Review articleVitamin D and autism: Clinical review
Highlights
► Systematic research review regarding the possible link between ASD and vitamin D. ► Narrative literature review of the role of vitamin D in various biological processes. ► There is some support for vitamin D deficiency's role in the pathogenesis of ASD. ► Vitamin D may, hypothetically, have a role in ASD development via the brain and gene regulation. ► We argue for the recognition of this possibly important role of vitamin D in ASD.
Introduction
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with multiple genetic and environmental risk factors (Cannell, 2010, Coleman and Gillberg, 2011). There is no agreement as to whether ASD prevalence is genuinely on the rise or if a higher reported rate in recent years might be secondary to better awareness, changing diagnostic trends and more sensitive diagnostic system (Coleman & Gillberg, 2011). However, gene–environment interaction has recently become the focus of intensified ASD research (Freitag, Staal, Klauck, Duketis, & Waltes, 2010).
Among several proposed epidemiological influences on the development of ASD are the (a) much higher monozygotic (60–90%) than dizygotic (0–10%) twin concordance rates (Lichtenstein et al., 2010, Muhle et al., 2004); (b) large variability of phenotypic expression (even among monozygotic twins) (Lundström et al., 2012), (c) distinct gender ratio (2–4 males to 1 female) (Nygren et al., 2011); (d) relationship between autism and immune dysfunction (Coleman & Gillberg, 2011); and (e) much increased rate of ASD among dark skinned children living at Northern latitudes (Barnevik-Olsson et al., 2008, Cannell, 2008, Eyles, 2010, Gillberg et al., 1995, Goodman and Richards, 1995, Keen et al., 2010) that has led researchers to begin to address the potential role for Vitamin D in autism.
Vitamin D deficiency – either during pregnancy or early childhood – has recently been proposed as a possible environmental risk factor for ASD (Cannell, 2008, Grant and Soles, 2009). Interesting results, both at the molecular level and in animal experiments, begin to indicate the possible mechanisms for this potential risk.
Neurotoxins in the environment have been steadily on the rise, either in the form of industrial waste polluting soil, rivers and oceans, or in the form of additives in food and thousands of synthetic chemicals in materials of everyday life (Grandjean and Landrigan, 2006, Landrigan, 2010). Vitamin D deficiency has become common due to an increasingly urbanized lifestyle, rising rates of obesity, and recommendations to avoid sun exposure promulgated since the 1980s (Bosomworth, 2011, Cannell et al., 2008, Holick, 2005, Schwalfenberg, 2007). Moreover, at northern latitudes (e.g., in Scotland at 55°–61°N), sunlight with the ultraviolet B fraction is available only during a limited period of the summer. Dark skinned individuals require about 5–10 times longer exposure to sunlight to produce vitamin D compared to fair skinned individuals (Clemens, Adams, Henderson, & Holick, 1982). Therefore, when moving to northern countries, those with dark skin run the risk of not reaching satisfactory vitamin D levels.
Vitamin D has a unique role in brain homeostasis, embryogenesis and neurodevelopment, immunological modulation, (including the brain's own immune system), ageing, and also, importantly, in gene regulation (Sigmundsdottir, 2011, Harms et al., 2011, Ramagopalan et al., 2010). In addition to these effects, vitamin D is now believed to be involved in numerous other functions in the organism. To date, it has been shown to bind to more than 2700 genes and to regulate the expression of more than 200 of them (Ramagopalan et al., 2010). Vitamin D is also known to be involved in healing processes by reducing the risk of cells becoming malignant (Sigmundsdottir, 2011).
Vitamin D is not really a vitamin, since it is produced in the body by a cascade of chemical transformations, commencing with a key photochemical reaction in the skin on exposure to the ultraviolet rays of the sun, followed by a series of further chemical transformations. Its receptors have been found in many tissues and organs. The biosynthesis of calcitriol, the active form of vitamin D of vertebrates, starts from its prime precursor 7-dehydrocholesterol, which first undergoes the key photochemical electrocyclization reaction in the skin, producing an intermediate that is spontaneously converted into calciferol (vitamin D3), or cholecalciferol to be precise and to emphasize its chemical relation to cholesterol. Since the first reaction requires irradiation with UV light (at 290–315 nm), it can only proceed in the skin, e.g., within the reach of the UV rays. Cholecalciferol is then transported to the liver, where it is hydroxylated in the side-chain (at position 25) to produce calcidiol [25-hydroxycalciferol, 25(OH)D, or cholecalcidiol]. Finally, the latter compound is transported to the kidneys, where it is further hydroxylated (at position 1α) to finally produce calcitriol [1,25-dihydroxycalciferol, 1,25(OH)2D, or cholecalcitriol], the active compound (Feldman and Pike, 2011, Fiester and Fieser, 1959). The levels of the enzyme required for the final hydroxylation are controlled by parathyroid hormone, whose secretion is, in turn, triggered by low concentrations of calcium or phosphate (Cheng et al., 2004, Holick et al., 1995). The latter enzymatic hydroxylation reaction, producing calcitriol, has also been found to occur in lymphocytes and in the brain in microglia (Eyles, Smith, Kinobe, Hewison, & McGrath, 2005).
For the sake of simplicity and to avoid confusion, which is widespread in the literature, we will use the following nomenclature for the vitamin D family originating from 7-dehydrocholesterol: calciferol for cholecalciferol (vitamin D3), calcidiol for 25-hydroxy-cholecaciferol, and calcitriol for 1,25-dihydroxy-cholecalciferol. Where the literature does not discriminate, we will refer to vitamin D in general.
The best known role of vitamin D is to facilitate calcium and phosphate absorption in the intestine, impacting directly on the formation of the bones and their density. Vitamin D in the body follows first-order mass action kinetics (Holick, 2005), which means that at serum levels lower than 20 ng/ml (50 nmol/L) the majority of ingested or sun-derived vitamin D is immediately diverted to metabolic needs, namely bone formation, leaving nothing to its higher functions within the brain, immune system, or gene regulation.
There are two main areas of involvement of vitamin D in the human body, which may have direct impact on the development of ASD: (1) the brain (its homeostasis, immune system and neurodevelopment) and (2) gene regulation.
The aim of the current paper is to review the research findings regarding the connection between ASD and vitamin D.
Section snippets
Methods
A literature search covering the period January 1 1995 through October 31 2011 was made in PubMed, the Web of Knowledge, EBSCO OVID, MEDLINE, PsycARTICLES, Psychology and Behavioural Sciences Collection, PsycINFO, SocINDEX databases with Full Text Number of Hits.
The search strategy was as follows: vitamin d or vitamin D or ergocalciferol or vitamin d2 or vitamin D2 or vitamin d 2 or vitamin D 2 or cholecalciferol or vitamin d3 or vitamin D3 or vitamin d 3 or vitamin D 3 or calcitriol or vitamin
Systematic review
A systematic literature search yielded 35 articles from PubMed that dealt directly with autism and vitamin D in one way or another. Only four studies have looked at vitamin D serum levels in human subjects with diagnosed ASD or their mothers (Table 1). Nine further studies reported on nutritional deficiencies (including vitamin D) in ASD.
Discussion
Vitamin D deficiency – either during pregnancy or early childhood – has recently been proposed as a possible environmental risk factor for ASD. A large number of studies support the role of vitamin D in numerous cellular functions, in particular, cell differentiation, neurotrophic factor expression, cytokine regulation, neurotransmitter synthesis, intracellular calcium signalling and anti-oxidant activity. In animal studies its ability to partially reverse brain damage has been demonstrated (
Conclusion
Vitamin D deficiency – either during pregnancy or early childhood – has recently been proposed as a possible environmental risk factor for ASD. The findings obtained over the past 15 years, including animal studies, human molecular, cellular and physiologic research, post-mortem brain, neuro-imaging, and genetic studies, suggest that vitamin D plays numerous roles in various processes in the human body. However, the literature is very limited as regards clinical studies of individuals with
Acknowledgements
We acknowledge the valuable assistance of Dr. Helen Marlborough regarding the literature search and the administrative help of Irene O’Neill in preparation of this manuscript.
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