Autism and vitamin D

Summary

Any theory of autism’s etiology must take into account its strong genetic basis while explaining its striking epidemiology. The apparent increase in the prevalence of autism over the last 20 years corresponds with increasing medical advice to avoid the sun, advice that has probably lowered vitamin D levels and would theoretically greatly lower activated vitamin D (calcitriol) levels in developing brains. Animal data has repeatedly shown that severe vitamin D deficiency during gestation dysregulates dozens of proteins involved in brain development and leads to rat pups with increased brain size and enlarged ventricles, abnormalities similar to those found in autistic children. Children with the Williams Syndrome, who can have greatly elevated calcitriol levels in early infancy, usually have phenotypes that are the opposite of autism. Children with vitamin D deficient rickets have several autistic markers that apparently disappear with high-dose vitamin D treatment. Estrogen and testosterone have very different effects on calcitriol’s metabolism, differences that may explain the striking male/female sex ratios in autism. Calcitriol down-regulates production of inflammatory cytokines in the brain, cytokines that have been associated with autism. Consumption of vitamin D containing fish during pregnancy reduces autistic symptoms in offspring. Autism is more common in areas of impaired UVB penetration such as poleward latitudes, urban areas, areas with high air pollution, and areas of high precipitation. Autism is more common in dark-skinned persons and severe maternal vitamin D deficiency is exceptionally common the dark-skinned. Conclusion: simple Gaussian distributions of the enzyme that activates neural calcitriol combined with widespread gestational and/or early childhood vitamin D deficiency may explain both the genetics and epidemiology of autism. If so, much of the disease is iatrogenic, brought on by medical advice to avoid the sun. Several types of studies could easily test the theory.

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).