Thursday 31 May 2012

Gustational sensitivity and autism: a matter of taste

A sensory friend @ Paul Whiteley
Given the all-but accepted revisions for diagnosing autism spectrum conditions in DSM-5, there is one area of change to the Diagnostic & Statistical Manual entry that I think most people would be satisfied with: the overt inclusion of criteria surrounding unusual reactivity/interest to sensory input or sensory aspects of the environment.

Indeed whilst such sensory - perceptual issues in cases of autism have been known about for some years, many people (including me) have probably wondered to themselves why has it taken so long for this important factor for many people with autism to be included as part of the way the condition is assessed and diagnosed. Well now it is.. or at least will be fairly soon, minus any last minute changes that is.

Having said all that, just because such sensory issues are to be included in the diagnostic text, doesn't mean there is necessarily any consensus on what can be done about them as and when required, as per the recent policy statement by the American Academy of Pediatrics* (full-text).

I digress.

You could literally write a whole book about sensory issues in relation to autism - indeed some people have - but for this post, I'm zooming in on one part of that sensory issue dealing with taste or to use the proper scientific term, gustational sensitivity. I'm also sticking with the term 'sensitivity' in this post as per the assumption that some people on the autism spectrum seem to be particularly sensitive - hypersensitive - to certain types of taste and acknowledging also the opposing result, hyposensitivity to be also potentially present. I hasten to add that everyone, whether autistic or not, has their own individual tastes, likes and dislikes; taste is a very personal thing as per the various discussions on phenylthiocarbamide (PTC) perception which some may remember with regards to 'diagnosing' schizophrenia.

I remember about 15 years ago seeing gustational sensitivity in action with a child with autism. It was during a visit to see a child involved in one of our early research studies to talk to the parents about the food and feeding patterns they were seeing. The child was thirsty and mum brought a drink of cordial for the child. The drink seemed pretty concentrated and when asked about this, mum replied something along the lines of "XX always likes lots of cordial". Indeed not being a connoisseur of cordial drinks, even I could see that there was more cordial than water. That drink would probably have been pretty strong. Such observations have been accompanied by other anecdotal reports of preferences for strong tasting foods in cases of autism. I hasten to add however that not everyone with autism can be found tucking into a vindaloo curry at every opportunity for example, as per this abstract from IMFAR 2012.

Research into the gustational aspects to some cases of autism is still quite thin on the ground. It all really kicked off in the early noughties with this study** by quite a familiar name, Sally Rogers (and colleagues) who noted some interesting differences in parent reported sensory symptoms in children with autism. Taste and smell seemed to show the greatest difference in autism compared with cases of developmental delay, Fragile X syndrome and asymptomatic controls. Sample sizes were relatively small but the results were interesting.

Sue Leekam and colleagues*** (previously from Durham University just down the road from me) were among other groups to further categorise sensory issues in cases of autism; again, with specific reference to smell and taste. This paper by Bennetto and colleagues**** (full-text) put some 'meat on to the bones' with their characterisation of taste (sweet, salty, sour & bitter) perception in autism. I note also reference to a bit of a blast from the past with the use of 'Sniffin' sticks'.

A couple of more papers to mention then I'm finished. This paper by Lane and colleagues***** (including another familiar name, Manya Angley) looked at the possibility of subtyping children with autism on the basis of sensory processing including category headers like taste and smell. And finally, Tavassoli and Baron-Cohen****** add to the evidence base on issues with taste in adults with autism.

From this and other evidence, both scientific and from lay sources, it is fairly clear that at least some people on the autism spectrum seem to present with issues related to the sensory aspects of taste. I've not really talked about related issues such as smell, texture (food texture) and issues like pica which seem also to be related to gustation but nevertheless one needs to bear these in mind also.

The mechanism is still unclear as to why taste perception might be attenuated for some people, accepting that personal preference should not be excluded from any explanation and the realisation of some degree of inter-relatedness between the various senses we all use. I could speculate on one possible mechanism of effect although with the caveat that lots of processes will most likely be (variably) involved, including some recent suggestion of more physiological issues potentially present as per the article from Betalli and colleagues****** (which probably deserves a blog post on its own).

To finish, taste can mean more than one thing; and to show that I have very little of it when it comes to fashions and trends, and in honour of this years Eurovision... whatever it was, nul points for Jemini back in 2003. (Bravo to the Hump for not coming last).

P.S. The hedgehog picture was taken a few nights back outside my house as the little critter was foraging for some tasty earthworms in the garden.


* Sensory Integration Therapies for Children With Developmental and Behavioral Disorders.
Section on complementary and integrative medicine; Council on children with disabilities.
Pediatrics. May 2012

** Rogers SJ. et al. Parent reports of sensory symptoms in toddlers with autism and those with other developmental disorders. JADD. 2003; 33: 631-642.

*** Leekam SR. et al. Describing the sensory abnormalities of children and adults with autism. JADD. 2007; 37: 894-910.

**** Bennetto L. et al. Olfaction and taste processing in autism. Biological Psychiatry. 2007; 62: 1015-1021.

***** Lane AE. et al. Sensory processing subtypes in autism: association with adaptive behavior. JADD. 2010; 40: 112-122.

****** Tavassoli T. & Baron-Cohen S. Taste identification in adults with autism spectrum conditions. JADD.  October 2011.

******* Betalli P. et al. Autism and esophageal achalasia in childhood: a possible correlation? Report on three cases. Diseases of the Esophagus. May 2012
DOI: 10.1111/j.1442-2050.2012.01358.x

Tuesday 29 May 2012

Co-factor this: tetrahydrobiopterin and autism

Tetrahydrobiopterin [tetra - hydro... yes the spelling is right] has made an appearance previously on this blog in relation to phenylketonuria (PKU) and its mopping up qualities when it comes to excessive blood phenylalanine. Also known as sapropterin or BH4, I want to quickly run through some of the (emerging) evidence for its potential connection to autism spectrum conditions in this post, spurred on by some interesting research recently presented at IMFAR 2012.

BH4 does have some history when it comes to autism. There was for example some suggestion of lower levels of 6R-5,6,7,8-tetrahydrobiopterin in samples of cerebrospinal fluid (CSF) from people with autism as per this study by Tani and colleagues. Likewise, experimental use of BH4 have hinted at some potential positive effects to be had in some cases of autism as per this trial by Danfors and colleagues. Social interaction seems to be a target behaviour in most of the trials described so far, perhaps mirroring another compound of interest at IMFAR 2012, oxytocin - the cuddle hormone. The caveat being that not everyone with autism seemed to benefit from BH4 supplementation. Now where have I heard that before?

Indeed Richard Frye, a name attached to the fairly recent folate receptor autoantibody story in autism, seems to have done quite a bit on BH4 as per this paper* and this review paper**. I'm not going through these papers with excruciating details or anything but do want to pick up on a few points raised in one or other.

The thing that always struck me about BH4 is its flexibility. In particular how it is used by three pretty important enzymes as a co-factor, tyrosine hydroxylase, tryptophan hydroxylase and phenylalanine hydroxylase; enzymes used in some pretty important reactions with regards to neurostransmitters like serotonin and dopamine. Avid readers might remember mention of the three amino acids (tyrosine, tryptophan and phenylalanine) in this post on the aromatic amino acids and their gut bacterial link which included some interesting speculation on an important compound to me, indolyl-3-acryloylglycine (IAG) derived from tryptophan. Indeed, if one is suggesting that levels of BH4 may be sub-optimal in some cases of autism, the potential knock-on effects for enzyme function and onward production of those all-important neurotransmitters and their intermediaries might be positively eyebrow raising.

I was interested in Dr Frye's paper* looking at markers which might determine lower and higher CSF levels of BH4. Anyone who has seen or experienced a lumbar puncture (don't click on the link if you don't like surgery) used to collect CSF samples will know that this is a very invasive procedure and is probably not something most people would like to undergo if they can help it. His suggestion therefore that serum levels of the amino acids citrulline and methionine (yes, the methionine cycle) might potentially match up with low and high BH4 concentrations noted in a group of people with autism amongst other diagnoses, is a welcome finding requiring further validation with larger participant numbers.

Given the way that BH4 is synthesized in the body, one has to wonder what processes might potentially be disrupted leading to BH4 deficiency in some cases of autism. I note that the purine nucleotide guanosine-5'- triphosphate (GTP) is the starting point for BH4 and couldn't help but wonder what, if any, effect all those early findings on the purines in some cases of autism might contribute. I hasten to add that I am not an expert on purine metabolism, so just speculating.

There are a few other points of interest tied into BH4 which I have neither the expertise nor time to discuss in detail aside from mentioning; not least how BH4 seems to be tied into nitric oxide (NO) production and the slightly unusual findings of elevated NO being reported in quite a few cases of autism. Whether or not PKU (or even elevated levels of phenylalanine or issues with phenylalanine hydroxylase) might show some link to cases of autism is another question which has received only limited investigation. Either way, I'd like to think that there is enough literature on tetrahydrobiopterin - BH4 - and autism for some serious larger scale research interest in both its measurement and use.

To finish and speaking of co-factors, I always thought that Jason & Kylie were like enzyme and co-factor; just not quite complete without each other...

* Frye RE. Central tetrahydrobiopterin concentration in neurodevelopmental disorders. Frontiers in Neuropharmacology. 2010; 4: 52.
DOI: 10.3389/fnins.2010.00052

** Frye RE. et al. Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics. 2010; 7: 241-249.
DOI: 10.1016/j.nurt.2010.05.004

Saturday 26 May 2012

PCOS, DOGMA and autism with a pinch of salt

I really have to stop doing this. Speculating. Taking a few scoops of relatively small scale research, often in quite disparate areas and making a meal out of them. I don't know if it is the freedom of a lack of peer-review that follows with blogging or just my silly brain making mountains out of molehills, but tenuous links seem to be coming thick and fast at the moment. Perhaps I need a break and some sunshine...

But just before I do, and with a rather large pinch of salt in hand...

Polycystic ovary syndrome (PCOS) has been coming to my attention a few times over the last few days. I readily admit that my knowledge of PCOS is fairly limited, but from what I understand here is a condition which is said to affect anywhere from round about 6% to 10-12% of women. I wouldn't wish to provide a definitive definition of PCOS aside from the fact that it is an endocrine disorder defined by an imbalance in the androgenic sex hormones (hyperandrogenism) which affects ovulation. I should point out that endocrine disorder is not to be confused with endocrine disruptor as per some recent discussions on phthalates and autism.

What else to say about PCOS? Well, there is a suggestion of association with lifestyle-related health conditions such as type-2 diabetes, high blood pressure and weight gain / obesity. This is something I remember seeing on a TV program recently - the Food Hospital - which quite nicely explained how insulin resistance might lead to PCOS, and how higher levels of insulin being produced leads to higher levels of testosterone. I'll come back to testosterone shortly.

Indeed the potential elevation of such lifestyle conditions brings me to the first paper which caught my eye; a speculative paper by Tremellen & Pearce* in a speculative journal. Tremellen & Pearce make an interesting (speculative) suggestion that Dysbiosis Of Gut Microbiota (DOGMA) might be implicated in cases of PCOS. I was always going to be drawn to this paper, simply because (a) who wouldn't with an acronym like DOGMA and (b) it making mention of a mechanism which seems to be coming up time and time again whereby gut bacterial disturbances lead to the so-called leaky gut (gut hyperpermeability) which allows passage of bits of gut bacteria into places they shouldn't really be found which in turn switches the immune system into 'eye of Sauron' mode with potential onward effects on health. The recent Sutterella-autism paper suggested something quite similar. The authors speculate that the immune activation resulting from detection of these foreign bodies interferes with insulin receptor functioning which starts the cascade of rising insulin levels and PCOS as a possible end-point. I'm not really in a position to argue for or against this immune-insulin link but have blogged before about a potential link between diabetes, inflammation and gut permeability. Make of that what you will.

The second paper in this grand speculative post is this one by Palomba and colleagues** looking at offspring of women with PCOS in terms of their scores on various measures of autistic traits. MJ over at Autism Jabberwocky recently discussed everyone's favourite sweeping autism generalisation theory 'the Extreme Male Brain Theory' which has graced previous posts on this blog before. The connection between PCOS and autism (apparently) is testosterone and how the sex hormone biological fingerprint might confer some risk for autistic traits. Interestingly Palomba and co. reported higher levels of autistic traits in children of mums with PCOS compared to non-PCOS controls. Interesting also that female offspring of mums with PCOS seemed to be the ones who quote: "seem to have a higher risk for PDDs".

The final piece [bear with me] of this jagged little post goes back to that very interesting paper by Brent Williams and colleagues*** on carbohydrate metabolism and gut dysbiosis in a small group of children with autism which was discussed here and here. To reiterate: issues with the 'starting material' for enzymes used to process carbohydrates in cases of autism and potential signs of gut bacteria dysbiosis. No specific mention of gut permeability issues, but the words 'maldigestion' and 'malabsorption' are used a few times.

Taken as a whole and with quite a few pinches of salt, I'm speculating on a few things with this post. So for example, dysbiosis is a starting point; where, for whatever reason, disturbances to gut bacteria begin a cycle of physiological changes eventually resulting in elevated levels of insulin and further elevations in testosterone in PCOS. I know some people will look at a concept like dysbiosis and think that it is something fresh out of the 'alt-med' camp complete with lashings of new-age, tofu tomfoolery. The fact of the matter however is that DOGMA(!) is quite a widely reported phenomenon and not just the stuff of fluffy organic dreams.

A second speculation is that, accepting a link between increasing insulin levels and increasing testosterone levels, albeit not necessarily the only way that testosterone levels can be increased, one questions the possibility that testosterone levels could be artificially inflated by environment or lifestyle means (as per this recent study) and what implications this might have for the testosterone-autism hypothesis. Understanding that not every woman with PCOS will have a child with autism, I do wonder about the recent obesity-autism hypothesis and whether there may be grounds for a study looking at maternal insulin and testosterone levels as a function of offspring risk of autism. When saying this I am also sensitive to the fact that maternal obesity / signs of metabolic syndrome are not a universal connection in autism and that quite a few mums (and dads) with children with autism might be getting a little tired of all the 'risks' being reported in relation to autism.

I think I've exhausted my salt supplies with the speculation in this post. Readers are advised that nothing should be taken as fact in this post aside from the results presented in the peer-reviewed journals. I am truly interested to see how the work in these various areas advances and whether issues like DOGMA are indeed able to crack some of the other dogma present in autism and other research circles.

To finish, some Salt-n-Peppa going easy on the salt please.

* Tremellen K & Pearce K. Dysbiosis of Gut Microbiota (DOGMA) - A novel theory for the development of Polycystic Ovarian Syndrome. Medical Hypotheses. April 2012

** Palomba S. et al. Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Clinical Endocrinology. May 2012.
DOI: 10.1111/j.1365-2265.2012.04443.x

*** 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.

Thursday 24 May 2012

CHARGE, you give me fever

The recent passing away of Robin Gibb is a sad loss to the music world. The falsetto tones of the Bee Gees made them one of the most instantly recognisable groups with their string of hits worldwide. Many of their best loved songs were part and parcel of the film 'Saturday Night Fever' in which John Travolta single-handedly shaped a disco generation mirroring millions of male preparations for that Saturday disco odyssey. Move over Disco Stu.

Fever of another sort has also been making news of late with specific reference to autism or more precisely to the offspring risk of autism spectrum conditions in mums-to-be reporting fever or the more scientific term pyrexia (I assume from the Greek to mean fire). The paper in question is this one by Zerbo and colleagues* reporting yet more results from the CHARGE initiative and their cleverly worded website 'beincharge'.

I'm not going to give this paper the mega-post treatment but a few details are noteworthy:

  • Data for upwards of 500 children diagnosed with an autism spectrum condition were compared with that from children with a developmental delay (n=163) and asymptomatic controls (n=421). Such data for this paper included quite a bit of information around pregnancy in terms of mum's report of illness, fever and medications taken during the mum-to-be period.
  • No significant link was found between either reports of maternal influenza or flu vaccination during pregnancy and subsequent offspring autism. When it came to asking about fever during pregnancy, this was a slightly different story as the odds ratios show (OR = 2.12 CI: 1.17-3.84) where offspring autism was over twice as likely to be present in mums reporting fever during pregnancy. Having said that the OR was even greater for those children diagnosed with developmental delays (OR = 2.5 CI: 1.2-5.2).
  • Self-medicating for fever during pregnancy using antipyretics such as ibuprofen or paracetamol (acetaminophen) seemed to be associated with a reduction in the risk of offspring autism.

OK let's take a step back before we get too readily involved in these findings. CHARGE whilst being a good starting point for ascertaining any potential environmental links to autism is still very much a preliminary attempt to look at any associations. Asking about fevers retrospectively is a good idea but still open to some degree of bias. Nine months pregnancy, equivalent to about 280 days, is quite a long time period to look into retrospectively. This is aside from the fact that one person's fever might be another person's 'off-day' and as for medication practices over that time, particularly self-medication (presumably OTC not requiring a prescription) ... I'll leave you to decide on potential accuracy.

Having said all that there are some potential nuggets of information to be derived from this study. Inflammation and those dastardly proinflammatory cytokines are a pretty well recognised feature of at least some cases of autism. I'm not necessarily saying that they are causative or anything like that, but some clues seem to be attached to such findings. I seem to remember some findings from not so long ago in relation to MET and autism attached to the CHARGE study which may very well tie into this latest offering and in particular, lower levels of the anti-inflammatory cytokine IL-10 among other things.

CHARGE has also suggested quite a few other potential associations between pregnancy and risk of offspring autism including: obesity, vits and SNPs, and living next to a motorway (freeway). I would be very interested in seeing some grand analysis of all of these factors published by the CHARGE team just to see how all these various elements might tie together. Even based on each individual participants throughout the various studies, one gets the impression that there is some valuable data to be mined from the initiative pertinent to the formulation of more prospective trials.

To finish, some associated clips to relive those Halcyon days of Boogie.

* Zerbo O. et al. Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study. JADD. May 2012.

Wednesday 23 May 2012

Worldwide autism

Autism spectrum conditions within a global context has been a topic of some interest in recent days as per papers like this one and posts like this one. Without trying to jump on the bandwagon, I offer this post on autism worldwide for your interest. I will warn you that there are some quite sensitive issues described in this post and no offence is intended.

In the post 'Is autism the same all over the world?' I attempted to discuss a few issues around autism within a more global context. No specific conclusions were reached in that post given a bit of a gap in the research literature when it came to autism outside of Europe and the USA; aside that is, from the fact that autism is a global phenomenon. Since then, quite a few papers have emerged discussing various aspects of autism in other countries. Some of these papers had some interesting content which got me thinking.

This paper by Sayyed Ali Samadi and Roy McConkey* (full-text) is, by my reckoning, quite a good read when looking at a model of autism in the developing world. The authors focused on Iran as a template for autism in other developing countries in terms of (i) prevalence, (ii) understanding of the condition and (iii) the application of resources where money is not exactly flowing, or at least not to the standards seen in other countries even with the current economic downturn in mind.

Without wishing to regurgitate the entire paper contents, a few details were striking:

  • Prevalence data on autism is limited in developing countries. I could probably think of quite a few reasons as to why this might be so, but the more obvious ones are things like money, resources and accessibility. Add to that certain cultural nuances as per those described in the SK study and the fact that most of the instruments currently used for screening and assessing autism are in English (with population norms to match), and the waters start to become a little clearer as to why prevalence data might be so limited.
  • Related to the issue of cultural 'norms' are the various effects of knowledge and understanding about autism. The fact that 12% of the parents interviewed in a different study completed by some of the authors (here) believed that their child's autism was as a result of ".. God’s test and probable sins that they might have done unconsciously" is noteworthy. Appreciating that such views might seem a little out of place to some people, I don't want to belittle what has been said or try and put a 'Western slant' on to it because of the need to respect individual beliefs. I'm sure also that most parents of a child with autism, and lots of other conditions, might have at one time or other questioned the how and why, including some spiritual aspect also. What this does perhaps illustrate is how culture and beliefs - whether individual or societal, fluid or stable - can influence perceptions of conditions like autism. 
  • The relatively small contribution of genetics to autism aetiology cited by parents included in the same study (7%) compared with environmental factors (23%) is also striking bearing in mind recent history in that region. This contrasts with other research conducted with European and North American parents where brain and genes seem to be more commonly regarded as 'causative' factors.
  • Parental stress associated with raising a child with autism receives mention as it has done in previous research. Not to dwell too much on the spiritual aspect, the authors discuss how coping strategies might to some degree be derived from Faith and to quote: "Taking care of children is an order from Allah to all Muslim parents". I found this study by Ekas and colleagues** which offered some insight into how religion and spirituality may influence coping patterns and styles used by parents of children with autism. The caveat being that parents seem to derive coping strength from lots of different sources at different stages of their, and their child's, development including, I assume, what provisions society makes available to help families, whether this be by religious or social means.

A second paper also well worth a look is this one by Bakare and colleagues*** (full-text). This paper is more of an analytical type as per its aim to look at potential variations in language acquisition and age at presentation in cases of autism in Africa. The authors report some interesting findings based on their meta-analysis but perhaps the more relevant material to this post comes from their discussions of knowledge and awareness of autism in Africa.

Such that:

  • What the authors describe as 'preternatural and supernatural aetiological explanations' for autism were notable in some reports. I assume that this coincides with culture and superstitions which even today still contribute to modern life in some areas of the World. 
  • Whether because of superstition or because of a lack of awareness and training on autism, general knowledge about autism seemed to be quite sparse. This has obvious repercussions for screening, diagnosis and the possibility of early intervention for cases of autism.

Cumulatively, these and other papers provide some thought-provoking insights into autism in parts of the world not necessarily thought about as much as they should be. I do think there is a balance to be struck when talking about autism in developing nations. On the one hand, there is a need to ensure that people with autism, wherever they are, have access to the necessary and appropriate services and opportunities to enable their potential to be reached including suitable support for families. On the other hand is a respect for cultural and personal values, such that systems and values more commonly associated with the so-called developed countries are not forced upon others who might have a slightly different perspective.

Autism has been the focus of this post, but I assume that lots of different conditions could be transposed on to these findings with similar cultural differences reported. Just in case however that you thought things were 'all developed and rosy' in our part of the world with regards to autism, bear in mind that there is still some distance to go even right on our own doorstep.

* Samadi SA. & McConkey R. Autism in developing countries: lessons from Iran. Autism Research & Treatment. 2011
DOI: 10.1155/2011/145359

** Ekas NV. et al. Religiosity, spirituality, and socioemotional functioning in mothers of children with autism spectrum disorder. JADD 2009; 39: 706-719

*** Bakare MO. et al. Excess of non-verbal cases of autism spectrum disorders presenting to orthodox clinical practice in Africa – a trend possibly resulting from late diagnosis and intervention. The South African Journal of Psychiatry. 2011; 17: 118-120

Monday 21 May 2012

Predicting gluten avoidance outside of coeliac disease

The suggestion that dietary intervention may be a useful tool in ameliorating some of the core and/or peripheral signs and symptoms associated with some cases of autism spectrum conditions has been banded around for quite a few years now.

Of course like every 'intervention' suggested for autism, there is no universal 'one size fits all' as per the heterogeneity and comorbidity which accompany the condition. Combined with a lack of information on the whys and hows of dietary intervention, one perhaps needs to be a little bit cautious on how data on the use of gluten- and casein-free diets, for example, are reported and used.

With this in mind, I stumbled upon an interesting article by Tanpowpong and colleagues* looking at the various symptoms and conditions which might be predictive of the use of a gluten-free diet outside of the more mainstream application in cases of coeliac (celiac) disease (CD). I apologise that I can't post the full-text article but do let me summarise the study and main findings:

  • A database was created based on all patients who presented at Massachusetts General Hospital, Boston (USA) between January 2000 and December 2010 for initial evaluation of possible coeliac (UK spelling) disease (N=720, aged 1-19 years).
  • Lots and lots of information were collected from patients including demographic data, information on signs and presenting symptoms and the medical stuff like serological markers including an old friend, tissue transglutaminase (tTG). Dietary gluten avoidance and physician-recommended / parent instigated use of gluten-free diet (GFD) data were also collected as patients were grouped into three age bands: toddlers / pre-school (aged 1-5 years), school-aged (6-11 yrs) and adolescents (12-19 yrs).
  • Results: only 579 children made it to the final analysis based on things like getting a CD diagnosis elsewhere or issues with confirming use of a GFD. Most patients initially presented with abdominal complaints or issues with bowel movements. Forty-three of the 579 children (7.4%) had some history of dietary gluten avoidance without a confirmed diagnosis of CD. Interestingly, quite a few factors seemed to related to avoidance including: having another family member with CD, complaints of irritability and poor temper control, a history of food allergy and a diagnosis of pervasive developmental disorder (PDD). Just in case you aren't aware, PDD is a sort of wrap around term for autism, Asperger syndrome and the like according to current diagnostic schedules. I say 'current' because as everyone keeps saying, the times they are a changin'.
  • Indeed when it came to the statistics of prediction regarding gluten avoidance, a PDD diagnosis seemed to be particularly predictive, with an unadjusted odds ratio, OR of 6.76 (CI: 2.97 - 15.37). With the application of multivariate logistic regression, the OR ratio for PDD came down slightly (OR = 5.34) but still remained highly significant as a predictor. 
  • It continued. One hundred and forty three patients who were negative for either serological or endoscopic markers of CD were inspected further - 32 of which implemented a GFD without a diagnosis of CD.  Predicting physician-led or parent-initiated use of a GFD revealed again that PDD was again a significant factor; indeed the most significant factor (OR = 7.9) among the few other descriptions.

There are a few messages to take from this data. For some of them I am in agreement with the authors, for others perhaps not so much.

Primary among these messages is that there is a perception that a confirmed diagnosis of CD might not be the only condition where a GFD might be viewed as being useful. We've already seen hints of this in the past few years; starting with the study by Jessica Biesiekierski and colleagues on non-coeliac gluten intolerance early in 2011 and continuing with the 'game-changer' that was Anna Sapone and colleagues on the spectrum of gluten-related disorders published this year (2012). With no disrespect intended to anyone I've talked to down the years about gluten-free diets and autism, there was always a degree of 'snobbery' about gluten and CD as in, if it 'aint coeliac disease, don't bother with a GFD. How things change.

I assume from this study that information about the gluten- and casein-free diet was/is quite widely disseminated in PDD circles. I was very interested in why the word 'autism' does not appear in this paper outside of the references (including our own trial). Don't get me wrong, PDD is factually correct when it comes to the blanket description of autism - something I've used myself - and the various other conditions in diagnostic manuals such as DSM and ICD (bearing in mind that they seemed to have used ICD-9 for their diagnoses). That being said, I found it slightly strange that further analysis was not undertaken on the individual diagnoses included under the PDD umbrella. At the very least it would have been useful to know for example, whether those with an autism diagnosis or those with a diagnosis of Asperger syndrome were more likely to be in the gluten-free dieting group as a function of behaviour and/or communication as per the diagnostic differences. Indeed one could inquire whether all the participants were cases of Rett syndrome or childhood disintegrative disorder which are also included in the PDD diagnostic fold? That and the lack of information about how many participants with PDD had CD or issues with tTG for example, are important omissions in my view.

I would perhaps also take issue with one sentence in their text "Moreover, no clear positive effects from the use of a gluten-free, casein-free diet have been shown in children with PDD". No it hasn't, but (a) referencing our ScanBrit trial and our conclusions that stated "Our results suggest that dietary intervention may positively affect developmental outcome for some children diagnosed with ASD" is probably not the best example of this message and (b) the fact that most interventions for autism have no "clear positive effect" in a population-wide sense, makes me a little uneasy about the wording of the conclusions being reached. I've felt this uneasiness before as per the Mayo Clinic conclusions on dietary intervention for autism (see here); to quote from a favourite film saga: 'I have a bad feeling about this'.

Finally(!), there is a distinct lack of follow-up information included in this paper. OK, you could argue that was not what they set out to look at, and I'm fine with that. Having said that, covering the number of patients they did and for the number of years across the study information, you would perhaps expect to see some small detail if only to say that no-one in the non-CD group showed any benefit whatsoever from the use of a gluten-free diet. Or did they...?

I hope that I've not turned this post from science into a rant. This is still an informative paper and adds to the growing science base about adoption of a GFD in cases of non-CD. That also and reiterating a possible need to screen for CD in cases of PDD?

* Tanpowpong P. et al. Predictors of gluten avoidance and implementation of a gluten-free diet in children and adolescents without confirmed celiac disease. The Journal of Pediatrics. May 2012.
DOI: 10.1016/j.jpeds.2012.02.049

Sunday 20 May 2012

P-glycoprotein: lock on transporters

During a post a while back, I did promise that I would discuss an interesting compound called P-glycoprotein in relation to the blood-brain barrier and its helping, transporting hand. Well here is it is. A recent article titled "P-glycoprotein: Why this drug transporter may be clinically important" attracted my attention in timely fashion discussing drug interactions which, as coincidence would have it, is something that I have also been reading about recently.

This paper by van Assema and colleagues* cropped up on my Twitter radar recently. In it, the authors describe how problems with a pretty important transporter system, P-glycoprotein (otherwise known as ATP-binding cassette sub-family B member 1, ABCB1) might put some fundamental observations in Alzheimer's disease (AD) into perspective.

I don't want to rehash the whole AD story because it has been summarised in other posts. The watchwords are: beta-amyloid peptide fragment, reactivity, and plaques. Dr/Prof. van Assema and team carried out some investigations on P-glycoprotein function in a small number of patients with AD compared with controls. They reported lower P-glycoprotein functioning and concluding that the ability to transport things out of the brain through the blood-brain barrier might be problematic at least in some cases of AD. 

This is not the first time that P-glycoprotein has been implicated in AD. This paper and its accompanying commentary hinted at similar things in a mouse model looking at transporting those pesky beta-amyloid peptides away and reducing the accumulation. I note that there is some growing interest in this and related areas following the news that AD might have some interesting spreading capability

As per my previous post on amyloid precursor protein, AD is not autism. Indeed, the evidence seems quite the contrary when it comes to looking at both the precursor protein and plasma levels of the nasty peptide fragment/s in relation to autism.

Having said that P-glycoprotein has been looked at in cases of autism; specifically to account for the variable effectiveness of some medications given to manage peripheral issues such as hyperactivity. This paper by McCracken and colleagues** suggested that individual responses to the drug guanfacine might be influenced quite strongly by certain genetic differences in the p-glycoprotein gene. So the presence of a certain mutation (SNP) might account for lower levels of P-glycoprotein, which in turn means less 'hold my hand' transport of the drug across the blood-brain barrier to exert an effect. 

Acknowledging that the blood-brain barrier is a highly complex barrier and that we need to tread cautiously in terms of what we allow in and out across this barrier, there is a whole new world to be explored here perhaps rivaling that other barrier of great interest in relation to autism and a few other things. 

* van Assema et al. Blood–brain barrier P-glycoprotein function in Alzheimer's disease. Brain. November 2011.

** McCracken JT. et al. Possible influence of variant of the P-glycoprotein gene (MDR1/ABCB1) on clinical response to guanfacine in children with pervasive developmental disorders and hyperactivity. Journal of Child & Adolescent Psychopharmacology. February 2010.

Thursday 17 May 2012

Hypochlorhydria and autism?

I'm in speculative mode in this post so you will have to humour me a little. I know, I know, this is a blog which is supposed to be about autism research, so why the tangent? Well, let's just say that there are a few ideas for further study potentially included in this post should anyone care. The caveat as always is that no medical advice is intended or given. So, got your pinch of salt ready?

Part of the title of this post - hypochlorhydria - refers to a state rather than a condition, whereby the level of gastric acid is low and potentially below that required to fulfil certain gastrointestinal duties optimally. Gastric acid is predominantly composed of hydrochloric acid (HCl) alongside various other buffer solutions which moderate the pH or acidity of the mix. It's main task is to digest and aid in the digestion of food. Where there might be issues with the appropriate level of HCl, hypo- or achlorhydria (an absence of acid) can arise with several potential consequences.

There are several reasons why hypochlorhydria might be present. Perhaps one of the more widely discussed relates to the use of a certain class of medications under the umbrella of proton-pump inhibitors whose main aim is to reduce gastric acid production in the treatment of things like dyspepsia.

There have been rumblings down the years that gastric acid might require a little more study with autism spectrum conditions in mind. Finegold and colleagues* (full-text) reported on cases of hypochlorhydria during their study looking at intestinal flora in autism. Indeed, Finegold's findings *could* tie into quite a large body of evidence which seems to implicate overgrowth of intestinal bacteria such as Clostridium difficile and gastrointestinal acid suppression as per reviews like this one from Chun Shin Kwok and colleagues**.

I first heard about hypochlorhydria with autism in mind quite early on in my research career alongside a few potentially positive anecdotal reports following the use of preparations such as betaine hydrochloride (trimethylglycine). Betaine HCl (for which I offer no endorsement) is a source of HCl, for which, to coin a phrase of a mentor of mine, "there is general consumer resistance to drinking neat HCl". The theory went that betaine HCl was a way to prop up any issues with HCl generation in the stomach, which subsequently relates back to the function of pepsin, an enzyme whose main aim is to chop up food proteins. Pepsin and its parent pepsinogen rely on acidic conditions to 'spread its wings' in terms of protein degradation.

Some people might have heard about trimethylglycine (TMG) and dimethylglycine (DMG) with autism in mind. DMG is the daughter product of TMG after the loss of a methyl group which might very well take us back to the issue of methylation noted in a few research papers on autism like this one from Melnyk and colleagues on impaired methylation capacity.

I know that this has been a bit of a speculative post and hope that readers will see it in that light. There are lots of other potential links which I could go on about such as the knock-on effects of hypochlorhydria and downstream peptide chemistry which litter the autism research landscape. I note for example, that the current interest in the CM-AT preparation by Dr Joan Fallon's company Curemark which continues with protein digestion in mind (see also a presentation at IMFAR 2012 here).

Indeed I'm going to end with a paper from Cater*** published twenty years ago and some more speculation on the links between hypochlorhydria, intestinal bacterial overgrowth and a triad of amino acids (tyrosine, tryptophan, phenylalanine) which might prove very interesting...

* Finegold SM. et al. Gastrointestinal microflora studies in late-onset autism. Clinical Infectious Diseases. 2002; 35 (supplement 1): S6-S16

** Kwok CS. et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. American Journal of Gastroeneterology. April 2012.
DOI: 10.1038/ajg.2012.108

*** Cater RE. The clinical importance of hypochlorhydria (a consequence of chronic Helicobacter infection): its possible etiological role in mineral and amino acid malabsorption, depression, and other syndromes. Medical Hypotheses. 1992; 39: 375-383.

Wednesday 16 May 2012

Autism and obesity

Not a day seemingly goes by in the world of peer-reviewed science when a paper isn't published somewhere in the world suggesting an association between obesity and ...... [fill in the blank] to account for the 'obesity epidemic' we constantly hear about. Gone it seems, are the days of the rather over-simplified relationship between balancing energy in and energy out to be replaced with something altogether more complicated despite some lingering prejudice. Genes, environment, biochemistry and even that old favourite gut bacteria, have all found themselves in the frame as moderating the risk of obesity. Food intake, eating patterns and exercise should of course be given their fair dues in terms of obesity and being overweight, but not it appears exclusive rights.

Indeed in recent weeks, obesity has even found itself being tied into autism as per the study by Krakowiak and colleagues on maternal obesity and risk of autism. As perhaps expected, this study was not exactly received with welcome arms; to quote one mum's rather entertaining description "I am a big fat load and my out of control eating caused my son's autism". Satire of course, but with an important message about 'association' and 'risk' and their communication in science.

Continuing the autism-obesity speculation, a new paper by Jyoti Rajan Sharma and colleagues* (full-text) has entered the frame reviewing the evidence for a link between autism and obesity. Just before you click away, perhaps to IMFAR 2012 in Toronto, thinking that this topic is probably not going to be too interesting, bear in mind that people with autism have at least the same risk as everyone else of presenting with weight issues as per the old mantra: a diagnosis of autism is seemingly protective of nothing.

I'm not going to go into excruciating detail about this paper aside from the fact that it discusses some important issues:

  • the differing prevalence rates for obesity in cases of autism worldwide (covered in a past blog post),
  • the very wide range of possibilities which might affect the weight of people with autism such as dietary choices, physical activity levels and importantly, side effects associated with pharmacotherapy,
  • the genetic overlap between autism and obesity - that is, the genetic findings which seem to cross both conditions, 
  • the overlap between medications used in cases of autism and those used in obesity.

As with any review paper, there is very little in the way of novel material emerging from this manuscript in terms of new scientific findings. That being said, the authors' suggestions that at a genetic level, there may be some sharing of findings between autism and obesity is interesting and could potentially pave the way for future studies for example, looking at cases of obesity in autism as a kind of endophenotype. The obvious caveats being the requirement to see this with the appropriate non-autism control groups as comparators and the need to look at epigenetic issues as well as genomic changes.

I don't want to underplay the role that diet and physical activity can have on weight, and how autism, like many other conditions, can often be associated with various health and social inequalities compounded by external issues resulting from medication use for example. Whether however common threads predisposing to obesity and related biological parameters (e.g. metabolic syndrome, cholesterol findings - with some interesting observations in cases of autism) might be prevalent in cases of autism, is an interesting field and bearing in mind the physical health consequences, something perhaps requiring quite a bit more inquiry.

* Sharma JR. et al. Autism and obesity: prevalence, molecular basis and potential therapies. Autism Insights. May 2012.
DOI: 10.4137/AUI.S9138

Tuesday 15 May 2012

Immune function in Chronic Fatigue Syndrome

Discussions on research pertaining to chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) have appeared now and again on this blog. Whether it be in connection to diagnosis, or prevalence, or the very contentious topic of XMRV, CFS/ME research seems never to be far away from controversy (remembering also the PACE trial and a retort from a colleague of mine, Prof. Malcolm Hooper). While headlines abound about the conditions (notice the use of the plural), one has to remember that accompanying every diagnosis there is a person; and in some cases, the distress and disability that the condition bestows is, quite frankly, life-destroying.

Questions are still being asked about CFS/ME and in particular taken from a recent article - Why can’t medical science figure out chronic fatigue syndrome? I don't profess to have any answers but there are some interesting themes emerging from the peer-reviewed evidence arena.

Two papers recently published offer some interesting areas ideas about the nature of CFS/ME and quite possibly, some core biology related to the conditions. The first paper* by quite a familiar name, Dr Michael Maes (no advert intended) and colleagues suggested that based on several questionnaire and biological criteria, it may be possible to accurately distinguish between CFS, ME and patients with chronic fatigue (CF). The second paper by Brenu and colleagues** (full-text) looked at immune function in patients with CFS/ME over the course of a year and reported on Natural Killer (NK) cell cytotoxic activity and cytokine function over the study period. Dr Maes' research in particular holds some interest for me given his focus on things like gut permeability and use of the amino acid glutamine.

Indeed starting first with the paper by Maes and colleagues*, they looked at whether the reporting of post-exertional malaise (PEM) a key feature of the diagnosis of CFS/ME, could be used to distinguish sub-groups within the diagnoses alongside the measurement of various cytokines as external validating criteria. Their answer: to some degree, ME, CFS and CF are distinct categories; biological markers of IL-1, TNFα, and neopterin also suggested that; and might also be able to distinguish ME/CFS from CF. Interestingly, the authors suggest a potential revision to one of the schedules commonly used - the Fukuda criteria - based on the expression of PEM or not.

The paper by Brenu and colleagues** proceeds down a slightly different path in that they reported significantly reduced NK cell cytotoxic activity consistently across the three testing periods in a small group of patients with CFS/ME compared to non-fatigue controls. They also make mention of that very magical word 'biomarker' given the consistency of their results although I have to question the power of the study.

Aside from the diagnostic delineation of the Maes study, the cumulative results of these two studies stress involvement of the immune system in cases of CFS/ME. I note that the low NK cell activity is something that has cropped up in other conditions, including in autism, as per this paper by Ari Vojdani and colleagues from a few years back. I don't suggest any specific connection on this parameter between the conditions because for example, when it comes to glutathione and CFS/ME, the results don't seem to be comparable to those noted in cases of autism. One has to however be careful at comparing just individual parameters across conditions.

These works add to the considerable body of evidence suggesting that irregularities in immune function seem to coincide with at least some cases of CFS/ME. I know this is probably not new news to those in the know about CFS/ME but for the wider population, where mis-information about the conditions seems still rife, studies like these need to be highlighted if only to move more people into asking the question 'why can't medical science figure out chronic fatigue syndrome?'

* Maes M. et al. Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: Results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Research. April 2012.

** Brenu EW. et al. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. Journal of Translational Medicine. May 2012.
DOI: 10.1186/1479-5876-10-88

Sunday 13 May 2012

SOD it: AA & DHA on ASCs (and a PUFA DJ)

Acronyms. I love them. OMG, LOL, IMO or even IMHO. David Cameron (the current UK prime minister) also likes to use them - even if only to mean 'lots of love'! My old English schoolteacher would probably be horrified at such flagrant disregard for the correct use of my mother tongue; IMO that is.

The acronyms making up the title of this post have already been discussed on this blog with relation to the research on fatty acids and autism. AA, also known as ARA, stands for arachidonic acid and DHA, docosahexaenoic acid. PUFA refers to a polyunsaturated fatty acid. I assume most people understand that ASCs are the autism spectrum conditions.

I am returning to fatty acids in light of some fairly new research by Kunio Yui and colleagues - paper 1* - (full-text) who reported on the results of a small trial of AA/DHA for autism. I have labelled this manuscript paper 1 simply because there is another paper** by the same authors which seems to recite the same study but based on different outcome measures (paper 2) which I shall also briefly touch on.

Paper 1 is open-access but to summarise:

  • The effect of large doses of AA added to DHA on social interaction and repetitive behaviour in individuals diagnosed with autism was examined in this double-blind, randomised, placebo-controlled trial. That and the measurement of plasma levels of PUFAs such as AA, DHA and EPA, eicosapentaenoic acid, following supplementation.
  • Thirteen participants (I said it was a small trial) were randomly assigned to either active (n=7) or placebo groups (n=6). Active treatment consisted in the most part of 6 capsule of this stuff (SUNTGA40S) per day, compared against olive oil placebo for 16 weeks. Assessments of social and repetitive behaviours were undertaken using the Aberrant Behaviour Checklist (ABC) and repetitive behaviour subdomains of the ADI-R at 4 week intervals.
  • Results: social withdrawal as measured via the ABC and repetitive behaviour measures on the ADI-R showed significant reductions compared with the placebo group scores. The number of individuals achieving 50% improvements in total scores for the ADI-R subdomain analysed was significantly greater than the placebo group.
  • A significant increase in plasma levels of AA were noted in the experimental group over controls when comparing baseline and 16 week levels. The authors have kinda focused on this point quite a bit with regards to the behavioural improvement noted.

I am still waiting to get hold of paper 2 in its full-text form but from what I gather it was based on the same number and grouping of participants, the same supplementary regime over the same time period although using slightly different outcome measures and scales. The net result from that study was that various facets of the social interactive part of autism seemed to be positively affected by the fatty acid supplement. That and levels of transferrin and superoxidase dismutase (SOD) seem to be affected by supplementation although at the present time I can't say in which direction and of what relevance this might be.

To reiterate, although gold standard in terms of methodology, this was a very, very small trial in terms of participant numbers. I know that I seem to be posting on quite a few small-scale studies recently but that's how the cards have fallen. Whether also the use of the ADI-R over 4 week periods might introduce some kind of 'practice' effects also remains to be answered.

So what does this all mean I hear you ask? Well, I can't profess to be the wise (not so old) sage in this case because my fatty acid chemistry is pretty basic at best. Quite a good overview of the whole lipid metabolism area in relation to autism can be found here by Tamiji & Crawford*** (full-text) and provides a good introduction to the evidence base so far.

AA is an omega 6 fatty acid which in some circles has been taken to mean 'bad' particularly when talking about the omega 3: omega 6 ratio of our modern day diets. Similar things have been reported in cases of autism. Like just about everything related to biochemistry, the hype however hides a number of important functions for AA, primarily because AA is a PUFA, the same as DHA, and an important intermediary in the production of things like prostaglandins (certain ones of which have recently been linked to cerebellar development with autism in mind). The authors speculate in paper 1 on the connection between AA and ".. up-regulation of signal transduction in relation to neuronal network function..". In this way I think they are suggesting that AA might actually be a good thing for autism and in particular how various systems / brain areas communicate with each other. The flip side to large doses of AA potentially having a central effect is the view of some of the compounds linked to AA which might not be all that optimal in terms of things like inflammation.

The whole fatty acids thing both in relation to autism and more generally to population health is still in need of quite a bit more investigation and at the moment I would like to see a little more done on AA before this becomes mainstream.

To finish, there is a DJ in the title to this post so without further ado, I present Mr Robbie Williams and Rock DJ (probably not a good video to watch if you are currently eating, or are vegetarian, or both).

* Yui K. et al. Efficacy of adding large doses of arachidonic acid to docosahexaenoic acid against restricted repetitive behaviors in individuals with autism spectrum disorders: a placebo-controlled trial. Journal of Addiction Research & Therapy. December 2011.
DOI: 10.4172/2155-6105.S4-006

** Yui K. et al. Effects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in individuals with autism spectrum disorders: a double-blind, placebo-controlled, randomized trial. Journal of Clinical Psychopathology. February 2012.

*** Tamiji J. & Crawford DA. The neurobiology of lipid metabolism in autism spectrum disorders. Neuro-signals. 2010; 18: 98-112.
DOI: 10.1159/00032318

Thursday 10 May 2012

Psychosis, gluten and vitamin D

I'm wandering a little outside of my area of primary interest with this post on possible dietary correlates attached to the risk of psychosis. I therefore tread carefully and hopefully succinctly with this post based on two independent pieces of research recently published by Gracious and colleagues* (full-text) and Karlsson and colleagues**.

Perhaps best to start with a very brief description of what psychosis is and isn't. Psychosis is more of a symptom rather than a stand-alone condition involving a loss of contact with reality where a person is described as not being able to distinguish between what is real and what is imagination. Symptoms include hallucinations, delusions, confused and disturbed thoughts and a lack of insight and self-awareness. I say not a condition in its own right but there had been some discussion in the preparations for DSM-5 to include a new category called 'attenuated psychosis syndrome' which seems to have been dropped from the latest manifestiation. I should also point out that psychosis does not mean psychopath or anything similar.

The causes of psychosis are still the source of some speculation but generally speaking, three main areas have been put forward as reasons for psychosis including: (i) psychotic episodes linked to an underlying mental health conditions such as schizophrenia or bipolar disorder, (ii) episodes linked to more somatic health conditions such as hypoglycemia (low blood sugar) or dementia, and (iii) episodes following the taking of various drugs of abuse or in rare cases, more 'mainstream' pharmacotherapy. These areas are not exhaustive as per the suggestions about stress and social adversity also being risk factors.

The paper by Gracious and colleagues* suggested that vitamin D deficiency and insufficiency seemed to be quite a common occurrence in cases of adolescents presenting with mental health problems, and was particularly marked where psychosis was a feature of the expression of those problems. Their data also suggested that ethnicity and vitamin D levels seemed to be important factors. Similar data based on the examination of adult psychosis has suggested a related connection to the sunshine vitamin and indeed a potential 'protective' effect from adequate vitamin D intake. Takes me back to the whole vitamin D-autism debate acknowledging that autism is not psychosis and psychosis is not autism.

The paper by Karlsson and colleagues** was slightly different insofar as reporting on a possible connection between maternal circulating levels of IgG anti-gliadin antibodies and the presence of non-affective psychosis in offspring. To some degree this work ties into the wheat and schizophrenia link posited by people like the late Curt Dohan and followed up in the recent paper by Emily Severence and colleagues on food antigens and gastrointestinal inflammation in cases of schizophrenia. I'm also reminded of the very interesting work being done by Drs Marios Hadjivassiliou and David Sanders from right here in Blighty on the extra-intestinal manifestations of issues with gluten (see here and here).

Both the Gracious and Karlsson papers caught my eye given that both suggest an association between dietary components and mental health. Before you ask, yes, these were studies of association and let's face it, associations are abound in lots of areas nowadays so some caution needs to be applied. One could also argue that vitamin D whilst partially dietary-derived has a strong link with sunlight exposure and you would of course be right. Having said that don't underestimate how important dietary vitamin D might be especially in places where sunlight, the right kind of sunlight, is not necessarily always at a premium.

Diet potentially mediating behavioural symptom presentation - now where have we heard that before? Accepting that any link between food and mental health is likely to be complicated and influenced by lots of other factors, there are several potentially important points to make from these and other studies not least on how gut biology may very well have an influence on brain and behaviour with diet as an important factor. One does also wonder whether before reaching for the 'treatment' of these symptoms, medical science perhaps needs to have a more detailed look at how we might be able to influence the 'onset' of such symptoms via adequate dietary and nutritional means. Food for the body, food for the mind? (bearing in mind my caveats about not giving medical advice).

To finish, UK viewers might be tuning into The Voice on the BBC. I like Jesse J and but lets face it, Sir Tom (Jones) is the main event when it comes to a voice (sorry guys). So here he is with The Stereophonics (he looks much better with grey hair).

* Gracious BL. et al. Vitamin D deficiency and psychotic features in mentally ill adolescents: A cross-sectional study. BMC Psychiatry. May 2012.
DOI: 10.1186/1471-244X-12-38

** Karlsson H. et al. Maternal antibodies to dietary antigens and risk for nonaffective psychosis in offspring. American Journal of Psychiatry. April 2012.
DOI: 10.1176/appi.ajp.2012.11081197

Tuesday 8 May 2012

Carnitine & autism: genes, biochemistry & intervention ideas

Carnitine. Mention of carnitine has graced this blog before with regards to how a deficiency in carnitine might show some relationship with some cases of autism spectrum conditions and the knock-on effects with regards to areas such as mitochondrial dysfunction. The whole relationship between carnitine and autism is still very much a work in progress but the data so far opens up some interesting avenues.

A recent study by Celestino-Soper and colleagues* (full-text) continues the interest in carnitine and autism with the suggestion that issues with a gene, trimethyllysine hydroxylase, epsilon (TMLHE) involved in the biosynthesis of carnitine, might be associated with some cases of autism.

I was drawn to this paper on several levels, not least further evidence that amino acid chemistry might show some involvement to cases of autism and the authors' suggestion of another in-born error of metabolism to be added to a growing list in general medicine. The authorship content of the current paper is a veritable who's who in autism genetic research (here and here for example) bearing in mind some overlap with the recent Nature de novo papers.

The paper is full-text but here are a few highlights:

  • Based on previous findings of potential issues with TMLHE in cases of autism (here), the frequency of mutations in TMLHE was analysed in cases of autism and controls. Various sources were used to acquire participants including the Simons Simplex Collection (SSC) and the Autism Genetic Resource Exchange (AGRE) covering both simplex (one child in the family with autism) and multiplex families (more than one child diagnosed with autism).
  • Deletions of exon 2 seemed to be relatively common in both autism and control groups. So of the control male participants examined, roughly 1 in 366 showed deletions of exon 2. Looking at simplex participants in the autism group, the rate was 1 in 323 presenting with a deletion. When it came to looking at multiplex families, the rate of deletions in the autism group became stronger, estimated at 1 in 130. 
  • Based on this cumulative data, the authors write "The frequency of TMLHE deficiency is startling" suggesting that this in-born error of metabolism is relatively common, approximately 20 times more frequent than phenylketonuria (PKU) in males.
  • When it came to looking at the functional biological effects of exon 2 deletions, based on the activity of 6-N-trimethyllysine dioxygenase (TMLD), enzyme activity was low or undetectable for those carrying the deletion.
  • Urinary and plasma analysis for related metabolites, 6-N-trimethyllysine (TML) 3-hydroxy-6-N-trimethyllysine (HTML) and 4-N-trimethylaminobutyric acid [γ-butyrobetaine (γBB)] suggested alterations in the levels detected according to the presence of TMLHE exon 2 deletions. Some of these metabolites were even suggested to have 'diagnostic potential' for TMLHE deficiency.
  • Cognitive function did not seem to determine TMLHE deletions, varying widely among those with deletions.
  • The authors conclude that TMLHE deficiency is likely to be a risk factor for autism although with low genetic penetrance.

As per just about every genetics paper that I have ever attempted to read, this is quite a complex story to follow if you are not a molecular biologist or at least with some detailed interest in the ways and means of genetics research. It's not quite the dark art of EEG reading, but pretty close.

The authors make some interesting remarks in the manuscript discussion relating to their findings.

First, they talk about the disparity in their results when it came to simplex and mulitplex family findings. Without making too sweeping a generalisation, the argument goes something like this: having more than one child with autism in the family is more likely to represent a stronger genetic component to aetiology as being involved than those cases of a simplex child, bearing in mind the snapshot and 'what if' scenarios of future offspring attached to looking at simplex families. I can see the logic in this argument about single and multiple instances, and how, when it comes to the eternal question of genes vs. environment as per Trading Places and the $1 bet, the heterogeneity of autism might, to some degree become more homogeneous if autism research were to start looking at simplex vs. multiplex autism rather than bundling it all together.

Second, the authors talk about whether or not the 'risk' of autism could potentially be modified by dietary carnitine intake from birth in the early years, perhaps even prenatally and during gestation when it comes to mum's diet. With some degree of caution, I find myself interested in this suggestion, particularly with all the recent interest in epigenetics and how issues like maternal diet might have the propensity to modify offspring risk for lots of different conditions not just autism. I know epigenetic modification is not a large part of the current study but still, genetics is an awfully complicated business where genes being switched on or off by means other than mutation or deletion might be pertinent.

Finally, this is probably not the last we are going to hear about this area of research by this group. Two studies are being initiated we are told, one looking at carnitine metabolites in cerebrospinal fluid (CFS) of infants with autism with or without TMLHE deficiency; a second following on from other research by Geier and colleagues** on the supplementation of L-carnitine or γBB for cases of autism again with and without TMLHE deficiency. A case of watch this space.

Regular readers to this blog will perhaps know that the genetics of autism are becoming more and more complicated as more research emerges. The concept of an 'autism gene' is becoming an ever more distant memory as a result of the cumulative findings and a realisation that autism is an extremely nebulous condition. What I do like about the current paper is that not only does it detail results based on genetic findings, but more than that, it goes through how those findings relate to biochemistry (expression of the gene) and, in this case, the possibility that there may be ways to 'rescue' some of that biological functioning. I also wonder if through epigenetic means, issues with carnitine biosynthesis might also be present in cases of autism without the underlying genetic structural issues and what those all-important modifying variables might be. All that and the need to screen cases for those ever-so important in-born errors of metabolism, I'll be keeping a look out for further results from this group.

To finish something a little less mind-boggling but nevertheless with some bite: The Clash (the law won y'know and don't they keep telling us).

* Celestino-Soper PBS. et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. PNAS. May 2012.
DOI: 10.1073/pnas.1120210109

** Geier DA. et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Medical Science Monitor. 2011; 17: 15-23