An Examination of Changes in Urinary Metabolites and Behaviors with Use of Folinic Acid in Children with Autism Spectrum Disorder (ASD)

Background: Children with autism spectrum disorder (ASD) have been found to have a high prevalence of folate receptor auto-antibodies (FRAA) that either block or bind to the folate receptor alpha, which is believed to impair the normal transport of folate from blood into the cerebrospinal fluid (CSF). This creates the condition known as “cerebral folate deficiency,” where serum folate concentrations are normal but CSF folate concentrations are low. Folinic acid (FA) is believed to be able to bypass the impaired folate transport system through a secondary mechanism. A recent randomized controlled trial of FA supplementation in children with ASD found improvements in behavior and language development. We sought to test this treatment option through an ongoing research partnership at a local school for children with ASD to determine if FA would improve behavior and social skills. We further examined changes in urinary metabolites among treated children to attempt to identify a mechanism of action.

Objectives: The purpose of this study is to see if the behavior of children and young adults with autism improves in response to FA and to measure the urinary metabolites as a treatment biomarker.

Methods: Children attending a K-12 school for ASD were recruited and enrolled in an open-label, 12-week treatment study of high dose FA (2mg/kg/day, max dose 50mg/day). The primary outcome measures were the mean changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). We also examined changes in Pediatric Quality of Life (PedsQL). We further measured urinary metabolites at baseline and week 12 to examine their fold of change. Surveys at baseline and week 12 were analyzed using Paired Sample T-Tests.

Results: Twelve children aged 13 to 19 (2 girls, 10 boys) were enrolled in the study. Parents and teachers for these children completed all measures. The parent-reported mean of the differences in SRS showed a non-significant decrease of 7.8 points (95% CI -1.6 to 17.3, p = 0.095, Figure 1). The parent-reported ABC showed a non-significant decrease of 2.4 points (95% CI -6.4 to 11.3, p=0.56), and the teacher-reported ABC showed non-significant increase of -1.2 points (95% CI -7.6 to 5.2, p=0.68). The parent-reported PedsQL decreased insignificantly by 0.8 points (95% CI -3.5 to 5.2, p=0.69).

The top 5 urinary metabolites with the greatest fold of change were 5-methyltetrahydrofolate (24.9), 1-stearoyl-2-arachidonoyl-GPC (10.1), 1-stearoyl-2-oleoyl-GPC (9.3), alpha-tocopherol (9.2), and 1-stearoyl-2-linoleoyl-GPC (7.8).

Conclusions: In an open label study in an unselected, small sample of school-aged children with ASD, FA treatment did not lead to measurable improvements, but the small sample size limited the power to detect changes. The parent-reported SRS showed a non-significant improvement of 7.8 points, which is clinically important and worthy of future study with larger samples. The potential benefits of FA may be limited to children with a specific physiological abnormality (e.g., FRAA status) and may require a study with a targeted treatment approach to determine efficacy. Urinary metabolites may be a useful tool to identify children who are likely to respond to treatment.