Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups

Richard E Frye, Leanna Delhey, John Slattery, Marie Tippett, Rebecca Wynne, Shannon Rose, Stephen G Kahler, Sirish C Bennuri, Stepan Melnyk, Jeffrey M Sequeira, Edward Quadros, Richard E Frye, Leanna Delhey, John Slattery, Marie Tippett, Rebecca Wynne, Shannon Rose, Stephen G Kahler, Sirish C Bennuri, Stepan Melnyk, Jeffrey M Sequeira, Edward Quadros

Abstract

Folate receptor α (FRα) autoantibodies (FRAAs) are prevalent in autism spectrum disorder (ASD). They disrupt the transportation of folate across the blood-brain barrier by binding to the FRα. Children with ASD and FRAAs have been reported to respond well to treatment with a form of folate known as folinic acid, suggesting that they may be an important ASD subgroup to identify and treat. There has been no investigation of whether they manifest unique behavioral and physiological characteristics. Thus, in this study we measured both blocking and binding FRAAs, physiological measurements including indices of redox and methylation metabolism and inflammation as well as serum folate and B12 concentrations and measurements of development and behavior in 94 children with ASD. Children positive for the binding FRAA were found to have higher serum B12 levels as compared to those negative for binding FRAAs while children positive for the blocking FRAA were found to have relatively better redox metabolism and inflammation markers as compared to those negative for blocking FRAAs. In addition, ASD children positive for the blocking FRAA demonstrated better communication on the Vineland Adaptive Behavior Scale, stereotyped behavior on the Aberrant Behavioral Checklist and mannerisms on the Social Responsiveness Scale. This study suggests that FRAAs are associated with specific physiological and behavioral characteristics in children with ASD and provides support for the notion that these biomarkers may be useful for subgrouping children with ASD, especially with respect to targeted treatments.

Keywords: autism spectrum disorders; folate receptor autoantibody; folinic acid; glutathione; redox metabolism.

Figures

Figure 1
Figure 1
(A) Children with Autism Spectrum Disorder who are positive for the binding Folate Receptor Alpha Autoantibody have higher serum B12 concentrations than children negative for the binding Folate Receptor Alpha Autoantibody; (B) Serum Folate concentration does not differ across Folate Receptor Alpha Autoantibody status in children with Autism Spectrum Disorder.
Figure 2
Figure 2
Children with Autism Spectrum Disorder who are positive for the blocking Folate Receptor Alpha Autoantibody have more favorable total and free glutathione redox ratios (A,B) and marker of inflammation (C) as compared to those negative for the blocking FRAA. (D) Methylation metabolism was not different across Folate Receptor Alpha Autoantibody status.
Figure 3
Figure 3
Children with Autism Spectrum Disorder who are positive for the blocking Folate Receptor Alpha Autoantibody have more favorable (B) communication on the Vineland Adaptive Behavior Scale, (I) Stereotyped behavior on the Aberrant Behavior Checklist (ABC) and (Q) Mannerisms on the Social Responsiveness Scale (SRS) as compared to children negative for the blocking Folate Receptor Alpha Autoantibody. (R) In addition, children positive for the blocking FRAA have better total Social Responsiveness Scale score than those positive for the binding Folate Receptor Alpha Autoantibody. This figure depicts behavioral and Cognitive differences across Folate Receptor Alpha Autoantibody (FRAA) groups including difference in (A) Language, (B–F) Vineland Adaptive Behavioral Scale, (G–L) ABC, and (M–R) SRS.

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