Wednesday 30 November 2011

Autism and the thyroid

The thyroid has been mentioned quite a bit in the media and science circles this year. Following the catastrophic effects of the earthquake and tsunami in Japan this year, images of the Fukushima Daiichi nuclear plant going into meltdown were projected across the world. The fear was that because radioactive particles of iodine (and quite a few other things) have been released and given that thyroid cells are the only cells in the body that absorb iodine, there might be some risk. A similar effect seemed to be realised after the Chernobyl meltdown where rates of thyroid cancer roundabout shot up.

The thyroid is a small gland in the neck whose key job is to convert iodine into thyroid hormones. These thyroid hormones in turn regulate the metabolism of things like proteins, fats and carbohydrates and energy and metabolic processes. The main thyroid pre-hormone is thyroxin (T4) which in the liver is activated to triiodothyronine (T3), the active hormone. Smallish amounts of other hormones are also formed in the thyroid gland. Thyrotrophin releasing hormone (TRH) is released from the hypothalamus when T3 and T4 levels drop, which in turn asks the anterior pituitary to release thyroid stimulating hormone (TSH) to release more T3 and T4. Another good example of our amazing bodily feedback capabilities.

When things go wrong with the thyroid it normally goes one of two ways: hypothyroidism, where hormone production is lower than it should be (primary or secondary), or hyperthyroidism, where lots of hormone is produced. Graves' diseases is an autoimmune condition and a common form of hyperthyroidism.

OK thyroid 101 is over. What about any connection to autism spectrum conditions?

A fairly recent paper by Hoshiko and colleagues* adds to what is a small but growing body of work examining the thyroid and its minion hormones in relation to autism. Based on the combined strength of two study groups based in California, USA, 544 cases of autism were compared with 784 matched controls, and an elevated risk of autism was suggested where T4 levels were very low. The caveat to this statement is that significance was only reached for one cohort born in 1995. Remember T4 is the prehormone.

I have touched upon thyroid function and autism before on this blog. In that post, there was a suggestion of a link between autism and flame retardant materials containing PBDEs. Looking at the other research in this area, the results could best be described as mixed. This paper for example, again examining neonatal thyroxine levels in various neurodevelopmental conditions failed to find any significant association. Indeed quite a few of the earlier studies in this area reported no overall association between thyroid hormone concentrations and autism despite some individual cases potentially being linked.

That being said, don't rule out any thyroid connection just yet. Jim Adams and colleagues reported a 45% reduction in iodine levels in their cohort of children with autism which they speculated might tie into some problems with thyroid function (see here for an overview of iodine deficiency). This finding was part of a wider issue with other elements and perhaps mirrors similar problems recently reported on. Likewise this paper suggested that for those cases of autism where regression was reported, there might be an association with a family history of autoimmune thyroid disease. I have a post scheduled soon on the regression/brain overgrowth findings in autism reported recently; perhaps thyroid issues should form part of further phenotypic investigations?

With these collected research in mind, together with other 'possible' connections such as thyroid function and reelin (mentioned in autism research), I wouldn't necessarily close the book on any links between autism and thyroid function just yet. Indeed the link between the thyroid and psychiatry is just starting to get quite interesting..

* Hoshiko S. et al. Are thyroid hormone concentrations at birth associated with subsequent autism diagnosis? Autism Research. August 2011.

Sunday 27 November 2011

Joint hypermobility

Take a look at the picture in this post taken from this link describing joint hypermobility on the NHS Choices website. Notice the unusual orientation of the thumb in the picture, something that most of us would be unable to do without at least having a rather painful broken thumb. This is one example of joint hypermobility, where joints are able to stretch further than normal.

Source: NHS Choices website
I don't know about you but I had several contortionists in the making in my classes at school. Kids who were pretty well versed in showing off their hypermobile joints (often to the detriment of us not so talented children). Not surprisingly these were probably the same kids who easily perfected 'the caterpillar' and similar electric boogaloo moves whilst the rest of us ended up just doin' the slug.

It is probably not surprising that quite a few of the population possess at least one hypermobile joint party trick. Indeed joint laxity or double-jointedness, as it is also (rightly or wrongly) called, seems to be present in an estimated 10-20% of people, mostly without causing any problems. But that is not to say that such suppleness is not without cost in some cases, where joint hypermobility can be linked with pain and other symptoms in some cases to form joint hypermobility syndrome (JHS). Diagnosing JHS is a relatively straight-forward process given the availability of information such as the Brighton criteria although there is still some discussion on the recognition and acceptance of JHS.

Although perhaps an unusual relationship, it has long been known that patients with JHS also present with a variety of other symptoms not necessarily connected to musculoskeletal symptoms. This paper highlighted a range of symptoms stretching (pardon the wordplay) from cardio-respiratory to gastrointestinal (GI) to other effects like migraine and sleep disturbances. My eye was immediately drawn to the GI issues suggested to be associated with JHS primarily because JHS is a disorder of connective tissue. Under such a broad heading, some (like this paper) have suggested a possible link between JHS and functional bowel problems of unexplained origin. Moving further into the GI-JHS link, a recent paper also asked a few questions about screening for coeliac (celiac) disease in cases of JHS (linked also to Ehlers-Danlos syndrome).

For quite a few years now, there have been rumblings about a possible connection between joint hypermobility and some cases of autism; that is children and adults with autism who seem to be very, very supple. Without trying to make any judgments, UK readers might remember a very nimble young chap with autism who did very well on Britain's Got Talent (quite the photo I am sure you will agree).

Searching the published scientific literature all I have been able to find is the odd case study like this one suggestive of an 'association' in individual cases of rare genetic findings. I note however that joint hypermobility has not yet been explored in a more population-wide systematic way for autism spectrum conditions so reports remain anecdotal.

To finish, and keeping the breakdance theme alive, Run DMC reloaded.

Thursday 24 November 2011

Glutathione and autism

I am going to be fairly brief with this topic on this occasion. Part of this is to ensure that I don't take up too much of my American readers' time on Thanksgiving Day and partly because this post is really more for me to get things straight in my mind about glutathione and its potential links with at least some cases of autism. If it helps you too, all the better.

USDA Agricultural Research Service
Glutathione (GSH) is fast becoming one of the elephants in the room compounds in relation to autism as it might also be in some other conditions. Quite a few people have been talking about it and its various chemical relations in connection to autism spectrum conditions for a while now. I have been following a few of those discussions down the years but always felt a little out of my depth when trying to piece together where it might fit into the heterogeneity that is autism.

A few things have changed of late which have made me take a little more interest in glutathione in general. First is a growing appreciation of the whole homocysteine-methionine cycle (the big 'H' in particular). Second is a little more understanding about oxidative stress and antioxidants (particularly the recycling of antioxidants). Finally a recent look back at just how important the work of Rosemary Waring on sulphation might actually be to some cases of autism.

A new paper has appeared on glutathione and autism from Yusra Al-Yafee and colleagues* (full-text) which has turned my head. Yes, it was another King Saud University publication to add to the many. For any UK-based academics watching, this is one research group who if were ever submitted, would not be fretting over the publications element to REF 2014.

Before I go on I should perhaps give a brief description of what glutathione is. So with a Twitter limit (140 characters or less): tri-peptide, antioxidant, xenobiotic metabolism, cofactor, DNA synthesis, nitric oxide, NAC, one-carbon metabolism. Out of this description, one of the most important functions for glutathione is its antioxidant capability and the link between low levels and oxidative stress. So, the reduced form of glutathione is basically the active, able to 'grab a free radical' version of glutathione and should be present in the greatest proportion when compared with the oxidised form, the 'I already have a free radical' form (glutathione disulfide), which is then recycled back to its reduced form to continue its scavenge. Ain't human bodies great things?

The current paper reported that levels of total glutathione were low in participants with autism, and when I say low, I mean low: 100% of participants were below the lowest level of total glutathione determined in the control group. For the second time in only a few days, the characters AUC and 1 has appeared on this blog, denoting that at least within this participant group, glutathione levels at a certain cut-off point seemed to distinguish 100% of autistic samples from control samples (and on more than one parameter, see table 3).  Of course the sample groups were small (n=20 apiece) so perhaps we should not read too much into this finding at the present time but it is interesting.

I probably will come back to glutathione in the near future to describe and discuss further. With all this talk of scavenging and mopping up, how about a bit of domestic routine courtesy of the late, great Freddie who passed away 20 years ago today.

* Al-Yaff A. et al. Novel metabolic biomarkers related to sulfur-dependent detoxification pathways
in autistic patients of Saudi Arabia. BMC Neurology. November 2011

Tuesday 22 November 2011

CNVs and intellectual disability

A very quick post based on an interesting paper published in PLoS Genetics by Girirajan and colleagues* on our old friends the copy number variations (CNVs).

The paper is open access so no need for me to summarise too much but I will say:

  • Samples from over 1200 individuals were analysed for the frequency of large CNVs in genomic hotspots. Individuals were grouped into those with dyslexia, autism and intellectual disability (ID) (with an asymptomatic control group also included).
  • The appearance of various large CNVs between the groups seemed to suggest that the presence of intellectual disability was the primary correlate. So in the ID group (n=501) the odds ratio of possessing a large CNV was 13.71 with a p-value (significance) going down to about 17 decimal places (highly significant). The autism group (n=350) also showed greater odds of possessing a large CNV (odds ratio = 2.99) although nowhere near as significant as in the ID group (p=0.012). The dyslexia group also relative to controls showed... nothing.
  • Dividing the autism group up into those with (n=97) and without ID (n=253) continued the trend towards a relationship between large CNVs and cases with ID, although this was not found to be significantly different between the groups (p=0.102).
  • When looking at rare CNVs (less than 50% overlap of CNV length with those found in controls) there was more of an association with autism (10% of participants carrying 36 rare CNVs, odds ratio=6) and also continuing the relationship with ID (16% of participants carrying 77 rare CNVs, odds ratio=10). Dyslexia with regards to rare CNVs again showed nothing compared to asymptomatic controls. Nearly half of the rare CNVs reported in autism or ID groups seemed to be de novo (so not passed from parents).

There is a lot more data in this paper on what was found CNV-wise and in which group. Interesting was the degree of overlap between the results from the conditions looked at; so for example, CNVs in the region coding for the AUTS2 variant being found in two cases of dyslexia. Interesting also that the numbers of cases of autism carrying CNVs is about the same as picked up in other studies (10-11%).

I was struck by the relationship suggested in this study between large CNVs and intellectual disability. Very recently I posted an entry regarding CNVs and ADHD which seemed to arrive at a similar conclusion on the involvement of intellectual disability and CNVs. This combined with the current study and the fact that dyslexia is not usually viewed as an intellectual disability (as opposed to a learning or reading disability) adds further weight to the relationship.

The bottom line I suppose from this study is that autism is a very complicated condition, and the whole really is greater than the sum of its parts in terms of the various comorbidity which can and do appear alongside. CNVs may represent one strand of that complexity but with 90% of cases from this study showing no rare CNVs, perhaps we should be looking elsewhere, perhaps to epigentics and environment for some of the answers?

* Girirajan S. et al. Relative burden of large CNVs on a range of neurodevelopmental phenotypes. PLoS Genetics. November 2011.

Monday 21 November 2011

OCD and autism: symptom overlap or discrete conditions?

Hoarding and the personal/familial effects of hoarding behaviours has been very briefly mentioned on this blog. The various elements to hoarding behaviour based on things like compulsion and explanations on the 'functionality' of hoarded objects makes for quite a complicated condition.

A recent paper by Pertusa and colleagues* asked a few questions about whether: (i) hoarding behaviours might be related to certain autistic traits and (ii) how hoarding behaviour in cases of autism might manifest with regards to comorbidity. Their results were complicated in that yes, those engaging in hoarding behaviours showed a greater degree of autistic traits compared to asymptomatic controls. Hoarding behaviour in this non-autism group were however also reportedly related to the presence of obsessive-compulsive traits. By comparison, hoarding behaviour noted in a group diagnosed with autism seemed to be unrelated to any comorbid obsessive-compulsive issues.

On the back of such research I want to talk about the association between OCD (Obsessive Compulsive Disorder) and autism, and in particular, OCD as a discrete clinical diagnosis in cases of autism, where many people might assume that some of core traits associated with autism are/overlay with OCD. The traits in question are those associated with the repetitive behaviour domain which in some cases, may seem to develop certain 'obsessional' or 'compulsive' aspects to them. So for example, talking about one particular subject or at least consistently steering a conversation towards that topic, and the insistence on following a certain routine (with often notable anxiety if not carried out to specification). Whilst there is little doubt that such repetitive behaviours can become compulsive and obsessional in nature, the question posed is: do they fit the criteria for OCD as a discrete diagnosis?

As you might imagine there is no straight-forward, universal answer to this question, but there are some clues. Clues which seem to suggest that rather than assigning every single behaviour seen in autism to autism, there are some presentations which may merit additional investigation and potential discrete diagnosis based on their frequency and severity. I suppose I have covered similar ground in my previous posts on PTSD and autism and also suggesting that at the moment, autism does not seem to confer any protection against developing other conditions during my various musings on autism and things like ADHD.

It may be worthwhile showing you the diagnostic criteria for OCD in both current versions of DSM and ICD. I wouldn't really do the diagnosis justice if I tried to describe OCD in just a few words, but the watch words are (a) obsession/s - the same images, ideas or impulses being thought about again and again, (b) compulsion/s - repetitive behaviours or mental acts often applied quite rigidly and (c) anxiety and distress - either caused by such obsessions and/or compulsions or as a result if certain actions aren't carried out.

For those with some experience of autism, you can perhaps see how OCD and autism might, in some cases, be quite difficult to separate out. Indeed much of the research literature on OCD and autism spectrum conditions has a pretty hard time teasing out the differences (here and here).

A recent study by van Steensel and colleague (full-text)** however looking at anxiety-related conditions presented concurrent to autism reported that 17% of people with an autism spectrum condition also presented with a verifiable DSM-IV diagnosis of OCD. The strength of this study lay in the fact that it was a meta-analysis and hence combines to form quite a large participant sample (N=2000+). Aside from going back to that 'not everything is caused by autism' notion, there are a few other important consequences of these findings, not least the various strategies potentially available to alleviate the obsessive/compulsive aspects to OCD and the resultant anxiety. Some of the main strategies are detailed here (noting that I am not offering any advice or guidance). Given the recent post on SSRIs and autism, I might perhaps be a little cautious about their use when autism is co-morbid. Having said that, it is not outside the realms of possibility that those 'best-responders' to SSRI-based pharmacotherapy might be those people with autism with significant OCD issues. A case of pharmacotherapy not targeting the core symptoms but rather the peripheral ones which then impact on core presentation (as argued previously here).

There are no easy or straight-forward answers to the autism-OCD link. What this and other research does however point to is that when it comes to the assessment of autism currently made, and those to be made in future when schedules like DSM-V are enacted, clinicians need to be vigilant for lots of different behavioural pointers. These may not necessarily be just those related to the presentation of autism; mindful that conditions like OCD can also develop at later stages.

* Pertusa A. et al. Do patients with hoarding disorder have autistic traits? Depression & Anxiety. November 2011.

** van Steensel FJA. et al. Anxiety disorders in children and adolescents with autistic spectrum disorders: a meta-analysis. Clinical Child & Family Psychology Review. 2011: 14: 302-317

Thursday 17 November 2011

Starring autism in DSM-5

It has been several years in the making but like a Hollywood blockbuster come May 2013, DSM-5 or DSM-V if you prefer, will be heading to a psychologist, psychiatrist or combined CAMHS team near you, rated... well I will leave that decision to you.

There have been quite a few debates about DSM-5. More generally both the American Psychological Association and the British Psychological Society (BPS) have voiced some concern over several issues with the proposals which have been summarised in an open letter. The main factors highlighted include: the rapid expansion of the diagnostic system, a perceived lack of scientific rigor and review and an overly-complex dimensional aspect to many conditions within the DSM-5. The BPS is also particularly concerned about the apparent lack of recognition of social factors such as poverty as being pertinent to a person' psychological health and wellbeing and the impact of stigma. I covered something similar to this in a recent post on the current woes of Greece.

We will see what becomes of these concerns voiced by such learned societies.

With autism spectrum conditions specifically in mind, I have previously covered a few topics of potential interest to DSM-5 on this blog. There have for example, been subtle clues to how autism will pan out in the new DSM revision for quite a few years now as evidenced by things like changes to the algorithm used as part of ADOS and papers looking at historical recall with regards to the cut-off ages for presentation of the autism.

Another clue to the changes to autism diagnosis came quite recently following the publication of a paper by Catherine Lord and colleagues* on the lack of consensus about best-estimate diagnostic sub-groups labels applied across different trained groups.

The paper by Lord (who has fairly recently moved jobs) et al has received quite a lot of press, along the lines of 'Autism or Asperger's? It might depend on your doctor' reiterating what has perhaps been known about for many years: physicians are artists and brush stokes vary from physician to physician. The latest paper looked at just over 2100 children diagnosed with autism via ADI-R and/or ADOS spread across 12 participating sites. Based on various pieces of information covering various autism- and cognitive-related measures, best-estimate diagnostic labels were compared across the sites and lo and behold, the artists, sorry physicians, were not in total agreement about labels. So a child's final diagnostic label is, to a degree, dependent on who synthesised the pertinent material and gave the diagnosis.

I note that quite a few 'I told you so' soundbites have followed this study. I pass no comment on these except for the fact that DSM-IV, and its modifications, has been with us for 17 years so far and perhaps therefore the question of why it has taken so long to do a study like this should be asked. Did no-one ever think that this should have been part of the field testing for DSM-IV?

I digress. The study has been used as evidence for the assignment of a dimensional description to the triad (sorry dyad) of symptoms as per the DSM-5 recommendations. There is some growing support for the options laid out in DSM-5 from other sources; so imaging studies, more imaging studies and co-morbidity research. Despite this, the research is not all one-way; not at all. I don't think this will be the last piece of research to be published pertinent to the important diagnostic changes put forward in DSM-5.

Finally, I do think we should try and keep in mind two important things: (i) autism or whatever variant detailed is not just a label; it is not just a collection of symptoms gathered under a few sentences of descriptions, it is real life and as complicated as 'not autism', and (ii) changes to those labels need to be done for the right reasons; so if it means that people will better receive the help, support, services, etc they need/want under DSM-5, targeted to that persons strengths and weaknesses, so be it. If it however means that it is just easier to categorise people for a research study or investigation based on where they appear on the autism spectrum, I would perhaps suggest that we should be investing more in suitable research tools for this purpose.

Speaking of physicians as artists, have a read through this recent article** (click the 'Article as PDF' option in the right sidebar to download it, not forgetting to scan for viruses first).

* Lord C. et al. A multisite study of the clinical diagnosis of different autism spectrum disorders. Archives of General Psychiatry. November 2011.
** Gupta VB. & Lauffer D. Should the diagnosis of autism be made only on the basis of a standardized test? Journal of Developmental & Behavioral Pediatrics. November 2011

Tuesday 15 November 2011

The bean counters of autism

Good economic management is an absolute prerequisite for any business. Formulating an accurate business plan, projecting income and expenditure and eventually balancing the books all makes for a healthy venture and the avoidance of future problems. I don't think anyone would disagree with these notions; not even when applied to businesses as large as Government and the various services it offers.

The thing about economics and finance when applied to 'people' services, such as health and social spending, is however that they can tend to resign people to mere statistics. Words like 'cost-benefit ratio' then start to be introduced as per what seems to be happening with childhood heart units here in the UK. I tend to get nervous when I see such words because people, individual statistics, then start getting grouped into larger statistics, which can in some cases lose sight of the individual and their individual needs.

A recent paper published by Barrett and colleagues* adds to what is a growing number of research looking at the economics of autism spectrum conditions. Coincidentally I happened to be reading this blog post asking the question: how expensive is autism? The author's answer, not cheap, but to coin a phrase 'you're worth it'.

Barratt et al considered the various services and wider societal costs of very young children with autism in the UK as part of the PACT consortium study (which unfortunately reported only limited benefit from their parent communication intervention). The figure they arrived at per child with autism ranged from about £53 - £1,116 per month, with an average of £430 or about $680 (US). This figure covered everything from contact with healthcare professionals and other hospital and community services. Interestingly some of the families of the 152 children included in the report received little statutory support.

Other papers have detailed similar economic analyses of autism. This paper for example looked at range of childhood developmental conditions and concluded that aside from severe cognitive impairment, the range of autistic conditions carried one of the more significant economic costs to the public sector. Similar studies have reported similar results (here and here). The 2001 paper by Järbrink & Knapp estimated a cost of £1 billion per year for autism here in the UK, although that was based on an assumed prevalence of 5 per 10,000 people!

There are some difficult questions to ask from this collected number crunching: the numbers of cases, availability of services throughout the lifetime, the financial effects on parents/caregivers, use of intervention and intervening to modify symptom presentation; made all the more difficult by the various 'austerity' measures that are starting to impact on everybody's life in these uncertain times. Unfortunately, questions aplenty, solutions seem to be in short supply.

To finish, I had the pleasure of seeing an updated, reformed version of Arthur 2 Stroke in South Shields a few days back so here is a blast from the past (happy birthday Jane & Geoff).

* Barrett B. et al. Service and wider societal costs of very young children with autism in the UK. JADD. November 2011.

Saturday 12 November 2011

Cholesterol levels in autism: Vader or Skywalker?

Cholesterol is a substance with a bad reputation. Blamed for everything from causing an increased risk of coronary heart disease to upping the risk of stroke via things like the very curiously titled metabolic syndrome, high total cholesterol levels are the Darth Vader of health, the dark side incarnate (at least episode IV & V dark side). As a result, modern society has been mobilised to do everything it can to reduce cholesterol; be it through food, medication, or exercise.

I have discussed the concept of risk quite a few times on this blog and how risk, whilst generally important, takes little account of our individual differences and circumstances. I don't feel that I am suitably qualified to contribute too much to any general debate about cholesterol and health, although my reading around this topic would perhaps suggest that the relationship between cholesterol and health is perhaps not as simple as many people might believe; a point highlighted by this recent post in Scientific American. Indeed Anakin Skywalker (episodes II, III and VI) over Darth Vader might be a better description of cholesterol: a bit of good and a bit of the dark side.

There are a few findings emerging in the area of cholesterol and developmentally-defined conditions which are worthy of some comment, some of which have already been discussed in the blogosphere. Fairly recently cholesterol featured in a post about chronic illness risk and autism. I will at this point repeat my well-chanted mantra: no medical advice is intended or given and please consult with your physician before making any changes to any dietary or medication regime.

Not surprisingly quite a bit of the literature on cholesterol and autism focuses on lifestyle issues like being overweight / levels of obesity and the possible physical side-effects from various medications associated with autism spectrum conditions. Whilst not wishing to downplay such health inequalities, I will instead focus on a few other areas of interest: measured levels of cholesterol and autism's association with other cholesterol-linked conditions.

When it comes to measured cholesterol levels in autism, there are a few, mixed trends appearing including this one pointing towards higher total cholesterol levels and higher low-density lipoprotein (LDL) levels (LDL = the 'bad' cholesterol) in a small trial of people with Asperger syndrome. This is contrasted with this study reporting values from children with autism where no significant difference was noted in either total or LDL levels compared to controls. This study based on samples from the AGRE dataset, found that about a fifth of participants with autism studied actually had low levels of cholesterol, defined as below the 5th centile in population terms. There are some obvious differences between these studies in terms of age, diagnosis and ethnicity which perhaps should be kept in mind before getting too carried away. One should perhaps also realise that measuring cholesterol on its own might mean very little without any other correlations related to symptom presentation or other health-related factors going back to metabolic syndrome.

One condition linked to cholesterol seems to crop up quite a lot in the various searches: the association between autism and Smith-Lemli Opitz syndrome (SLOS). SLOS is a genetic condition which biochemically, is characterised by a failure to make enough cholesterol and the subsequent knock-on effects this has. Interestingly, vitamin D is synthesised from cholesterol, going back to my previous post on the sunshine chemical. The limited research on vitamin D status in SLOS is however a little mixed regarding any deficiency being potentially present.

There is quite a lot of evidence for the appearance of autism or rather autistic symptoms occurring in many cases of SLOS, although as per the study previously highlighted by Tierney and colleagues, the reverse - SLOS appearing in many cases of autism - does not appear to be true. Having said that in those cases of autism where cholesterol is low, discussions have centred on the use of cholesterol supplements to increase circulating levels. Given that Mr Vader reputation for cholesterol, many people might find the idea of giving cholesterol slightly counter-intuitive to our modern-day health messages. This is probably why, at the time of writing, there is a bit of a hole in the research literature when it comes to cholesterol supplementation for autism. I did find this article reviewing its potential use and there are apparently trials on-going with regards to its potential effectiveness for cases of autism. This paper (full-text) again featuring Elaine Tierney offers a few other ideas. We wait and see what they report.

I don't want anyone to assume that from this post I am anti- anti-cholesterol because I am not (?). I do however believe that our modern-day relationship with cholesterol, like so many other things, is complicated. It was not so long ago for example that we were talking about violent deaths being associated with the lowering of cholesterol, in particular suicide attempts and low cholesterol in things like bipolar disorder, something which has resurfaced in discussions this year. Perhaps counter to my previous posts trying to assert the importance of environment alongside genes to many conditions including cases of autism, here I suggest that genes are also potentially as important as environment when it comes to cholesterol and autism and perhaps lots of other things too.

So then, Vader or Skywalker?

Friday 11 November 2011

In Flanders fields the poppies blow

I pause today, as many millions of others do, to remember. To remember the end of the War to end all Wars on the 11th hour of the 11th day of the 11th month and the fallen ever since, around the world, who have paid the ultimate sacrifice.
Source: Daily Telegraph (UK)

No research, no analysis, no commentary just a poem by John McCrae lest we forget:

In Flanders fields the poppies blow
Between the crosses, row on row,
That mark our place; and in the sky
The larks, still bravely singing, fly
Scarce heard amid the guns below.

We are the Dead. Short days ago
We lived, felt dawn, saw sunset glow,
Loved and were loved, and now we lie,
In Flanders fields.

Take up our quarrel with the foe:
To you from failing hands we throw
The torch; be yours to hold it high.
If ye break faith with us who die
We shall not sleep, though poppies grow
In Flanders fields.

Wednesday 9 November 2011

Brains, epigenetics and neuron numbers

In a post a few months back on 'what do we know about autism' I discussed some of the various views and opinions that certain professionals have about autism spectrum conditions. Although not exactly a complete picture of such a heterogeneous condition like autism, summarising what we know (and don't know) about 'general autism' at least provides a starting point for where research might want to 'project' itself in future.

In among the various findings, research on the brain and autism figured heavily; highlighting the issue of head size and brain growth alongside the fact that autism is not, generally speaking, due to a localised brain issue. With this in mind, a few interesting studies have been published in recent days which require some comment.

The first study by probably one of the most well-known names in autism brain research, Eric Courchesne and colleagues* suggested that in one part of the brain, the prefrontal cortex, children with autism might have more brain cells (neurons) than control children.  Based on examination of post-mortem prefrontal brain tissue, the numbers of neurons were counted from 7 children with autism and compared with 6 controls. The results suggested that the total numbers of neurons were increased in the autism group, and specifically in the dorsolateral prefrontal cortex. This alongside findings of a heavier brain in autism compared to controls.

Bearing in mind the small participant numbers and the fact the neurons can only really be counted when someone is deceased, there is some interest in this paper. The prefrontal cortex (I am reliably informed) is linked to quite a few things including social and communicative behaviours; areas with more than a passing relationship to autism. I would hasten to add that there are lots of other correlated functions and behaviours to this area as there is with other brain areas. You might think, more neurons = better functioning in these areas but unfortunately things are not so straight-forward, hence the reason why we tend prune our brain cells during certain points of our lives. Efficiency it seems trumps quantity.

The second paper, by Shulha and colleagues** also looked at brains and indeed the same region of the brain as Courchesne and colleagues, the prefrontal cortex, looking to characterise the epigenetic signature of autism. Epigenetics is basically environment; changes to gene activity not down to changes in DNA. Looking at post-mortem brain tissue from 16 people with autism and 16 controls, they examined samples for a specific epigenetic signature, histone methylation, and found many, many loci affected by altered histone methylation, most of which were not down to DNA mutation. In most cases, genes were switched on or off for reasons other than mutation (SNPs).

In both these papers, there is an interesting intersection between brain, genes and environment. The prefrontal cortex is one of the majority of brain areas that develop early on in-utero hence speculation has turned to some prenatal factor as potentially being involved. My mind wanders back to the study on vits and SNPs at this point, as one of a number of potentially interesting correlations. I do wonder if we ought also to be looking back at some older research on a possible role for disordered endogenous opioid peptide chemistry as potentially being involved in their role as neuronal pruning agents. Without trying to sound too 'he does not know what he is talking about' how about any involvement from the caspases also?

* Courchesne E. et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. Novemeber 2011.
** Shulha HP. et al. Epigenetic signatures of autism. Archives of General Psychiatry. November 2011.

Monday 7 November 2011

The link with zinc

A while back on this blog, the mineral zinc was discussed in relation to quite a few things ranging from the common cold to alcohol metabolism to developmental conditions like autism and ADHD. The collected data on zinc and ADHD were perhaps most interesting and most suggestive of some relationship between reduced levels and specific symptoms like inattention, with the fairly large caveat of a need for more detailed study.

A possible link between zinc and autism was a little more tenuous; some limited suggestion of zinc deficiency in some cases but at the same time reports of an excess of zinc also being found in other cases. A new paper enters the zinc arena followed by some pretty big headlines.

The paper by Hiroshi Yasuda and colleagues* (full-text) reports on measures of hair zinc concentrations from quite a large group (n=1967) of children with autism. Based on ICP-Mass Spectrometric analysis, the authors report that a sizeable proportion of their participant group (males 0-3 years old: 43.5%, females: 52,5%) seemed to be deficient in zinc compared with other reference ranges. They go on to suggest that perhaps through epigenetic processes such deficiency might be contributory to the aetiology of autism (in some cases).

As per such findings, media headlines follow, such as this one from the UK Daily Mail 'Children with low levels of zinc may be at higher risk of autism'. Fairs fair, the headline is balanced by a couple of comments on the lack of appropriate control groups and whether results imply causation or are merely epiphenomenal.

I am however intrigued by this data. Whilst not disagreeing with the requirement for appropriate independent age- and sex-matched control groups when looking at any sort of parameter for autism or anything else, I note that the reference ranges used were actually partially derived from the same research team under different publication coupled with other datasets. I suppose this point would be remedied further by more control population data being produced by the same lab; so looking at comparison groups like learning disability or speech and language disorder (without autism) for example. The accompanying point about ensuring that ethnicity was also controlled for might also be relevant.

Irrespective of any autism-causation link or not, here are results which suggest that quite a large number of children might be pretty deficient in what is quite an important mineral. The question must surely be asked, why? I note that the words 'leaky gut' crop up in the paper as one possible explanation and no doubt some people will have read this and sighed, 'not that again'. As mentioned quite a few times on this blog, hyperpermeability of the gastrointestinal membrane is however slowly starting to move out of the realms of fantasy as being documented in at least a proportion of cases of autism spectrum conditions. Remember de Magistris and colleagues? As per what happens in other conditions where leaky gut is present, deficiencies of nutrients occurs and only when permeability issues are put right do you see something approaching normal absorption. There is also some indication that, in certain bowel complaints, zinc might also play a role on the gut barrier function. It makes me wonder whether any of this participant group were screened for malabsorption causing states like coeliac disease or perhaps even just given the mannitol lactulose test?

I look forward to seeing more research done on zinc and other vitamins and minerals with regards to autism and related conditions. Knowing what problems in early nutrition might be capable of from things like the Barker hypothesis, the onus is surely to investigate such issues further. I must finally add that I am in no way advocating supplementation with zinc or any other nutrient without the appropriate clinical supervision. Don't mess with the vitamins and minerals man!

To finish a touch of spoof metal from the Darkness.

* Yasuda H. et al. Infantile zinc deficiency: association with autism spectrum disorders. Scientific Reports. November 2011.

Saturday 5 November 2011

Grandparental age and future generation risk

Most people with an interest in autism research will, at some point, have heard about the proposed equation: increasing paternal age = greater risk of autism diagnosis in offspring. I say 'equation', but unlike most mathematical and statistical formulae, the 'certainty' of the advancing parental age hypothesis of autism is actually not as certain as one might have been led to believe from papers like that included in the recent Nature series. Risk is risk not certainty.

On one of the sister/brother/sibling(?) blogs to this one, I linked to a study published last summer (2010) by Golding and colleagues*. The data derived from the ALSPAC study, suggested that parental (paternal and maternal) age effects whilst potentially important to autism might actually be secondary to age effects going further back a generation. In particular grandmother's age came under the spotlight and the revelation that Grandmum's who were over 35 years old at conception/birth of mums of children with autism might be over-represented in the cases of autism identified during the ALSPAC study.

Golding and colleagues were very cautious about their findings and provided some limited speculation of how the 'meiotic mismatch methylation (3M) hypothesis' might come into play. I can't claim to fully understand all of the 3M hypothesis but risk alleles, DNA methylation and the subsequent skipping of a generation are the watchwords. Speculative but interesting.

A more recent study has also emerged discussing similar concepts as potentially being relevant to schizophrenia. The paper by Frans and colleagues** based on another very substantial cohort number suggested again that older dads (particularly those above 55 years of age) were associated with an increased risk of offspring developing schizophrenia. They also found that older maternal grandfathers age (at conception of mums) might be associated with an increased risk of schizophrenia. The authors reason some involvement of the X chromosome 'differentially' being involved.

Whilst I am in no way suggesting that autism and schizophrenia are one and the same, and bearing in mind the multitude of factors, variables and biases inherent to this kind of cross-linking work, I do find it interesting that another set of commonalities might be coming to the research surface. Quite a lot is being made about SNPs, CNVs and such like in research examining developmental, behavioural and psychiatrically-defined conditions but little has been so far offered about how and why such point mutations, deletions and insertions might come about. Yes, they may be spontaneous, they may be age-related and potentially even evolutionary but what is/are the underlying process(es)?

What these collected research suggest is that generationally, there may be good reason to start looking back at extended family as and when possible for some of the genetic clues to conditions like autism. I know that in some cases this might not be possible, but given that autism is a condition manifesting in early childhood, there are good odds that grandparents and beyond might still be around. I hasten to add that I am not talking about looking for any 'eccentric grandfathers' or anything behaviourally-defined at this point following the slew of speculation asking questions like did this person or that person have autism or Asperger syndrome. Rather asking some sensible questions about how things like age at conception and the possibility that other environmental factors which parents, grandparents (and even great grandparents) were brought up in and exposed to might have the propensity to affect the genetic make-up of subsequent generations. Bear in mind also that just because we have only fairly recently been able to catalogue such genetic features in lots of different conditions and asymptomy, does not mean that they haven't been around mutating, adding and subtracting themselves, for whatever reason, for an awful lot longer.

Just in case you need to visualise how generational research could be done, have a look at this paper from a few years back..

* Golding J. et al. Parental and grandparental ages in the autistic spectrum disorders: a birth cohort study. PLoS ONE. April 2010.
** Frans EM. et al. Advanced parental and grandparental age and schizophrenia: a three-generation perspective. Schizophrenia Research. October 2011.

Thursday 3 November 2011

Nature on autism part two

Yesterday I posted a link to the Nature special series on autism spectrum conditions. There was quite a bit of information to take on-board from the various articles and discussion pieces included, but after a little time reading, I feel there are a few issues worthy of some discussion in this separate post.

This was quite a wide-ranging series covering most of the main talking points about autism and where we think we are in terms of things like definition, research and the various aspects on possible aetiology, intervention and politics. With multiple authors and commentators, opinions abound; some to be agreed with, others to be debated depending on your point of view.


The numbers game
For any undergraduate student faced with a question on a term paper like: are cases of autism increasing? the paper by Karen Weintruab gives about as good and up-to-date a picture on prevalence (and incidence) as you might need. The short answer is yes, the numbers of diagnoses have increased over the years, although the reasons for the increase are complex. Covering old favourites like better awareness, diagnostic substitution (changing criteria), parental age [I have a new post on this topic scheduled for the weekend], etc as reasons for the increase, the various commentators included in this article suggest that just over half of the increase in cases of autism might already be explicable. Given my reading of the various research down the years, this estimate might not be too far of the mark. Fine you might say, but what about the remaining 46% of the increase? What about the fact that different weighting to different factors at different time periods might pertain? 'Describe and discuss..' (making sure you use evidence-based critical thinking).

Systemisers, empathisers and assortative mating theory
Historically, the discipline of psychology is replete with generalised theories of people and explanations of their behaviour. I remember my first psychology textbook, Richard Gross 'Psychology: the science of mind and behaviour'. To read it you would assume that humans are perfectly predictable creatures and like the laws of physics (pre-CERN), put us in a specific situation and nod knowingly as we behave as expected. Psychology is however changing. Individual differences, people not living in a vacuum (or a psychology lab), and importantly the old gestalt phrase 'the whole is greater than the sum of its parts' are coming and pushing aside many of those generalised theories. The realisation that just because a person has one condition/issue/diagnosis does not mean that they can't have others which might exert some effect also seems to be in the pipeline.

So many of these concepts appear to align with our current understanding of autism. I think most people have by now figured out that there is probably no global, over-arching theory of autism which covers the entire spectrum of ability and disability. We have seen theories come and go; probably the most widely covered, again from a psychological perspective, has been the suggestion of a lack of theory of mind and the subsequent evolution of such ideas into systemisers and empathisers and to quote Francesca Happé the concept of 'geek chic'. The paper by Lizzie Buchen takes on the various suggestions proposed and comes to about the same conclusions: interesting, and not to say relevant for some on (and off) the autism spectrum, but please don't generalise and bear in mind that the spectrum of autism extends to quite a few people where life is not just about engineering or mathematical prowess.

Autism in the Middle East
Regular readers of this blog probably know that I am more than impressed with the autism research efforts coming out of the Gulf region. If you need to be reminded, have a look at this post and this one, both of which head into some pretty novel areas for further study originating from the Kingdom of Saudi Arabia. Mo Costandi (one of the first to tweet about the Nature special on autism) talks about autism in the Gulf states and also the genetic research goldmine that is consanguineous marriages and very large families. The impression is that autism, research and practice, is starting to take centre stage in Middle Eastern climes and parents and professionals are embracing education and other behavioural interventions for autism alongside social and cultural shifts in the region about autism.

From the limited contact I have had with people involved with autism in places like Saudi Arabia, Kuwait and the UAE, there are lots of good things happening. And unlike the jagged history of autism in more Western nations, the Middle East benefits from what we have learned down the years and also the mistakes we have made (without having to make them all over again).

Other papers discussing the ins and outs of biomarkers for autism for example, included as part of the series have already been covered on this blog.

Asking myself what more could have been said in the Nature series, I perhaps would have a few suggestions which hopefully won't come across as a rant. First, what about comorbidity? The various comorbidities, somatic and psychiatric, and what relationship they might have to autism, indeed to what degree some comorbidities in some cases can be more 'disabling' than the core autistic features. Yes, some of those comorbidities might be a little uncomfortable to discuss but science is science (apparently) and Nature is never one for shying away from uncomfortable issues. Second, talking about education and behavioural intervention is all well and good, but why stop there? How about recognising some of the other data available on the biology / biochemistry of autism as is being done in other conditions, or even things closer to my heart like that on diet and nutrition? No unanimous, universal effect for strategies like the gluten- and casein-free diet but that goes for just about every intervention for autism doesn't it? Finally, genes, SNPs and CNVs. Interesting and dare I say one of the primary ways forward in research bearing in mind recent lessons from other conditions. But how about the bigger picture, genes interacting with environment, as per Tom Insel's oft-quoted piece on the 'Autism Spring'? Environment covers a lot and a lot has changed environmentally over the period of the growth in cases of autism. Maybe a special edition all of its own.

With all things nature and the natural world in mind, I end with a song (it means 'no worries' apparently).

Wednesday 2 November 2011

Nature on autism

A very, very quick post to direct readers to a special edition on autism spectrum conditions carried by Nature. I am still reading through the various articles which cover topics such as the numbers game, the assortative mating theory, biomarkers and much, much more.

Stay tuned for a Nature on autism part two post (as soon as I manage to read through the interesting bits).

Tuesday 1 November 2011

ADHD with and without CNVs

As per previous posts on this blog, the shift from the 'one gene condition' hypothesis to that of a more 'lots and lots of genes involved probably with some variable environmental contribution' hypothesis in cases of autism and related conditions seems to have taken hold with some vigour over the last few years.  Lots of fancy acronyms like SNPs and CNVs, combined with words like pleiotropy and epigenetics, have sprung up accompanying our realisation that no matter what your diagnostic label or not, we are all seemingly a product of our various mutations and any interplay between our genes, our mutations, and environment is likely to be complex.

I say all this because of a recent article appearing by Langley and colleagues* which very interestingly looked at cases of attention-deficit hyperactivity disorder (ADHD), comparing those who carried various CNVs against those who didn't and finding, well, very little difference between the cases in terms of things like symptom presentation. Many of the authors on this paper are no stranger to ADHD research, looking at things like comorbidity of bipolar disorder and ADHD and also having some pretty outspoken views about what ADHD might be.

The paper is full-text so I won't start copying and pasting large parts of it, but will provide a short summary:

  • Children/young adults (n=567) diagnosed with ADHD (or hyperkinetic disorder) were included for study. Participants were also screened for an autism spectrum condition and excluded from the dataset if autism was suspected.
  • The sample was divided up into those with at least one large rare CNV (n=77) and those without (n=490) and compared on various measures.
  • Those ADHD cases with CNV(s) presented more commonly with intellectual disability (ID) (IQ<70); although this finding was not mutually exclusive to the CNV group. No other measure or variable of early developmental history or symptom severity was significantly different between the CNV(s) and non-CNV(s) groups (maternal smoking during pregnancy being slightly higher in the CNV group wasn't that far off at p=0.07).

The authors report that this finding points to no presence of an 'atypical' group of children where ADHD is comorbid to CNVs. They also point to a few caveats based on things like sample sizes and power, whether CNVs were de novo or inherited and the 'scattergun' approach they used (looking at CNVs located at various different parts of the genome with various potential weightings in relation to symptom presentation). Bear also in mind that these participants were all white, British children, predominantantly male, and some carried other behavioural comorbidities, and therefore to what group/population the results are probably going to be most applicable to.

I agree with all this issues and tread cautiously as a result. One thing does however stick out from this work about CNVs and ADHD and the question of whether the presence of CNVs might be more related to intellectual disability (ID) rather than other presentations like ADHD or even autism spectrum conditions? Looking at the degree of significance (table 1), the ID difference was pretty stark between the groups (p=0.0001). I know, I know, I am compartmentalising and that is never a good idea (the whole being greater than the sum of its parts and all that). One possibility to answer this question would be to look at an independent sample of children (white, British) with and without ID, screening negative for ADHD and autism as per the same instruments used in the current study and see what the rates of similar CNVs are. The list of CNVs is available at the foot of this article as a supplementary PDF. Indeed how about a similar study comparing groups of children with autism with and without those CNVs (given the suggested overlap) and see if this illuminates the path any better?

* Langley K. et al. Clinical and cognitive characteristics of children with attention-deficit hyperactivity disorder, with and without copy number variants. Br J Psychiatry. November 2011.