The role and mechanisms of folate receptor autoantibodies in neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) are a group of complex conditions that arise from abnormal brain development and function early in life, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder, intellectual disability, and epilepsy. With a global prevalence of approximately 4.14% among children aged 0–14 years (GBD 2021), NDDs have emerged as a pressing public health challenge worldwide. Folate (vitamin B9) is indispensable for central nervous system development, as it mediates nucleotide synthesis, DNA methylation, and neurotransmitter metabolism—processes critical for myelination and neuronal function. The transport of folate across the blood-brain barrier and maternal-fetal barrier relies exclusively on folate receptor alpha (FRα), a key protein highly expressed in choroid plexus epithelial cells and placental syncytiotrophoblasts, which specifically mediates the uptake of 5-methyltetrahydrofolate (5-MTHF), the bioactive form of folate, into the cerebrospinal fluid (CSF) and developing embryo. The discovery of folate receptor autoantibodies (FRAAs) in 2004 revolutionized our understanding of NDD pathogenesis, uncovering an autoimmune mechanism that disrupts FRα-mediated folate transport. FRAAs are classified into two functionally distinct subtypes: blocking antibodies and binding antibodies. Blocking antibodies directly compete with 5-MTHF for the folate-binding pocket of FRα, while binding antibodies attach to other epitopes, potentially inducing conformational changes or inciting an immune-inflammatory response. Both impair FRα function, leading to cerebral folate deficiency (CFD), a condition characterized by low CSF 5-MTHF levels despite normal blood folate concentrations. This localized folate deficit disrupts critical neurodevelopmental processes, including neurotransmitter synthesis, myelination, and epigenetic regulation via DNA methylation. Substantial evidence has established the correlation between FRAAs and a spectrum of NDDs. During embryogenesis, maternal FRAAs can compromise folate transport across the placenta, increasing the risk of neural tube defects (NTDs) or other birth defects. Postnatally, FRAAs are a major etiological factor for CFD syndrome, manifesting as irritability, epilepsy, movement disorders, and ASD-like features, with 89% of CFD children testing positive for blocking FRAAs. In ASD, FRAAs exhibit a high prevalence (47%–60% for blocking antibodies, 44% for binding antibodies), and their presence correlates with more severe social communication deficits and irritability. Notably, FRAA positivity shows strong familial aggregation: first-degree relatives of ASD patients have significantly higher FRAA rates than the general population, supported by genetic evidence linking folate metabolism gene variants (e.g., MTHFR rs1801133) to elevated FRAA levels. Importantly, FRAAs hold significant promise both as predictive biomarkers and therapeutic targets for NDDs. Randomized controlled trials demonstrate that high-dose folinic acid (the reduced form of folate) improves core ASD symptoms in 67% of patients, with superior responses observed in FRAA-positive individuals. This review systematically elaborates on the discovery, classification, and pathogenic mechanisms of FRAAs, with a focus on their associations with NTDs, CFD, ASD, and other birth defects. We also discuss the challenges in translating FRAA testing into routine clinical practice. A deeper understanding of the role of FRAAs is crucial for advancing the biological subtyping of NDDs, developing early diagnostic biomarkers, and formulating targeted intervention strategies, such as the early initiation of folinic acid supplementation and immunomodulation, to improve neurodevelopmental outcomes.