Resurrecting XMRV in Chronic Fatigue Syndrome?

The letters X-M-R-V in relation to Chronic Fatigue Syndrome (CFS) have had their fair share of controversy in recent years. For those who don't know about XMRV - xenotropic murine leukemia virus-related virus - there is ample discussion about this topic on the web or you can browse my past posts covering the story here and here. I'm sure that a feature film or TV mini-series will be made eventually about XMRV and CFS including the back-story of Dr Judy Mikovtis and the whole WPI saga. I'll leave you to make up your own film title.

After all the excitement of contamination, missing notebooks and scientific retractions, you'd think this would be a 'leave well alone' area for many researchers not really wanting to get involved, given the career-tarnishing effects it seems to have. It was with some interest therefore that I stumbled across this fairly recent article by Paolucci and colleagues* (full-text) and their findings on XMRV and CFS adding to the mix.

It is a short paper but nevertheless contains some interesting facts which I'll try and summarise:

• Twelve participants diagnosed with CFS and some 40 controls (including asymptomatic, those confirmed as HIV positive or hepatitis C infection and transplant recipients) were investigated for the presence of XMRV "and polytropic MLV-related provirus". This last bit taps into some now author retracted research published by Lo and colleagues** (full-text).
• I can't claim to understand all the ins-and-outs of the process for trying to detect XMRV or its friends but PCR was the name of the game, looking for fragments of DNA from the respective viruses.
• Results: nothing for the control participants when it came to the potential presence of XMRV or its friends. For the CFS participants, in the majority nothing also except in two participants who "were positive for gag PCR and integrase PCR respectively". Further study of positive participant number 1 suggested that "the retrovirus was more closely related to the polytropic MLV rather than to XMRV (identity 100% vs. 96%)". For participant 2, further analysis "confirmed the similarity with the XMRV sequence".
• Given the methods used by the authors, the contamination issue that overshadowed the previous research were excluded.

I'm not making too much of this paper at the current time given that other contemporary studies have reported no presence of XMRV in cohorts of participants with CFS (see here and here) alongside the relatively small participant group included as part of the Paolucci study. As per my previous reporting of this area of research, detecting such viruses is not by any means an easy task and no doubt there are still gaps in the methodology and science that need patching up. Even with the virus detected, there is a substantial leap to make before one is able to suggest the virus might be 'causative' of CFS or anything else.

What we can perhaps infer from the Paolucci paper is that the XMRV chapter of CFS research history might not be ready for the scientific scrapheap just yet. The big 'final say' study from virus hunter Ian Lipkin - yes, he of the autism and Sutterella research - has, at the time of writing, still not found its way into the peer-reviewed literature as far as I can see despite some signs it would be here already.

So we wait and see...

While waiting perhaps you would like to hear which Disney song currently fills my house. I've got a dream y'know..

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* Paolucci S. et al. Xenotropic and polytropic murine leukemia virus-related sequences are not detected in the majority of patients with chronic fatigue syndrome. New Microbiologica. 2012; 35: 341-344.

** Lo SC. et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. PNAS. 2010. 107: 15874-9 [RETRACTED].

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Paolucci S, Piralla A, Zanello C, Minoli L, & Baldanti F (2012). Xenotropic and polytropic murine leukemia virus-related sequences are not detected in the majority of patients with chronic fatigue syndrome. The new microbiologica, 35 (3), 341-4 PMID: 22842604

Autism and microglia

An interesting paper has appeared by Beumer and colleagues* with the grandiose title: The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. It's an intriguing paper linking specific actions of the immune system on brain areas in connection to various conditions including depression and schizophrenia via a biological entity that seems to be gaining some research interest: microglia.

On the basis of this publication I therefore resisted no longer and decided to set off on the voyage of discovery that is a possible role for microglia in cases of autism. Please understand that I undertake this post with some trepidation as my skill set does not readily encompass the hows and whys of microglia, so be at the ready with that rather large pinch of salt.

Quite a good overview of microglia is here by Kettenmann and colleagues** (full-text) alongside some discussion on their 'constant gardening' effect in this piece by Virginia Hughes*** (full-text). Apparently constituting as much as 10% of the cells of the central nervous system, microglia derive from cells of the immune system and activate in response to injury or inflammation. More than that however, there is some emerging evidence that microglia might also play a role in the pruning process which the developing brain undertakes during the early years and perhaps beyond.

With autism specifically in mind, I've already linked in previous posts to an interesting blog piece from Paul Patterson on microglia potentially eating synapses in autism as a consequence of some interesting research suggesting increased microglial activation in some cases of autism****. I draw your attention also to another interesting blog post on the SFARI website which strengthens a possible connection between microglia and a mouse model of Rett syndrome, noting also the controversial issue of bone marrow transplant as a potential route to "generating healthy microglia". I might add that I am not getting too obsessed with stem cells and the such like, but in light of Prof. Patterson's recent paper, one has to keep an open mind.

Other research on microglia and autism:

• Starting from the early days of the PubMed catalogue on this topic a few familiar names crop up with microglia in mind. Andrew Zimmerman and colleagues***** (he of the 'can you grow out of autism' research) talked about neuroglial activation and neuroinflammation quite a few years ago. They reported "marked activation of microglia" alongside several other inflammatory related findings in the brains of people with autism. Similar follow-up studies from this research group also talked about paradoxical lower levels of quinolinic acid in cerebrospinal fluid which  brings us back to everyone's favourite aromatic amino acid, tryptophan. I'll leave that for now.
• Propionic acid (PPA), the topic of quite a recent blog post, also gets a look-in with microglia in mind as per the paper by Derek MacFabe and colleagues******. They report that during their 'inject PPA into rodent brain' experiments, increases in activated microglia was one of the effects contributing to the neuroinflammatory process described. Whilst I would love to be able to say this might tie into the short chain fatty acid findings also talked about with PPA and autism in mind (here), it is probably not unexpected that PPA administration so directly and at such quantities would provoke a reaction from microglia given their activation at the first sight of any foreign invaders.
• Other research speculates on the role of microglia and autism (here, here and here), in some cases speculating on the potential environmental factors which may exacerbate microglial priming. I was also drawn to this paper by Schwarz & Bilbo******* who discuss how gender differences in the colonisation and function of glia may offer some interesting explanations for the gender differences seen in conditions like autism, acknowledging that glia includes more than just microglia.

There is still some way to go with regards to the microglia-autism story but so far the research base could be described as very interesting. Inflammation, as I have said before, seems to be playing many hands in at least some cases of autism. Whilst the chicken-and-egg debate about immune function and autism continues, there is little doubt that for some, immune involvement - whether mediated/described by microglia activation, circulating cytokines or other markers of inflammation and immune over- or -under activation, seems to be a facet of symptom presentation. The puzzle is still far from complete however.

Finally, there is the question about what can be done about over or chronic activation of microglia. Reiterating my caveat about not giving medical advice or anything approximating such advice and aside from the bone marrow transplant data already touched upon, I was interested to read the various literature on the effect of administration of the tetracycline antibiotic, minocycline on microglial activation as per studies likes this one and this one (both full-text). Accepting that certain antibiotics might be a bit of a double-edged sword for some cases of autism (see this post) as well as such compounds having other, more recognised antimicrobial action - potentially important in some cases of autism - it does make me wonder whether targeting such interventions at activated microglia at a critical time might be a research area worth investing in.

To finish, I'm in the mood for some Ska. So without further ado, the Specials and Too Much Too Young.

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* Beumer W. et al. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. Journal of Leukocyte Biology. August 2012.

** Kettenmann H. et al. Physiology of microglia. Physiological Reviews. 2011; 91: 461-553.

*** Hughes V. Microglia: the constant gardeners. Nature. 2012; 485: 570-572.

**** Morgan JT. et al. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biological Psychiatry. 2010; 68: 368-376.

***** Vargas DL. et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology. 2005; 57: 67-81.

****** MacFabe DF. et al. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behavioral Brain Research. 2007; 176: 149-169.

******* Schwarz JM. & Bilbo SD. Sex, glia, and development: Interactions in health and disease. Hormones & Behavior. February 2012.

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Beumer W, Gibney SM, & Drexhage RC (2012). The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes J Leukoc Biol. DOI: 10.1189/jlb.0212100

Vitamin D and autoimmunity and autism

Heavens above @ Paul Whiteley

They're at it again. The very marvellous Saudi-Egyptian autism research tag-team that is Gehan Mostafa and Laila Al-Ayadhi and another very, very interesting article titled: Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity* (full-text here).

I'd kinda been waiting for an article like this to come along given the shifting Eye of Sauron onto a possible role for the sunshine vitamin in cases of autism. You can find a little more background on the whole vitamin D-autism research base in a previous post I wrote some while back (here). I might also at this point plug a few other previous posts focused on vitamin D: leaky gut? (here), mental health and vitamin D deficiency? (here) and synthesis of vitamin D and the "evil" cholesterol (here). OK, stop with the self-promotion already.

The latest paper is full-text but to briefly summarise:

• This wasn't just a study to see whether children with autism were deficient in vitamin D, or rather the active form of the vitamin, 25-hydroxy vitamin D, but rather also some inspection of any link between vitamin D levels and a feature of autoimmunity given the proposed immunological effects of vitamin D and the previously discussed suggestion of a link between autoimmunity and cases of autism.
• Fifty children with autism (aged 5-12 years) were compared against 30 asymptomatic control children. Sunshine exposure data were collected, supplementation controlled for, and serum levels of 25-hydroxy vitamin D were ascertained during the spring/summer months (April-September).
• Levels of anti-myelin-associated glycoprotein (anti-MAG) auto-antibodies were also measured in both groups. The presence of anti-MAG antibodies is basically a sign that the body is attacking myelin associated glycoproteins; myelin being an essential part of proper neuronal functioning. Elevations in anti-MAG antibodies is a sign that brain tissue is being targeted by the bodies own immune system.
• The results: as a group, the children with autism presented with lower levels of 25-hydroxy vitamin D than controls (P<0.001), with about 40% of the autism group being classified as vitamin D deficient (<10ng/mL). None of the controls fell into the deficient range (although about 20% were classified as being 'insufficent' <30ng/mL). These results were based on pretty much equivalent sunshine exposure between the groups. There was also a suggestion of a negative correlation between 25-hydroxy vitamin D levels and scores on the CARS.
• Children with autism as a group also presented with significantly higher levels of anti-MAG auto-antibodies compared to controls (P<0.001). Indeed increased levels were found in about 70% of participants with autism.
• Serum 25-hydroxy vitamin D levels also significantly negatively correlated with anti-MAG auto-antibodies in children with autism.

Accepting that the participant groups were relatively small and the findings based on children I assume of Saudi origin, it is quite telling that children with autism living in a country where sunshine is probably not in short supply were still in the majority deficient in the active form of vitamin D. Appreciating the health advice that is provided nowadays when it comes to being 'sun aware' I still find some difficulty in accepting the fact that people in this region might not be getting enough sunshine to synthesise vitamin D as a way of accounting for the results. Could it be that autism, some cases of autism, confer problems with the biological synthesis and metabolism of vitamin D or even with the functioning of vitamin D receptors? If so, what are the implications for supplementation for example?

Anti-MAG antibodies is a new one for me in the autism research arena. Linked to a variety of autoimmune peripheral neuropathies, anti-MAG antibodies have actually been reported previously in cases of autism** (by the same authors). In that study, the authors introduced the possibility that "autism could be, in part, one of the pediatric autoimmune neuropsychiatric disorders". I'm not going to get too bogged down in the potential impact of anti-MAG antibodies and autism at this point though as more reading on my part is required.

So in short, a few more potential pointers for further investigations from the Saudi-Egyptian research team and another intriguing connection between vitamins and autism.  

To finish, I'm in the mood for a little Stranglers at the moment and a lovely tune called Gordon Brown... sorry, Golden Brown to at least remember what the sun looks like.

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* Mostafa G. & Al-Ayadhi LY. Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. Journal of Neuroinflammation. August 2012.

** Mostafa GA. et al. Serum anti-myelin—associated glycoprotein antibodies in Egyptian autistic children. Journal of Child Neurology. 2008; 23: 1413-1418.

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Mostafa G, & Al-Ayadhi L (2012). Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity Journal of Neuroinflammation
DOI: 10.1186/1742-2094-9-201

Are gut problems in autism linked to anxiety and sensory issues?

I'd been waiting to get hold of the recent article by Dr Micah Mazurek and colleagues titled: Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders* (abstract here) for quite a few days before posting about it.

This paper was always going to catch my eye given the focus on gastrointestinal (GI) problems comorbid to cases of autism. That and the authors connecting issues with anxiety and sensory issues to the presence of such functional GI problems in cases of autism, which really neatly falls within the remit of my interest in our second brain and how it might do some much more than just digest food. Don't get me wrong, I know all about the difference between correlation and causation - as in one does not necessarily mean the other - and tread carefully when discussing Dr Mazurek's findings.

Perhaps a few study details first:

• Quite a large sample of children aged between 2-17 years old (N=2973) diagnosed with an autism spectrum disorder were included for study derived from the Autism Treatment Network (ATN). This means that we can reliably assume that (a) participants were diagnosed with autism, and (b) diagnosis was confirmed by gold-standard instruments such as ADOS.
• Parent report data was collected on various features pertinent to the current study including a subset of items derived from the Short Sensory Profile (SSP), the Anxiety Problem T-score from the Child Behaviour Checklist (CBCL) and a GI Symptom Inventory Questionnaire to measure GI health related to five chronic functional GI symptoms. Cognitive functioning was also assessed.
• The results: about a quarter of the participants studied presented with at least one chronic GI problem - that is a GI problem "within the past 3 months, duration of 3 or more months"; most frequently constipation. Children with chronic GI issues (n=733) scored higher on the CBCL Anxiety Problem scale than those (n=2239) without. Children with a chronic GI problem also presented with greater sensory over-responsivity (SOS) than those without such issues. SOS included features such as tactile sensitivity, taste-smell sensitivity (see here), movement sensitivity and visual-auditory sensitivity (see here). 
• Finally, logistic regression analyses seemed to indicate that both anxiety and SOS "significantly contribute to the prediction of chronic constipation, chronic abdominal pain, chronic bloating and chronic nausea".

To my mind, these findings make for some very persuasive reading. One could argue about whether parent report is the most accurate way of collecting such data. I would however highlight two studies in the autism research field which suggest that parent reporting might not be totally off the mark as per developmental history recall (here) and that very important study by Phillip Gorrindo and colleagues** on parent reporting of GI issues in autism.

What more to say that has not already been said. The possibility that functional GI issues might be over-represented in cases of autism is to my mind a point which requires little more research in light of research like this and this and this. Obviously not everyone with autism presents with such bowel problems and not everyone with such bowel problems presents with autism. Science still needs to determine whether there might be a specific autism phenotype where bowel issues are a primary somatic symptom as per the findings on lactose intolerance from Tim Buie and colleagues. But for those who, for whatever reason, would once argue that comorbid bowel features are merely a fluke finding to autism, some autism... show me your evidence.

Such bowel issues if present are more than likely going to affect people with autism at least to the same extent as they do to those with not-autism particular when in the paediatric population. I think back to the Autism Now series aired April 2011 and vaguely recall some description of a child with autism also with bowel problems and the way their behaviour seemed to manifest such issues. It certainly is not outside the realms of possibility that a person with autism with a comorbid bowel issue like constipation for example, might well have some accompanying stress and anxiety over going to the toilet for a number two with the expectation of the discomfort that this might well bring. In terms of more chronic generalised anxiety, well the research literature suggests that functional bowel problems and anxiety might already share the same bed as per studies like this one from Waters and colleagues***.

An important implication from the Mazurek findings is that if there is a connection between functional GI issues, anxiety and sensory issues, one would expect that attempts to resolve the GI issues may very well impact on the other symptom areas too and vice-versa. The authors talk about the use of cognitive behavioural therapy (CBT) as one potential avenue of intervention for these overlapping issues. Personally I'm not a great fan of CBT as being particularly useful to "treat" bowel problems in autism either directly or periperhally; to coin a phrase from a good friend of mine, bowel problems are probably not present as a result of some unconscious desire to obsessively collect bus tickets or anything like that. Rather better looking at a more physical - somatic causation is likely to yield more productive, long-term positive effects.

I've talked previously about how those trillion or so bacteria which make up our gut microbiota might very well have the ability to influence our behaviour - or at least in animal models. A friend of mine (thanks Dr Mark Wetherell) also put another interesting recent article my way by Dinan & Cryan**** which talks about the stress response potentially being affected by aspects of the gut microbiota. If we assume that the functional bowel issues noted in cases of autism might very well be partially present as a result of some bacterial issues - such as those here and here, it's not too difficult to suggest some tentative connection.

I hope I'm not getting too speculative when I also bring to your attention studies like this one from Messaoudi and colleagues***** and the use of probiotic formulations to reduce stress and anxiety responses in both animals and human volunteers. OK, no mention is specifically made about functional bowel problems in the Messaoudi paper, although similar probiotic formulations have been suggested to also affect bowel issues like constipation****** (full-text).

I do also wonder about the more traditional pharmacotherapies used to treat constipation and diarrhoea or indeed more serious underlying issues such as inflammatory bowel diseases and whether there could be potential positive effects from those also in cases of autism. This paper makes mention of the "symptomatic improvement in their behavior and general well-being after bowel clearance before colonoscopy" noted in cases of autism. I've often wondered whether interventions like the gluten- and casein-free diet which seem also to impact on bowel issues in cases of autism might be another case in point.

More research needed on the gut-brain axis in autism perhaps?

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* Mazurek M. et al. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. Journal of Abnormal Child Psychology. August 2012.

** Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Research. 2012; 5: 101-108.

*** Waters AM. et al. Functional gastrointestinal symptoms in children with anxiety disorders. Journal of Abnormal Child Psychology. July 2012.

**** Dinan TG. & Cryan JF. Regulation of the stress response by the gut microbiota: Implications for psychoneuroendocrinology. Psychoneuroendocrinology. 2012; 37: 1369-1378.

***** Messaoudi M. et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. British Journal of Nutrition. 2011; 105: 755-764.

****** Guerra PV. et al. Pediatric functional constipation treatment with Bifidobacterium-containing yogurt: a crossover, double-blind, controlled trial. World Journal of Gastroenterology. 2011; 17: 3916-3921.

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Mazurek MO, Vasa RA, Kalb LG, Kanne SM, Rosenberg D, Keefer A, Murray DS, Freedman B, & Lowery LA (2012). Anxiety, Sensory Over-Responsivity, and Gastrointestinal Problems in Children with Autism Spectrum Disorders. Journal of abnormal child psychology PMID: 22850932

Propionic acid and autism

Another post, another organic acid (!) but please don't click away just yet as I attempt once again not to blind you with science. The topic of the day today is propionic acid (PPA) otherwise known as propanoic acid and the very tentative suggestions of some link to autism. 

Search on-line for propionic acid and you're quite likely to get lots of industrial chemical information about it including a materials safety data sheet (MSDS) (here) implying that this stuff is toxic, combustible and corrosive. So why on earth am I talking about it with regards to autism?

Well, like many things in modern life, the chemical industry isn't the only source of 'chemicals' as per our wonderful chemical factory that is the human body and the surprising effects of some of the bacteria which inhabit us. Not for the first time, I might add, has bacteria and biochemistry come together on this blog (see here) and probably not the last time either.

PPA is an organic acid - a short chain fatty acid - which as well as being used as a food additive / preservative and used in the process of polymer production apparently, is also what might be considered a natural product as a result of its endogenous production. Short chain fatty acid you say? Y'mean like the ones discussed not so long ago in relation to autism by Wang and colleagues? Yes, the very same.

Continuing with autism in mind, I am taken back to this news report from 2007 where Dr Derrick MacFabe discussed this piece of research* (followed up by this study** too) suggesting that you are what you eat in terms of foodstuffs and bacteria combining to produce PPA and what effect it had on the rat brain following "intraventricular infusions" (to you and me injecting the stuff directly into rat brains). Dr MacFabe has very definitely taken the lead when it comes to looking at PPA and autism. 

Indeed I was interested to see the effects of PPA administration on rat brains including activated microglia and decreased glutathione alongside the more overt effects on rat behaviour. Understanding that rats (like mice and fish) are not humans, indications of issues with glutathione have been quite strongly shown to be related to cases of autism and indeed the brain has become a recent focus for this area of research. As for microglia, I would once again refer you to this post by Paul Patterson on the suggested dietary habits of microglia in autism with the promise of a post on this research area soon.

Other research groups have also entertained a possible role for PPA in autism. The paper by El-Ansary and colleagues*** replicated the results from the MacFabe group and indeed added a few new aspects also making mention of lactate dehydrogenase and elevations in IL-6 among other things; both factors having been reported in connection to autism (here and here respectively). I think we can, with some degree of confidence, assume from this collected work, that propionic acid injections are probably not good news for rats.

We move onwards then to another piece of research by El-Ansary and colleague**** (full-text) looking at the possibility that supplementation with omega-3 fatty acids might afford some protection against the effects of PPA administration to rats. They reported that omega-3 supplementation did indeed alter some of the parameters associated with PPA administration including some interesting data on caspase-3, an executioner molecule involved in apoptosis previously reported in cases of autism (see here for more information). It seems rats fed a diet rich in omega-3 fatty acids might have some protection against various effects of PPA administration. I assume this ties into this paper by Thomas and colleagues***** (including Dr MacFabe).

So to summarise. An overlap between direct PPA administration and some key biochemical changes noted in cases of autism. Fine. A potential protective effect via use of omega-3 fatty supplementation from PPA administration. OK (fatty acids have some history in cases of autism as per this older post). PPA found to be elevated in cases of autism (based on the analysis of stools). Right.

Reading all that might convince some people of a role for PPA in autism but I'm going to play devil's advocate for a second and suggest why we need more research in this area. First, as mentioned rats aren't human beings. Rats might make good models for human being - as do some mice - but rats are not human beings. Second, administration of PPA was either intracerebroventricularly or at "neurotoxic doses" over 3 days (250mg/kg body weight). Either of these two factors whilst good for studying rats in a lab over a relatively short space of time is probably not going to be representative of chronic PPA exposure in people with autism. Unless of course that is, that something causes a huge acute surge in PPA that is. Finally(!) aside from the Wang findings on fecal PPA levels, the research in this area is still a little bit scant in terms of PPA levels in other biofluids. I haven't for example, seen anything as of yet looking at whether rates of the metabolic disorder propionic acidaemia is any more prevalent in cases of autism than not autism or likewise whether propionic acidaemia is accompanied by an increase in cases of autism accepting the seriousness and poor prognosis of this rare metabolic conditions. A few possible routes to further study perhaps.

That being said, I am still intrigued about propionic acid and the research done so far with regards to autism whether animal model-based or direct measurement. The whole connection back to short chain fatty acids, digestion and gut bacteria is an interesting and very under-researched area with autism in mind -  indeed with lots of other behavioural / cognitive / psychiatric conditions in mind. Could it hurt to put a little more research efforts into this area?

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* MacFabe DF. et al. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behavioral Brain Research. 2007; 176: 149-169.

** MacFabe DF. et al. Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behavioral Brain Research. 2011; 217: 47-54.

*** El-Ansary AK. et al. Etiology of autistic features: the persisting neurotoxic effects of propionic acid. Journal of Neuroinflammation. April 2012.
DOI: 10.1186/1742-2094-9-74

**** El-Ansary AK. et al. On the protective effect of omega-3 against propionic acid-induced neurotoxicity in rat pups. Lipids in Health & Disease. 2011; 10: 142.

***** Thomas RH. et al. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. Journal of Neuroinflammation. 2012; 9: 153.

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No single SNP associated with autism?

A quote to begin this relatively short post:

"Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level."

One of the conclusions reached in this article by Richard Anney and colleagues* (full-text). SNPs (single nucleotide polymorphism(s) are the tiny rearrangements in our genetic code which have all but replaced the older research fashion of one gene - one condition from times gone by. The theory being that these small mutations might offer some assistance with regards to for example, identifying an individuals risk or response to a condition or pharmacotherapy for disease as has been noted in conditions like breast cancer.

SNPs in relation to autism have been discussed previously on this blog as per posts like this one and this one.  The net result so far suggest that such genetic glitches are present in at least some cases of autism, but - and it is rather a large but - SNPs are a rather complicated area of genetic research. As per the Anney paper, consistent individual SNPs across all cases of autism are not yet apparent.

I don't want to make to much of a meal of the Anney results with regards to the modest individual effects noted by the authors. Suffice to say that based on quite a large dataset numbering in the couple of thousands of participants "no genome-wide significant association with specific common variants" was reported.

Where next I hear you ask? Well, it was unlikely that one single SNP would be apparent across the whole of the autism spectrum similar to the findings based on the long and as yet unsuccessful search for the 'autism gene'. Everyone carries their own mutations and in the most part these don't seem to unduly affect day-to-day health and wellbeing bearing in mind important interfering variables like comorbidity - as in, is the SNP/s related to autism or related to other things like learning disability or epilepsy or other more somatic things? The fact that autism is a constellation of symptoms also makes the interpretation of any findings even more problematic.

More likely that more than one SNP is going to be involved in specific 'types' of autism and there is some degree of interaction between them. A fantastic case for looking more at endophenotypes based on symptoms presentation (including regression as per the latest study from Barger and colleagues**) or even based on possible responsiveness to specific interventions. That and/or the possibility that epigenetics and the methylation / acetylation / phosphorylation of DNA, or histones, is likely to be a more fruitful area of research combining both genes and environment as per the recent suggestion by Emily Simonoff***.

To finish, London has bid farewell to the 2012 Olympic flame and so I leave you with a song from the best of British, Paul McCartney / Wings and 'Live and Let Die'. One small note to the closing ceremony organisers: if you are going to play a Kate Bush song to denote something 'British' outside of just a reference to a hill, make sure its Wuthering Heights. Looking forward to the Rio party.

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* Anney R. et al. Individual common variants exert weak effects on risk for Autism Spectrum Disorders. Human Molecular Genetics. July 2012.

** Barger BD. et al. Prevalence and onset of regression within autism spectrum disorders: a meta-analytic review. JADD. Ausgust 2012.

** Simonoff E. Autism spectrum disorder: prevalence and cause may be bound together. British Journal of Psychiatry. 2012; 201: 88-89.

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