FOCUSING ON METHIONINE CYCLE MECHANISMS AND FOLATE’S ROLE IN AUTISM SPECTRUM DISORDER: A NARRATIVE REVIEW

Abstract

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by challenges in social communication and repetitive and restricted activities and behavior. According to etiology, it is a multifactorial disease where genetic and environmental factors are predominant. The pathogenesis of ASD involves disruptions in neurotransmitter production, DNA methylation, immune function, oxidation and antioxidant balance, and vitamin D metabolism. In addition, exposure to toxic chemicals, such as heavy metals and phthalates, is a major environmental risk factor in ASD. Folate is a water-soluble vitamin involved in the production of methyl groups through the methionine cycle. The methionine cycle produces methionine and metabolizes homocysteine, which is a neurotoxic substance, through transulfuration to cysteine. Cysteine is a structural component of glutathione, which is a crucial non-enzymatic antioxidant. The aim of this study is to observe the role of folate and its mechanism of action, through the methionine cycle, on the pathogenesis of ASD.

Methods: This study is a literature review that summarizes results of 40 research articles related to the keywords autism, folate, methionine cycle, and homocysteine, published in 2023 and 2024. Google Scholar, PubMed, and Science Direct databases are used for searching research articles, and all studies conducted on humans, written in the English language, and available in full text, are included in this review.

Results:  As a result of this literature review, ASD pathogenesis is relevant to the activity of folate as a cofactor for pathways involved in the production of monoamine neurotransmitters such as dopamine. This study explains the major role of folate in the balance of excitatory and inhibitory neurotransmitters, which is crucial for neurodevelopment. Besides this, explore the importance of folate in vitamin D metabolism, which is vital for neuroprotection and neurotropism. This review sheds light on the role of folate in the methionine cycle, which produces methionine, an important amino acid for neurodevelopment. In addition, this study explicates the role of folate in ameliorating heavy metal toxicity because this vitamin increases antioxidant capacity by enhancing glutathione formation, and also has a direct role in methylation, which increases the excretion of toxic metals. The role of folate in DNA methylation, which is one of the epigenetic mechanisms involved in ASD pathogenesis, is also interpreted in this study.

Conclusion: It can be concluded that folate is important for neurodevelopment and lowering the incidence of ASD in children, because as a vital cofactor, it has a potential effect on the methionine cycle, synthetic pathways related to neurotransmitter and vitamin D metabolism. In addition, ameliorates the toxic effects of heavy metals on the brain.