Cody Schilhab

 Background: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by variable impaired social communication and restricted or repetitive sensory-motor behaviors¹. Prevalence of ASD is high and has increased from 1/150 in 2000 to 1/36 in 2016, with a 4:1 male to female ratio². Recent studies show significant association of folate receptor alpha autoantibodies (FRαAbs) with ASD in children³. FRαAbs can result in folate receptor alpha (FRα) blockage and inadequate folate transport into the CNS⁴. Stunted neurological development from folate deficiency has been linked to ASD behavioral symptoms⁴. Folinic acid, a form of folate found in foods, uses the reduced folate carrier and does not require FRα for transport⁴. Administration of low-dose folinic acid in adjunct with other therapies could have clinical use in normalizing CSF folate and improving behavioral symptoms in ASD children expressing FRαAbs^1,5.

Objective: This review aims to evaluate the potential for folinic acid supplementation to restore CSF folate and improve behavioral symptoms in children with ASD.

Search Methods: Using the PubMed database accessed from the Texas A&M University library, an online search was conducted using articles from 2017 to 2023 covering “autism spectrum disorder”, “folinic acid”, “folate”, and “folate receptor alpha”.

Results: In a placebo controlled animal study, rats exposed to FRαAbs birthed pups exhibiting ASD like symptoms⁶. Rats exposed to FRαAbs and administered folinic acid birthed pups that exhibited improved social interaction, reduced repetitive behaviors, and improved communication abilities compared to the offspring of rats exposed to FRαAbs without folinic acid supplementation⁶. A double-blind placebo controlled human clinical study administered an average dose of 0.48 mg/kg/d over a span of 12 weeks to a test group of children with ASD¹. The study evaluated Autism Diagnostic Observation Schedule (ADOS) behavioral scores of the children, with lower scores meaning less symptomatic¹. At the end of the 12 weeks, ADOS scores decreased significantly in the test group compared to the control group¹. A similar self-controlled infant study administered an average of 0.5-2.0 mg/kg/d over a span of two years and found that significant improvements were observed in the infants’ behavioral symptoms associated with ASD⁵. These improvements were evaluated using the Childhood Autism Rating Scale (CARS) and included reduced irritability, hyperactivity, and repetitive behaviors⁵. It was also noted the infants showed enhanced receptive and expressive language abilities and demonstrated improvements in overall developmental progress⁵. Both human studies found no serious adverse effects with folinic acid supplementation, and found up to a 9-fold improvement of serum folate levels^1,5.

Conclusions: Studies have found that supplementation with folinic acid is able to restore CSF folate levels in ASD patients, thereby diminishing the effects of FRα blockage caused by FRαAbs. Patients with ASD exhibited improved behavioral scores in two different rating scales, CARS and ADOS, although adjunct therapy may prove more beneficial. Due to limited sample size, further studies are indicated to solidify the relationship between folinic acid supplementation and decreased ASD behavioral symptoms.

Works Cited:

1. Renard E, Leheup B, Guéant-Rodriguez RM, Oussalah A, Quadros EV, Guéant JL. Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial. Biochimie. 2020;173:57-61. doi:10.1016/j.biochi.2020.04.019
2. Sharma SR, Gonda X, Tarazi FI. Autism Spectrum Disorder: Classification, diagnosis and therapy. Pharmacol Ther. 2018;190:91-104. doi:10.1016/j.pharmthera.2018.05.007
3. Quadros EV, Sequeira JM, Brown WT, et al. Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents. Autism Res. 2018;11(5):707-712. doi:10.1002/aur.1934
4. Bobrowski-Khoury N, Ramaekers VT, Sequeira JM, Quadros EV. Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention. J Pers Med. 2021;11(8):710. Published 2021 Jul 24.
5. Ramaekers VT, Sequeira JM, DiDuca M, et al. Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial. Autism Res Treat. 2019;2019:7486431. Published 2019 Jun 18. doi:10.1155/2019/7486431
6. Desai A, Sequeira JM, Quadros EV. Prevention of behavioral deficits in rats exposed to folate receptor antibodies: implication in autism. Mol Psychiatry. 2017;22(9):1291-1297. doi:10.1038/mp.2016.153