Associations of hypomelanotic skin disorders with autism: Do they reflect the effects of genetic mutations and epigenetic factors on vitamin-D metabolism in individuals at risk for autism?

Vitamin D is crucial for full functioning in many genes, and vitamin-D deficiency interferes with many processes, including brain development and DNA repair. Several lines of evidence suggest that prenatal and early postnatal vitamin-D deficiency increases risk for autism, probably through multiple effects that include impaired brain development and increased de novo mutations. High rates of autism in several genetically based hypomelanotic skin disorders present a puzzle, because ultraviolet-B (UVB) radiation acting on skin is the major natural source of vitamin D, and lighter skin, which increases UVB penetration, helps protect against vitamin-D deficiency, especially at higher latitudes. Understanding autism's association with hypomelanosis may elucidate autism's etiology. We consider two hypotheses that may help explain autism's association with hypomelanotic disorders. Hypothesis 1) Because genetic and epigenetic variants that produce hypomelanotic conditions may help protect against vitamin-D deficiency, especially at higher latitudes, these variants may tend to decrease mortality - and increase the fertility - of individuals who also carry genetic or epigenetic factors that increase vulnerability to autism. Hypothesis 2) Children with hypomelanotic conditions will be more likely to develop autism, because children's photosensitivity and parental concerns about sunburn and skin cancer lead them to excessively reduce children's sun exposure and resultant vitamin-D levels. One approach to testing these hypotheses would involve comparing the genomes, epigenetic markers, skin pigmentation, and serum and brain levels of the active form of vitamin D in autistic individuals, with and without co-morbid hypomelanoses, as well as in their relatives and controls. Because availability of UVB radiation varies widely around the world, epidemiological and genetic studies of the co-morbidity in different regions would provide complementary means of testing the hypotheses. If test results support either hypothesis, they will add important evidence for an etiologic role of vitamin-D deficiency in autism, as well as supporting investigation of whether vitamin-D enhancement may aid treatment and prevention of autism.