An Examination of Changes in Urinary Metabolites and Behaviors with the Use of Leucovorin Calcium in Children with Autism Spectrum Disorder (ASD)

Abstract

Objectives Children with autism spectrum disorder (ASD) have been found to have a high prevalence of folate receptor autoantibodies (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.

Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis

“…As seen in Figure 1, 20 studies were identified which studied d,l-leucovorin treatment in individuals with ASD including four placebo-controlled studies [72][73][74][75], three prospective, controlled studies [37,44,76], nine prospective studies without a control group [20,21,[33][34][35][77][78][79][80] (two studies examined the same cohort of patients [78,79]), and four case reports/series [36,[67][68][69].…”

“…Supplementary Table S6 lists the five studies [37,72,74,80,81] performed by three different sets of investigators which have examined the use of d,l-leucovorin in children with idiopathic ASD without additional treatments in order to determine if d,l-leucovorin administered by itself is a useful treatment for ASD. Table 4 outlines the effect sizes of some of the key outcome measures used in these studies.…”

“…Nonsignificant improvements were observed on the ABC (2.4-point improvement) and SRS (7.8-point improvement) while a 0.8-point nonsignificant worsening on the PedsQL was also observed. Urinary metabolites showed changes during the study including a 24.8-fold increase in 5MTHF concentrations; a 10.1-fold increase in 1-stearoyl-2-arachidonoyl-GPC; a 9.3-fold increase in 1-stearoyl-2-oleoylGPC; a 9.2-fold increase in alpha-tocopherol; and a 7.8-fold increase in 1-stearoyl-2linoleoyl-GPC (7.8); however, the authors noted that the study lacked to power to determine if changes in urinary metabolites predicted treatment response [80].…”

“…The three sets of investigators used very different doses of d,l-leucovorin. Three studies [37,72,80] used a relatively high dose (2 mg/kg/day; maximum 50 mg/day) while one study [74] used a much lower dose (5 mg twice daily; 0.29-0.63 mg/kg/day) but both dosing parameters were associated with significant clinical improvements.…”