Autism Spectrum Disorder and The Role of Vitamin D Receptor Polymorphism

Autism Spectrum Disorders are disorders with multiple etiologies of genetic and non-genetic origins. Promising advances in research of ASD in recent years have provided several important information about the impact of Vitamin D as a causative factor of ASD. Vitamin D receptor polymorphism has an essential role in developing several neuropsychiatric disorders including ASD. In this article, we reviewed all the relevant studies available for Vitamin D receptor polymorphism in Autism Spectrum Disorder from PubMed, Google Scholar, Science direct, Cochrane library by using keywords and discarded the irrelevant studies irrespective of publication date. We found that several VDR variants FokI, BsmI and TaqI polymorphisms are related with ASD. Even paternal VDR polymorphism can be a causative factor for ASD in the offspring. The relation between FokI (ff) genotype polymorphism and increased level of serum 1,25(OH)D3 in ASD patients is a very significant finding. However, there are many questions which are still unsolved, need to get answered. How increased level of Vitamin D associated with ASD and which factors work for causing Vitamin D receptor polymorphism need to address.

Autism spectrum disorder attributes to a broad range of conditions portrayed by compromised social skills, repetitive behaviors, speech and nonverbal communications, as well as, by unique strengths and differences. Autism Spectrum Disorder affects >1% of children in the United States. ASD is mainly get defined by the sign and symptoms nor by aetiologies. Only 10-35% of ASD have a major known risk factor while in other cases the aetiologies are mostly unknown. Based on the predominant symptom of the children, there are different subgroups of ASD like Autism, Asperger syndrome and Pervasive –developmental disorder Not otherwise specified. Individuals with ASD have difficulties in establishing relationship with others, expressing and understanding emotions, inability to act in an appropriate way which makes it difficult for them to live freely.

Autism patients are also vulnerable to behavioral and medical problems. There is evidence that in Autism patients’ abnormalities in inflammatory markers, autoantibodies to brain and glutathione subsets which suggest that ASD is a disease related to systemic inflammation, autoimmunity and oxidative stress of our body. Prevalence of ASD is increasing dramatically in the last few years. Now it is a belief that there are some environmental risk factors and genetic causes which also play a role in ASD. Cannel's publication in 2008 revealed a hypothesis that low Vitamin D level in fetal life and even in early childhood has a strong role in ASD. Animal studies show Vit D deficiency in fetal life has an enormous effect on neurodevelopment in offspring, causing structural and functional changes in the brain as well as in behavior. Vitamin D has a strong role in neurotransmission, neuroprotection which defines the connection between several neuropsychiatric disorders in relation with Vitamin D.

Vitamin D

Vitamin D is a prohormone though classified as a vitamin. Generally, food is a rare source of Vitamin D except for fish liver oil and plants like Solanum glaucophyllum. Vit D which is a fat-soluble vitamin is a collection of steroids like substances ergocalciferol (D2)and cholecalciferol (D3). A significant source of Vit D is through exposure of skin to UVB radiation. On exposure to sun, 7-dihydroxycholesterol of epidermis and dermis, absorb the UVB and get converted to pre-vitamin D3. Through heat induced isomerization, pre-vitamin D3 changes to Vitamin D3. sun exposure Figure#1: Pathway of Vit D synthesis in the human body Vitamin D action pathways Vitamin D follows two pathways of action Genomic and Non-Genomic. In the genomic pathway, Vitamin D binds with the VDR, a member of the steroid/thyroid superfamily of transcription factors. After binding to vitamin D, in fetal VDR get phosphorylated; then get heterodimerized with retinoid X receptor which binds to VDRE within the genome to influence gene transcription.

A study done on 2,200 genomic positions of VDR confirmed that Vitamin D is pleiotropic. In the nongenomic pathway, Vitamin D binds to the membrane-bound VDR or a protein disulfide isomerase associated 3(PDIA3) protein. Following the signal transduction pathway, Vit D causes the release of an intracellular influx of Ca2+ leading to activation of protein kinase which eventually changes the phosphorylation of cellular proteins. The study showed that nongenomic pathway of Vitamin D action has an abundant role in cellular proliferation and immune function. In the human brain, both VDR and PDIA 3 got identified.

Functions of Vitamin D

Vitamin D is the primary hormone for calcium and phosphorus regulation. It also plays a role in bone formation, resorption, mineralization as well as in the maintenance of neuromuscular function. Rickets and Osteomalacia are two well-known conditions caused by Vitamin D deficiency, but there are many other conditions reported related to Vitamin D deficiency. 15 different types of Cancer, Osteoporosis, Orthostatic hypotension, Diabetes Mellitus, Hypertension, Hyperlipidaemia, Inflammatory bowel disease, Rheumatoid arthritis, Multiple sclerosis also reported being related with Vitamin D deficiency. Vitamin D role in ADHD, development Vitamin D metabolites signaling been detected in the human brain and as of having steroid-like properties. Metabolites Vitamin D can easily cross the blood-brain barrier. Cytochrome P450 enzymes regulating Vitamin D synthesis found in human fetal brain. CYP27B1 in fetal and adult human brain. In the adult brain, CYP27B1 was present in neurons, glial cells with schizophrenia, expression in substantia nigra, supraoptic and paraventricular nucleus of the hypothalamus. Distribution of CYP2ZB1 in adult brain prove that brain can synthesize the active metabolite 1,25(OH)2D3.

Vitamin D has a crucial role in pregnancy due to its primary role in developing brain of the fetus. Inadequate exposure to vitamin D causes several changes in the fetal brain which are responsible for adverse outcomes in brain function in later life. A study was done on BALB/c mice and showed that maternal Vitamin D deficiency caused being neuroanatomical alterations and revised gene expression. In fetal mice, Vitamin D deficiency caused suppression of neural FoxP2 and tyrosine hydroxylases especially in females. Fox P2 is an essential gene for speech and language developments causing dyspraxia, difficulties in expressive and receptive language, as well as this, is the pathway which gets hampered in some cases of ASD. FoxP2 knockout models showed delays in developments, altered motor function and impaired cerebellar morphology. There is a robust decrease in tyrosine hydroxylase level in mice brain with reduced staining of TH proteins in substantia nigra which shows a strong relation between Vitamin D deficiency and Dopamine dysfunction. Studies showed that 1,25(OH)2D3 can increase Tyrosine Hydroxylase and VDR expression in TH positive neurons of the substantia nigra in both human and rat fetal brain.

Developmental

Vitamin D deficiency can change dopamine cell phenotype expression in fetal rat mesencephalon, dopamine-dependent locomotion, dopamine turnover, dopamine transporters and several enzyme levels related to metabolism. Vitamin D deficient rat fetuses also showed changes in brain structure like the increased size of the lateral ventricle, decreased crown-rump and lambda-bregma length. There was the Increased size of the lateral ventricle with other neuroanatomical changes for schizophrenia-like behaviors. In humans also Schizophrenia is associated with increased lateral ventricular size. Vitamin D signaling pathway is essential to maintain healthy cell differentiation process. Developmental Vitamin D deficiency can alter cell proliferation, differentiation, and apoptosis in the developing brain of a fetus. Neuroprotection, Neurotransmission is also influenced by Vitamin D to a greater extent. Vitamin D deficiency in the prenatal and postnatal period are related to some neuropsychiatric disorders in later life like schizophrenia, autism and multiple sclerosis.

Changes of Vitamin D receptor in ASD

To execute functions, Vit D needs to bind with Vit D receptors present in the human body. VDR Mazahery, in the whole mammalian brain. The first expression of VDR happens in E12 in rat brain and on day E11. 5 in mouse brain. The time of VDR expression coincides with the window period of brain development when there is reduced cell proliferation, and increased cell elimination occurs. The VDR protein is present in multiple areas of rat and human brains such as the pontine-midbrain thalamus, hypothalamus, cerebellum, basal ganglia, amygdala hippocampus, olfactory system, and cerebral cortex(temporal, parietal, cingulate). The VDR gene is consisting of nine exons and nine introns which can be located in the chromosome 12q13. The VDR is a member of the neurosteroid family which signifies the role of VDR as a candidate gene for ASD. Animal studies done on mice with knocked out VDR gene showed impairment of their behavior as well as in hearing.

Conclusion

Understanding the pathophysiology of Autism Spectrum Disorder remained a big challenge. There are many etiologies like environmental, genetic, nutritional, got reported in several studies done till the date. In this literature review, we discussed the association of Vitamin D receptor changes and Autism Spectrum Disorder. Despite selecting all the relevant articles, this review might be the lack of some other related information's included in the excluded articles. Evidence compiled from animal and human studies showed that Vitamin D plays an essential role in developing fetal brain and any abnormality of Vitamin D metabolism in preconception or during pregnancy can affect the fetal neurodevelopmental outcome. Vitamin D receptor polymorphism in certain Vitamin D gene variants can influence Vitamin D uptake and metabolism in the human body. It needs more works to get a proper conclusion to answer the question of how Vitamin D receptor changes can be a factor in ASD. Very few human studies are available related to Vitamin D receptor polymorphism in ASD. More human studies with larger data sample should be conducted in ASD prone patient population to confirm the findings in this article and to implement clinical recommendations based on pieces of evidence to treat and prevent ASD.