Vitamin D and autism: a continuing saga

The "sunshine vitamin" that is vitamin D has cropped up quite a few times on this blog for all manner of reasons. The suggestion of a link (whatever that means) between vitamin D and the autism spectrum conditions has received the lion's share of coverage, be that in relation to measured levels of vitamin D (see here and see here) or more speculatively, the possible impact of something like deficiency of vitamin D to symptoms or physiology (see here and see here). I've also not been adverse to talking about the 'D' in relation to other conditions or states either (see here and see here).

Monet at dusk @ Wikipedia

Without trying to do a Linus Pauling on vitamin D [bearing in mind the pendulum potentially swinging partially his way], I am genuinely interested in how this stuff might show some connection to a condition like autism. Further, whether the reports of deficiency (as they invariably tend to show) reflect something important for core symptoms, or are tied into specific comorbidity [1] or are just purely epiphenomenal and reflective of a more widespread population deficiency [2]. A few papers add to my interest in this area, specifically from Dr John Cannell who heads the non-profit Vitamin D Council based in the US. For those of you who have started to use PubMed Commons, Dr Cannell is certainly putting this post-publication review option to very good use.

So, first up is the paper from Grant & Cannell [3] (open-access here) which looked at US autism prevalence estimates for 2010 "with respect to indices of solar UV-B (UVB) doses" according to state. Based on an analysis of prevalence estimates for autism coupled to variables such as ethnicity and geographical latitude, time of year and solar UVB doses, the authors concluded that "autism prevalence among those aged 6–17 y in 2010 was significantly inversely correlated with solar UVB doses". Further, they speculate about the effects of maternal vitamin D deficiency as a potentially important issue when it comes to offspring autism risk. There was some other media interest in these results at the time of publication in 2012.

Obviously I don't need to point out that this was a number-crunching paper which relies on a statistical association so one has to be quite careful of making too much of the findings. Yes, the authors looked at "other possible risk-modifying factors" such as air pollution (see here) and obesity (see here) but one needs always to be cautious when it comes to correlation (as in, not necessarily equalling causation). That also other researchers have downplayed the maternal vitamin D - offspring autism, sorry autistic traits, link (see here) is also important. Me being me though, I'm still interested in the Grant/Cannell findings, particularly when one considers that not-so-long-ago paper which looked at ADHD prevalence and solar intensity and the growing realisation that autism is probably not a stand-alone condition in terms of comorbidity.

Next up, another paper from Cannell & Grant [4] (open-access here) which is a rather more review type paper on the various biological processes which vitamin D is reported to be involved with and how these might link into autism. I'm not going to rehash the paper in its entirety because it is open-access. That being said, there are some familiar themes contained in the review - autoimmunity, mitochondrial issues, etc - which are all potentially important issues to at least some of the autisms. Picking out one detail however, which fell under the heading 'Comorbid Conditions' I was struck by the discussion about adiponectin levels with autism and vitamin D levels in mind. It may be a slightly off-the-wall thought but given mention of this adipokine and my recent interest in elevated leptin levels being reported in a fair few cases of autism I couldn't help but wonder whether there may be further investigations to be had on an effect of vitamin D in relation to leptin elevations [5] with an autism slant.

What I think is worth taking from these papers and the growing scientific interest in vitamin D and autism including that related to the issue of ethnicity and autism (see here) recently illustrated in the Somali-autism initiative, is that there is still much to do in this area of autism research. That vitamin D deficiency does seem to be an issue for some people with autism [6] should already imply that deficiency should be corrected, save any of the more classical problems coming about as a result [7].

Whether the effects of vitamin D extend further into autism and in particular, the presentation of autism or its suggested biological profile (see here for example), is something I'd like to see more on, with the promise of some potential answers already on the research horizon (see here and see here). Oh, and I should also mention the recent papers by Zhang and colleagues [8] and Patrick & Ames [9] too...

Smartphone vitamin D analysis anyone?

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[1] Anglin RE. et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013 Feb;202:100-7.

[2] Davies JH. et al. Epidemiology of vitamin D deficiency in children presenting to a pediatric orthopaedic service in the UK. J Pediatr Orthop. 2011 Oct-Nov;31(7):798-802.

[3] Grant WB. & Cannell JJ. Autism prevalence in the United States with respect to solar UV-B doses: An ecological study. Dermatoendocrinol. 2013 Jan 1;5(1):159-64.

[4] Cannell JJ. & Grant WB. What is the role of vitamin D in autism? Dermatoendocrinol. 2013 Jan 1;5(1):199-204.

[5] Long J. et al. 1,25-Dihydroxyvitamin D3 upregulates leptin expression in mouse adipose tissue. J Endocrinol. 2013 Jan 18;216(2):265-71.

[6] Duan XY. et al. Relationship between vitamin D and autism spectrum disorder. Zhongguo Dang Dai Er Ke Za Zhi. 2013 Aug;15(8):698-702.

[7] Stewart C. & Latif A. Symptomatic nutritional rickets in a teenager with autistic spectrum disorder. Child Care Health Dev. 2008 Mar;34(2):276-8.

[8] Zhang M. et al. Do children with mental disorders have higher prevalence of hypovitaminosis D? F1000Res. 2013 Jul 17;2:159.

[9] Patrick RP. & Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J. 2014 Feb 20

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Grant WB, & Cannell JJ (2013). Autism prevalence in the United States with respect to solar UV-B doses: An ecological study. Dermato-endocrinology, 5 (1), 159-64 PMID: 24494049

ADHD and a sunny disposition

'Light it up blue' is probably a familiar phrase to many of those involved with autism as being the message championed by Autism Speaks on World Autism Awareness Day (2 April). The intention is noble enough: to bring autism to the attention of the world at large and importantly, keep their attention and resources focused on autism. I might add that awareness is one thing; actually 'doing something about autism' - whether that means improving prospects or modifying the course of autism or just levelling the playing field - is quite another thing.

Light it up @ Wikipedia  

By a funny twist of Internet fate, I stumbled upon a review of the study published by Arns and colleagues* looking at the possibility of a link between solar intensity (SI) and the prevalence of attention-deficit hyperactivity disorder (ADHD). The very tentative light it up blue connection was a sentence or two in the study write-up which suggested that the sleep problems which apparently come with a diagnosis of ADHD might result from "exposure to blue-light during the evening" and that strong sunlight during the day "might reset the biological clock and act as an antidote to the evening exposure to artificial blue-light causing sleep onset problems". Yes, I know it isn't a great blue light pun, sorry about that.

It should be noted that the Arns paper appears in a pretty good journal (Biological Psychiatry) so whilst you might be thinking, 'solar intensity... eh?' this is a correlation which has passed what one would expect to have been quite a rigorous peer-review battlefield. I could at this point offer you some more detailed description of the paper but it seems that the authors have already done that on their website (see here - no endorsement given or intended).

In effect, they mapped the prevalence figures for ADHD across various parts of the US and beyond and cross-referenced them with official figures relating to SI. Yes, prevalence of ADHD were partly based on "self-report of professional diagnoses" but this was to some degree countered by the use of more formal assessment data in other sites. They found a correlation (negative correlation) between ADHD prevalence and SI when controlling for various potential confounders: "a lower prevalence of ADHD in areas with high SI for both U.S. and non-U.S. data".

Bearing in mind the issue of correlation/causation (see here), one could construe this data several ways. If for example you work for the tourist boards of Arizona, Nevada or California you have a potentially interesting advert: 'Come live here, we've got lots of solar resource and potentially less risk of your children developing ADHD'. Or words to that effect. And indeed, the CDC figures do seem to suggest that those high SI states might have a lower prevalence of ADHD (assuming that this doesn't reflect other issues such as awareness, identification, etc). On a more serious note are the suggestions that (a) ADHD might be related to circadian clock disturbances, and (b) that exposure to the various new-fangled technologies we are surrounded by might be part and parcel of those circadian clock disturbances.

Just before you reach for the click away button, like I almost did, mumbling 'blame it all on technology', there are a few papers to bring to your attention. Yes, sleep issues are associated with ADHD** and indeed if the recent paper from Blesch and Breese McCoy*** is anything to go by, we might also assume that ADHD - some cases of ADHD - could be mistaken for things like sleep apnoea. True also that issues with circadian function seem also to be tied into cases of ADHD as per studies like this one from Gamble and colleagues****. On balance, sleep seems to show some connection with ADHD.

That the part of the light spectrum labelled blue emanating from various technology use is the primary cause or significant contributor to the sleep issues noted even in some cases of ADHD is the slightly more difficult proposition for me to whole-heartedly (hoof hearted!) accept from this work. I don't doubt that many children and adults with ADHD use this kind of technology. But I have to ask whether their use and exposure to the artificial blue light is really any more significant than that of everyone else? Indeed, without being an expert on the different ranges or wavelengths of light and their physiological effects, are we just talking blue or are we talking other parts of the light spectrum too?

There are details from this study which I would like to see further explored given the potential for a relationship between SI and ADHD prevalence. Readers for example, might know that I am more than a little intrigued by another sun related variable, vitamin D, and its various connections (or not) to conditions like autism or chronic fatigue syndrome among others. The question would have to be whether the sunshine vitamin / steroid hormone might also show some relationship to the latest findings? Are vitamin D levels likely to be greater / the same / reduced in cases of ADHD dependent on the specific geography and SI? Vitamin D receptors all in good working order*****? No significant drug interactions where medication is being used? Indeed, whether other correlates such as altitude - which also seem to map onto the SI exposure plots - might come into play?

There are questions which require some follow-up from this work but for now, and with all caveats in good working order when it comes to population studies of association - as with other recent results too, I'm intrigued by the Arns data and the suggested overlap. And also that ADHD might not be the only condition being looked at with a sun-related variable (see this study by Davis & Lowell******, full-text).

To close, after recently watching the quite brilliant film 'Rock of Ages' which satisfied all my 1980s rock needs, a taste of Sheffield's finest.

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* Arns M. et al. Geographic Variation in the Prevalence of Attention-Deficit/Hyperactivity Disorder: The Sunny Perspective. Biol Psychiatry. March 2013.

** Yürümez E. & Kiliç BG. Relationship Between Sleep Problems and Quality of Life in Children With ADHD. J Atten Disord. March 2013.

*** Blesch L. & Breese McCoy SJ. Obstructive Sleep Apnea Mimics Attention Deficit Disorder. J Atten Disord. March 2013.

**** Gamble KL. et al. Delayed Sleep Timing and Symptoms in Adults With Attention-Deficit/Hyperactivity Disorder: A Controlled Actigraphy Study. Chronobiol Int. February 2013.

***** Malik S. et al. Common variants of the vitamin D binding protein gene and adverse health outcomes. Crit Rev Clin Lab Sci. 2013; 50: 1-22.

****** Davis GE. & Lowell WE. Variation in ultraviolet radiation and diabetes: evidence of an epigenetic effect that modulates diabetics' lifespan. Clinical Epigenetics. 2013; 5: 5.

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Arns M, van der Heijden KB, Arnold LE, & Kenemans JL (2013). Geographic Variation in the Prevalence of Attention-Deficit/Hyperactivity Disorder: The Sunny Perspective. Biological psychiatry PMID: 23523340