Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms

<b>Background/Objectives:</b> Research on the safety and efficacy of high-dose folinic acid in Chinese children with autism spectrum disorder (ASD) is limited, and the impact of folate metabolism gene polymorphisms on its efficacy remains unclear. This trial aimed to evaluate the safety and efficacy of high-dose folinic acid intervention in Chinese children with ASD and explore the association between folate metabolism gene polymorphisms and efficacy. <b>Methods:</b> A 12-week randomized clinical trial was conducted, including 80 eligible children with ASD, randomly assigned to an intervention group (<i>n</i> = 50) or a control group (<i>n</i> = 30). The intervention group was administered folinic acid (2 mg/kg/day, max 50 mg/day) in two divided doses. Efficacy was measured using the Psycho-Educational Profile, Third Edition (PEP-3) at baseline and 12 weeks by two trained professionals blind to the group assignments. Methylenetetrahydrofolate reductase (<i>MTHFR</i> C677T, <i>MTHFR</i> A1298C), methionine synthase (<i>MTR</i> A2756G), and methionine synthase reductase (<i>MTRR</i> A66G) were genotyped by the gold standard methods in the intervention group. <b>Results:</b> 49 participants in the intervention group and 27 in the control group completed this trial. Both groups showed improvements from baseline to 12 weeks across most outcome measures. The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group. Children with <i>MTHFR</i> A1298C or <i>MTRR</i> A66G mutations demonstrated greater improvements in various developmental domains than wild type. Folinic acid may be more effective in certain genotype combinations, such as <i>MTHFR</i> C677T and A1298C. No significant adverse effects were observed during the intervention. <b>Conclusions:</b> High-dose folinic acid may be a promising intervention for children with ASD, and its efficacy is associated with folate metabolism gene polymorphisms. High-dose folinic acid intervention may promote better neurodevelopmental outcomes by alleviating folate metabolism abnormalities caused by single or combined mutations in folate metabolism genes.