Patient Presentation
Some general pediatricians were discussing the new recommendations from the Federal Drug Administration (FDA) for the use of leucovorin to treat cerebral folate deficiency. “I’ve had a couple of families who just wanted more information and wanted to know if their child might benefit. I had another family who just wanted me to give them leucovorin,” said one. “I had one family who wanted me to order antibody testing. The testing from what I have read isn’t FDA approved,” another replied. “I think what we all want is the best for the kids and families. Maybe this is going to be the beginning of some additional treatment options for some families, but from what I’ve read probably not for most families. The answer is always “more research is needed,””the third commented.
Discussion
Leucovorin is also known as folinic acid, calcium folinate, or 5-formyl tetrahydrofolic acid. Folinic acid exists in nature whereas folic acid is a synthetic, water-soluble form of Vitamin B9 or folate. Folic acid needs to be converted to folinic acid to be biologically active. Folate is often added to foods to fortify them. A review of what foods have folic acid in them can be found here.
There is growing recognition of the possibilities that targeted metabolic therapies could play in the management of patients with specific subsets of Autism Spectrum Disorder (ASD). The FDA approved leucovorin for cerebral folate deficiency in September 2025. The FDA news release and Federal Register state approval is for “cerebral folate deficiency” but it appears that approval may be for patients with FOLR1 gene variants. [Additional information was not available from the FDA at the time of this writing]. FOLR1-related cerebral folate transport deficiency is among “…several causes of folate deficiency restricted to the central nervous system characterized by very low levels of cerebrospinal (CSF) folate in the absence of clinically significant systemic folate deficiency.” GeneReviews® notes that as of 1/11/24, 35 individuals from 21 families have been reported with FOLR1-related cerebral folate transport deficiency. Other causes of CNS folate deficiency include disorders of transport in the choroid plexus due to mitochondrial dysfunction, several hereditary disorders of folate metabolism and FOLR1 autoantibodies.
There have been some studies of patients with ASD who tested positive for anti-folate receptor antibodies who were treated with leucovorin and who showed some improvements. One example is a randomized-controlled, double-blinded, placebo-controlled trial published in 2024 which included 80 participants who were followed for 24 weeks. Other examples include an open-label trial of 44 children with ASD with followup for 4 months, and another double-blind placebo controlled trial with 48 children followed for 3 months. Note that these are studies with small numbers of patients, followed for only a relatively short period of time. Also prevalence in the general population of these antibodies is estimated at 7-15%, so the antibodies are not a specific indication of ASD. Current testing for antibodies is not FDA approved or cleared. This means that testing including “…clinical interpretation standards, validation, and analytic performance are established by the performing laboratory rather than by an FDA-reviewed labeling process.” For proprietary reasons, some or all of the testing procedures and result interpretation criteria are not available for review.
Learning Point
Leucovorin’s FDA-approved indications for use are for treating:
- Chemotherapy side-effect modulator such as methotrexate
- Megaloblastic anemia
- Cerebral folate deficiency
Leucovorin is not FDA approved for all patients with ASD.
The American Academy of Pediatrics (AAP) notes that there are limits to the current research on leucovorin use in patients with ASD including that there are few patients in the studies, there are concerns about some of the study methods, most of the studies are from the same group of researchers and the studies need reproducibility from other research groups to verify the results, large safety and efficacy trials have not been completed, and “[a] conclusion of all of the published studies is that more research is needed, and the AAP concurs.”
The AAP at the time of this writing states that “…the current evidence base remains too limited to support specific clinical recommendations” for use of leucovorin in patients with ASD.
The search for ASD causes and definitive treatment needs to continue with peer-reviewed research to answer these questions, and concurrently ensuring that patients and families are receiving the services and supports they need to live healthy lives as valued community members.
The President of the Society of Inherited Metabolic Disorders stated in a letter to the Department of Health and Human Services, “…[W]e want to reiterate a foundational principle: the presence of autism in any child is not the parents’ fault. As we continue to expand our understanding of the biological underpinnings of autism, compassion must guide our messaging, to avoid pointing blame and creating guilt.”
Questions for Further Discussion
- What are some indications for genetic testing for individuals with neurodevelopmental delays? A review can be found here
- What are some causes of intellectual disability? A review can be found here
- What are indications for referral to speech therapy? A review can be found here
Related Cases
- Disease: Leucovorin | Folic Acid | Autism | Genetic Disorders | Child Behavior Disorders
- Symptom/Presentation: Behavior Problems | Developmental Delay
- Specialty: Developmental Disabilities | Genetics | Neurology / Neurosurgery | Nutrition / Dietetics
- Age: None
To Learn More
To view pediatric review articles on this topic from the past year check PubMed.
Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.
Information prescriptions for patients can be found at MedlinePlus for these topics: Autism and Leucovorin.
To view current news articles on this topic check Google News.
To view images related to this topic check Google Images.
To view videos related to this topic check YouTube Videos.
Frye RE, Rossignol DA, Scahill L, McDougle CJ, Huberman H, Quadros EV. Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder. Semin Pediatr Neurol. 2020;35:100835. doi:10.1016/j.spen.2020.100835
Panda PK, Sharawat IK, Saha S, Gupta D, Palayullakandi A, Meena K. Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: a randomized double-blind, placebo-controlled trial. Eur J Pediatr. 2024;183(11):4827-4835. doi:10.1007/s00431-024-05762-6
Goldman ID. FOLR1-Related Cerebral Folate Transport Deficiency. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. GeneReviews®. University of Washington, Seattle; 1993. Posted 1/11/24. Accessed October 28, 2025. http://www.ncbi.nlm.nih.gov/books/NBK599286/
Gristan YD, Patel P, Moosavi L. Folinic Acid. In: StatPearls. StatPearls Publishing; 2025. Accessed October 27, 2025. http://www.ncbi.nlm.nih.gov/books/NBK545232/
FDA News Release. FDA Takes Action to Make a Treatment Available for Autism Symptoms. FDA. September 22, 2025. Accessed October 27, 2025. https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms
Approval of Previously Withdrawn New Drug Application for WELLCOVORIN (Leucovorin Calcium) Tablets. Federal Register. September 24, 2025. Accessed October 28, 2025. https://www.federalregister.gov/documents/2025/09/24/2025-18510/approval-of-previously-withdrawn-new-drug-application-for-wellcovorin-leucovorin-calcium-tablets
OMIM®Folate Receptor, Alpha;FOLR1, Entry 136430.https://www.omim.org/entry/136430?search=136430&highlight=136430, Accessed 10/28/25
OMIM® Neurodegeneration due to Cerebral Folate Transport Deficiency; NCFTD. Entry 613068. https://www.omim.org/entry/613068?search=613068&highlight=613068. Accessed 10/28/25
Reigier DS. President of the Society for Inherited Metabolic Disorders. Letter to Robert F. Kennedy, Jr., dated October 1, 2025.
Frequently Asked Questions (FAQs) for Pediatricians and other Prescribing Pediatric Clinicians: Leucovorin Use in Autism and Cerebral Folate Deficiency. Accessed November 3, 2025. https://www.aap.org/en/patient-care/autism/use-of-leucovorin-in-autistic-pediatric-patients/frequently-asked-questions-faqs-for-pediatricians-and-other-prescribing-pediatric-clinicians/
Interim Guidance from the American Academy of Pediatrics: Use of Leucovorin in Autistic Pediatric Patients. Accessed November 3, 2025. https://www.aap.org/en/patient-care/autism/use-of-leucovorin-in-autistic-pediatric-patients/
Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

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