Abstract
Objectives
Children with autism spectrum disorder (ASD) have been found to have a high prevalence of folate receptor auto-antibodies (FRAA), which may impair the normal transport of folate from blood into the cerebrospinal fluid (CSF). Leucovorin calcium (LC) is believed to bypass the folate transport system and restore function. We sought to examine changes in behavior and urinary metabolites in children and young adults with ASD being treated with LC.
Methods
Students attending a K-12 school for ASD were recruited for an open-label, 12-week study of high-dose LC (2 mg/kg/day, max dose 50 mg/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) and urinary metabolites. Changes were assessed with paired sample t-tests.
Results
Twelve students aged 13 to 19 (2 girls, 10 boys) completed the study. The parent-reported SRS showed a non-significant decrease (improvement) of 7.8 points (95% CI − 1.6 to 17.3, p = 0.095), and the ABC showed a non-significant decrease of 2.4 points (95% CI − 6.4 to 11.3, p = 0.56). The teacher-reported ABC and the parent-reported PedsQL showed very little change. Urinary metabolites with the greatest changes were involved in folate, phosphatidylcholine, and tocopherol metabolism.
Conclusions
In an open-label study of school-aged children with ASD, LC treatment did not lead to significant improvements. 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 LC may be limited to children with a specific physiological abnormality (e.g., FRAA status) and may require a targeted treatment approach. Urinary metabolites may be a useful tool to identify children who are likely to respond to treatment.
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Acknowledgments
The authors wish to express their gratitude to the students, families, and Oak Hill School staff members who participated in this project.
Funding
This work was supported by the JS Foundation, Mill Valley, CA.
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All authors contributed to the study conception and design. Clinical oversight and review of eligibility of all participants was performed by Robert L. Hendren. Material preparation and data collection were performed by Felicia Widjaja, Yingtong Chen, Jessica Wahlberg, and Michael G. McDonald. Data analysis was performed by Yingtong Chen and Stephen Bent. The first draft of the manuscript was written by Stephen Bent, and all authors commented on previous version of the manuscript. All authors read and approved the final manuscript.
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Conflict of Interest
Robert L. Hendren reports receiving research grants in the past year from Curemark, Roche, and Otsuka. He is also on Advisory Boards for BioMarin, Axial Therapeutics, and Janssen. He has conducted reviews and grants for Autism Speaks, the Simons Foundation, and Brain Canada. He receives royalties from Oxford, Routledge, and American Psychiatric Associating Publishing. He is not part of any Speakers Bureaus. All other authors declare that they have no conflict of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (University of California, San Francisco Committee on Human Research reference number 17-22860) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed Consent
All participants went through an informed consent process that was approved by the University of California, San Francisco Committee on Human Research, prior to participating in any study-related activities.
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Bent, S., Chen, Y., McDonald, M.G. et al. An Examination of Changes in Urinary Metabolites and Behaviors with the Use of Leucovorin Calcium in Children with Autism Spectrum Disorder (ASD). Adv Neurodev Disord 4, 241–246 (2020). https://doi.org/10.1007/s41252-020-00157-8
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DOI: https://doi.org/10.1007/s41252-020-00157-8