{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:55:25Z","timestamp":1792011325585,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFC2707801"],"award-info":[{"award-number":["2024YFC2707801"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["LX202302122"],"award-info":[{"award-number":["LX202302122"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["JCYJ20230807143800002"],"award-info":[{"award-number":["JCYJ20230807143800002"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Soft Science Research Program of Luohu District","award":["2024YFC2707801"],"award-info":[{"award-number":["2024YFC2707801"]}]},{"name":"Soft Science Research Program of Luohu District","award":["LX202302122"],"award-info":[{"award-number":["LX202302122"]}]},{"name":"Soft Science Research Program of Luohu District","award":["JCYJ20230807143800002"],"award-info":[{"award-number":["JCYJ20230807143800002"]}]},{"name":"Science and Technology Innovation Commission of Shenzhen","award":["2024YFC2707801"],"award-info":[{"award-number":["2024YFC2707801"]}]},{"name":"Science and Technology Innovation Commission of Shenzhen","award":["LX202302122"],"award-info":[{"award-number":["LX202302122"]}]},{"name":"Science and Technology Innovation Commission of Shenzhen","award":["JCYJ20230807143800002"],"award-info":[{"award-number":["JCYJ20230807143800002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: 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. Methods: A 12-week randomized clinical trial was conducted, including 80 eligible children with ASD, randomly assigned to an intervention group (n = 50) or a control group (n = 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 (MTHFR C677T, MTHFR A1298C), methionine synthase (MTR A2756G), and methionine synthase reductase (MTRR A66G) were genotyped by the gold standard methods in the intervention group. Results: 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 MTHFR A1298C or MTRR A66G mutations demonstrated greater improvements in various developmental domains than wild type. Folinic acid may be more effective in certain genotype combinations, such as MTHFR C677T and A1298C. No significant adverse effects were observed during the intervention. Conclusions: 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.<\/jats:p>","DOI":"10.3390\/nu17091602","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T11:46:19Z","timestamp":1746618379000},"page":"1602","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms"],"prefix":"10.3390","volume":"17","author":[{"given":"Caiyun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-sen University, Guangzhou 510275, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurorehabilitation, Maternity and Children Health Care Hospital of Luohu District, Shenzhen 518019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurorehabilitation, Maternity and Children Health Care Hospital of Luohu District, Shenzhen 518019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzhi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-sen University, Guangzhou 510275, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-sen University, Guangzhou 510275, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5213-2158","authenticated-orcid":false,"given":"Lan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-sen University, Guangzhou 510275, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9671-9412","authenticated-orcid":false,"given":"Caixia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-sen University, Guangzhou 510275, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurorehabilitation, Maternity and Children Health Care Hospital of Luohu District, Shenzhen 518019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciyong","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510275, China"},{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-sen University, Guangzhou 510275, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/s12519-022-00555-z","article-title":"Efficacy and Moderating Factors of the Early Start Denver Model in Chinese Toddlers with Autism Spectrum Disorder: A Longitudinal Study","volume":"19","author":"Wang","year":"2023","journal-title":"World J. 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