Folate Receptor Alpha Autoantibodies in Vector-Borne Disease Populations

Vector-borne diseases (VBDs) caused by Borrelia spp., Bartonella spp., and Babesia spp. are associated with neuropsychiatric morbidity. Cerebral folate deficiency (CFD), primarily caused by folate receptor-α autoantibodies (FRAAs) impairing folate blood-brain barrier transport, is a treatable contributor to neurodevelopmental disorders including pediatric acute-onset neuropsychiatric syndrome (PANS) and autism spectrum disorder. Despite overlapping clinical manifestations, FRAA prevalence in VBD populations has not been investigated. This study aimed to determine the prevalence of FRAA in patients with confirmed VBDs.

This retrospective cohort study included 68 VBD-positive patients with and without PANS evaluated at a single clinical practice. VBD testing was performed by IGeneX Laboratories; FRAA analysis including binding, blocking, and soluble folate receptor (sFR) testing was performed by Religen Laboratories (Plymouth Meeting, PA). Statistical associations were assessed using Fisher's exact test with Wilson 95% confidence intervals.

Of the 68 VBD-positive patients, 42 (61.8%; 95% CI: 49.9-72.4%) were also FRAA-positive. Soluble folate receptor (sFR) was detected in eight patients (11.8%; 95% CI: 6.1-21.5%), all of whom were binding FRAA-positive, with 87.5% carrying confirmed evidence of Borrelia species infection. Neuropsychiatric symptoms were highly prevalent across both groups but did not significantly differentiate FRAA-positive from FRAA-negative patients (all p > 0.05).

This study demonstrates a high prevalence of FRAA in a pediatric VBD cohort. The sFR was strongly associated with Borrelia species infection, suggesting a potential mechanistic link between spirochetal infection and folate receptor autoimmunity. These findings support the consideration of FRAA testing in patients with VBDs and warrant further investigation in larger prospective cohorts.