Vitamin D and autism: same old story?

I have to say that I wasn't all that surprised when I read the conclusions to the study by Eva Kočovská and colleagues [1] (open-access here) talking about significantly lower levels of 25-Hydroxyvitamin D3 (25(OH)D3) levels detected in their small cohort of young adults diagnosed with an autism spectrum disorder (ASD) compared with various control populations.

A deficiency or insufficiency of vitamin D - the sunshine vitamin/hormone - in relation to quite a few cases of autism is something that has been talked about more than once on this blog (see here). The value-added bit to the Kočovská findings was the suggestion that lower levels were detected "in young adolescents/adults with ASD" based in the Faroe Islands, where a lack of UVB exposure as a function of geographic position is to some extent compensated by "a diet rich in large oily fish containing vitamin D". I might add that this authorship group have talked vitamin D and autism in a previous paper [2].

The Kočovská paper is open-access but a few pointers might be in order:

• Young adults with autism, "their siblings and parents, and.. a typically-developing comparison group in the Faroe Islands" were the target populations under study as part of a wider investigation on the prevalence of autism in the Faroe Islands [3]. Blood draws "for [the] analysis of various environmental factors" enabled researchers to assay for vitamin D - 25(OH)D3 serum concentrations - by the gold standard that is mass spectrometry. The assay was apparently conducted here in Blighty.
• Results: "The ASD group had significantly lower levels of 25(OH)D3 [median (IQR) = 24.8 (27.5) nmol/L] compared to the healthy comparison group [median (IQR) = 37.6 (32.3) nmol/L], (95 % CI 5.0–22.5), p = 0.002 to their siblings [median (IQR) = 46.1 (28.3) nmol/L] (95 % CI 9.4–24.8), and parents [median (IQR) = 46.7 (36.2) nmol/L) (95 % CI 11.0–27.74], (p < 0.001 in both instances)". Of all participants in the ASD group, only 1 person had a result falling into the sufficiency range (≥75 nmol/L) and that seemed to be an outlier described as a female: "her 25(OH)D3 level was much higher than all other participants’ at 153 nmol/L".
• Quite a few participants from across the various control groups included for analysis were vitamin D deficient (58-65%). But: "In the ASD group, 88 % were vitamin D deficient". 
• Insofar as possible correlates, well, there was a "slight over-representation of spring births among the ASD group (32.5 %) and corresponding lowest level of vitamin D in this group". There was also a trend towards lower levels of vitamin D in males with ASD and their siblings. But diagnosis within the autism spectrum and scores on the ADOS showed no significant correlation.

The authors are rightly cautious about drawing too many conclusions from their results as they stand. They talk about low vitamin D levels in cases of autism potentially being linked to issues like being a picky eater [4] or "autism impacting on a family/child’s lifestyle" as per a preference for more indoor activities rather than those more likely to provide some sun exposure (see here). Body mass index (BMI) is also talked about as a function of the growing interest in vitamin D levels in those who are categorised as overweight or obese [5] which is something that continues to crop up in the autism research literature (see here). We can't also rule out some effect from comorbidity - ESSENCE as one of the Kočovská authors has described it - particularly in light of other research starting to talk about ADHD (attention-deficit hyperactivity disorder) and vitamin D deficiency (see here) and what seems to be emerging about the heightened comorbid prevalence of autism and ADHD (see here). Same also goes for something like depression too (see here) and its links with at least some autism [6]. Plenty of variables which have the ability to influence the Kočovská results.

But... on the back of previous studies indicating that vitamin D levels might be perturbed in some cases of autism I find myself similarly drawn to another conclusion reached by the authors: "the low vitamin D levels could be an indication of life-long vitamin D deficiency in ASD, and this hormone deficiency could, at least theoretically, have been involved in early aberrant development of the brain in these individuals, leading to the development of ASD". I say this acknowledging that Kočovská et al only looked at a single measurement of vitamin D and the evidence that maternal or cord blood levels of vitamin D don't seem to have much of an effect in this process as per the findings from Whitehouse and colleagues (discussed here) and some more recent work [7]. I don't think though anyone has actually tracked vitamin D levels across the child- and adulthood with autism in mind...

I might also draw your attention to a few other areas where vitamin D deficiency in cases of autism might also merit additional research... stop me if you've heard me talk about these before. So: autoimmunity and vitamin D levels as per the Mostafa findings (see here). GcMAF and vitamin D as per the Hornig/Lipkin patent application (see here). And then there is leaky gut and vitamin D (see here) in light of another area with some autism interest (see here); all worthy of further research consideration alongside further examination of those vitamin D receptors which are currently lacking in the autism research literature.

The news recently of "a remarkably consistent" relationship between "the lowest quintile of serum 25(OH)D concentration.. associated with increased all-cause and cardiovascular mortality" based on the findings from Schöttker and colleagues [8] (open-access here) is potentially pertinent. Without using scare tactics or anything like that, such findings should perhaps have special meaning in light of the Kočovská results and the news that over half of their autism cohort presented in the severe deficiency range (<25 nmmol/l). With no medical or clinical advice given or intended, I will draw your attention to the paper by Aloia and colleagues [9] (open-access) and the guidance they provide on potentially overcoming deficiency...

Music to close: Pulp and Common People. 

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[1] Kočovská E. et al. Vitamin D in the General Population of Young Adults with Autism in the Faroe Islands. J Autism Dev Disord. 2014 Jun 14.

[2] Kočovská E. et al. Vitamin D and autism: clinical review. Res Dev Disabil. 2012 Sep-Oct;33(5):1541-50.

[3] Kočovská E. et al. The rising prevalence of autism: a prospective longitudinal study in the Faroe Islands. J Autism Dev Disord. 2012 Sep;42(9):1959-66.

[4] Cermak SA. et al. Food selectivity and sensory sensitivity in children with autism spectrum disorders. J Am Diet Assoc. 2010 Feb;110(2):238-46.

[5] Vimaleswaran KS. et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013;10(2):e1001383.

[6] Matson JL. & Williams LW. Depression and mood disorders among persons with Autism Spectrum Disorders. Res Dev Disabil. 2014 May 23;35(9):2003-2007.

[7] Keim SA. et al. Maternal and Cord Blood 25(OH)-Vitamin D Concentrations in Relation to Child Development and Behaviour. Paediatr Perinat Epidemiol. 2014 Jun 17.

[8] Schöttker B. et al. Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States. BMJ. 2014 Jun 17;348:g3656.

[9] Aloia JF. et al. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr. 2008 Jun;87(6):1952-8.

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Kočovská E, Andorsdóttir G, Weihe P, Halling J, Fernell E, Stóra T, Biskupstø R, Gillberg IC, Shea R, Billstedt E, Bourgeron T, Minnis H, & Gillberg C (2014). Vitamin D in the General Population of Young Adults with Autism in the Faroe Islands. Journal of autism and developmental disorders PMID: 24927807

Waiting patent-ly: Gc globulin, vitamin D and autism?

As summer inevitably turns to Autumn and the prospect of those colder, darker winter days and nights further encroaches, I find myself again talking about the growing body of research and speculation suggestive of a link between autism (or at least some of the autisms) and the sunshine vitamin - vitamin D - and its related biochemistry.

Autumn @ Wikipedia 

I was brought to this post by an interesting patent application by The Trustees Of Columbia University In The City Of New York regarding an invention by two very well known and renowned scientists: Ian Lipkin and Mady Hornig titled: "Autism-associated biomarkers and uses thereof" (see here*).

Filed earlier this year (2013) the application discusses quite a few things with a focus on vitamin D and autism and in particular: "detecting whether or not there is an alteration in the express of a Gc globulin protein in the subject as compared to a non-autistic subject".

OK, some background just in case you need it. Vitamin D is something of a rock star in health research circles of late. Traditionally thought to be just the stuff needed to help the absorption of calcium, a more varied role has been reported for the sunshine vitamin in recent years covering lots and lots of ailments and conditions. With autism in mind, vitamin D has been the source of quite a bit of speculation** and research (see my previous posts here and here and here). Although requiring further investigation, it would be a brave/foolish (delete as appropriate) person to say that it shows absolutely no link to autism or at least certain facets or cases of autism on the basis of the existing evidence.

Researchers, Ian Lipkin and Mady Hornig, are also highly respected on this blog. Regular readers might remember their names in relation to quite a few topics I've talked about including the old XMRV-CFS/ME de-discovery story (see here) and the fascinating work on autism and Sutterella (see here). Prof Lipkin was also credited in bringing 'science to Hollywood' in his role as an adviser for the film Contagion (see here) and they both share credit for the 'three strikes hypothesis'. Indeed, this is not the first time that their autism work has entered the patent arena (see here).

The recent patent application, I have to admit, was hard going for me in terms of all the details it contained. My trawl for some background information on Gc globulin protein - also I think called vitamin D binding protein (DBP) - revealed that this protein is principally involved in getting vitamin D and its relations around the body among other things***. Specifically the patent is built on: "the finding that increased levels in the Gc globulin GcFl (which is a vitamin D binding protein) can serve as a biomarker for human Autism Spectrum Disorders". This I interpret to mean that too much Gc globulin being present means that too much vitamin D gets bound up with the stuff and levels of free, available vitamin D (and metabolites) might therefore be lower than that required. The patent goes on: "elevated levels of Gc globulin in the umbilical cord plasma of ASD patients were observed relative to control cases".

These are potentially big words. At the time of writing (September 2013) I was unable to find anything in the peer-reviewed research literature looking at Gc globulin in relation to autism, let alone anything suggesting that increased levels of the protein might be the stuff of biomarkers. That's not to say that there may not be something waiting in the pre-publication arena about this, as per the patent talking about proteomic analysis of "umbilical cord blood plasma samples from children diagnosed with autism (n=l 1 cases) and children without evidence of developmental disorder (n=12 controls)". Proteomics you say?

Further down the patent I noted other points. So: "administering to the subject a therapeutic amount of GcMAF, thereby treating or preventing autism or an ASD". Without getting into any debates about treatment and prevention (which seems to be a common theme as per the MAR autism letter recently), Gc-MAF is another interesting part of this application. Regular readers might have seen my post on Gc-MAF and nagalase in relation to autism (see here) and the early-day connections being made there (see here also).

A quick non-expert look at the connection between Gc globulin and Gc-MAF reveals that Gc globulin is the precursor to Gc-MAF****. I think (and it is just that) the patent is suggesting that because greater than usual quantities of vitamin D might be bound up with Gc globulin, there are knock-on immune effects resulting from this vitamin D deficiency, ergo: "administering to the subject a therapeutic amount of GcMAF, thereby treating or preventing the vitamin D deficiency-related immune deficit." Onwards, the assumption is that this might have an effect on the presentation of autism too. Again, with my non-expert hat on, administration of Gc-MAF does seem to affect Gc globulin activity (at least in the lab and using cells from patients with systemic lupus erythematosus*****). Don't quote me on that by the way.

There is quite a bit more information included in this patent which I can't cover here in one post. As if you needed more evidence that vitamin D deficiency might be quite prevalent in autism (and across different geographies) I would also refer you to the recent papers by Duan and colleagues****** & Gong and colleagues******* based in China. That being said, if the Lipkin/Hornig patent turns out to be correct at least for some on the autism spectrum, simply adding more vitamin D into the diet or supplementing or increasing sunshine exposure when a deficiency is present alongside high levels of Gc globulin, might not necessarily be the most desirable course of action.

Finally, I should point out that this is a patent application and not peer-reviewed science so whilst being as enthused as I am about the potential for this line of inquiry, one has to take a step back. As with all patent applications, the aim is protection; protection for the your work, the intellectual property of your work and indeed, the commercialisation of your work from being copied by others presumably for profit. Autism has seen its fair share of patents down the years, over 98,000 at the time I looked, and whilst many would love to see these patents actually produce some real-life benefits for people with autism and their families, the question is: how many actually do?

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* Autism-associated biomarkers and uses thereof. The Trustees Of Columbia University In The City Of New York. WO2013130953 A2. Application number PCT/US2013/028589. Filed: March 1 2013. Published: September 6 2013.

** Cannell JJ. Autism, will vitamin D treat core symptoms? Med Hypotheses. 2013 Aug;81(2):195-8. doi: 10.1016/j.mehy.2013.05.004.

*** Haddad JG. Plasma vitamin D-binding protein (Gc-globulin): Multiple tasks. J Steroid Biochem Mol Biol. 1995; 53: 579-582.

**** Nagasawa H. et al. Gc Protein (Vitamin D-binding Protein): Gc Genotyping and GcMAF Precursor Activity. Anticancer Res. 2005; 25: 3689-3696.

***** Yamamoto N. et al. Deglycosylation of serum vitamin D3-binding protein by alpha-N-acetylgalactosaminidase detected in the plasma of patients with systemic lupus erythematosus. Clin Immunol Immunopathol. 1997 Mar;82(3):290-8.

****** 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.

******* Gong ZL. et al. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. [Epub ahead of print]

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Cannell JJ (2013). Autism, will vitamin D treat core symptoms? Medical hypotheses, 81 (2), 195-8 PMID: 23725905