Research article Vitamin A improves the symptoms of autism spectrum disorders and decreases 5-hydroxytryptamine (5-HT): A pilot study

Research article Vitamin A improves the symptoms of autism spectrum disorders and decreases 5-hydroxytryptamine (5-HT): A pilot study

Highlights

• ASD children have lower serum retinol and higher 5-HT levels than control children.

•Autistic children’s symptoms improved and serum 5-HT levels decreased after VAS.

•Compared to baseline, mRNA expression levels of RARα, γ and TpH 1 were changed significantly after VAS.

Abstract

Autism spectrum disorders (ASD) are complicated neurodevelopmental disorders. Many studies have demonstrated that children with autism have multiple nutritional deficiencies and increased serum 5-hydroxytryptamine (5-HT) levels. In our previous study, 77.9% of autistic children were found to have vitamin A deficiency, and the concentration of vitamin A was negatively associated with the CARS score. In the present study, we sought to test whether vitamin A supplementation could improve autistic symptoms and decrease serum 5-HT levels. The DSM-V criteria and CARS score were used for symptom description and symptom assessment of the patients, respectively, before and after vitamin A supplementation (VAS). Serum retinol and 5-HT levels, mRNA levels of RAR α, β, and γ and TpH 1 expression were detected in autistic children before and after VAS and in normal children. Serum retinol levels in children with ASD were significantly lower than in control children. Serum 5-HT levels in children with ASD were higher than in control children, which were correlated with symptom severity of children with autism. After VA supplementation, the children with ASD exhibited significant improvement in autism symptoms. Serum retinol concentrations of children with ASD were significantly increased, and serum 5-HT levels were decreased. Moreover, statistically significant changes were observed in mRNA expression levels of RAR α, RAR γ and TpH 1 after VAS compared to baseline. This study suggested that VA supplementation may improve symptoms and reduce 5-HT levels in children with ASD, indicating that VA supplementation is a reasonable therapy at least for a subset of children with autism.

Introduction

Autism spectrum disorders (ASD) are a group of developmental disabilities characterized by impaired social interaction and communication, repetitive stereotypical behaviors and restricted interests (Grzadzinski et al., 2013). In the past ten years, ASD have been the most prevailing pediatric disorders, and its prevalence is increasing throughout the world, with an estimated 1 in 68 8-year-old American children affected by ASD (Developmental Disabilities Monitoring Network Surveillance Year Principal, Centers for Disease and Prevention, 2014). With continuously elevated incidence, ASD have become the primary disease among psychiatric disabilities and is a significant burden to families and society. Currently, the etiology and pathology of ASD remains unexplained. As a subset of autistic patients have been consistently observed with hyperserotonemia, the serotonergic system is thought to be implicated in ASD etiology. Serotonin is synthesized much more in nonautistic children before 5 years of age than in adults, and the synthesis reduces thereafter. In contrast, serotonin synthesis in children with autism raises continuously until 15 years of age to 1.5 times adult levels (Chugani et al., 1999). Accumulating evidence suggests that autism is correlated with serotonergic abnormalities. The perspective that a significantly elevated blood serotonin (5-hydroxytryptamine; 5-HT) level exists in autistic patients’ peripheral blood compared to normal individuals has been progressively formed since Schain and Freedman first proposed it in 1961 (Schain and Freedman, 1961). Further studies found that the serotonin levels in platelet-rich plasma and in the serum of children with autism are significantly enhanced compared to controls (Naffah-Mazzacoratti et al., 1993, Gabriele et al., 2014). It was described that approximately one-third of autistic patients exhibited hyperserotonemia, and their blood serotonin level was pertinent to symptoms of self-injury (Kolevzon et al., 2010), making it a potential candidate biomarker for ASD.

Required vitamins and minerals play vital and irreplaceable roles in the health maintenance of various cellular biochemical reactions, such as the production of neurotransmitters and fatty acid metabolism. It is reasonable to speculate that nutrient deficiency and unbalanced metabolism elicited by the self-limited dietary habits of autistic may aggravate ASD symptoms. In particular, children with ASD have problems with food selectivity, limited food variety and inadequacy of some food intake, implying risks of nutritional deficiencies (Mari-Bauset et al., 2015). They experience significantly more feeding problems versus their peers, and nutrient analyses revealed significantly lower intake of calcium and protein in ASD patients (Sharp et al., 2013). Reports by Bandini et al. and Hyman et al. demonstrated that nutrients inadequacy (include vitamin A, vitamin D, vitamin E, calcium, etc.) were more common in children with ASD than in typically developing children (Bandini et al., 2010, Hyman et al., 2012). In China, a study by Sun et al. showed that the levels of vitamin A, vitamin B6, Zn and Ca intake were less than 4/5 of the dietary reference intake in children with autism. In addition, compared with normal children, serum Ca, vitamin A and folate levels in autistic children were significantly lower (Sun et al., 2013). In our previous research, 77.9% autistic children were found to have vitamin A deficiency, with the highest deficiency rate in the nutrients we studied (including vitamin D, vitamin B12, and folic acid), and concentration of vitamin A was negatively associated with CARS score (Liu et al., 2016). In addition, we also have demonstrated that vitamin A was correlated with cognitive function and spatial learning and memory (Jiang et al., 2012, Hou et al., 2015). Therefore, we surmise that a low serum vitamin A level may exacerbate symptoms of ASD, leading to a vicious cycle of illness. In the present study, we performed vitamin A supplementation in children with ASD to observe whether it could ameliorate their symptoms.

Section snippets

Patients and treatment

Thirty-three ASD patients (mean: 5.14 ± 1.33 years old) including 28 boys and 5 girls were followed over a period of approximately 6 months. All patients were diagnosed by developmental pediatricians and psychologists at Children’s Hospital of Chongqing Medical University through a series of structured interviews and based on of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria. Furthermore, Autism Behavior Checklist (ABC) (score for normal children should be <53) and

Participant characteristics

This study enrolled thirty-three children with autism (5.14 ± 1.33 years) and thirty-two typically developing children (5.18 ± 0.87 years) as control group. The ratios of male to female were 5.6:1 and 4.3:1, respectively. There were no statistically significant differences between the two groups with respect to age, sex, and Z score of weight-for-age (Z WA), height-for-age (Z HA) and body mass index-for-age (Z BMIA) (Table 1).

GDS score of children with ASD

Most children with ASD are found to be developmentally delayed. In this study,

Discussion

ASD is a neurodevelopmental disorder characterized by social communication deficits, repetitive behaviors and restricted interests. After incessant investigation, correlations between various biomarkers, including some vitamins, minerals, and plasma amino acids, and autism severity scales have been proposed. Sun et al. proposed that significantly lower serum Ca, vitamin A and folate levels were detected in autistic children than in control children (Sun et al., 2013). In light of the

Conclusion

Vitamin A supplementation contributes to symptoms improvement in autistic children and reducing 5-HT levels in the serum.

Funding

This work was supported by grants from the National Natural Science Foundation of China: 81471518 (to T.L), 81771223 (to T.L) and 81770526 (to J.C).

Conflicts of interest

No potential conflict of interests relevant to this article.

Acknowledgments

TL participated in the design of the study. MG performed the data acquisition, interpretation, and drafted and revised the manuscript. JZ, XL, and TY assisted with the data acquisition and analyses. XL and JL performed the diagnoses of patients. JC performed the data interpretation and human resource supervision in the laboratory. The authors thank all the families and children who participated in the survey. All authors reviewed the manuscript.

The authors thank AJE (American Journal experts)

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