Familial Recurrence of Autism Spectrum Disorder (again)

The paper by Neil Risch and colleagues [1] adds to the growing literature looking at the question of familial recurrence of autism i.e. if one child has a diagnosis of autism, how likely are subsequent children to be similarly diagnosed. The answer according to this latest data: "The overall sibling recurrence risk was 10.1%" compared with 0.5% in siblings of asymptomatic controls. This figure is pretty much the same as that reported by Sandin and colleagues [2] covered not so long ago (see here).

Sister. So you have a twin sister... @ Wikipedia 

Cross-linking data derived from "California Department of Developmental Services records with state birth certificates" authors set about identifying "all siblings and half siblings of individuals affected with ASD born between 1990 and 2003". They looked at subsequent births "born after ASD [autism spectrum disorder] index cases" and compared them with control participant data for a diagnosis of ASD.

The value-added bit to the Risch data is that alongside looking at birth order and any effect on risk of ASD - second born children in autism cases were found to be at greater risk than later born siblings (11.5% vs. 7.3% respectively) of subsequent diagnosis - the authors also looked at the issue of inter-birth interval and whether that exerted any effect. It did as it happens: "the recurrence risk reaching 14.4% for an interbirth interval of 18 months or less, compared with 6.8% for an interval of 4 years or more". This issue under the name inter-pregnancy interval (IPI) is something which has also graced this blog on a previous occasion (see here) with autism in mind. On that previous post, I covered some of the possible hows and whys when it comes to a short IPI and autism risk...

There is little more for me to say about the Risch paper and what it means for something like genetic counselling when it comes to autism risk. I should point out that not every piece of research on this topic has arrived at the same figure (see here and see here for example) but one can perhaps see how variables such as geography and gender might affect recurrence risk. I will also drop in the paper by Hoffmann and colleagues [3] (yes, the same authorship team) on reproductive stoppage as also being relevant at this point covered in a previous post (see here).

Music to close.... Anything Goes (Indiana Jones style).

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[1] Risch N. et al. Familial Recurrence of Autism Spectrum Disorder: Evaluating Genetic and Environmental Contributions. Am J Psychiatry. 2014 Jun 27. doi: 10.1176/appi.ajp.2014.13101359.

[2] Sandin S. et al. The Familial Risk of Autism. JAMA 2014; 311: 1770-1777.

[3] Hoffmann TJ. et al. Evidence of Reproductive Stoppage in Families With Autism Spectrum Disorder: A Large, Population-Based Cohort Study. JAMA Psychiatry. 2014 Jun 18. doi: 10.1001/jamapsychiatry.2014.420.

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Risch, N., Hoffmann, T., Anderson, M., Croen, L., Grether, J., & Windham, G. (2014). Familial Recurrence of Autism Spectrum Disorder: Evaluating Genetic and Environmental Contributions American Journal of Psychiatry DOI: 10.1176/appi.ajp.2014.13101359

Coenzyme Q10 and autism

The paper by Frederick Crane and colleagues [1] (open-access here) caught my eye recently and their suggestion that when it comes to autism there may be more research to do on coenzyme Q10. Indeed, the old grey-pinkish matter started grinding into action as to whether there may be a wider research literature on CoQ10 with a focus on autism...

A helping hand? @ Wikipedia 

Coenzyme Q10 otherwise known as ubiquinone, has appeared before on this blog for various reasons (see here and see here). Described as a fat soluble vitamin-like substance, there are apparently a few important steps in the production of CoQ10 implicating one to two old friends - aromatic amino acid friends - involving the "synthesis of the benzoquinone structure" from said aromatic friends (tyrosine or phenylalanine) alongside the "synthesis of the isoprene side chain from acetyl-coenzyme A (CoA) via the mevalonate pathway". It's then a case of marrying the two reaction products together to form something which as the name 'co-enzyme' suggests, is pretty important to quite a few enzymatic reactions.

In terms of the functions of CoQ10, well quite a few of them overlap with areas of interest when it comes to autism. The word 'mitochondria' springs up quite a bit and the important role CoQ10 plays in the production of energy or involvement with ATP (adenosine triphosphate) at least. The antioxidant activity that CoQ10 also seems to possess, at least in it's reduced form - ubiquinol - is also something pretty important. Both mitochondrial function and the concept of oxidative stress have surfaced in the autism research literature in recent years (see here and see here).

The Crane paper presents quite a bit of biochemistry pertinent to "a hypothesis that autism is controlled by a coenzyme Q-dependent redox system in the porin channels". Putting aside my reluctance towards grand, over-arching theories about autism (sorry, the autisms) I'll be honest and tell you that I found the reading pretty heavy going on this topic bearing in mind my very limited knowledge on porin channels and all-things when it comes to transportation in and out of cells. I'm not then going to provide some detailed critique of the author's hypothesis aside from mentioning the paper by Freedenfeld and colleagues [2] on the use "of ribose therapy and NADH therapy on children with autism" (NADH being oxidised by coenzyme Q). NADH is something that Crane et al have talked about in other papers too [3].

The wider autism literature on CoQ10 and autism is best described as limited at the moment. I came across the paper by Gvozdjáková and colleagues [4] (open-access here) talking about results from a preliminary open trial of ubiquinol in a small number of children diagnosed with an autism spectrum disorder (ASD). Following an initial daily dose starting at 50mg of "Liquid liposomal ubiquinol" increased to 100mg daily, authors reported on both behaviour and various biochemical measures including CoQ10 (total) and TBARS "the end product of lipid peroxidation in the body". Bearing in mind the study methodology, the authors reported that a: "Beneficial effect of ubiquinol in children with autism has been demonstrated for the first time". That being said, I note that only the 'CoQ10-TOTAL' biochemical measure came out as significantly affected by ubiquinol supplementation (which is kinda what one would expect) and as someone has already [slightly harshly] noted using PubMed Commons "There is no way in which these observations can be interpreted as a "demonstration" of a "beneficial effect".

I do however believe that there may be more to do from a research point of view when it comes to coenzyme Q10 and autism. Thinking back to the Jim Adams double-blind, placebo-controlled trial looking at a vitamin and mineral supplement for autism (see here) I note that their preparation included CoQ10 (see here) among lots of other things. Granted, lots of other nutrients might have been contributory to the effects they noted, but one cannot, at the moment, rule out any specific effect from CoQ10 either. This is something also mentioned in the new-ish paper from Frye & Rossignol [5]. I'm also minded to mention the various discussions about the use of CoQ10 in relation to cases of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) too (see here) as per papers like the one from Maes and colleagues [6]. Following my mantra about autism seemingly not being protective against any other condition or state, one might further consider additional research as to whether overlap or similar processes might unite at least some autism and at least some CFS/ME or not?

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[1] Crane FL. et al. Plasma membrane coenzyme Q: evidence for a role in autism. Biologics. 2014 May 29;8:199-205.

[2] Freedenfeld SH. et al. Biochemical Effects of Ribose and NADH Therapy in Children with Autism. Autism Insights. 2011; 3: 3-13.

[3] Löw H. et al. Putting together a plasma membrane NADH oxidase: a tale of three laboratories. Int J Biochem Cell Biol. 2012 Nov;44(11):1834-8.

[4] Gvozdjáková A. et al. Ubiquinol improves symptoms in children with autism. Oxid Med Cell Longev. 2014;2014:798957.

[5] Frye RE. & Rossignol D. Treatments for Biomedical Abnormalities Associated with Autism Spectrum Disorder. Front. Pediatr. 2014. doi: 10.3389/fped.2014.00066

[6] Maes M. et al. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009;30(4):470-6.

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Crane FL, Löw H, Sun I, Navas P, & Gvozdjáková A (2014). Plasma membrane coenzyme Q: evidence for a role in autism. Biologics : targets & therapy, 8, 199-205 PMID: 24920882

Reproductive stoppage related to autism

The paper by Thomas Hoffmann and colleagues [1] on reproductive stoppage - the decision to not have more children - in couples with a child already diagnosed with an autism spectrum disorder (ASD) is the source for today's post. This is both an important and delicate area to talk about so I tread very carefully in my discussions.

The Holy Infants @ Wikipedia 

A few details first:

• Based on records held at the California Department of Developmental Services, children born between 1990 and 2003 with a subsequent diagnosis of ASD were identified, and details on full and half-siblings extracted.
• Data from control participants without any record of autism or ASD were compared to ascertain "the reproductive behaviors of parents after the birth of a child with ASD vs an unaffected child".
• Results: 19 710 "case families" were initially identified from Services records and compared against data from 36 215 "pure control families". Whilst for the first few years after the birth of a child who was subsequently diagnosed with an ASD case families showed reproductive behaviour "similar to that of control parents", as time went on reproductive stoppage became more pronounced. Families with a child with autism were about a third less likely to have subsequent children than control families. This effect was also noted when later-born children were diagnosed with an ASD and "among women who changed partners".

Although the precise reasons why reproductive stoppage occurred with greater frequency among families affected by ASD are not given in the Hoffmann paper, some of the associated media discussion of this study (see here) talk about possible influences. It "could be due to concerns about having another child with the disorder or that parents feel they are unable to care for additional children after having one on the spectrum already" are some of the ideas being suggested. Parental stress is another concept banded around by some too.

Having talked about recurrence risk and autism previously on this blog (see here), there is another important message to be taken from the Hoffmann study outside of reproductive behaviours in families with a child with ASD. The issue of stoppage can have an important effect on discussions about recurrence risk as per other reports on this topic [2] and as has been suggested in the latest paper, how recurrence risk estimates can be under-estimated as a result. Indeed, the authors reported that when taking stoppage into account, recurrence risk estimates move up a few percentage points for both full and half siblings (8% full siblings becomes 10% and 3% for half-siblings becomes ~5%) based on their data. I might add that birth order studies in connection to ASD may also be similarly influenced by stoppage too [3].

I was also taken by some discussion on a paradox as a function of the Hoffmann results. The idea being that if autism was wholly genetic, then such reproductive stoppage should be "diminishing" any classical genetic fragility to autism over time. Clearly however, this is not the case as rates of autism, estimated rates of autism, are still climbing and much greater focus is being directed to other factors in autism causation outside of the 'genes are king/queen' mantra. Interestingly, published in the same journal as the Hoffmann paper, another paper by Kristen Lyall and colleagues [4] perhaps provides some further discussion on this topic and their conclusions supporting a: "role of additive genetic influences in concentrating inherited ASD susceptibility in successive generations and the potential role of preferential mating, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits". I might add that I'm not necessarily coming down on the side of assortative mating being the ultimate factor affecting offspring autism risk, but it might offer at least some explanation for the autism genetics paradox also tied into concepts like the broader autism phenotype (BAP) too.

As mentioned at the beginning of this post, the issue of reproductive stoppage when it comes to families touched by autism is both an important and sensitive issue. The decision or not to have additional children when a family is already affected by autism is a personal one and most likely influenced by many different and often very individual factors. I don't doubt that some of those factors are the same that every family faces irrespective of autism or not: time, space, money, etc. but perhaps with the added discussions about 'risk' and the various 'what if' scenarios...

Music to close, and another song doin' the rounds in our house: Let it go (from Disney's Frozen movie). A treat also for some of my brood for bringing home their first Martial Arts trophies... Kiai!

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[1] Hoffmann TJ. et al. Evidence of Reproductive Stoppage in Families With Autism Spectrum Disorder. JAMA Psychiatry. 2014. June 18.

[2] Jones MB. & Szatmari P. Stoppage rules and genetic studies of autism. J Autism Dev Disord. 1988 Mar;18(1):31-40.

[3] Schmidt K. et al. Brief report: Asperger's syndrome and sibling birth order. J Autism Dev Disord. 2013 Apr;43(4):973-7.

[4] Lyall K. et al. Parental Social Responsiveness and Risk of Autism Spectrum Disorder in Offspring. JAMA Psychiatry. 2014. June 18.

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Hoffmann, T., Windham, G., Anderson, M., Croen, L., Grether, J., & Risch, N. (2014). Evidence of Reproductive Stoppage in Families With Autism Spectrum Disorder JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.420

DNA methylation patterns and autism: buccal up

"The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD [autism spectrum disorder]". That was the very clinical primary conclusion reached in the study by Esther Berko and colleagues [1] (open-access here). They looked at DNA methylation patterns in cheek cell samples for a small sample of children diagnosed with an ASD (n=47) "born to mothers aged 35 and over" compared with samples from an asymptomatic control group (n=48) and found some potentially important differences.

Cheek of it.. @ Wikipedia 

Some of the accompanying press for this paper can be found here. As per the headline: "Study shows environmental influences may cause autism in some cases" the results have been suggested to further add to the notion that genetics may not be the be-all-and-end-all of autism, at least some cases of autism. We'll see about that. That alongside the body of research which seems to suggest that offspring of older mums might be at increased risk of being diagnosed with autism (see here) makes for some interesting reading.

Before going on, I should perhaps define a few terms which have or will crop up in this post. So, buccal swabs refers to a way of collecting cells and DNA [non-invasively] from the inside of a person's cheek. Ectoderm refers to the outer layer of germ cells which eventually give rise to hair, skin, the lens of the eye and importantly, the nervous system including neurons and glial cells, as well as the mucus membrane of the mouth. DNA methylation is something which has been covered a few times on this blog (see here and see here) and is part of that wonderful concept of epigenetics and one of the ways that genes are turned on or off depending on their methylation status.

The Berko paper is open-access but a few pointers might be useful:

• Buccal cells were examined as a sort of proxy for brain cells (which generally aren't harvested from live donors). As per the description previously, the ectodermal origins of buccal cells cross that proxy bridge. DNA was extracted from the buccal cells and subjected to various genetic and epigenetic analyses.
• Researchers used the Mosaic Alteration Detection (MAD) algorithm [2] to test "for abnormal chromosome numbers as well as other chromosomal defects". No evidence of chromosome aneuploidy was detected in either cases or controls which kinda ruled out more traditional genetic effects being related to advancing maternal age.
• Methylation was then the name of the game, and as I've talked about on a previous post (see here) various ways and means of looking at the methylation status of those little genetic islands: CpG sites. 
• Results:  "a first pass" approach looking at DNA methylation patterns between the groups identified "3560 differentially methylated GCs". Researchers then further refined their analysis by means of something called bump-hunting which took into account age and ancestry as potential effectors of DNA methylation and something called co-methylation network analysis. They were then left with 15 differentially methylated regions (DMRs) on 14 genes "distinguishing the ASD and TD [typically developing] samples". Even further refinement taking into account the overlapping presence of copy number variations (CNVs) (see here for an explanation) boiled the total down and looked at which genes might be associated with DMRs.
• "The candidate DMRs from the genome-wide analysis were associated with genes, of which many have already been implicated in previous studies with ASD" shown in Table 1 of the paper. Further: "The model that results is of mosaic epigenetic dysregulation affecting the same networks and pathways targeted by mutational mechanisms, creating comparable deleterious effects on neuronal function". In other words, the more traditional genetic mutations noted in other work on some genes in relation to autism might also be complemented by epigenetic changes affecting those gene functions too. 

I found the results of this paper to be absolutely fascinating. Not only that the emphasis was on cells which share some source commonality with those found in the grey-pink matter which has been a primary focus of autism research but also that genetic mutations and epigenetic changes may potentially work synergistically in cases of autism. The added detail that this tied into the seemingly enhanced risk of autism in older mothers [3] (at conception) adds further interest to this work. As the authors noted: "The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD". Chromatin by the way, is something of an upcoming star in autism research [4] (open-access here).

Obviously there is quite a bit more work to do in this area not least to test whether the Berko findings are also applicable to children with autism born to younger mothers and any influence from the various overlapping conditions which can and do occur in cases of autism such as epilepsy (see here) or intellectual disability. I also hark back to some interesting work presented at IMFAR this year (2014) by Feinberg and colleagues who talked about age-related methylation changes found in semen as being something to watch when it comes to the older dads and autism risk work (see here) which might point to a cumulative effect. Combined with what is already being reported about methylation status and something like those HERVs in relation to autism (see here) and even ADHD (see here), epigenetics is certainly continuing its rise and rise in autism research [5].

Music then to close. Hey Ya!

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[1] Berko ER. et al. Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder. PLoS Genet. 2014 May 29;10(5):e1004402.

[2] González JR. et al. A fast and accurate method to detect allelic genomic imbalances underlying mosaic rearrangements using SNP array data. BMC Bioinformatics 2011, 12:166

[3] Gillberg C. Maternal age and infantile autism. J Autism Dev Disord. 1980 Sep;10(3):293-7.

[4] Lasalle JM. Autism genes keep turning up chromatin. OA Autism. 2013 Jun 19;1(2):14.

[5] Siniscalco D. et al. Epigenetic Findings in Autism: New Perspectives for Therapy. Int. J. Environ. Res. Public Health. 2013; 10: 4261-4273.

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Berko ER, Suzuki M, Beren F, Lemetre C, Alaimo CM, Calder RB, Ballaban-Gil K, Gounder B, Kampf K, Kirschen J, Maqbool SB, Momin Z, Reynolds DM, Russo N, Shulman L, Stasiek E, Tozour J, Valicenti-McDermott M, Wang S, Abrahams BS, Hargitai J, Inbar D, Zhang Z, Buxbaum JD, Molholm S, Foxe JJ, Marion RW, Auton A, & Greally JM (2014). Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder. PLoS genetics, 10 (5) PMID: 24875834

Quality of life and autism

The BBC ran an interesting article on their website recently titled: Happiness and disability. Discussions about the disability paradox - whereby some people with often significant and persistent disability report experiencing a good or excellent quality of life (QoL) - got me thinking about QoL and in particular, how it might relate to the very wide and very heterogeneous autism spectrum. I might add that I am not insinuating that everyone diagnosed on the autism spectrum are 'disabled' but rather that as per the UK definition of the word (see here), "a ‘substantial’ and ‘long-term’ negative effect on your ability to do normal daily activities" is a hallmark for quite a proportion of people on the autism spectrum.

At the same time, the findings from the literature review by Chiang and Wineman [1] should really be making people sit up and take note: "The majority of the individuals with ASD [autism spectrum disorder] had poor QoL [quality of life]". Indeed, not for the first time have such sentiments been voiced in the research literature as per another meta-analysis by van Heijst & Geurts [2] who reported: "Across the lifespan, people with autism experience a much lower quality of life compared to people without autism".

What a view... @ Wikipedia 

Quality of life by the way, can mean quite a few things but for the purposes of this post I'm talking about overall wellbeing including things like life satisfaction and health including mental and physical health.

As stated, QoL is often a very subjective thing influenced by all manner of variables, some social, some biological and some psychological. As one example I'd draw your attention to the concept of resilience [3] and the effect that can have but there are many others.

QoL is also a dynamic concept which can and does change for everyone following life's ebbs and flows. If I happened to scoop the lottery tomorrow I'd wager that my QoL would probably increase a few points (albeit with potential caveats). Likewise, when it comes to one of the most important influences on QoL, physical health, some people will know what happens to QoL when health deteriorates or when faced with the prospect of even short-term restrictions to normal activities.

I should also mention that just because I'm talking about research in the most part suggesting poorer QoL in relation to autism, I'm not trying to stigmatise or anything like that. Poor QoL is not an exclusively autism-related feature; just as I appreciate that for some people on the autism spectrum, QoL is actually pretty good.

A trawl through some of the research literature in this area highlights a few common themes.

Social contact and networks
I've talked before on this blog about issues such as loneliness and how detrimental it might potentially be for one's health (see here). Loneliness or a lack of friends or social support can be an issue for some on the autism spectrum, although I'd hasten to add that sweeping generalisations about everyone with autism craving lots of social contact might be misplaced; not everyone wants to be the life and soul of the party. There has been some focus on how loneliness and social isolation can and do impact on QoL with autism in mind. The paper by Renty & Roeyers [4] talked about how the availability of a "supportive social network" seemed to be an important factor when it came to QoL in high-functioning adults with autism. Just as an aside, I didn't pick the term 'high-functioning', the authors did.

The paper by Micah Mazurek [5] (a favourite researcher on this blog) similarly pointed to the detrimental effects that loneliness seemed to have in cases of autism on subsequent QoL. Based on self-report (something which I'll be coming to shortly) "loneliness was associated with increased depression and anxiety and decreased life satisfaction and self-esteem, even after controlling for symptoms of autism spectrum disorders". A "greater quantity and quality of friendships were associated with decreased loneliness" was another rather obvious finding, implying one possible target for possible intervention. Perhaps also relevant to the whole issue of QoL and autism was the focus on comorbidity in this paper: "number of friends provided unique independent effects in predicting self-esteem, depression, and anxiety above and beyond the effects of loneliness".

Social contact / participation issues were also addressed in the paper by Lee and colleagues [6] looking children with autism with QoL in mind. They reported: "Children with autism were significantly less likely to attend religious services, more likely to miss school, and less likely to participate in organized activities". Likewise, Orsmond and colleagues [7] reported similar things: "Young adults with an ASD were significantly more likely to never see friends, never get called by friends, never be invited to activities, and be socially isolated". I could go on but I won't. Suffice to say that social contact and participation seem to be big influencers on QoL in quite a few cases of autism.

Comorbidity
Having already mentioned how certain comorbidity might also be linked to measures of QoL it's also worthwhile going through some of the other research in this area. I'm pretty enthusiastic that comorbidity when it comes to autism is something deserving of a lot more investigation (see here). By comorbidity, I'm talking about both psychological comorbidity such as depression and anxiety (especially anxiety) all the way up to something like psychosis (see here) or schizophrenia (see here) and the other more somatic comorbidity reported in some cases of autism (see here). I don't also doubt that there is a relationship between psychologically-manifesting comorbidity and physiological comorbidity with autism in mind (see here).

Anyhow, I start this section with reference to the paper by Bauman [8] who very succinctly described how medical comorbidity can be a "challenge to diagnosis and treatment" when it comes to autism. Perhaps most relevant to the topic of this post was the assertion: "Many of these medical conditions are treatable, often resulting in improved developmental gains and quality of life for the patient and family". Certainly looking back to a post I did fairly recently on undetected medical comorbidity and autism (see here) I wouldn't argue with such a sentence. Included in the area of health and medical comorbidity potentially impacting on QoL in autism is the various research looking at issues like obesity and autism [9] and conditions which can have the most severe impact on QoL such as epilepsy and even something like self-injury and aggression.

The paper by van Steensel and colleagues [10] looking at how anxiety and anxiety disorders comorbid to autism "predicted a lower quality of life" is an important finding. As previously mentioned, anxiety is something which can be absolutely disabling when it comes to autism (see here) potentially even over and above the experience of more core symptoms for some people. It's little wonder that when present, it has such a huge impact on QoL.

Employment
I've singled out employment as being an important area for QoL in autism because there is quite a lot of research on the topic. I know there are many more moves nowadays to raise the issue of under-employment following a diagnosis of autism, and certainly it seems like common-sense to assume that having a job - a meaningful and appropriately paid job - will almost certainly impact on a persons QoL, whether they have autism or not. The findings from Mavranezouli and colleagues [11] provide as stark a message as is possible in terms of the current employment prospects when someone is in receipt of a diagnosis on the autism spectrum. The findings from Barneveld and colleagues [12] highlighted how most people with autism included in that study "were less satisfied about their work or education.." than other groups examined based on the finding that quite a large proportion of this cohort were without paid employment and "many were social security recipients". Other studies have arrived at similar conclusions [13]. I probably don't need to say much more on the topic of unemployment and how it may adversely affect QoL in autism aside from perhaps also putting the opposing viewpoint across that employment under the wrong conditions can also be a source of stress and anxiety for some on the spectrum [14] and onwards lead to a reduction in QoL. It's about finding a balance.

Who reports?
I've included this section to reflect the body of research literature looking at similarities/differences in terms of who reports about QoL when it comes to autism: first-person accounts and reports vs. other persons. This issue has surfaced in discussions on other topics; for example, the work looking at anxiety and autism [15]. The paper by Sheldrick and colleagues [16] talked about differing opinions of QoL in adolescents with autism based on self-report and parental reports. Ikdea and colleagues [17] found a similar situation. There are lots of ways that second-hand reports can 'bias' very subjective concepts like QoL; parents and caregivers for example, may be more inclined to make comparisons with other, non-autistic populations which will invariably impact on how the QoL of their own children is perceived. The paper from Shipman and colleagues [18] might have noted something like this with their results: "parents of adolescents [with autism] reporting lower QoL when compared with adolescent reports". The main point from this collected work being that, where feasible, measures of QoL in autism should be reported by those with autism.

Intervention
Although intervention is not a universally welcomed word when it comes to the very wide and very heterogeneous autism spectrum, I'm pretty sure that this is one area where there might be more agreement among the autism community. In the broadest sense, intervention to improve QoL for people on the autism spectrum implies addressing some of the topics I've previously discussed in this post as and when required. Opportunities seems to be an important word.

I'm a great believer in sport and leisure as being roads to improving health and wellbeing for everyone and onwards QoL. Autism is no exception as per studies like the one from Fragala-Pinkham and colleagues [19] talking about a group swimming and aquatic exercise program for kids with autism. Martial arts programs are another option; also potentially having some interesting knock-on effects based on the use of Kata training as per the study by Bahrami and colleagues [20] talked about in a previous post. Attendance at leisure clubs and societies might also be something considered to influence QoL in autism following the results from García-Villamisar and colleagues [21]. Importantly, they also talked about stress reduction being linked to improved QoL. For adults, similar social and group situations may likewise be useful to consider, bearing in mind that using something like social media as a substitute for social contact might not necessarily help with issues such as loneliness [22].

The slightly more contentious topic of interventions aimed at reducing or ameliorating the signs and symptoms of autism being potentially linked to an improved QoL is another side to this story. I've touched upon the issue of QoL in relation to some of my peer-reviewed work looking at dietary intervention in cases of autism [23]. We didn't actually measure QoL (although we perhaps should have done) but certainly considering the study by Kushak and colleagues [24] talked about in a previous post (see here) highlighting how lactose intolerance "may contribute to abdominal discomfort, pain and observed aberrant behavior" one might see how something like pain could adversely affect QoL. Certainly this adds a new dimension to the chatter about the resurrected PETA advert recently (see here) which I've kinda covered in another post.

The paper by Ramirez and colleagues [25] follows a similar line of thought and how their intervention led to a "reduction in aberrant behaviors, increased gastrointestinal function, and improved quality of life". I might add that I'm just using that case report as an example rather than making any specific recommendation. And then there is the question of medication as a means to improving QoL in cases of autism. At least one review paper has hinted that where measured, QoL can be positively influenced by certain medications [26] but I dare say that individual measures of QoL are going to be governed by factors such as response to medication and the presence or not of those all-important side-effects.

More to do
Although I have gone on a bit in this post, I've only really scratched the surface when it comes to the various research on QoL in autism. I've not talked about the possibility of gender differences in QoL with autism in mind, nor how autism might impact on the QoL for other family members including siblings. Whether QoL measurements might also differ across the autism spectrum as a function of factors such as optimal outcome (see here) or cognitive abilities or even ageing are other areas for exploration. These are perhaps ramblings for another day. What does come across from the collected literature in this area is that QoL is an important concept in relation to autism. Whilst not everyone on the autism spectrum presents with a poorer QoL than other groups or the more general population, further efforts should be directed towards those that need and want improvements in their QoL in order for lives to be lived to their full potential as per the findings from Ahlström & Wentz [27].

Music to close, and based on the assumption that live music therapy may be beneficial to QoL for some... here is the Boss who is arguably one of the best live acts ever to grace the musical stage: Glory Days.

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[1] Chiang H-M. & Wineman I. Factors associated with quality of life in individuals with autism spectrum disorders: A review of literature. Res Autism Spec Disord. 2014; 8:974-986.

[2] van Heijst BF. & Geurts HM. Quality of life in autism across the lifespan: A meta-analysis. Autism. 2014 Jan 17.

[3] Hildon Z. et al. Examining resilience of quality of life in the face of health-related and psychosocial adversity at older ages: what is "right" about the way we age? Gerontologist. 2010 Feb;50(1):36-47.

[4] Renty JO. & Roeyers H. Quality of life in high-functioning adults with autism spectrum disorder: The predictive value of disability and support characteristics. Autism. 2006 Sep;10(5):511-24.

[5] Mazurek MO. Loneliness, friendship, and well-being in adults with autism spectrum disorders. Autism. 2014 Apr;18(3):223-32.

[6] Lee LC. et al. Children with autism: quality of life and parental concerns. J Autism Dev Disord. 2008 Jul;38(6):1147-60.

[7] Orsmond GI. et al. Social participation among young adults with an autism spectrum disorder. J Autism Dev Disord. 2013 Nov;43(11):2710-9.

[8] Bauman ML. Medical comorbidities in autism: challenges to diagnosis and treatment. Neurotherapeutics. 2010 Jul;7(3):320-7.

[9] Curtin C. et al. Obesity in children with autism spectrum disorder. Harv Rev Psychiatry. 2014 Mar-Apr;22(2):93-103.

[10] van Steensel FJ. et al. Anxiety and quality of life: clinically anxious children with and without autism spectrum disorders compared. J Clin Child Adolesc Psychol. 2012;41(6):731-8.

[11] Mavranezouli I. et al. The cost-effectiveness of supported employment for adults with autism in the United Kingdom. Autism. 2014 Apr 29.

[12] Barneveld PS. et al. Quality of life: a case-controlled long-term follow-up study, comparing young high-functioning adults with autism spectrum disorders with adults with other psychiatric disorders diagnosed in childhood. Compr Psychiatry. 2014 Feb;55(2):302-10.

[13] Griffith GM. et al. 'I just don't fit anywhere': support experiences and future support needs of individuals with Asperger syndrome in middle adulthood. Autism. 2012 Sep;16(5):532-46.

[14] Baldwin S. et al. Employment Activities and Experiences of Adults with High-Functioning Autism and Asperger's Disorder. J Autism Dev Disord. 2014 Apr 9.

[15] Storch EA. et al. Multiple informant agreement on the anxiety disorders interview schedule in youth with autism spectrum disorders. J Child Adolesc Psychopharmacol. 2012 Aug;22(4):292-9.

[16] Sheldrick RC. et al. Quality of life of adolescents with autism spectrum disorders: concordance among adolescents' self-reports, parents' reports, and parents' proxy reports. Qual Life Res. 2012 Feb;21(1):53-7.

[17] Ikeda E. et al. Assessment of quality of life in children and youth with autism spectrum disorder: a critical review. Qual Life Res. 2014 May;23(4):1069-85.

[18] Shipman DL. et al. Quality of life in adolescents with autism spectrum disorders: reliability and validity of self-reports. J Dev Behav Pediatr. 2011 Feb-Mar;32(2):85-9.

[19] Fragala-Pinkham MA. et al. Group swimming and aquatic exercise programme for children with autism spectrum disorders: a pilot study. Dev Neurorehabil. 2011;14(4):230-41.

[20] Bahrami F. et al. Kata techniques training consistently decreases stereotypy in children with autism spectrum disorder. Res Dev Disabil. 2012 Jul-Aug;33(4):1183-93.

[21] García-Villamisar DA. & Dattilo J. Effects of a leisure programme on quality of life and stress of individuals with ASD. J Intellect Disabil Res. 2010 Jul;54(7):611-9.

[22] Mazurek MO. Social media use among adults with autism spectrum disorders. Computers in Huam Behaviour. 2013; 29: 1709-1714.

[23] Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2013 Jan 4;6:344.

[24] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

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[26] Moyal WN. et al. Quality of life in children and adolescents with autism spectrum disorders: what is known about the effects of pharmacotherapy? Paediatr Drugs. 2014 Apr;16(2):123-8.

[27] Ahlström BH. & Wentz E. Difficulties in everyday life: Young persons with attention-deficit/hyperactivity disorder and autism spectrum disorders perspectives. A chat-log analysis. Int J Qual Stud Health Well-being. 2014 May 28;9:23376.

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Chiang, H., & Wineman, I. (2014). Factors associated with quality of life in individuals with autism spectrum disorders: A review of literature Research in Autism Spectrum Disorders, 8 (8), 974-986 DOI: 10.1016/j.rasd.2014.05.003

Mercury exposure and autism or ADHD meta-analysed

The paper by Yoshimasu and colleagues [1] is the talking point today, and their assertion following meta-analysis that: "Moderate adverse effects were observed only between environmental inorganic or organic mercury exposures and ASD/ADHD".

Eruption... @ Wikipedia 

For clarity, ASD means autism spectrum disorder and ADHD refers to attention-deficit hyperactivity disorder. Inorganic and organic mercury refer to some of the different forms of mercury. Meta-analysis, as I've said before, is all about collating results from various studies and coming up with some consensus viewpoint. As per the author's comment though: "the number of epidemiological studies on this issue was limited and still at an early stage".

Still, inorganic mercury sourced from air pollution was significantly associated with autism risk based on studies like this one from Palmer and colleagues [2] and this one from, er, Palmer and colleagues [3]. Methylmercury derived from maternal fish consumption was associated with offspring ADHD as per the study by Sagiv and colleagues [4] for example.

When it came to that most contentious of topics - vaccination and autism - Yoshimasu et al concluded that vaccine sources of mercury (defined as clinical exposure) "did not show any material associations with an increased risk of ASD or ADHD" based on their analysis of the available data. Rather as discussed, it seems that other environmental sources of the stuff were where further investigations might be indicated.

I know mention of the word 'mercury' and autism (outside of the film Mercury Rising) has the ability to furrow brows and heat up discussion in some circles. I don't intend to get caught up in this debate with this post simply because I'm not an expert on such matters. I can direct you to the analysis by Taylor and colleagues (see here) who recently concluded that there was similarly no evidence for a link between the vaccine sources of mercury and autism risk as part of their meta-analysis of [some of] the vaccination and autism literature. I might also drop in the findings of Maglione and colleagues [5] at this point too. The even more recent paper by Hooker and colleagues [6] (open-access) might also be something to have a look at because of the overlap in studies they and Taylor examined, yet their drawing a slightly opposing conclusion (bearing in mind the conflicts of interest reported both in their data and for the authors themselves).

Acknowledging the controversy about mercury and autism, I do think science has more to do in this area. I think back to the various studies which have indicated a higher functional biological burden of heavy metals [7] like mercury identified in some cases of autism (see here and see here for example). The Wright study [8] in particular, hinting at outliers - "results appear to be influenced strongly by a small number of extreme values in the ASD and special school group" - suggests that mercury if it is an issue, is probably not going to be a universal factor for everyone with autism, bearing in mind this study only took a snapshot of mercury levels and did not look at the possibility of early exposures [9] for example. Combined with other issues such as geographical location [10] one might assume that further investigations should perhaps be focused on specific groups on the autism (and ADHD) spectrum to try and answer the questions of why mercury levels are elevated, any implications from such elevations and what can be done to reduce elevated levels?

And just before I go, the FDA guidance on fish consumption during pregnancy and for the young has recently changed to reflect the fact that (a) fish are actually pretty nutritious and (b) not every type of fish is teeming with mercury.

Of course we already have a grand tradition of eating fish here in Blighty... and long may it continue.

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[1] Yoshimasu K. et al. A meta-analysis of the evidence on the impact of prenatal and early infancy exposures to mercury on autism and attention deficit/hyperactivity disorder in the childhood. Neurotoxicology. 2014 Jun 18. pii: S0161-813X(14)00098-9.

[2] Palmer RF. et al. Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas. Health & Place. 2006; 12: 203-209.

[3] Palmer RF. et al. Proximity to point sources of environmental mercury release as a predictor of autism prevalence. Health & Place. 2009; 15: 18-24.

[4] Sagiv SK. et al. Prenatal Exposure to Mercury and Fish Consumption During Pregnancy and Attention-Deficit/Hyperactivity Disorder–Related Behavior in Children. Arch Pediatr Adolesc Med. 2012 Dec;166(12):1123-31.

[5] Maglione MA. et al. Safety of Vaccines Used for Routine Immunization of US Children: A Systematic Review. Pediatrics. 2014. 1 July.

[6] Hooker B. et al. Methodological Issues and Evidence of Malfeasance in Research Purporting to Show Thimerosal in Vaccines Is Safe. BioMed Research International. 2014; 247218.

[7] Gorini F. et al. The Role of Heavy Metal Pollution in Neurobehavioral Disorders: a Focus on Autism. Review Journal of Autism and Developmental Disorders. 2014. June 27.

[8] Wright B. et al. A comparison of urinary mercury between children with autism spectrum disorders and control children. PLoS One. 2012;7(2):e29547.

[9] Adams JB. et al. Mercury, lead, and zinc in baby teeth of children with autism versus controls. J Toxicol Environ Health A. 2007 Jun;70(12):1046-51.

[10] Ando T. et al. Mercury distribution in seawater of Kagoshima Bay near the active Volcano, Mt. Sakurajima in Japan. Bull Environ Contam Toxicol. 2010 Apr;84(4):477-81.

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Yoshimasu K, Kiyohara C, Takemura S, & Nakai K (2014). A meta-analysis of the evidence on the impact of prenatal and early infancy exposures to mercury on autism and attention deficit/hyperactivity disorder in the childhood. Neurotoxicology PMID: 24952233