Understanding FRAT Testing: History, Purpose, and Clinical Relevance

Understanding FRAT Testing: History, Purpose, and Clinical Relevance

When families or individuals explore new approaches to health, one test that may come up is the Folate Receptor Antibody Test (FRAT). Originally studied in women with pregnancies complicated by neural tube defects, FRAT testing is now being considered in a wide range of conditions where the body’s ability to use folate may be disrupted. These include:

• Autism Spectrum Disorder (ASD) – where folate receptor antibodies (FRAAs) are often present and treatment with folinic acid (leucovorin) may improve communication and behavior.

• PANS/PANDAS – immune-related neuropsychiatric syndromes where folate disruption may contribute to symptoms.

• Treatment-Resistant Depression (TRD) – where poor folate utilization may underlie limited antidepressant response.

• Fertility and Pregnancy Complications – where FRAAs were first discovered and may explain certain cases of miscarriage or infertility.

Because folate metabolism touches brain development, immune function, and reproductive health, FRAT testing can provide valuable insights across multiple areas of medicine.

The Origins of FRAT Testing

The story of FRAT testing begins in 2004, when researchers published a landmark study in the New England Journal of Medicine. They discovered that some women whose pregnancies were affected by neural tube defects (NTDs) carried folate receptor autoantibodies (FRAAs)—immune proteins that interfere with the body’s ability to transport folate into cells.

This finding was groundbreaking because it showed that folate problems aren’t always due to low dietary intake. Instead, the immune system itself can block folate receptors. Later, scientists found that FRAAs were also common in children with autism spectrum disorder, opening the door to new treatment strategies.

What the FRAT Test Looks For

The FRAT test measures whether a person has antibodies that interfere with folate receptors, particularly the folate receptor alpha (FRα). There are three possible findings:

• Binding Antibodies – Stick to the receptor, potentially causing inflammation.

• Blocking Antibodies – Prevent folate from entering the brain (the most concerning finding).

• Soluble Folate Receptor – A rare result (~2% of people) where free-floating receptors soak up folate in the bloodstream.

If antibodies are present, folate may not reach the brain effectively—even if blood folate levels look normal. This state is sometimes referred to as Cerebral Folate Deficiency (CFD), a condition recognized in both children and adults【Ramaekers & Quadros 2022】.

Why It Matters: Treatment Implications

In children with autism, folate receptor autoantibodies can be bypassed with leucovorin (folinic acid), which uses alternate pathways to enter the brain. 

For more on the powerful role leucovorin is playing in Autism, watch Dr. Danish’s video on leucovorin here. 

• A large randomized controlled trial in France (EFFET study) found that leucovorin significantly improved communication and core autism symptoms in children with ASD, particularly in those with FRAAs【Renard 2020】.

• A 2024 clinical trial reinforced these findings, showing that oral folinic acid improved language, social interaction, and irritability scores in children with ASD【Panda 2024】.

At Philadelphia Integrative Psychiatry, Dr. Danish does not require FRAT testing before starting leucovorin if a patient already has a valid ASD diagnosis. However, testing can be helpful for families who want confirmation or to better understand the underlying biology.

For other conditions such as PANS/PANDAS, fertility challenges, or treatment-resistant depression (TRD), we do recommend obtaining a positive FRAT test before prescribing leucovorin. This helps ensure that treatment is being directed toward the right biological target, since the research evidence is strongest for using leucovorin in these settings when folate receptor autoantibodies are present.

It is also important to note that a small percentage of patients may have false negative results, meaning that antibodies could still be interfering with folate transport even if the test does not detect them.

Beyond Autism: Other Conditions Where FRAT May Help

Research has expanded the role of folate receptor autoantibodies beyond autism:

• PANS/PANDAS: A 2024 study in Journal of Personalized Medicine found FRAAs in many children with PANS/PANDAS, suggesting that folate disruption may play a role in inflammation-driven neuropsychiatric symptoms【Wells 2024】.

• Treatment-Resistant Depression (TRD): Folate receptor dysfunction is increasingly recognized as a contributor to poor antidepressant response. Early studies suggest that folinic acid may augment traditional antidepressants【Quadros, multiple studies】.

• Fertility and Pregnancy Complications: FRAAs were first discovered in women with pregnancies complicated by neural tube defects. More recent work suggests they may also play a role in recurrent miscarriage and infertility【Rothenberg 2004】.
  

Limitations of FRAT Testing

• While FRAT testing can provide valuable insights, it also comes with several limitations that families should be aware of.

• First, insurance coverage is limited, and the test is usually not available through major commercial labs such as Quest or LabCorp. This means that families often need to pay out of pocket, and the cost can be high. For many, this raises an important practical question: is it better to invest in testing, or to simply try leucovorin (folinic acid), which has a relatively favorable side effect profile and growing clinical evidence for benefit in autism and related conditions?

• Second, false negatives are possible. This means that even if the test comes back negative, it does not completely rule out the presence of folate receptor autoantibodies. Some individuals who test negative still respond positively to leucovorin, likely because the test does not capture every possible antibody or mechanism of folate transport disruption.

• Third, the turnaround time can be long. At the time of this writing, results can take up to three months to return, depending on demand and lab availability. For families who are eager to start treatment, this wait can feel discouraging.

• Finally, a positive FRAT test does not guarantee benefit from leucovorin. While research suggests that FRAA-positive individuals are more likely to improve with treatment, response is still variable. Conversely, some FRAA-negative individuals may still benefit from leucovorin, which is why many clinicians—including Dr. Danish—are comfortable starting leucovorin in children with a valid autism diagnosis even without FRAT testing.

Takeaway

FRAT testing has an important place in the history of folate research, helping explain why some children and adults respond dramatically to folinic acid (leucovorin) even when blood folate levels appear normal. While Dr. Danish does not require FRAT testing before starting treatment in ASD, it can provide additional clarity and reassurance for families—and it may guide care in other conditions like PANS, TRD, or fertility challenges.

The research continues to grow, with multiple clinical trials showing that folinic acid can improve symptoms across a range of neuropsychiatric and developmental disorders. For some families, FRAT testing provides a window into the “why” behind treatment response.

References

1. Rothenberg SP, Da Costa MP, Sequeira JM, et al. Autoantibodies against Folate Receptors in Women with a Pregnancy Complicated by a Neural-Tube Defect. N Engl J Med. 2004;350:134–142.https://pubmed.ncbi.nlm.nih.gov/14711912/

2. Ramaekers VT, Quadros EV. Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies. Nutrients. 2022;14(15):3096. https://doi.org/10.3390/nu14153096

3. Panda PK, Sharawat IK, Natarajan V, et al. Efficacy of Oral Folinic Acid Supplementation in Children with Autism Spectrum Disorder. Eur J Pediatr. 2024. https://doi.org/10.1007/s00431-024-05762-6

4. Wells L, Brown K, Williams K, et al. Folate Receptor Alpha Autoantibodies in PANS/PANDAS. J Pers Med. 2024;14(2):166. https://doi.org/10.3390/jpm14020166

5. Renard E, Ben Amor L, Iannuzzi S, et al. Folinic Acid Improves Autism Symptoms in the EFFET Trial. Biochimie. 2020;173:57–61. https://doi.org/10.1016/j.biochi.2020.04.019
   
   Binding Folate Receptor Alpha Autoantibody Is a Biomarker for Leucovorin Treatment Response in Autism Spectrum Disorder [https://pubmed.ncbi.nlm.nih.gov/38248763/