A familial element to homocysteine elevations in schizophrenia?

Homocysteine - the big H - really should have its own Twitter hashtag... #thebigH.

Not only because of the range of health-related conditions which seem to be correlated with particular levels of this amino acid - think coronary heart disease and elevated homocysteine for example* or more recently cerebrovascular disease** - but also because of the body of work linking elevated homocysteine levels to diagnoses like autism and schizophrenia. (Yes, I know correlation does not equal causation).

The Benzon daughters @ Wikpedia 

In this post, I'm laying off the fairly numerous studies looking at homocysteine in relation to autism (see here and here for example) and how it potentially fits into all that folate and methionine cycle stuff.

Instead I'm concentrating on the paper by Geller and colleagues*** reporting on an interesting observation of elevated homocysteine levels in male siblings of people diagnosed with schizophrenia.

I was drawn to post about this paper for several reasons: (a) continuing the link between the big H and schizophrenia (see here), (b) the suggestion that the big H link might also have a familial element and (c) ergo, the possibility of a kind of shared biological phenotype being present in at least some families of those diagnosed with schizophrenia. This last point in particular might not necessarily just mean elevated risk of schizophrenia - if one is to assume that elevated levels of homocysteine is a factor - but also all those other health-related links being made with homocysteine.

The familial element also brought me back to autism and concepts like the broader autism phenotype (BAP) and indeed, some of the shared biochemistry that seems to be present in some cases of autism (see here). On that basis, I guess it should be no surprise about what Geller et al found if one is to assume some similar scenario also pertaining across schizophrenia or the schizophrenia spectrum.

There's little more for me to say about the Geller findings aside from replication please and perhaps detailing a little more about those siblings (i.e. did they go on to develop schizophrenia or any other related condition?) In passing I mentioned about the folate and methionine link which brings in those letter MTHFR; by all accounts, this seems to be quite an important part of that homocysteine link****. Oh and then there's the body of research which seems to imply we might be able to do something about hyper-homocysteine***** and related parameters (see here). Bearing in mind that I give no medical or clinical advice about this...

Music: Don't Stop Believin' by Journey. Please, proper English gentlemen... believing.

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* Humphrey LL. et al. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc. 2008 Nov;83(11):1203-12.

** Yan J. et al. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease. Neurology. 2013; 81: 1298-1307.

*** Geller V. et al. Elevated homocysteine level in siblings of patients with schizophrenia. Psychiatry Res. 2013 Sep 16. pii: S0165-1781(13)00476-9. doi: 10.1016/j.psychres.2013.08.016.

**** Muntjewerff JW. et al. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry. 2006 Feb;11(2):143-9.

***** Miodownik C. et al. High-dose vitamin B6 decreases homocysteine serum levels in patients with schizophrenia and schizoaffective disorders: a preliminary study. Clin Neuropharmacol. 2007 Jan-Feb;30(1):13-7.

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Geller V, Friger M, Sela BA, & Levine J (2013). Elevated homocysteine level in siblings of patients with schizophrenia. Psychiatry research PMID: 24051177

Prenatal paracetamol exposure and offspring outcome

Pain. Nobody particularly likes it, but with the pharmaceutical arsenal of pain relief medication at our disposal these days, many cases of pain can be tackled in one way or another.

Tablets (before tablets) @ Wikipedia 

For those who watched the recent BBC series by the ever-intrepid Dr Michael Mosley titled 'Pain, pus and poison' on some of the important history behind the modern medical, chemical and pharmacy professions, pain was a feature of quite a few of the developments discussed.

Indeed, it was a real eye-opener to learn that one of our most famous forms of pain relief - aspirin - was at one time rejected in favour of another equally famous drug, heroin (see here for the background to the Bayer story).

With pain relief medication in mind, today I'm talking about the paper by Brandlistuen and colleagues* who reported: "Children exposed to long-term use of paracetamol during pregnancy had substantially adverse developmental outcomes at 3 years of age". Some of the accompanying media about this study can be found here.

Paracetamol or acetaminophen to our cousins over the Pond, has a special place when it comes to modern pain relief. Not only does it have pain relief (analgesic) qualities but its antipyretic (fever reducing) properties also add an extra dimension to this widely available pharmaceutic. As the pin-up drug for pain relief, paracetamol also has a bit of dark side too. Paracetamol overdose is, unfortunately, an all too common occurrence these days**; on some occasions without users even realising that they've overdone it (see here). And just in case you were wondering, it is a really horrible way to leave this mortal coil (see here).

Brandlistuen et al relied on data derived from the Norwegian Mother and Child Cohort Study otherwise known as MoBa which some readers might remember from a recent post on this blog (see here). They asked pregnant women about their paracetamol usage at various stages of their pregnancy and a few months after they had delivered. Relying on a comparison between sibling pairs (one exposed to paracetamol during pregnancy and the other unexposed), data on 2919 same-sex sibling pairs were analysed in relation to aspects of "psychomotor development" and things like temperament.

The results suggested that "children exposed to prenatal paracetamol for more than 28 days had poorer gross motor development [β 0.24, 95% confidence interval (CI) 0.12-0.51], communication (β 0.20, 95% CI 0.01-0.39), externalizing behaviour (β 0.28, 95% CI 0.15-0.42), internalizing behaviour (β 0.14, 95% CI 0.01-0.28), and higher activity levels (β 0.24, 95% CI 0.11-0.38)". Sorry for the very long quote but basically quite a few problem issues seemed to be more readily reported in the exposed siblings compared with unexposed control siblings.

Importantly, researchers were to a large extent able to rule out other pain relief medication such as ibuprofen, as being related to these findings and by doing so also to some degree answer the question of "whether the underlying illness could be the cause of the effect on the children, and not paracetamol itself".

This is not the first time that paracetamol usage during pregnancy has come under the research spotlight. Outside of the growing research base correlating pregnancy paracetamol use and a heightened risk of offspring asthma***, there have been murmurs down the years that other aspects of offspring development might also be associated with pregnancy paracetamol use; although nothing as methodologically strong as that of the Brandlistuen results.

I was always going to be interested in the Brandlistuen findings given my previous discussion on the issue of sulphation (or sulfation if you prefer) in relation to autism (see here and here). It is more of a peripheral connection than anything based on the way that medicines such as paracetamol are metabolised in the body**** and what happens when one of the major paracetamol processing pathways is disrupted in some cases of autism*****. That and the continuing interest in all things NAC and autism (see here).

In more recent times I've however noted quite a bit of speculation on how paracetamol use might have a more 'direct' effect on the autism numbers game as per the paper by Bill Shaw****** (open-access) which has received quite a lot of attention (see here). This bearing in mind, that Dr Shaw was not the first to suggest a connection as per the paper by Bauer and Kriebel******* (open-access). That and the quite controversial suggestion by Schultz and colleagues******** that: "acetaminophen use after measles-mumps-rubella vaccination was associated with autistic disorder" perhaps enquiring whether the issue of fever suppression might also be something to look at as per the speculations of Torres********* (open-access).

Stepping back a little, there are a few cautions to take before reading too much into this area of research interest. As the authors note in the accompanying press on this work: "Importantly, we cannot assume that there is a causal relationship between maternal use of paracetamol during pregnancy and adverse effects in children from an epidemiological study". I'd second that notion of correlation not necessarily being the same as causation. The use of 'maternal report' for paracetamol usage is also probably going to be subject to some degree of bias. Scoring for example, when you took a pill and noting its brand and strength is not the same as looking at doctor prescriptions or pharmacist notes, even without the issue of medication adherence to contend with too.

As far as I can see, the Brandlistuen results did not mention autism as an outcome measure from their trial so one has to be careful of making any sweeping generalisations to the autism spectrum based on this particular study. I've mentioned autism in this post because of that potential sulphation research link but imply nothing more at present.

The Brandlistuen work also talked about quite chronic exposure to pregnancy paracetamol use (more than 28 days) as showing the stronger association over shorter exposure periods, which could be interpreted as a dose-response relationship. In a real-life setting and understanding that medicines, all medicines, have the propensity for side-effects, one might look at alternative methods of pain relief during pregnancy or some all-important medicines management as being key to balancing why medication is needed vs. potential risks or side-effects as per what needs to be done with other medicines taken during pregnancy. Did I also mention correlation is not the same as causation?

I'm reserving my last words on this post with a reiteration of my oft-cited caveat on this blog about not giving medical or clinical advice. If you need to talk to someone about this issue and the concept of risk, have a chat with your medical healthcare provider.

To close, for any Pharmacists out there: do you fancy a trip to the House of Fun? (This is a chemists, not a joke shop)

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* Brandlistuen RE. et al. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013 Oct 24.

** Hawton K. et al. Impact of different pack sizes of paracetamol in the United Kingdom and Ireland on intentional overdoses: a comparative study. BMC Public Health 2011; 11: 460.

*** Andersen AB. et al. Use of prescription paracetamol during pregnancy and risk of asthma in children: a population-based Danish cohort study. Clin Epidemiol. 2012; 4: 33-40.

**** Jensen LS. et al. The quantification of paracetamol, paracetamol glucuronide and paracetamol sulphate in plasma and urine using a single high-performance liquid chromatography assay. J Pharm Biomed Anal. 2004 Feb 18;34(3):585-93.

***** Alberti A. et al. Sulphation deficit in "low-functioning" autistic children: a pilot study. Biol Psychiatry. 1999 Aug 1;46(3):420-4.

****** Shaw W. Evidence that Increased Acetaminophen use in Genetically Vulnerable Children Appears to be a Major Cause of the Epidemics of Autism, Attention Deficit with Hyperactivity, and Asthma. Journal of Restorative Medicine 2013; 2: 1.

******* Bauer AZ. & Kriebel D. Prenatal and perinatal analgesic exposure and autism: an ecological link. Environ Health. 2013; 12: 41.

******** Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

********* Torres AR. Is fever suppression involved in the etiology of autism and neurodevelopmental disorders? BMC Pediatr. 2003; 3: 9.

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Brandlistuen RE, Ystrom E, Nulman I, Koren G, & Nordeng H (2013). Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. International journal of epidemiology PMID: 24163279

A bottom-up approach to autism research?

If anything else, the recent discussions on the principles of RDoC - Research Domain Criteria (see here) - being applied to psychiatry have prompted many to question whether our current diagnostic labels are actually fit for purpose when it comes to answering the big research questions of how and why.

Bottoms up? @ Wikipedia 

RDoC, for those of you who might not know, is described by the US National Institute of Mental Health (NIMH) as an attempt to: "define basic dimensions of functioning (such as fear circuitry or working memory) to be studied across multiple units of analysis, from genes to neural circuits to behaviors, cutting across disorders as traditionally defined".

In other words, by all means use the DSM or ICD as your diagnostic key, but don't necessarily expect the genes (and epigenetics), biochemistry and brain / body physiology to also fit neatly into those categories that you diagnose with. The proof for this disparity is laid out in front of us all as labels such as autism or schizophrenia or ADHD remain in the most part a mystery when it comes to aetiology, common biological signatures (including replicative work) and consequently generalised intervention options to improve quality of life and functioning.

Even before RDoC I, like quite a few others, often thought that the reliance on something like the label of autism or autism spectrum as a research starting point offered little when it came to autism science. In a previous post, I did talk about the possibility of overcoming this issue as per the discussions on focusing on phenotypes - smaller subgroups on the autism spectrum - characterised by something like response to intervention for example (see here). Indeed, my recent droning on the area of dietary intervention for autism (see here) exemplified how such a shift in focus might yet yield some testable results.

Enter then another modified example of this approach with the paper by Lisa Unwin and colleagues* (open-access version here) and their discussions on a bottom-up approach to autism research. I admit that I was always going to be interested in this paper because of (a) the presence of Andrew Whitehouse on the authorship list (see previous posts here and here) and (b) mention of the 'autisms' over the more 'unitary' label of autism (see here).

As Unwin et al describe, the bottom-up approach used in the paper refers to "known aetiological risk factors, and whether individuals exposed to these risk factors have a more homogenous phenotype". In this case, low birth weight and independently maternal use of SSRIs during pregnancy (see here) were the starting points and then "examining the homogeneity within the groups based on medical complaints such as sleep problems and gastrointestinal complaints in addition to core features of ASD such as social behavior, language characteristics, and severity". Actually on the point of anti-depressant use during pregnancy and autism risk, I'm minded to bring in other, more recent evidence that suggests risk may have been over-inflated?

The first part of the Unwin paper looked at those children with an ASD where maternal SSRI use was reported during pregnancy and suggested that "children with ASD whose mothers took SSRIs during pregnancy were significantly more likely to experience gastrointestinal complaints during childhood" compared with no maternal SSRI history. The second study included in the paper examined children with ASD with a low birth weight compared against those with a normal range birth weight. They suggested "greater sleep disturbances" to be present in the former group.

Whilst the participant numbers included in this paper were low and the results are crying out for replication, I find this approach to be a breath of fresh air when it comes to autism research. Not only because of the realisation that there may be different phenotypes within the autism spectrum as a function of suggested risk factors - of which there may several (see here and here for example) - but also because the authors expanded their horizons outside of just looking at the core behavioural symptoms associated with autism. Indeed the focus on bowel issues (see here) and sleep issues (see here) reflect how frequently these variables crop up and how, for some people, they can so significantly affect quality of life.

There are some other nuggets of research gold to come out of this paper which are worthy of comment. So, "it seems reasonable that environmental factors may be related to the expression of non-core ASD symptoms among these children rather than to any variance in core symptomatology". In other words, autism might actually be greater than the sum of its triadic (sorry dyadic) parts. As per my chatter about the 'autisms' previously, the authors also note: "A key question facing the field is whether the long-held view that autism is a unitary disorder with a single causal pathway is correct, or whether autism may best be conceptualized as an umbrella term for a collection of behavioral disorders resulting from a range of causal pathways, analogous to cerebral palsy". Not surprisingly the authors conclude that the plural autism might be "a more accurate representation".

Tom Insel of the NIMH is quoted along similar lines with his phrase: "Clearly autism is many disorders". I'd have to say that I agree and that 'range' of conditions falling under the autism umbrella seems to be growing all the time.

Music maestro.... Common People by Pulp?

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* Unwin LM. et al. A "bottom-up" approach to aetiological research in autism spectrum disorders. Front Hum Neurosci. 2013 Sep 19;7:606. doi: 10.3389/fnhum.2013.00606.

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Unwin LM, Maybery MT, Wray JA, Whitehouse AJ. (2013). A "bottom-up" approach to aetiological research in autism spectrum disorders. Front Hum Neurosci. DOI: 10.3389/fnhum.2013.00606

Synaesthesia prevalent in autism?

The BBC headline 'Study links synaesthesia to autism' recently caught my eye (and nose!) discussing the paper by Baron-Cohen and colleagues* (open-access) who suggested that: "The rate of synaesthesia in adults with autism was 18.9% (31 out of 164), almost three times greater than in controls".

Colour and sensation @ Wikipedia 

Synaesthesia according to the UK Synaesthesia Association is best described as a "union of the senses" whereby "two or more of the five senses that are normally experienced separately are involuntarily and automatically joined together".

In other words, some people might experience certain words as tastes or see colours when they hear music. The BBC follow-up their coverage of the Baron-Cohen paper with a story about a man who can taste the London Underground map and his efforts to re-design the Tube map according to 'sausage and eggs' and 'putrid meat'.

In their paper, the authors tested the suggestion of overlap between autism - adults with "high-functioning autism or Asperger's syndrome" - and synaesthesia by asking participants with autism and asymptomatic controls to complete a questionnaire on any experiences of synaesthesia alongside something called the Test of Genuineness-Revised (ToG-R) "to validate any self-reported auditory-visual forms of grapheme-colour (GC) and sound-colour (SC) synaesthesia and was sent to all participants in order to detect true and false positives and negatives". That being said, response rates to the ToG-R were not brilliant; as per another quote: "Telephone follow-up to find out why ToG-Rs were not being completed revealed that participants with autism reported fatigue from the 241 possible choices".

Based on their data however, they report that "The rate of synaesthesia in autism (18.9%) was almost three times greater than in the typical sample (7.22%)". They also suggest that this figure might be an under-estimate given that some participants with autism "claimed they did not have synaesthesia, but were judged by the experimenters to have synaesthesia on the basis of their questionnaire responses".

I have to say that I'm very interested in these results. Sensory issues with regards to the autism spectrum are something of growing importance given the effect that they can have on both how a person perceives the world around them and also how such perceptions can impact on day-to-day functioning and quality of life. Even the latest version of DSM saw fit to include sensory issues in their latest redefinition of the autism spectrum (see here).

That being said I still want to see more on this topic done before I totally commit to the likelihood that synaesthesia is frequently prevalent in cases of autism. Questions about how representative these results are for example, to those who present with a greater severity of autistic symptoms or with comorbid learning disability remain as does the question of mechanism and whether there are genetic or biological commonalities to be seen.

I'd also hazard a guess that synaesthesia is just the tip of the iceberg when it comes to sensory and visual issues and autism; indeed whether as per the exclusion criteria for acquired synaesthesia in the Baron-Cohen study "the person had any medical conditions affecting vision". Well, if the Ikeda results are anything to go on, yes would probably be the answer for anything up to 40% of those with autism. How such vision issues would impact on the presentation of synaesthesia remains to be seen. And finally there is the question of whether any other -sia conditions also reported in cases of autism might also show some involvement, as per the chatter about prosopagnosia (face-blindness)?

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* Baron-Cohen S. et al. Is synaesthesia more common in autism? Molecular Autism 2013, 4:40

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Simon Baron-Cohen, Donielle Johnson, Julian Asher, Sally Wheelwright, Simon E Fisher, Peter K Gregersen, & Carrie Allison (2013). Is synaesthesia more common in autism? Molecular Autism, 4 DOI: 10.1186/2040-2392-4-40

Sedentary behaviours and autism

Standing up is better for your health than sitting down according to the BBC website. As one of those people known to wear a pedometer pretty regularly and generally be quite 'obsessive' about my 10,000 steps per day (or should that be 6000 steps per day [1]), I wasn't surprised by some of the discussions on this topic and how quite a proportion of the population at large could really do with standing up and indeed, moving a little more each day.

 The Ministry... @ Wikipedia 

We are all seemingly bombarded these days with information mixed in with a healthy sprinkling of science suggesting that one needn't be pounding the streets for hours on end in order to get a little bit more healthy. It's all about making sure that we aren't too sedentary and perhaps enjoying a little more of the great outdoors even if at a leisurely pace.

With this in mind, I was very interested to read the paper by Avivia Must and colleagues [2] who upon comparing a small-ish group of children diagnosed with an autism spectrum condition (n=53) with typically developing peers (n=58), found that "children with autism spectrum disorder spent an hour more in sedentary behaviors on weekdays compared to typically developing children". Further Must et al also reported quite a bit of that increase in sedentary behaviour was apportioned to an increase in screen time (TV and computer) and "sedentary behaiour is linked to relative weight status" in the group of children with autism. Think screen time and autism and I think about the work of Micah Mazurek as exemplified by this paper [3] and more recently with the issue of sleep in mind [4].

Some more digging into the various research done on exercise and autism revealed some equally interesting findings. The same authorship group have looked at this issue before as per the article by Bandini and colleagues [5] who suggested based on the same spread of participants (autism, n=53, not-autism, n=58) "moderate and vigorous activity was similar in children with ASD (50.0 minutes/day and typically developing children 57.1 minutes/day)". That being said, the authors did report that children with autism participated in "fewer physical activities and for less time according to parental report" highlighting potential issues with the measurement schedule employed to examine activity levels.

These and other similar research on activity levels and autism perhaps represent the other side of the research coin in terms of the increasing interest in the use of technology to improve quality of life for those on the autism spectrum. The rise and rise of the use of tablet technology for example, whilst often a significant step forward for some on the autism spectrum, not necessarily being great news for levels of physical activity if replacing time that could be used on non-sedentary activities.

The question of whether physical activity might also have some added benefits outside of just physical health has also been looked at. Oriel and colleagues [6] reported that "aerobic exercise prior to classroom activities may improve academic responding in young children with autism spectrum disorder". I'm not for one minute suggesting that every classroom should be installing a treadmill so as to increase 'correct' responses to I assume, questions posed by the teacher. But as I've indicated on a previous post about stress (see here), physical exercise often goes so much further than just improving physical health and that applies to autism too [7]. Other research reviews whilst highlighting a lack of good quality evidence in this area, have nonetheless suggested that exercise participation might have a least some short-term bearing on the presentation of facets of autism also [8].

With all the mind, the question of what kind of activities might increase activity levels in cases of autism in childhood has similarly been examined in autism research circles.

Walking is often a good place to start when it comes to increasing activity levels. The paper by Pitetti and colleagues [9] reported that even for those at the more severe end of the autism spectrum, the implementation of a walking program may well have some important benefits. Correspondingly, I've heard a few people talk about young people and adults with autism (again towards the more severe end of the autism spectrum) who very much enjoy long (sometimes very long) walks in all weathers. One wonders whether they might know more than us about what makes them feel good?

Swimming is another option to consider as per the paper by Fragala-Pinkham and colleagues [10]. Granted their results weren't astounding in terms of fitness outcomes for some participants (although contrasted with previous work of theirs [11]) but one might suggest that anything which increases activity is worthwhile. That and the often life-saving skills that are gained by learning to swim. Indeed, Pan [12] reported on some other potentially important changes noted following implementation of a water exercise swimming program with a small group of children with autism.

And then there are other exercise options to consider. Horseback riding (see here) assuming no fear of such animals and something which has cropped up before on this blog, the various martial arts (see this post) might also be good ways of increasing activity levels and decreasing sedentary behaviours. I suppose it's all about finding something that the individual enjoys.

Recognising that a sedentary lifestyle is not really ideal for anyone, there are perhaps some important lessons to be learned about increasing activity levels among children and adults with autism. Physical activity is an important part of physical health, and as we've seen in relation to schizophrenia, there is an emerging gap appearing in terms of health inequality which includes the issue of physical activity levels. That physical activity levels may also have important knock-on effects for things like bone health (see this post) and possibly exposure to sunshine and that all-important vitamin D (see this post) are also important considerations too.

To close, a song about walking by two brothers who are talking about walking an awfully long way. Oh and for those who were also wondering about the word 'haver', some background can be found here.

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[1] Tudor-Locke C. & Bassett DR Jnr. How many steps/day are enough? Sports Med. 2004: 34: 1-8.

[2] Must A. et al. Comparison of sedentary behaviors between children with autism spectrum disorders and typically developing children. Autism. 2013 Oct 10.

[3] Mazurek MO. & Wenstrup C. Television, video game and social media use among children with ASD and typically developing siblings. J Autism Dev Disord. 2013 Jun;43(6):1258-71.

[4] Engelhardt CR. et al. Media Use and Sleep Among Boys With Autism Spectrum Disorder, ADHD, or Typical Development. Pediatrics. November 2013.

[5] Bandini LG. et al. Comparison of physical activity between children with autism spectrum disorders and typically developing children. Autism. 2013 Jan;17(1):44-54.

[6] Oriel KN. et al. The effects of aerobic exercise on academic engagement in young children with autism spectrum disorder. Pediatr Phys Ther. 2011 Summer;23(2):187-93.

[7] 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.

[8] Petrus C. et al. Effects of exercise interventions on stereotypic behaviours in children with autism spectrum disorder. Physiother Can. 2008 Spring;60(2):134-45.

[9] Pitetti KH. et al. The efficacy of a 9-month treadmill walking program on the exercise capacity and weight reduction for adolescents with severe autism. J Autism Dev Disord. 2007 Jul;37(6):997-1006.

[10] 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.

[11] Fragala-Pinkham M. et al. Group aquatic aerobic exercise for children with disabilities. Dev Med Child Neurol. 2008 Nov;50(11):822-7.

[12] Pan CY. Effects of water exercise swimming program on aquatic skills and social behaviors in children with autism spectrum disorders. Autism. 2010 Jan;14(1):9-28.

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Must A, Phillips SM, Curtin C, Anderson SE, Maslin M, Lividini K, & Bandini LG (2013). Comparison of sedentary behaviors between children with autism spectrum disorders and typically developing children. Autism : the international journal of research and practice PMID: 24113339

Iodine deficiency and autism

With all the recent-ish chatter about dietary quality for those on the spectrum (see here), coupled with a hint of something like the mechanisms of malabsorption being linked to specific cases (see here), the potential issue of 'nutritional deficiency' in relation to autism represents a pretty constant research topic these days.

 Iodine @ Wikipedia

I've talked before about research defining a deficiency in certain vitamins and minerals in relation to cases of autism on this blog; be it in relation to the vitamin-of-the-hour, vitamin D (see here) or vitamin B12 (see here) or something like zinc (see here).

The picture is a complicated one and not necessarily a universal one in terms of prevalence across the autism spectrum nor being solely due to poor eating patterns. But given the increasing understanding of the importance of nutrition to mental and physical health and wellbeing, one would expect quite a lot more to be said on this topic over the coming years.

The paper by Rasha Hamza and colleagues* detailing findings in relation to iodine in cases of autism and other family members adds to the interest. Based on a relatively small participant group, the authors reported that: "Of autistic children and their mothers, 54% and 58%, respectively, were iodine deficient". This contrasted with none of the 50 control group children or mothers presenting with iodine deficiency (ID).

Before progressing through the Hamza study further, I might point out that the British Dietetic Association (BDA) carries quite a detailed information sheet about iodine (see here) as does the US Office of Dietary Supplements (see here). Iodine is sourced mainly from food, and as you'll see from the links, outside of seafood and shellfish, milk and dairy products are one of the biggest dietary sources of iodine. Casein-free diet anyone?

A primary use for iodine in the body is for the production of thyroid hormones. Without going over previous ground, there is some research history when it comes to thyroid hormone and autism as per discussions on the measurement of thyroid hormone levels in autism (see here) and more recent research talking about maternal thyroid levels and offspring 'autistic symptoms' (see here). Dare I even mention the possible environmental variables which have been associated with thyroid function too?

Back to the Hamza paper. As well as measuring levels of urinary iodine (UI) - which apparently is quite a good way of measuring iodine intake** - the researchers also scored child participants with autism using the CARS so as to have some measure of the extent of their presented symptoms. That and examining levels of some of the various thyroid hormones, they were able to arrive at a few other preliminary, but potentially important conclusions.

"Childhood Autism Rating Scale (CARS) score correlated negatively with UI (r = -0.94, p <0.001)". I'm no statistician (add it to the long list of things for which I'm more amateur than professional) but a correlation (r) of -0.94 seems pretty good to me bearing in mind that (1) or (-1) indicates a perfect positive and negative correlation respectively. This data translates as a higher CARS score being generally associated with lower levels of urinary iodine. Further, when looking maternal and child UI output and other thyroid hormones, the authors reported some interesting positive correlations between child and mother values obtained.

It would be easy to say that the Hamza study has some methodological issues. Outside of the quite small participant group, and their exclusive focus on Egyptian families, this was very much a snapshot study in terms of looking at participants at a particular point in time. CARS, like many other autism screening and assessment instruments, is still quite a subjective measure also and who's to say that if this study was repeated a week or a month later, whether similar results would be had with the same group. And then there is that milk-free dietary issue to also consider...

But with all that in mind, this remains an interesting study. I note that other independent groups have also reported issues with iodine being related to cases of autism as per the findings by Blaurock-Busch and colleagues*** (open-access here) and a familiar name to this blog (see here) Jim Adams and his paper***. I was also drawn to an interesting communication on the topic of iodine deficiency as being related to autism from Sullivan & Maberly**** as food for thought, bearing in mind I'm less inclined to believe there is just one factor linked to the increasing numbers of cases of autism being reported.

So, perhaps on that collected basis, there is a little more research to do when it comes to iodine and autism? Oh, and with my blogging caveat about no medical or clinical advice given or intended, please take some proper medical advice if you're thinking about supplementing with iodine (see here).

To close, The Life of Riley by the Lightning Seeds (not to be confused with the life of Whiteley).

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* Hamza RT. et al. Iodine Deficiency in Egyptian Autistic Children and Their Mothers: Relation to Disease Severity. Arch Med Res. 2013 Oct 9. pii: S0188-4409(13)00222-1. doi: 10.1016/j.arcmed.2013.09.012.

** Delange F. et al. Determining median urinary iodine concentration that indicates adequate iodine intake at population level. Bulletin of the World Health Organization. 2002; 80: 633-636.

*** Blaurock-Busch E. et al. Toxic Metals and Essential Elements in Hair and Severity of Symptoms among Children with Autism. Maedica (Buchar). 2012 Jan;7(1):38-48.

**** Adams JB. et al. Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers. Biol Trace Elem Res. 2006 Jun;110(3):193-209.

***** Sullivan KM. & Maberly GF. Iodine deficiency as a cause of autism? BMJ. Rapid Response. 13 October 2004.

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Hamza RT, Hewedi DH, & Sallam MT (2013). Iodine Deficiency in Egyptian Autistic Children and Their Mothers: Relation to Disease Severity. Archives of medical research PMID: 24120386

Methylcobalamin and folinic acid for autism? Hold it right there...

The title of this post should also have included the word 'glutathione' too based on the results reported by Richard Frye and colleagues* (open-access) describing behavioural and biochemical data from a 3-month open trial of methylcobalamin, a vitamin B12 'vitamer', and folinic acid with a group of children diagnosed with an autism spectrum disorder (ASD).

Dr Frye and his various research are no stranger to this blog; ranging from mitochondrial dysfunction linked to cases of autism (see here), through to tetrahydrobiopterin (BH4) and autism (see here), and folate receptor autoantibodies and autism (see here). Indeed that last link on folate receptor autoantibodies brings into view a potential reason why folinic acid was included in their recent study. That and the inclusion of Jill James on the authorship list and her previous studies looking at combined methylcobalamin and folinic acid supplementation for autism** (open-access) discussed as part of a previous post (see here).

The crux of this study was the suggestion that in the great and complex pathway which links the recycling of homocysteine (the big 'H') and the folate cycle, there is potentially enough going on in cases of autism to interfere with (a) the process of methylation (see here) and (b) that most useful of compounds, glutathione (see here), well reduced glutathione anyway. I'm also inclined to point readers the way of the very thorough analysis of glutathione and autism produced by Main and colleagues*** (open-access) a while back (see here) just in case you think I'm talking biochemical mumbo-jumbo.

Readers might already have seen mention of the words 'open trial' at the top of this post. This indicating that the latest study from Frye and colleagues was a case of following 37 children who fitted the entrance criteria - including "abnormal methylation capacity (SAM/SAH < 3.0) and glutathione redox metabolism (GSH/GSSG < 6.0)" - and seeing how they went over the course of a "sterile subcutaneous injection of methylcobalamin in the fatty tissue of the buttocks" every 3 days combined with oral delivery of folinic acid twice daily mixed with food. For those wincing or furrowing their brows about those injections of methylcobalamin with children with autism, I'll just say that the issue of drug delivery has been talked about in a previous post and this study was passed through an ethics committee "at the University of Arkansas for Medical Sciences".

The results are interesting. Quite a few behavioural changes were documented according to use of the VABS. This bearing in mind that (a) there was no control or placebo group and (b) VABS is a parent-report schedule which in this case merely looked at unblinded pre- and post-intervention scores. Nonetheless, the intervention resulted in "significant increases in VABS scores for all domains, including daily living, social, and communication skills, with an average effect size of 0.59, which is in the medium-to-large range." The authors even went as far to say that the VABS changes indicated something like an average 7.7 month gain over the 3 month period of study.

All well and good with that open-trial caveat well and truly in place. It is however the details regarding the biochemical measure of glutathione measurement that I was more interested in. Indeed, if I had to suggest one improvement to this paper, it would have been to include a simple table showing glutathione measures - GSH/GSSG - at baseline compared with at 3 months. Instead, the glutathione results are all bundled up with the VABS results as per the example of figure 3 showing: "the change in the glutathione redox status (reduced-to-oxidized glutathione ratio) and change in subscales of the Vineland Adaptive Behavior Scale (VABS) subscales".

What I did manage to glean is that: "the overall glutathione redox status was not related to VABS subscales, indicating that overall development did not appear to be related to overall glutathione redox status". Fair enough, a possible selection issue based on the group eventually included for study. It was the change in glutathione redox status after intervention which seemed to tie into the VABS results reported. Still, I would have liked to have the biochemical data presented as a stand-alone table.

I'm trying not to be overly-critical of this paper and results contained within. As with many other researchers, I'm guilty of the odd open-trial forming part of my CV (see here). Whilst useful as a starting point for looking at a particular intervention or trying to get others to do a more methodologically-sound study, one has to be quite cautious of such work and the myriad of biases that they contain.

I do get the impression that outside of just a more methodologically-sound trial, a lot more questions need to be asked about this intervention regime before it can be considered as something more mainstream. Outside of the 2 children who dropped out of the study because "parents were uncomfortable giving the methylcobalamin injections", there's also a question of what such an intervention is actually doing. I note the authors when discussing the previous James trial**, are quoted as saying: "The fact that the treatment [methylcobalamin and folinic acid] improved but did not normalize methionine, SAM and glutathione concentrations may reflect ongoing metabolic compensation for incompletely resolved oxidative stress". This may very well be true, but could also indicate that intervention was also working on other biological systems too.

That also mention is made of the Hardan trial of N-acetlycysteine (NAC) for autism (see here) and NAC being a direct glutathione precursor, suggests to me that when it comes to glutathione production, the shortest point might be A to B bearing in mind what results have been obtained from direct glutathione supplementation**** (open-access).

To close, the Clash have a question for you.... (it's the indecisions which bug me).

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* Frye RE. et al. Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status. Autism Res Treat. 2013: 609705.

** James SJ. et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr. 2009 January; 89(1): 425–430.

*** Main PA. et al. The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutr Metab (Lond). 2012 Apr 24;9:35.

**** Kern JK. et al. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011 Dec;17(12):CR677-82.

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Richard Frye, Stepan Melnyk, George Fuchs, Tyra Reid, Stefanie Jernigan, Oleksandra Pavliv, Amanda Hubanks, David W. Gaylor, Laura Walters, S. Jill James (2013). Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status Autism Research and Treatment DOI: 10.1155/2013/609705

Sutterella and autism: replicated

Whilst quite a lot of attention is currently being paid to the study by Warren Jones and Ami Klin* on 'Autism signs being present in first months of life' I'm heading off in a slightly different direction in this post. It's not that I don't find the possibility that the eyes may be more than just the windows to the soul, or at least "a decline in gazing at eyes [might] accurately predict the development of autism" an exciting prospect, it's just that I'm waiting for some more confirmatory evidence before getting too enthusiastic about this. Replication, as you'll see later in this post, is an important part of autism research these days and the autisms are a very heterogeneous set of conditions.

Bowel not bowl... @ Wikipedia 

My post a while back on the paper by Brent Williams and colleagues** (open-access) regarding the detection of gut bacteria belonging to the genus Sutterella in cases of autism (see here) continues to be one of the most read entries on this blog. It follows a trend that seems to be apparent on this site: readers seem to be very interested in bowels and stools and bacteria all in the name of autism research and science. Or maybe it's just me being a little too obsessed with writing about them?

No mind. I personally found the Williams findings to be absolutely fascinating. Not only because of the fact that they report that "Sutterella is a major component of the microbiota in over half of children with autism and gastrointestinal dysfunction (AUT-GI) and is absent in children with only gastrointestinal dysfunction (Control-GI)" but also the implications of their finding of "plasma IgG or IgM antibody reactivity to Sutterella wadsworthensis antigens in 11 AUT-GI patients, 8 of whom were also PCR positive, indicating the presence of an immune response to Sutterella in some children" which also brings the concept of gut hyperpermeability squarely into the frame (see here). The authorship group also held significant prowess.

Bearing in mind the variable research base on a possible role for gut bacteria in cases of autism (see this post and this post) reflective of this being an emerging area for autism research, I'd like to think that the paper by Lynn Wang and colleagues*** (open-access) is another important addition to the collected text. If anything, their findings that "numbers of Sutterella spp. are elevated in feces of ASD children relative to controls" are a useful part of the scientific issue of replication, which we've been hearing something about with autism research in mind in recent times (see here).

The short report from Wang et al details findings based on the examination of fecal samples from a small group of children diagnosed with an autism spectrum disorder (ASD) compared with sibling and typically developing controls. There is an obvious difference between this paper and the one by Williams and colleagues around the tissue type used to assay for bacterial content; Williams relied on biopsy samples taken from various sections of the gastrointestinal (GI) tract. That being said, this difference is not necessarily a bad thing as per the assertion by Wang that "fecal samples may suffice for the detection and quantification of Sutterella in the human gut, including children with ASD". Biopsy = invasive, poo sample = not invasive (or at least not as invasive in terms of collection, but just make sure you wash your hands afterwards).

I was also interested to read about the very preliminary observation when comparing those children with GI issues - caregiver reported GI issues - and another type of bacteria called Ruminococcus torques. Another quote from the paper I'm afraid: "Significantly elevated absolute numbers of R. torques were evident in children with ASD whose caregivers reported them having a FGID (nine individuals) compared to those without reported FGID (14 individuals)".

FGID by the way, means functional GI disorder à la things like constipation and diarrhoea (see here); conditions which have very recently been confirmed as associated with autism**** yet again (see here for some commentary). Yes, it was only a very small number of participants and yes, it was based on bowel habit data solely derived from parental report. But don't underestimate the power of the parental report when it comes to such toileting issues with autism in mind (see here). Interestingly, this is also not the first time that R. torques has been mentioned with autism in mind as per the study from Sid Finegold and colleagues***** (open-access) a few years back.

I had heard that this new Sutterella paper would be arriving to the peer-reviewed table as far back as May this year (2013) as per a poster delivered at IMFAR (see here). Indeed Dr Wang's publications as part of a very active research consortium including Dr Manya Angley and colleagues at the University of South Australia are a favourite on this blog as per mention of things like Akkermansia muciniphila and autism (see here) which has also gone on to other things (see here). Indeed I was honoured to be able to read Lynn's very comprehensive PhD thesis which, I have to say, certainly put my efforts a few years back to shame.

Questions still remain about this issue of Sutterella and autism outside of just being identified as being present more frequently in cases of autism. How does it become predominant for example? And as per the chatter about baby immune systems and the process of bacterial colonisation, is early infancy the key or are we talking later on in development? I note also that the initial talk about Sutterella being linked to conditions like inflammatory bowel disease (IBD) has subsided following further exploration of any relationship****** (open-access) so the question of what role or association it might play is still up for grabs.

Indeed, I don't think either we're currently, definitively, able for example, to say that such bacteria (and potentially others) can actually influence the overt presentation of autism as per the psychobacteriomics paper recently reported. That being said, I think back to the gut decontamination study of Sandler and colleagues talked about in this post and their use of the potent antibiotic vancomycin as possibly presenting some new avenues of research exploration. As I've said a few times on this blog, the triad of immune function, gut barrier integrity and gut bacteria might eventually turn out to be important for some cases of autism (as they seem to be in other areas of research), but the relationship between these elements and onwards to the presentation of more commonly described symptoms is still quite a bit of a mystery.

Still, replication is replication. And with the Sutterella story, scientific replication with gut issues in relation to some of the autisms in mind is moving along rather nicely.

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* Jones W. & Klin A. Attention to eyes is present but in decline in 2–6-month-old infants later diagnosed with autism. Nature. November 2013.

** Williams BL. et al. Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. MBio. 2012 Jan 10;3(1).

*** Wang L. et al. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Molecular Autism. 2013; 4:42.

**** Chaidez V. et al. Gastrointestinal Problems in Children with Autism, Developmental Delays or Typical Development. J Autism Dev Disorder. November 2013.

***** Finegold S. et al. Gastrointestinal Microflora Studies in Late-Onset Autism. Clin Infect Dis. 2002; 35 (Supplement 1): S6-S16.

****** Hansen R. et al. The microaerophilic microbiota of de-novo paediatric inflammatory bowel disease: the BISCUIT study. PLoS One. 2013;8(3):e58825.

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Lv Wang, Claus T Christophersen, Michael J Sorich, Jacobus P Gerber, Manya T Angley, Michael A Conlon (2013). Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder Molecular Autism DOI: 10.1186/2040-2392-4-42

Anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis and autistic regression

Regression as part of the presentation of autism is still a topic which has the ability to create discussion and fuel controversy. I've talked about it a few times on this blog (see here and here) and how, after a bit of a laboured start, modern day autism research has finally come around to acknowledging that regression can occur in cases of autism.

Fire @ Wikipedia  

The cause(s) of regression associated with autism has been where a lot of the debate has been had over the years. I've talked for example, about how vitamin B12 deficiency has been associated with cases of Childhood Disintegrative Disorder (CDD) (see here). This being one of the less 'controversial' theories put forward for regression in autism or in an autistic-like presentation as per other papers analysing factors such as thimerosal (thiomersal) exposure* and that-which-should-not-be-mentioned**.

What I take from the collection of literature on this topic is that (a) autism is probably better defined as the autisms insofar as the regression being present or not for example, and (b) there probably isn't just one factor influencing regression where and when it occurs in relation to those autisms. Oh and (c) getting to the bottom of the causes of regression in cases of autism is a mighty difficult task.

For today's post I'm talking about the paper by Ori Scott and colleagues*** describing a case report of a child where anti-N-methyl-D-Aspartate (NMDA) receptor encephalitis was suspected "as the cause of autistic regression".

From the top, anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis is an autoimmune condition whereby a person generates antibodies against self, in particular, antibodies that target NMDA receptors in the brain. As per the paper by Florance and colleagues**** (open-access here) the presentation of the anti-NMDA receptor encephalitis in children and adolescents is not wholly dissimilar from that in adults including behaviour and personality changes albeit including "temper tantrums, behavioral change, agitation, aggression, and progressive speech deterioration as initial symptoms". For those more interested in the adult presentation of the condition, the book 'Brain on Fire' by Susannah Cahalan is probably a good starting point.

Scott and colleagues chart the clinical course of a young boy following "an upper respiratory tract infection" into what would eventually "fit the diagnostic criteria for autistic spectrum disorder". Said anti-NMDA receptor antibodies were detected in cerebrospinal fluid (CSF) and treatment with "intravenous immunoglobulins and steroids" brought about a resolution of some of the behavioural issues. I might add that this is not the first time that anti-NMDA receptor encephalitis has been mentioned with autism in mind***** including that cross-over with CDD.

Taking into account the Scott paper and the writings of Cahalan, I get the impression that luck played a big role in the resolution of both cases. As per the Grauniad (sorry, Guardian) write-up of her book "Cahalan is never in any doubt about the extent of her luck: the luck in finding a sensitive doctor who listened to her, and took her case on its own merits". One can perhaps see that other medics might have not offered a similar diagnosis to the one she was eventually given and upon which treatment was commenced.

The Scott paper also brings into sharp focus how, when presented with cases of "autistic regression", it may be worthwhile undertaking some pretty detailed medical examination to determine whether the source of the regression might just fall into the jurisdiction of something like anti-NMDA receptor encephalitis. This accepting that getting a sample of CSF is not the nicest of procedures although as per other case studies, a full medical work-up is indicated****** (open-access).

That there also may be a medical reason for such a regression to occur is another lesson for autism research as and when it is confronted by children presenting with a fairly rapid regression into autism or autistic-like symptoms. It for example, strikes me that there is a growing respect for anti-NMDA receptor encephalitis when it comes to the presentation of something like delerium******* or even some cases of schizophrenia******** (open-access here) even without seizures being present. So when such a regression occurs in younger children, are they any less deserving of such medical consideration too? Exactly how the Scott report might play into the blanket 'autism is a lifelong condition' is another consideration.

Finally, I have to point out that the Scott paper was a case report and before anyone gets too carried away, does not necessarily mean that every case of regression in autism is due to this factor. That being said, the use of something like IVIg as the chosen treatment method for anti-NMDA receptor encephalitis is not necessarily a stranger to autism research (see here). The use of steroids as immunosuppressive agents, indicated for certain autoimmune conditions, might also offer some clues about certain parts of those autisms (see here) too bearing in mind my caveat on this blog about not giving medical or clinical advice.

Some music to close this post I think. Oasis and Don't Look Back in Anger. "Please [Mr McGee], don't make me angry, you wouldn't like me when I'm angry" (he says hiding behind the sofa).

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* Kern JK. et al. Thimerosal exposure and the role of sulfation chemistry and thiol availability in autism. Int J Environ Res Public Health. 2013 Aug 20;10(8):3771-800.

** Richler J. et al. Is there a 'regressive phenotype' of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):299-316.

*** Scott O. et al. Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler. J Child Neurol. 2013 Oct 3. [Epub ahead of print]

**** Florance NR. et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009 Jul;66(1):11-8.

***** Creten C. et al. Anti-NMDA-receptor encephalitis: a new axis-III disorder in the differential diagnosis of childhood disintegrative disorder, early onset schizophrenia and late onset autism. Tijdschr Psychiatr. 2012;54(5):475-9.

****** Chapman MR. & Vause HE. Anti-NMDA Receptor Encephalitis: Diagnosis, Psychiatric Presentation, and Treatment. Am J Psychaitry. 2011; 168: 245-251.

******* Punja M. et al. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: an etiology worth considering in the differential diagnosis of delirium. Clin Toxicol (Phila). 2013 Sep;51(8):794-7.

******** Tsutsui K. et al. Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features. BMC Psychiatry. 2012 May 8;12:37.

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Scott O, Richer L, Forbes K, Sonnenberg L, Currie A, Eliyashevska M, Goez HR. (2013). Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler Journal of Child Neurology DOI: 10.1177/0883073813501875