A Folinic Acid Intervention for ASD: Links to Folate Receptor-alpha Autoimmunity & Redox Metabolism

Evidence-based interventions for autism spectrum disorders (ASD) are limited. Currently, there is no FDA approved medical therapy that addresses either core ASD symptoms or pathophysiological processes associated with ASD. For example, the two FDA approved antipsychotic medications for treating ASD are indicated for symptoms associated with ASD, not core ASD symptoms. Based on strong preliminary evidence, this study aims to improve core ASD symptoms with folinic acid. Two biological mechanisms for response to the intervention are proposed and investigated in this study.

Folate is an essential B vitamin required for normal neurodevelopment. Folinic acid is a reduced form of folate that has been shown to improve both the metabolic and core symptoms associated with ASD in an open-label study and large case-series. This study will extend this preliminary evidence to demonstrate clinical efficacy of folinic acid in a double-blind placebo-controlled manner while also evaluating the biological mechanisms associated with the clinical response.

Preliminary evidence for the efficacy of folinic acid is two-fold: First, several independent studies have demonstrated that a folinic acid intervention improves ASD core symptoms in ASD patients diagnosed with cerebral folate deficiency - a metabolic disorder in which the primary pathway for the transport of folate across the blood-brain barrier is dysfunctional. The primary transport pathway for folate across the blood-brain barrier uses the folate receptor α (FRα) and energy dependent endocytosis. A secondary pathway, the reduced folate carrier (RFC), can transport reduced forms of folate, such as folinic acid, across the blood-brain barrier. In case-series of children with ASD and cerebral folate deficiency, folinic acid (0.5 to 2 mg/kg/day) improved communication, social interaction, attention, and stereotypical behavior in some (3-6) and completely ameliorated ASD symptoms in others (6, 7).

The major cause of cerebral folate deficiency is an autoantibody that binds to the FRα and interferes with its ability to bind and transport folate. Recently, Frye et al. found that (a) autoantibodies to the FRα were present in approximately 75% of children with ASD, and (b) an intervention with folinic acid (2mg/kg/day; max 50mg) in children with ASD and FRα autoantibodies resulted in significant improvements in parental ratings of receptive and expressive language, verbal communication, stereotypic behavior, and attention as compared to parental rating for children that did not undergo any intervention (wait group) over a similar time period. This proposal will extend these preliminary findings by documenting response to a folinic acid intervention in a double-blind placebo-controlled manner and test whether FRα autoantibody titers predict response to a folinic acid intervention. If FRα autoantibody titers are found to predict response to the intervention, such titers could provide a biomarker to identify a subset of children with ASD that may benefit from a folinic acid intervention and may even predict the development of ASD symptoms in high risk siblings during the presymptomatic period.

Second, the ratio of reduced-to-oxidized glutathione (GSH/GSSG) is an established measure of systemic redox status and oxidative stress that has been shown in three independent case-control studies to be significantly decreased in many ASD children. James et al. have shown in a 3 month open-label clinical trial that an intervention of folinic acid and methyl-B12 significantly improved GSH/GSSG and Vineland scores for expressive language, receptive language, and socialization in ASD children. Important unanswered questions are (a) whether this preliminary data can be confirmed in a larger double-blind placebo-controlled study, (b) whether redox status before the folinic acid intervention can predict response to intervention and (c) whether improved systemic redox status is associated with improvement in core ASD symptoms.