeing a post about the potential for further study of bacteria in autism research on the Simons Foundation website. This kinda spurred me on to write this post on bacteria and more specifically dysbiosis with autism in mind following on from some previous interest in this topic; that and the publication of an opinion piece* by Dr Petra Louis from the University of Aberdeen.

Dysbiosis, or DOGMA if you wish(!), describes a state of 'imbalance' with regards to the multitude of microbes which call us humans (and animals) home. I suppose one could call it a sort of bacterial homeostatic dysregulation (if that makes any sense) illustrating how we should be at one with our bacteria which seem to be able to do all manner of things aside from just aiding digestion (see here about GABA and another link to inflammation). Excuse me for a moment while I bring my bacteria into planetary alignment...

Most mention of dysbiosis in the research literature tends to focus on bacterial dysbiosis of the gut, which is where I also want to focus attention with this post. Indeed dysbiosis is finding quite a comfortable spot when it comes to the gut, gastrointestinal (GI) tract if you will, as per the links being made with conditions such as inflammatory bowel disease (here) and coeliac disease (here). Don't however be fooled into thinking that bowel-related conditions have the monopoly as per other research in alcoholic liver disease (here) and conditions related to obesity (here). The important caveat however being that establishing cause and effect from dysbiosis is not yet cut-and-dried.

Aside from the quite speculative post discussing the possible associations made between PCOS, DOGMA and autism, dysbiosis has had another mention on this blog previously as part of the excellent Brent Williams paper on carbohydrate digestion** in cases of autism and gastrointestinal symptoms. I was, and remain, excited about the Williams paper despite the small sample group and preliminary nature of the findings reported not only because of the authorship group (Buie, Bauman, Lipkin) but also because results spanned genetics, biochemistry and importantly, endophenotypes. I await further confirmatory studies with some expectation.

There is other research on dysbiosis and autism in the research literature, some of which mentions dysbiosis, others not overtly so:

• Dr Parris Kidd seemed to be ahead of the game with his two papers (here and here) which speculatively talked about dysbiosis and autism among other things. That and another paper published by Richard Blaylock (here), seemed to introduce the possibility that dysbiosis may be a feature of some cases of autism alongside a few other bits of speculation. Looking at these paper, I could imagine that some people would be put off by for example, the types of publishing journals used for these works, which almost seem to stress that dysbiosis is 'alternative' or 'complementary' and hence just for the 'tree-huggers'. It's not by the way - unless that is, you think Nature for example, is of a similar ilk (see here).
• Dysbiosis has been mentioned by a favourite researcher of mine, Harumi Jyonouchi (of SPAD fame) as part of this paper*** which was discussed in this post. The long and short of it was the potential for innate immune system issues in cases of autism to perhaps place someone at greater risk of things like dysbiosis. I was interested how this work might tie into quite a new piece of research looking at innate lymphoid cells (in mice) and how the immune system might act as a barricade to keeping gut bacteria from connecting with neighbouring tissues (see here). More work perhaps required on IL-22?
• Clinical findings suggestive of the presence of dysbiosis via analysis of organic acids have also been reported.  Another name mentioned in a previous post crops up, Dr Joanna Kałużna-Czaplińska, and her studies on urinary organic acids (here**** and here*****). Indeed, although not specifically mentioning dysbiosis in the title, the results published by Bill Shaw****** on the detection of 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA) in the urine of a group of people with autism might also be relevant. I could also at this point mention the Yap/Nicholson paper and that recent speculative paper from Dr Clayton on bacteria and amino acids as part of the mix.

Obviously there are quite a few gaps in the research base with regards to autism and dysbiosis. The primary problem being that these and all the other studies which have been done on gut bacteria and autism are still very preliminary, based on relatively small participant numbers and really just 'fishing expeditions' in the absence of a reliable picture of what should or shouldn't be happening to gut bacteria in a more general sense.  As per the Williams paper, there is also the added interference from comorbidity to think about, noting the extent to which the HMP had to go to rule out some important variables like gum disease for example from complicating their results.

The next question is what can be done about dysbiosis if present? This is where I need to be careful and stick to my mantra about not giving medical advice or anything approximating medical advice. I have thought about this quite a bit and wondered if it is so easy as to just look at supplementing with probiotics or that other 'undesirable' therapy particularly where dysbiosis might be chronic rather than acute following use of antimicrobials for example. As a sidenote to that 'undesirable' therapy, I was interested to read a proper Doctor's take on this with autism in mind (here).

Going back to the Williams paper on carbs and autism, they (and their other paper) seemed to suggest that issues with the enzymes used to process carbs might be an initial starting point for dysbiosis. If this is true, the logical answer would be to either supplement with the relevant carb metabolising enzymes (or their cofactors if needed) or look at removing the foods which a person may have issues with metabolising. Whether or not this could tie into Dr Fallon's CM-AT preparation or even the usefulness of diets like the gluten- and casein-free intervention / GAPS diet is still source for investigation. I might add again that no advice or endorsement is intended.


I have a 'gut feeling' that gut bacteria and dysbiosis is going to crop up a lot more in autism research circles following the HMP publications and dare say this is not the last that you will hear from me on the topic. 


To finish, songs don't normally translate into images for me; aside that is from a dark, rainy Friday night at the guitar club described in the Sultans of Swing. "He can play the honky tonk like anything" apparently and as for the rain, it's a British summertime, what do we expect? 

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* Louis P. Does the human gut microbiota contribute to the etiology of autism spectrum disorders? Digestive Diseases & Sciences. June 2012.

** Williams B. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE. September 2011.
DOI: 10.1371/journal.pone.0024585

*** Jyonouchi H. et al. Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes. Journal of Neuroimmunology. 2011; 238: 73-80.

**** Kałużna-Czaplińska J. Noninvasive urinary organic acids test to assess biochemical and nutritional individuality in autistic children. Clinical Biochemistry. 2011; 44: 686-691.

***** Kałużna-Czaplińska J. et al. B vitamin supplementation reduces excretion of urinary dicarboxylic acids in autistic children. Nutrition Research. 2011; 31: 497-502.

****** Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutritional Neuroscience. 2010; 13: 135-143.

The BTBR mouse and autism

Danger Mouse (from Wikipedia)

It is slightly overwhelming to see the wide range of investigative and research techniques on offer to the modern day scientist when it comes to researching conditions like autism. Indeed, the variety of disciplines and the tools of their trade involved in looking at autism from almost every conceivable research angle, makes it all the more difficult to understand why, at the time of writing, we continue to know so little about autism - aetiology, underlying pathology, etc. - despite such intensive efforts. I'm not here to answer that question by the way; aside that is from mentioning about heterogeneity, comorbidity, genetics-epigentics-environment and the well-trodden path that is 'if you've met one person with autism, you've met one person with autism'.

As per many other conditions / diseases / states, autism research has more than dabbled in the science of trying to establish suitable animal models for the condition as per this review by Paul Patterson* who runs quite a good blog (here). Without wishing to enter into any moral or ethical arguments with anyone about it, quite a few mice, rats, zebrafish and other creatures have met their Maker over the years in the name of autism research. Suffice to say that many more animals are probably going to join them in future; at least more than those who would have been involved in cosmetic research now the European Cosmetics Directive comes into final force (March 2013).

Animal models survive however because of the perceived comparison they can provide where investigations on human beings would not dare to tread. So, inserting genes, deleting genes, controlled exposure to various chemical and drug residues, and lots of other investigations all figure in autism animal research; studies which would not even be entertained to be involving real human beings. The big question though is: how much do such animal models truly tell us about a complex and heterogeneous condition like autism?

Bearing that question in mind, there is one particular animal model of autism which seems to be part of quite a few studies: the BTBR mouse or to give it the full title: the BTBR T+tf/J inbred mouse strain. I should add that I was brought to doing this entry partly following this post on the SFARI website.

Aside from being described as an 'exceptional breeder'(!), the BTBR mouse is of potential interest to autism research because it 'seems' to share quite a few overt behaviours more usually associated with autism spectrum conditions such those involved in social interaction, repetitive behaviours and impairments in play behaviour (see this paper). Even communication by the BTBR mouse has been suggested to some degree, to mirror that seen in autism (here). Throw in indications of 'high anxiety' and it all makes for an attractive animal model of autism.

So what has been noted about this mouse:

• Silverman and colleagues** reported that administration of 2-Methyl-6-(phenylethynyl)pyridine (MPEP), an antagonist for the metabotropic glutamate receptor subtype mGluR5, seemed to reduce the instance of repetitive (self-grooming) behaviour in BTBR mice. Regular readers to this blog might remember my post on glutamate (and glutamine) and autism and some news not so long about about GRN-529 and autism which caused a bit of a stir.
• Frye & Llaneza*** reported on elevations in circulating and brain levels of the neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP) - a metabolite of progesterone - in the BTBR mouse. The endocrine system has shown more than a passing relationship to cases of autism; be it through the hypothalamus (dopamine, oxytocin, vasopressin) or the link posited between autism and sex hormones (see recent post on PCOS and autism). Dare I even make mention of endocrine disruptors?
• Mercier and colleagues**** indicated the potential presence of connective tissue issues (?) when looking at the anatomy of the meninges in the BTBR mouse. Putting aside my obsession with leaky barriers and autism (and other conditions) and appreciating the difference between the meninges and the blood-brain barrier, I can't help but wonder...
• Heo and colleagues***** reported on elevated levels of anti-brain antibodies amongst other things in relation to immune function of the BTBR mouse. To quote from the authors: "The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors". Inflammation... say no more.
• Finally, I've already talked about the paper by Corley and colleagues****** and their findings of low plasma sulphate (sulfate) in the BTBR mouse (see here) so won't say too much more now.

With the weight of this evidence you can perhaps see why the BTBR mouse might find some favour as a model of autism. There seems to be something for every research palate in among the various studies of the BTBR mouse. I'm certainly not going to poo-poo any comparisons but do have a few minor points to make aside from those already mentioned.

I am genuinely interested in what you might use as a comparator in mouse terms to the BTBR model. Most human studies around autism, certainly interventional or parameter-based, tend to use an asymptomatic control group (hopefully age- and sex-matched) or if you are very lucky, a further group of people with conditions like learning disability or a speech and language disorder (without autism) or the equivalent as comparators. I might be missing important details here but what do you compare an 'autistic mouse' with when ascertaining a specific biological or genetic parameter? Is there such a thing as an 'asymptomatic' mouse or a mouse with learning disability for example or is autism a spectrum of presentation in mice too? (no cheap jokes about systemising mice please).

A further point relates to the something that has cropped up on previous posts in terms of lab mice vs. wild mice and in particular the effects of environment on each as per this article by Boysen and colleagues*******. To quote: "These findings indicate a high degree of pre-activation of NK cells of free-living mice, indicating a strong environmental impact on NK cells, which may be highly relevant for interpretation of studies in the mouse model". In other words, lab mice in their nice sterile, clean-living, environment might not be hardened by the cruel outside world and therefore one questions their representativeness to the real world.

Indeed whilst animal models of 'disease' are the backbone of many a genetic or biological study, there are still some questions about whether they are truly delivering what they promised in terms of translating from lab bench to real-life as per the paper by van der Worp and colleagues******** (full-text) from a few years back. If this is the case, where does this leave the BTBR mouse?


[The picture included in this post will be recognisable to quite a few 'older kids' raised on 1980s UK television. For those who have not had the pleasure of watching Danger Mouse and his sidekick Penfold, here's some more information and that theme tune].

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* Patterson PH. Modelling autistic features in animals. Pediatric Research. 2011; 69: 34R-40R

** Silverman JL. et al. Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology. 2010; 35: 976-989.

*** Frye CA. & Llaneza DC. Corticosteroid and neurosteroid dysregulation in an animal model of autism, BTBR mice. Physiology & Behaviour. 2010; 100: 264-267.

**** Mercier F. et al. Meningeal/vascular alterations and loss of extracellular matrix in the neurogenic zone of adult BTBR T+ tf/J mice, animal model for autism. Neuroscience Letters. 2011; 498: 173-178.

***** Heo Y. et al. Aberrant immune responses in a mouse with behavioral disorders. PLoS One. 2011; 6: e20912

****** Corley MJ. et al.Reduced sulfate plasma concentrations in the BTBR T+tf/J mouse model of autism. Physiology & Behaviour. April 2012.

******* Boysen P. et al. Natural killer cells in free-living Mus musculus have a primed phenotype. Molecular Ecology. 2011; 20: 5103-5110.

******** van der Worp HB. et al. Can animal models of disease reliably inform human studies? PLoS Medicine. 2010;  7: e1000245.

Will that do NICEly for adults with autism?

A very quick post to bring to readers attention the publication today of the second strand of guidance on autism issued by the UK National Institute for Health & Clinical Excellence (NICE) looking at adults on the autism spectrum (full-text of document available here).

Many people, people with autism, their parents and professionals, will no doubt have already heard about NICE and the guidance being developed to cover the autism spectrum conditions in terms of diagnosis, care and management (see previous post); setting standards to cover what was quite a variable approach to autism throughout the lifespan.

The first strand of guidance examining the issues and best practices on the pathways to diagnosis of autism in children and young adults (see here) has already been published.

The final strand looking at the management of autism in children and young people (here) remains under development with an expected publication date of November 2013.

Metabolomics and Chronic Fatigue Syndrome

There were lots of things I could have blogged about in this post. The recent EEG autism biomarkers study by Duffy and Als* (full-text) which seems to be generating lots and lots of interest, despite the fact that we've kinda been here before (see this post on the Dark Arts); the interesting case study reported by Sildorf and colleagues** on remission without insulin therapy following use of a gluten-free diet in a pediatric case of type-1 diabetes; or even the high prevalence of vitamin D deficiency in psychiatric in-patients reported by Menkes and colleagues*** (full-text). All noteworthy findings and very much within the remit of this blog and its previous posts.

But instead, I'm turning my attention to another paper by Armstrong and colleagues**** and their application of a field close to my research heart, turning the scientific eye of metabolomics to Chronic Fatigue Syndrome (CFS).

Aside from a metabolomics link and the use of some quite powerful analytical technology, NMR, which has been previously applied to both autism (here) and schizophrenia research (here), this study also caught my eye because of what they reported finding.

A very brief summary:

• Blood samples from a small patient group (n=11) diagnosed with CFS were analysed and compared with a small asymptomatic control group (n=10) via NMR. These participant groups are quite small but bear in mind the task ahead of the researchers given the number of potential compounds present in a blood sample (see this paper by Psychogios and colleagues***** on how many they found in human serum). I hasten to add that even in our lab we have found considerably more compounds to be present in other mediums like urine.
• Significant reductions in the amino acids glutamine and ornithine were detected in the CFS group compared with controls. These findings also correlated with other metabolites linked to glucogenic amino acids and metabolites of the urea cycle.
• I believe this to be only one of a handful of papers (that I can find) that discusses the application of techniques like NMR to CFS. On other occasions some interesting bacterial findings have been reported as per this paper by Sheedy and colleagues****** who I think might have been part of the same group (including Dr Henry Butt and the whole CFSUM1 and CFSUM2 episode).

My attention was immediately drawn to the reductions in glutamine which were present in this small participant group. Drawn because of the previously discussed 'possibility' of gut hyperpermeability in cases of CFS and the various suggestions that glutamine might play a role in intestinal permeability, or at least as an aid to improving such permeability in both animals (here) and humans (here). I might also add that lower levels of plasma glutamine have also cropped up in autism research too, bearing in mind that no direct connection between the conditions is intended. 

The literature on glutamine and CFS is still a little sparse. Aside from this paper looking at glutamine levels being related to something called 'overtraining syndrome' there's really not that much more to compare with. I note that exercise can induce changes to intestinal permeability (here) but wouldn't like to speculate on the mechanisms of this effect and any role for glutamine. I am on purpose also excluding the findings on glutamine related to ancillary conditions like fibromyalgia such as a raised glutamate/glutamine ratio (now where have I seen that before?)

I'm going to stop there with this interesting area of research which requires replication with much greater numbers. I've not really discussed the ornithine findings reported, simply because (a) there is even less research on this with CFS in mind, and (b) ornithine in relation to the urea cycle gets really, really complicated and my head is starting to hurt. Suffice to say that amino acid chemistry once again reveals itself as a possible correlate to another one of our heterogeneous medical syndromes without clues to causation. The question is: is the link with glutamine causation, association or just epiphenomenal?

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* Duffy FH. & Als H. A stable pattern of EEG spectral coherence distinguishes children with autism from neuro-typical controls - a large case control study. BMC Medicine. June 2012.

** Sildorf SM. et al. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Reports. June 2012

*** Menkes DB. et al. Vitamin D status of psychiatric inpatients in New Zealand's Waikato region. BMC Psychiatry. June 2012.

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