How many adults have autism in the UK: part 2

A quick post this one based on some new data recently published estimating the prevalence of autism in adults in the UK. Regular readers might have seen this topic covered previously in this post and this report * from 2009 which estimated the prevalence of autism in adults in the UK to be 1%.

The revised report** (full-text) extends the dataset with the addition of further interviews and suggests that autism (or rather an autism spectrum condition, ASC) may be more widespread amongst people diagnosed with a learning disability living either at home or in 'communal care establishments'. The revised prevalence figure among adults aged 18 or over is 1.1%.

There are a few other interesting facts to come from this new information including:

• Based on the combined prevalence data, the rate of ASCs in men was 2.0% and in women 0.3%. 
• The reported prevalence of ASCs among people with learning disability based in either a home or residential setting was 35.4% and 31% respectively. 
• When specifically looking at those with a learning disability and either home-based or in a residential setting, the rates according to gender were: home: men = 41.5% vs. women = 28.9% and residential: men = 31.1% vs women 30.9%.
• There were no statistically significant differences across ethnicity, although prevalence rates between Whites and those of South Asian descent differed (1.2% vs. 0.8%).
• Highest ASC prevalence was noted among people with more profound learning disability.

Noting that ADOS was used as part of this study and assuming that this did not include the most recent revisions to the scoring algorithm, the prevalence data produced in this study is based on DSM-IV criteria for diagnosis. In light of the various discussions on-going regarding what might happen if an unchanged DSM-V is rolled out, I do wonder how adult prevalence estimates of autism in future may pan out. I suppose the good thing about the current studies by Brugha and colleagues is that they potentially offer a direct comparison against the new DSM-V criteria, should anyone wish to undertake a reanalysis of this population in future.

*  Brugha T. et al. Autism Spectrum Disorders in adults living in households throughout England. Report from the Adult Psychiatric Morbidity Survey 2007. England: The NHS Information Centre for health and
social care, 2009

** Brugha T. et al. Estimating the prevalence of Autism Spectrum Conditions in adults: Extending the 2007 Adult Psychiatric  Morbidity Survey. England: The NHS Information Centre for health and
social care, 2012

Household chemicals and immunity

Mucky paw prints @ Paul Whiteley

Looking around most homes, it is easy to spot the modern face of physics and chemistry in action. I'm not specifically talking about microwave ovens or those other technological labour-saving gadgets like that fancy espresso coffee-maker that we seem so hooked on; but rather more humble examples like the non-stick frying pan or the variety of grease and stain resistant compounds we use to save hours and hours of cleaning and scrubbing.

Whilst it is perhaps slightly unfair to demonise all the chemicals we use - as per this article on the misrepresentation of the words 'chemical-free' - there is a growing recognition that collectively, we have not paid as much attention to the potential effects of some of these everyday substances as we should have done. I'm thinking back to older posts on things like polybrominated diphenyl ethers (PBDEs) for example.

Another case in point is this recent article by Grandjean and colleagues* linking exposure to perfluorinated compounds (PFCs) with a reduction in humoral immune response and in particular, the production of antibodies to two routine childhood vaccines. Quite a good summary of PFCs is here.

There has been some pretty widespread coverage of this paper in both the science and lay media. A summary of the research:

• Based in the Faroe Islands, 587 children born between 1999 and 2001 were included for study.
• Levels of several PFCs including perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), were analysed from maternal blood samples taken during pregnancy alongside children' blood samples drawn at ages 5 and 7 years reflective of pre- and post-natal exposures. PFC values were subsequently compared against children's antibody responses following tetanus and diphtheria immunisation.
• There was a relationship between levels of PFCs and the concentration of antibodies detected in that pretty uniformly PFCs were negatively correlated with antibody levels. That is a higher concentration of PFCs were associated with lower antibody response. Indeed under certain conditions, PFC levels placed children at risk of not having clinically protective levels of antibodies to these diseases. 

The potential implications of this work are pretty far-reaching although there are perhaps a few things to note. This is not the first time that PFCs have been linked to immune effects. Cord blood IgE levels correlated with PFC according to this study and those dastardly proinflammatory cytokines were connected according to this research. This and other similar research points towards immunomodulatary effects from PFCs outside of their other possible links to things like cholesterol and reproductive ability.

In terms of source, PFCs have been detected in several dietary sources particularly seafoods including fish and shellfish. Given the placement of the Faroe Islands (i.e. islands in the North Atlantic), it is not surprising that seafood is high on the menu including some more traditional dishes such as dried fish. Exposure-wise therefore, whilst the focus of the current study is on more everyday objects as being a source for PFCs, intake through food should also be kept in mind.

As with every study, replication is required. Replication not just in children (and mums) from the Faroe Islands but also from other parts of the world. A little more understanding about the relative contribution of genetics and other environmental factors influencing susceptibility might also be useful given that we all seem to be carrying at least some quantity of these compounds around with us. If the results are replicated, it is then up to the various companies and regulatory bodies to make some important decisions on the basis of perceived cost and benefit. As with many chemicals in regular use, it is not just a case of stopping production tomorrow and everything immediately changes overnight. The persistence of these compounds is such that any changes now won't really be seen for several years; the US EPA for example, estimating the serum half-life of PFOS in humans at 5.4 years.

I try not to be alarmist on this blog because ultimately these are studies which whilst providing data on association, cannot possibly take into account the wide variety of other factors potentially involved any relationship. Having said that, the evidence against PFCs is starting to accumulate from both animal and human studies. Perhaps the next time I want to fry my bacon rashers - yes, some people still do that - in healthy olive oil of course, I might just reach old skool for the non non-stick pan.

To finish, how about a little punk rock about that most sensible of floor surfaces, linoleum?

* Grandjean P. et al. Serum vaccine antibody concentrations in children exposed to perfluorinated compounds. JAMA. January 2011. DOI: 10.1001/jama.2011.2034

Epigenetics 101 and autism

Just relaxing @ Paul Whiteley

Ladies and Gentlemen. In the red corner, several million/billion years in the making, the current champion, genetics. In the blue corner, weighing in at several billion/trillion pounds, the challenger, environment.

[OK fellas, a good clean fight].

Ladies and Gentlemen... lets get ready to rumble!

Dramatic opening to post finished as I offer one of my more descriptive entries on the emerging field of epigenetics and some of the research already carried out with specific regards to autism spectrum conditions. I admit that I am sailing on the waves of current interest in this field with this post, being brought to it by the news that we may be seeing a lot more of the word 'epigenetics' in autism research circles soon as per this announcement on funding for Prof. Margaret Daniele Fallin based at Johns Hopkins Bloomberg School of Public Health and an accompanying 'what is epigenetics' post by Autism Speaks. The news that poverty might also have an epigenetic angle also took my interest (take note Politicians the world over).

Epigenetics has been mentioned before on this blog; normally posting a link to this piece in Time magazine about why your DNA is not necessarily your destiny. In short, epigenetics is the study of changes to gene activity without alterations to the genetic code passed down at least one generation. Epigenetics is quite an intellectually satisfying approach for lots of reasons; primarily perhaps because instead of pitting genes against environment in some kind of grudge match boxing contest, it actually suggests that our environment - our diet, our various stresses and exposures right from our earliest days - can affect gene activity by switching genes on or off. Synergy in action.

Another interesting article on epigenetics recently appeared on the Scientific American blog. I don't want to plagiarise what is a very good article, but there are some interesting data and concepts discussed which I do want to mention.

• I can't pretend to be an expert in this area so I won't try. Instead I refer you to quite a good introduction which presents the terms chromatin (the stuff of chromosomes), the DNA-protein mix nicely packaged up to fit into a cell nucleus, and histone, the scaffold around which DNA is wrapped to form nucleosomes.
• There are various ways that histone can be 'modified' including acetylation, methylation and phosphorylation. Such modifications have onward effects which have been described in a 'histone code' which seems to be growing all the time.
• The concept of Lamarckism is gaining in popularity as a consequence of the epigenetics tide. Lamarckism basically states that certain characteristics acquired by a parent can be passed to offspring. So coupled to epigenetics, parental (or grandparental) nutrition for example, might alter gene expression which then gets passed down to successive generations. I'm thinking Barker hypothesis and thin-fat bodies.

I've talked before about genetics on this blog and how whichever way you look at it, genes, mutations, etc. we are all very much a product of mutation and the emerging view is that genetics in relation to autism is a very, very, very complicated thing. I would hasten to add that concepts of Lamarckism are not to be viewed as another 'blame game' idea given that exposure events are likely to be multiple and complex and, as per the wartime famine studies related to the Barker hypothesis, events are not always likely to be under our control.

Very interesting, I (hope I) hear you say. But what about autism?

Well, epigenetics is obviously quite a new area for autism simply because a quick search of PubMed (26/01/12) only reveals 37 entries for the words 'autism and epigenetics'. That's not however to say that there isn't some interesting data already available to look at as I hope I will show.

This overview paper by N. Carolyn Schanen* (full-text) is as good a start as any. It is quite a long paper and not exactly easy to follow unless you are a molecular biologist, but nevertheless it offers some interesting discussions not least forecasting where we are today in terms of lacking any significant, universal genetic markers for autism.

This paper by Mehler and Purpura** (full-text) also has some interesting discussions about epigenetics. Appreciating that there is some degree of speculation in the text on their theory "of a functionally impaired locus coeruleus-noradrenergic (LC-NA) system", I find myself also drawn to their ideas on fever potentially affecting the presentation of symptoms in some cases of autism as per other research among the literature and the possible involvement of antipyretics in some cases.

Finally, this paper by Grafodatskaya and colleagues*** I think sets the tone for where genetics research might be heading in autism research with epigenetics at the helm. Noting that the authorship list includes Peter Szatmari who commented on the twins study published last year (the game changer!), it is difficult to argue against the notion that genes and genetic research is in the midst of a revolution. A revolution where the boxing match between nature and environment might just be replaced by an altogether more understanding relationship.

Cue the candle-lit dinner and (b)romantic music... (for my non-UK audience, read more about the background to this song here).

* Schanen NC. Epigenetics of autism spectrum disorders. Human Molecular Genetics. 2006; 15: R138-R150.

** Mehler MF. & Purpura DP. Autism, fever, epigenetics and the locus coeruleus. Brain Research Reviews. 2009; 59: 388-392.

*** Grafodatskaya D. et al. Autism spectrum disorders and epigenetics. Journal of the American Academy of Child and Adolescent Psychiatry. 2010; 49: 794-809.

The big H strikes again

Stop me if you've heard this one before but homocysteine has already made an appearance a few times on this blog. The studies on homocysteine in relation to autism spectrum conditions, whilst relatively few at the moment, seem to be pointing in a specific direction i.e. plasma levels seem to be elevated. That, combined with the suggestion that elevated plasma homocysteine levels might be influenced by vitamin supplementation at the same time also being under some genetic governance by potentially different mechanisms, hints that this is a compound that perhaps needs quite a bit more research attention.

A recent paper adds to the roll-call of a potential homocysteine-autism link. The paper by Amanat Ali and colleagues* is here (open-access) and reports on a case-control study of fasting plasma homocysteine levels in a small group of children with autism from the Sultanate of Oman. I noted that the paper lists Richard Deth (pronounced Deeth) as a co-author who some readers will know from his work on oxidative stress and methylation. As an aside, there was also a particularly interesting IMFAR poster from Deth and colleagues a couple of years back on how dietary-derived opiates might link into homocysteine and glutathione findings in autism (sorry its only an abstract).

I digress. Back to the paper in question:

• Forty Omani children with autism, aged between 3-5 years old were compared against 40 age- and sex-matched controls for levels of fasting plasma homocysteine, folate and vitamin B12. Immunoassays were the preferred choice of analysis.
• Mean levels of homocysteine were significantly higher in the children with autism over controls; indeed over double the average amount detected in controls. At the same time folate and vitamin B12 levels were significantly lower on average than controls; indeed levels were generally reported as being below the 'deficient' cut-off values described by other authors. I wonder if the folate findings might hark back to the reported folate receptor autoantibodies story?

There's not too much more to say about this paper aside from the fact that it seems to be reporting trends roughly in line with what other authors have previously said. The fact that this study relied on Omani children would tend to suggest that the previous homocysteine findings, limited as they are at the moment, might pass across different ethnicities which is interesting bearing in mind the genetic and environmental differences compared say with Europe or the US. If I was to be a nit-picker I might question the small participant group and could perhaps question the accuracy of immunoassays over other more direct separative analytical technologies particularly when teasing out homocysteine and its dimer homocystine. I don't however want to distract from the main findings which whilst still preliminary, are nevertheless important.

I will keep coming back to homocysteine and its buddy compounds in the methionine cycle and beyond (e.g. methylmalonic acid) as and when they crop up on the research radar.

To end a spot of Strauss to bring back some memories of a space odyssey or a seemingly distant New Years day (Das Neujahrskonzert der Wiener Philharmoniker).

* Ali A. et al. Hyperhomocysteinemia among Omani autistic children: a case-control study. Acta Biochmica Polonica. December 2011

Can you grow out of autism?

An intriguing question to open this post commenting on this study by Heather Close and colleagues* on comorbid conditions and the stability of autism as a diagnosis. In essence the paper suggests two things: (1) autism is rarely a stand-alone condition; a recurring theme on this blog, and (2) autism is not a static condition (see my previous post on diagnostic instability).

To summarise:

• Based on the 2007 National Survey of Children's Health, over 90,000 parents of children aged up to 17 years old were contacted. 
• Of the total population, 1,366 children were identified via parental report as having either a past or current diagnosis of an autism spectrum condition. 453 parents said their child had a diagnosis of autism but didn't anymore.
• Based on age divisions (young children, 3-5 years old), children (6-11 years old) and adolescents (12-17 years old), the authors analysed various responses of background information and the presence of comorbid conditions to ascertain whether there were any differences between those who had a current diagnosis of an autism spectrum condition (ASC) compared with those who had a past but not current (PBNC) diagnosis of an ASC. There were in effect 3 experiments running comparing those with a current diagnosis with those who 'lost' their diagnosis, across the 3 age groupings.
• The findings: youngest children with a current diagnosis of an ASC were more likely (a lot more likely) to have a concurrent learning disability or delayed development compared with the PBNC group. In the 6-11 age bracket, current diagnosis children were more likely to have past speech and hearing problems and concurrent anxiety issues than the PBNC group. In adolescents, past hearing problems and current speech and epilepsy issues were more likely in the current diagnosis group. Currently diagnosed children across the age groups were also more likely to have more comorbidities than the PBNC group. 
• The authors suggest that the presentation of these comorbid features, past or current presentation, likely influences whether or not a diagnosis is retained or 'outgrown'.

There are a few media reports and opinions about this work already. WebMD.com has the headline 'Why some children may 'grow out' of autism'.

Whilst very interested in these results, I find myself in a bit of a quandary. On the one hand is the pretty persistent line presented over the years that autism is a 'lifelong condition' which whilst exemplified by the changing/fluctuating presentation of symptoms as a consequence of things like maturation, in essence is immutable in terms of whether someone has autism or not. On the other hand, we have parents reporting in this study that some of their children having had an autism diagnosis, were no longer considered to have a current diagnosis. I suppose one could argue that the authors were not able to independently test these assumptions out either when diagnosis was originally given or after diagnosis was 'done away with' so a degree of subjectivity should be expected. One perhaps cannot also rule out the subclinical presentation of symptoms such like the ideas on the broader autism phenotype.

Having said that, quite a few people over the years have reported similar things in terms of their child no longer appearing to present on the autism spectrum. Few of these cases have been spontaneous; more often that not associated with some kind of intervention or following mis-diagnosis. I make no value judgements on either of these factors.

One of the authors of the current study, Andrew Zimmerman has quite an extensive autism research career which it has to be said, is perhaps slanted more towards the possibility that other factors/conditions/comorbidities seem to be associated with autism. So for example, familial autoimmunity and medical risk of autism, issues related to inflammation and neuroinflammation, and even a role for fever in abating some of the symptoms of autism. The current findings perhaps extend his interest.

What this latest study does reiterate is that a diagnosis of autism should not be the end-point to determining why a person behaves the way they do. Given recent posts on SPAD, CFD and all manner of other conditions potentially more prevalent in cases of autism (glutathione issues?), a diagnosis of autism should really be the starting point to try and ascertain whether these and/or other conditions contribute to the presentation of autism or at least whether they can adversely affect quality of life. Whilst token mention has been made about the impact of intervention on some cases of autism in this current paper, it does not seem beyond the realms of possibility that intervention might have had a role to play (with the caveat that much more targeted research is needed).

So the question remains: can you grow out of autism?

* Close H. et al. Co-occurring conditions and change in diagnosis in autism spectrum disorders. Pediatrics. January 2012.

Vitamin D and intestinal barrier integrity

I've learned some key lessons over the years when it comes to science and the interpretation of science. Probably the most important lesson is that rarely in science do you find a simple relationship between two variables. By this I mean that just because researchers report studying and finding a connection between one factor and one outcome does not necessarily mean it is that one factor which solely 'causes' or 'correlates' with that outcome. Indeed more often that not, several factors are connected to that outcome and the link is often pretty complex particularly when applied to the complexity of human (and animal) biochemistry.

I say all this because an interesting paper was passed to me a few weeks back authored by Kong and colleagues* (full-text) on the potential role of vitamin D and its receptors on the gastrointestinal (gut) barrier and in particular what happens to mice where vitamin receptor deficiency is present. There have been some interesting discussions on vitamin D in recent times. I note Emily Dean's post on vitamin D and depression as one. Keep this in mind for now.

With my autism research hat on, two primary concepts included in this paper were of immediate interest in that (i) 'issues' with the permeability of the gut barrier have been discussed for quite a few years with autism, some cases of autism, in mind and (ii) vitamin D deficiency has likewise been reported in some populations as a potential predisposing factor (think Sweden and Somali populations).

I admit that I am turning into quite a keen vitamin D research-watcher these days given the amount of research telling us that it does this and that. At the same time I am mindful that other vitamins/minerals/other compounds(?) have had a similar trendy following over previous years; thinking back to the age when vitamin C was the bees knees or more recently the tide that is omega-3 fish oils. We humans are a fickle bunch.

Anyhow back to Kong and colleagues. The paper is open access but once again the summary is as follows:

• Vitamin D receptor deficient mice were compared with wild positive mice when colitis was experimentally induced.
• Receptor deficient mice (homozygous for the deficiency) showed greater damage to the gut mucosa than those without the receptor mutation based on several different measures. The damage was pretty different between the two models and importantly, recovery of the mucosa following discontinuation of the induced colitis was less apparent in the deficient mice group than the control.
• Based on these results, the authors also reported on some experiments to assess why the damage occurred. So for example, they reported that treatment of various cells with vitamin D seemed to be linked to a stimulation of various tight junction proteins contributing to better mucosal integrity. They conclude that vitamin D deficiency might be linked to the increased incidence/prevalence of inflammatory bowel diseases (IBDs) in human populations based on this and other data.

OK perhaps I should have said that there were three potentially interesting links for this work back to autism with the additional suggestion that IBDs might also be involved (here).

Going back to how I started this post on one factor and one outcome, it is perhaps all too easy to overlay the findings back to autism and in particular, that potentially very important link with autism rates in immigrant populations in Sweden. As far as I am aware however there are a few important pieces of information missing from the current picture including (a) how many people with autism are actually deficient in vitamin D, (b) whether there are any problems with vitamin D receptors in cases of autism bearing in mind that receptor differences could be due to genetic issues or possibly infection, (c) whether Somali children/adults with autism show any difference in vitamin D levels or receptor activity compared with other ethnic groups with autism, and (d) is the incidence of gut hyperpermeability or IBDs any greater in Somali children/adults with autism over other groups with autism? Questions, questions, questions.

I might also add that gut hyperpermeability is a mighty complex thing which so far has not yet been studied in great detail with regards to autism. So alongside questions on what causes the hyperpermeability, there are issues concerned with what type of permeability is present (paracellular vs transcellular) and what about the expression of those all-important tight junction proteins with such lyrical names as zonula occludens 1 (ZO-1), the claudins and E-cadherin; all still requiring answers. It might also be useful to also know whether permeability if present, is limited to the gut or whether, as has been speculated by others, leaky gut might also translate into leaky other organs too (leaky kidneys perhaps?). The implications of the immune system meeting things like gut bacteria potentially as a result of leaky gut also need to be followed up.

I remain intrigued by the Kong findings on vitamin D and gut hyperpermeability in the mouse model and perhaps even more now, eagerly await the results of the promised studies looking in more detail at the risk of autism in Somali populations. Going back to the vitamin D-depression post, I do wonder how much this might overlap and whether another post by Dr Deans on depression and the leaky gut might, just might, figure in some shape or form.

To end a cover version of the Charlie Daniels Band classic by the Levellers. Fiddlers from Georgia at the ready...

* Kong J. et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol 294: G208–G216, 2008.