Autism and vitamin D
Introduction
Arguably, the five most striking epidemiological aspects of autism are its monozygotic (40–90%) versus dizygotic (0–10%) twin concordance rates [1], widely varying phenotypic expression even among monozygotic twins [2], striking male:female ratio (∼4:1), increased prevalence in African Americans (see below), and apparent rapid increase in prevalence over the last 20 years (see below). Whatever its genetic roots, and they are strong, autism hardly follows classic Mendelian inheritance.
When a disease with strong genetic roots displays such peculiar epidemiology, it is reasonable to seek an explanation among environmental responsive genes. While the predisposing autistic lesion is genetic, the above epidemiological observations indicate something in the environment, prenatally or postnatally, is affecting expression of the genotype, probably through gene–environment interactions. Such interactions have not hirtherto “received sufficient attention in autism genetics investigations” [3] (p. 671).
The environment directly influences environmental responsive genes and they, in turn, directly influence the genome, the neurosteroid hormones are a good example. That is, while neurosteroids are under genetic organization, something in the environment may lower neurosteroid concentrations, which, in turn, fails to signal fully the genetic expression of the neural proteins that steroid regulates.
Furthermore, if current claims of autism’s increasing prevalence over the last 20 years [4] (Fig. 1) are due to actual increases in incidence and not entirely due to diagnostic substitution [5] or increased diagnostic sensitivity [6] – and this seems increasingly likely [7], [8] – then it is reasonable to search for neurosteroids that have declined over the same time autism has increased. Furthermore, if a neurosteroid exists that significantly affects brain development, whose brain levels vary with human behavior, are increased by estrogen but not testosterone, and whose levels show racial variations similar to the racial variations in autism prevalence (see below), then surely that neurosteroid may be autism’s environmental genetic contributor.
Of the neurosteroids involved in brain development, activated vitamin D (calcitriol) is unique, the least understood, but, arguably, one of the most profound. McGrath et al. alerted us to this fact in 2001, pointing out that vitamin D is “the neglected neurosteroid” [9]. In the same paper, they pointed out that calcitriol is a potent up-regulator of nerve growth factor and that the vitamin D receptor (VDR) is found in a wide variety of brain tissue very early in embryogenesis. They were the first to conclude that “hypovitaminosis D should be examined in more detail as a candidate risk factor for neurodevelopmental . . . disorders” (p. 571).
In 2006, Kalueff et al. went further, suggesting vitamin D offers “neuroprotection, antiepileptic effects, immunomodulation, possible interplay with several brain neurotransmitter system and hormones, as well as regulation of behaviors [10] (p. 363). In 2007, Kalueff and Tuohimaa reviewed the pleiotropic and nootropic properties of vitamin D in even more detail and concluded extant data “stress the importance of prenatal, neonatal, and postnatal vitamin D supplementation for normal brain functioning” [11] (p. 16).
Section snippets
Candidate genes
If true, then candidate genes for autism should include all genes that code for the various proteins involved in the metabolism, catabolism, transport, or binding of calcitriol. Pseudo-vitamin D deficiency rickets, an inborn error of metabolism, involves the defective genetic production of CYP27B1, the enzyme that activates vitamin D. The disease is, nevertheless, responsive to high-doses of calcitriol’s precursor, vitamin D [12]. That is, despite the genetic lesion, vitamin D overcomes the
Vitamin D
Like all steroid hormones, calcitriol binds to a member of the nuclear hormone receptor superfamily where the complex then acts as a molecular switch to signal its target genes; about 0.5% of the human genome (200 genes) are primary targets of calcitriol and the list is steadily growing [10]. Vitamin D is the only known substrate for a steroid hormone system that – until recent sun-avoidance campaigns – always began in the skin, not in the mouth. Ninety percent of human vitamin D stores come
Calcitriol and the developing brain
In a series of recent animal experiments, an Australian group found severe maternal vitamin D deficiency in rats produces offspring with aberrant apoptosis and abnormal cell proliferation [24], reduced expression of a number of genes involved in neuronal structure [25], hyperlocomotion [26], and subtle alterations in both learning and memory [27]. When vitamin D deficiency is restricted to late gestation only, such deficiencies are sufficient to disrupt adult brain functioning [28].
Recently, a
Inflammation and heavy metals
Dysregulated immune responses are associated with both autism and vitamin D deficiency. For example, autistic individuals have T cell abnormalities and cytokine excesses [34] that show a striking similarity to the immune functions affected by vitamin D [35]. Animal evidence indicates some vitamin D deficiency induced brain damage may be malleable, that is, vitamin D may partially reverse the brain damage, if given early enough [36].
Both the brain and the blood of autistic individuals show
Sexual differences and vitamin D
Estrogen and testosterone appear to have strikingly different effects on vitamin D metabolism, which may explain the striking sex differences in autism. For example, Epstein and Schneider report, “the majority of studies have found a positive effect of estrogen on calcitriol levels” [45], but after reviewing studies on testosterone, they found no similar effects (p. 1261). If estrogen increases neural calcitriol, but testosterone does not; such differences during brain development may mean that
Vitamin D intake and autism
A placebo controlled three-month study of 20 autistic children found multivitamins with even low doses of vitamin D (150 units or 3.75 mcg) significantly improved sleep and gastrointestinal problems [46]. Further evidence that vitamin D may favorably affect mentation comes from a series of randomized controlled interventional studies evaluating the effect of vitamin D containing multivitamins on normal childhood cognition (for a review, see Schoenthaler et al. [47]). All 14 studies they
UVB light and autism
If the theory is valid, anything that increases the amount of UVB light in the atmosphere should decrease the incidence of autism. For example, the disorder should be less common at more sunny equatorial latitudes, at least before modern sun-avoidance. Grant and Soles found a strong positive association between latitude and prevalence of autism in international cohorts born before 1985 [53]. Recent CDC prevalence data from 14 states showed the state with the highest prevalence, New Jersey, was
Autism, rickets, medication, and seizures
If postnatal vitamin D deficiency caused autism, then autism would be common in vitamin D deficient rickets, although physicians treat rachitic children promptly with high-doses of vitamin D. To the best of my knowledge, no studies have looked at neuropsychological profiles of rachitic children, before or after treatment, although rachitic children are likely to be hypotonic, display decreased activity, and have developmental motor delays before treatment [65]. Interestingly, hypotonia is
Vitamin D and skin color
Vitamin D deficiency discriminates based on the amount of cutaneous melanin, a proficient and ever-present sunscreen. The vitamin D theory predicts that neurodevelopmental disorders would be more common in children born to darker-skinned mothers. Such studies are difficult as they raise sensitive social issues although three of four recent US studies found a higher incidence of autism in black children, sometimes appreciably higher [64], [74], [75], [76]. Furthermore, in Europe, autism rates
Discussion
The theory that vitamin D deficiency is a major cause of autism is of medical and social consequence, parsimonious, has a tenable mechanism of action, subsumes numerous other theories, implies simple prevention, hints at a widely available and inexpensive treatment effect, and is easily disprovable – all components of a useful theory. Predisposing genetic variations in some component of the vitamin D system – perhaps as simple as Gaussian variations in CYP27B1 – a genetic predisposition the
Conclusion
Baird et al. recently reported the prevalence of autism spectrum disorder in 56,000 British children was 1 in 86 children, numbers suggesting a calamitous epidemic [86]. It seems less and less likely that this entirely represents a change in diagnostic sensitivity or diagnostic substitution, but a real increase in incidence. Whatever its true incidence, the results are tragic and the cost immense. Families caring for autistic children are under more stress than those caring for a child with a
Declaration of Interest
Dr. Cannell heads the non-profit educational organization, the Vitamin D Council.
Acknowledgements
I wish to thank Professor Cedric Garland of the University of California at San Diego, San Diego, California, Dr. Alan Kaluev of the National Institutes of Mental Health, Bethesda, Maryland, Dr. Coleen Boyle, Centers for Disease Control, Atlanta, Georgia, Dr. Hjördis Atladottir of the University of Aarhus, Denmark, and Professor Robert Scragg of the University of Auckland, New Zealand, for reviewing the manuscript and making many useful suggestions.
References (89)
- et al.
Autism and environmental genomics
Neurotoxicology
(2006) Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D
J Nutr
(2005)- et al.
Maternal vitamin D3 deprivation and the regulation of apoptosis and cell cycle during rat brain development
Brain Res Dev Brain Res
(2004) - et al.
Developmental Vitamin D3 deficiency alters the adult rat brain
Brain Res Bull
(2005) - et al.
Transient prenatal Vitamin D deficiency is associated with hyperlocomotion in adult rats
Behav Brain Res
(2004) - et al.
Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats
Behav Brain Res
(2005) - et al.
Vitamin D deficiency during various stages of pregnancy in the rat; its impact on development and behaviour in adult offspring
Psychoneuroendocrinology
(2007) - et al.
Vitamin D3 and brain development
Neuroscience
(2003) - et al.
Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system
Am J Clin Nutr
(2004) - et al.
Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle
Physiol Behav
(2004)