The FRAT® (Folate Receptor Autoantibody Test) is an original functional assay developed by Dr. Edward V. Quadros and his research team at the State University of New York (SUNY) Downstate Health Sciences University, United States. According to the test provider, it is the only available diagnostic assay that detects both binding and blocking autoantibodies against the folate receptor alpha (FRα).
Sample analysis is performed exclusively in a CLIA-certified laboratory in the United States, where the assay's authentic, specialized methodology is applied.
Diagnostiki Athinon serves as a collaborating collection site, undertaking blood sample collection, proper pre-analytical handling, and secure international shipment of specimens to the certified laboratory, where the final analysis is conducted. This ensures patient access to the authentic FRAT® test in full compliance with international quality standards and biological material transport regulations.
Description of the Test
The FRAT® (Folate Receptor Autoantibody Test) is a specialized laboratory assay that detects and quantifies autoantibodies directed against the folate receptor alpha (Folate Receptor Alpha, FRα) in serum.
The FRα receptor is a high-affinity membrane glycoprotein responsible for the transport of 5-methyltetrahydrofolate (5-MTHF)—the biologically active and circulating form of folate—across the blood–brain barrier and other epithelial tissues. The presence of autoantibodies against the FRα receptor may inhibit or interfere with folate binding and transport, potentially leading to functional folate deficiency even when serum folate levels are within the normal range.
The assay differentiates between two principal types of autoantibodies:
- Binding antibodies, which attach to the receptor without necessarily directly inhibiting its function
- Blocking antibodies, which interfere with the binding of folate to the receptor
Measurement is primarily performed using a functional radioligand assay, a specialized laboratory method that quantitatively assesses autoantibodies' ability to inhibit folate binding to the receptor.
The FRAT® test does not measure circulating folate levels; rather, it evaluates the immunological mechanism that may impair receptor-mediated folate transport. Consequently, the FRAT® assay provides an assessment of folate bioavailability at the cellular level, particularly within the central nervous system.
Pathophysiological Interpretation
The detection of autoantibodies against the folate receptor alpha (FRα) reflects an immune-mediated mechanism disrupting folate homeostasis, with particular relevance to the central nervous system. The FRα receptor is highly expressed in the choroid plexus, where it mediates the transport of 5-methyltetrahydrofolate (5-MTHF) into the cerebrospinal fluid. The presence of blocking autoantibodies may reduce the availability of 5-MTHF within the brain, leading to a condition known as cerebral folate deficiency (CFD), despite normal or adequate serum folate concentrations.
Folate plays a critical role in one-carbon (1C) metabolism, nucleotide synthesis, DNA and RNA methylation, and neurotransmitter biosynthesis. Impaired folate delivery to the central nervous system may affect epigenetic regulation, myelination, and synaptic plasticity. The production of FRα autoantibodies appears to be associated with autoimmune mechanisms or other forms of immune dysregulation. In this context, the FRAT® test serves as a biomarker of a specific immune-mediated interference in folate metabolism, with potential neurodevelopmental and neuropsychiatric implications.
Interpretation of the assay is based on the quantitative detection of binding and/or blocking autoantibodies against the folate receptor alpha (FRα). A normal result is defined as the absence of detectable autoantibodies or titers below established laboratory reference thresholds, indicating no evidence of immune interference with folate transport. Conversely, elevated titers, particularly of blocking autoantibodies, suggest potential functional inhibition of 5-MTHF uptake and a possible risk of cerebral folate deficiency, even when serum folate levels fall within normal reference ranges.
Clinical Significance
Testing for autoantibodies against the folate receptor alpha (FRα) has primarily been studied in the context of cerebral folate deficiency (CFD), a clinical entity characterized by low cerebrospinal fluid levels of 5-methyltetrahydrofolate (5-MTHF) despite normal serum folate concentrations. Clinically, CFD may present with developmental delay, speech impairment, motor dysfunction, seizures, and features consistent with autism spectrum disorder (ASD). In pediatric populations, an increased prevalence of FRα autoantibodies has been reported in subgroups of children with ASD, particularly in those with associated gastrointestinal symptoms or developmental regression.
Additionally, the FRAT® test has been investigated in various neurological and neuropsychiatric contexts, including idiopathic epilepsy, developmental language disorders, and certain cases of schizophrenia or depression, where disturbances in one-carbon metabolism have been hypothesized. The test is not intended as a first-line screening tool for the general population; rather, it is used to target the evaluation of patients with suspected functional folate deficiency or unexplained neurodevelopmental symptoms, particularly when conventional biochemical folate markers are within normal limits.
The clinical relevance of FRα autoantibody detection depends on correlation with the patient’s clinical presentation and, when appropriate, cerebrospinal fluid 5-MTHF levels. The presence of autoantibodies does not, in itself, establish a diagnosis and requires a comprehensive clinical assessment. Potential confounding factors include fluctuations in antibody titers over time, transient immune responses, and possible cross-reactivity. The reported association between chronic dairy consumption and the presence of FRα autoantibodies relates to long-term immunological mechanisms and does not imply the need for dietary restriction prior to testing. Therefore, interpretation should be based on the overall clinical context rather than recent dietary factors.
Diagnostic Value of the Test
Detection of autoantibodies against the folate receptor alpha (FRα) is a specialized, contemporary diagnostic tool for investigating and identifying an immune-mediated mechanism of functional folate deficiency. Unlike conventional measurements of serum or red blood cell folate, this assay evaluates impairment in the transport of 5-methyltetrahydrofolate (5-MTHF) to the central nervous system. Consequently, it does not function as a general marker of nutritional folate deficiency but rather as a biomarker of a specific pathophysiological subtype with therapeutic implications.
The diagnostic value of the test lies primarily in its ability to identify patients who may benefit from targeted metabolic intervention (e.g., folinic acid), particularly within the context of multifactorial neurodevelopmental or neurological disorders.
When Is It Clinically Useful?
The test may be clinically useful in the following situations:
- In children with autism spectrum disorder (ASD), particularly when developmental regression or resistance to established interventions is observed.
- In patients with developmental delay of unknown etiology.
- In cases of confirmed or suspected cerebral folate deficiency (CFD).
- In children or adults with unexplained seizures, motor disorders, or neuropsychiatric symptoms, especially when standard biochemical folate markers are within normal limits.
- In clinical settings, an individualized, mechanism-based therapeutic approach is being considered within the framework of functional and metabolic medicine.
Last update: 24/02/2026
