FRAT® – The One and Only

The development of FRAT^® (Folate Receptor Autoantibody Test) by Professor Edward Quadros at SUNY Downstate Medical Center is a fascinating story that spans over two decades. It began with a simple, persistent question and, through meticulous research, led to a diagnostic tool now changing the lives of children with autism and their parents.

In the early 2000s, Dr. Edward V. Quadros, a Research Professor of Medicine and Cell Biology at SUNY Downstate, was focused on a puzzling clinical problem. Public health campaigns and food fortification with folic acid had successfully reduced the incidence of neural tube defects (NTDs) like spina bifida. However, a significant number of women were still having children with these severe birth defects, despite having normal folate levels in their blood. The standard blood tests for folate deficiency could not explain why folate was not reaching the developing fetus in these cases. Dr. Quadros hypothesized that an autoimmune mechanism, rather than a nutritional deficiency, might be the culprit.

To test his theory, Dr. Quadros and his team conducted a pivotal experiment. They injected an antibody against the folate receptor into pregnant rats. The results were striking; at high doses, the antibodies caused fetal brain malformations. At lower doses, the offspring later showed deficits in learning and memory. Crucially, these effects could be prevented by pre-treating the rats with folinic acid, a reduced form of folate that can enter cells through an alternative pathway. This animal model provided the first clear evidence that an autoimmune process targeting the folate receptor could disrupt brain development.

Building on this, Dr. Quadros, along with key colleagues like Sheldon P. Rothenberg and Jeffrey M. Sequeira, examined serum from women who had a pregnancy complicated by an NTD. In a landmark 2004 study published in the New England Journal of Medicine, they found that 9 out of 12 such women had autoantibodies that blocked the binding of folic acid to the folate receptor, compared to only 2 out of 24 control subjects. This was the first identification of folate receptor autoantibodies (FRAAs) in humans and the foundational discovery that would lead to the creation of a new diagnostic test.

Dr. Quadros’s research soon expanded beyond pregnancy. He partnered with Vincent Ramaekers, a pediatric neurologist in Belgium, to study children with cerebral folate deficiency (CFD) syndrome—a disorder where folate levels are low in the brain despite being normal in the blood. They discovered that 89% of these children tested positive for the same folate receptor-blocking autoantibodies. This finding was critical because the symptoms of CFD—such as developmental regression, movement disorders, and autism-like behaviors—overlapped significantly with autism spectrum disorder (ASD).

This led to further collaboration with Dr. Richard Frye, a neurologist and autism specialist. Their subsequent studies showed that approximately 70% of children with ASD also tested positive for these autoantibodies. Furthermore, double-blind, placebo-controlled trials demonstrated that treating these antibody-positive children with high-dose folinic acid led to significant improvements in core ASD symptoms, including communication, language, and social interaction.

The journey from a university lab to a globally available test was completed through technology transfer. The Research Foundation for SUNY licensed the technology for the Folate Receptor Antibody Test (FRAT^®) to Religen Inc, who has since validated the test in their CLIA-certified labs, trademarked it FRAT^®, and made available to the public in 2016. FRAT^® is available to physicians and their patients worldwide, helping to identify individuals who may benefit from folinic acid therapy. The test remains the only assay available that can screen for both blocking and binding folate receptor autoantibodies. This is a critical aspect of the test. Although FRAT^® may sound like one test, it has, in fact, two distinct components. It detects the presence of blocking autoantibodies to the folate receptor alpha and also detects the presence of binding autoantibodies to the folate receptor.

There is no other commercially available assay that screens for both types of autoantibodies.
Understanding why FRAT^® is important

Folate—commonly known as vitamin B9—has long been celebrated for its critical role in preventing neural tube defects during pregnancy. But what happens when the body’s own immune system interferes with this essential nutrient’s delivery? As we have seen, research reveals that autoantibodies targeting the folate receptor alpha (FRα) may explain a range of developmental disorders, from pregnancy complications to autism spectrum disorders (ASD). The FRAT^® test offers a powerful tool for early detection and intervention.

Folate receptor autoantibodies are immune system proteins that mistakenly attack the body’s own folate receptors—the “gateways” that allow folate to enter cells. These receptors are particularly abundant in reproductive tissues and play a vital role in delivering folate to developing embryos and the brain.

Two types of antibodies have been identified:

• Blocking antibodies: These physically prevent folate from binding to its receptor, disrupting nutrient transport
• Binding antibodies: These attach to the receptor and may trigger inflammatory responses that damage the receptor

Both immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies have been detected, with specific IgG subtypes varying by condition. Women with neural tube defect (NTD) pregnancies predominantly show IgG1 and IgG2 isotypes, while children with cerebral folate deficiency (CFD) syndrome typically exhibit IgG1 and IgG4 isotypes.

The FRα autoantibody test uses sophisticated methods to detect these antibodies in serum samples. As mentioned before, two complementary assays are employed.

The FRAT^® test offers several critical advantages:

Early Detection: Before symptoms appear, identifying at-risk women and children enables preventive intervention

Personalized Treatment: Confirms which patients may benefit from high-dose folinic acid therapy rather than standard folate supplementation

Monitoring Response: Tracks antibody levels over time to assess dietary interventions (like dairy elimination) and treatment efficacy

Family Screening: Given the familial association in ASD, testing parents and siblings may identify additional at-risk individuals

The discovery of folate receptor autoantibodies has transformed our understanding of folate-related disorders beyond simple nutritional deficiency. By identifying an autoimmune mechanism that disrupts folate transport to the brain and developing fetus, researchers have opened new diagnostic and therapeutic possibilities. The FRAT^® test, the only assay in the world that screens for blocking and binding autoantibodies, provides a simple blood-based method to identify individuals who may benefit from targeted interventions—potentially preventing or reversing devastating neurodevelopmental consequences.