FRAT® (Folate Receptor Autoantibody Test) and its Urgency.

Scientific development of diagnostics often takes a long time, and for many reasons.

Developing a hypothesis and designing experiments to test it requires careful planning and consideration. Collecting sufficient data to draw meaningful conclusions is time-consuming, particularly in fields requiring long-term observations or large sample sizes. Commercializing and distributing a diagnostic technology is a long and arduous road.

For a parent of a child with special needs, this slow evolution of science is frustrating. Urgency is certainly a priority in this case. Oftentimes the parent will become the advocate, and this is necessary.

In the summer of 2003, a unique assay (test) was developed in the SUNY Downstate laboratory of Dr. Edward Quadros. This test, termed FRAT^® (folate receptor autoantibody test), was created to identify the presence of folate receptor autoantibodies.

FRAT^® (folate receptor autoantibody test) measures the presence of autoantibodies against folate receptors in the body. These autoantibodies can interfere with the normal function of folate receptors, which are critical for the uptake and utilization of Folate (vitamin B9) in cells.

Folate is a critical nutrient (also known as Vitamin B9) that is essential for full and normal brain development and function. Additionally, Folate is needed for neurotransmitter synthesis, DNA synthesis, DNA and Phospholipid methylation, Myelin formation, axonal healing, and synapse formation. These are all vital functions and Folate helps them run efficiently and effectively.

Folate is transported from the circulation to the brain through the high-affinity Folate Receptor A (or alpha; FRA) and the low affinity Reduced Folate Carrier (RFC). Unhindered delivery of Folate to the brain is especially essential for a healthy functioning brain. If not enough Folate is available, then a folate deficiency in the brain can arise. This is a cause for concern.

There are 2 major reasons why not enough Folate reaches the brain:

1. Not enough Folate in diet or poor absorption/conversion in the gut.
2. Blockage in transporting the Folate from the blood across into the brain.

The most common cause of blockage in transport to the brain is circulating autoantibodies to the FRA. There are at least 2 types of autoantibodies: blocking (directly competing for folate transport) and binding (affecting the position or alignment of the receptor).

When present, these autoantibodies impede the proper absorption of Folate (vitamin B9) into critically important tissues such as the brain, placenta, ovaries, among others. Both blocking and binding autoantibodies negatively affect folate absorption, potentially leading to a mode of folate deficiency which may contribute to neuro-developmental disorders such as autism spectrum disorders, cerebral folate deficiency, neural tube defects, subfertility, and pregnancy complications such as miscarriage and pre-maturity.

Folate deficiency in the brain is quite common in children with autism, and a large percentage of these children test positive for the autoantibodies. If a child is on the spectrum or is suspected to have symptoms of Autism, then FRAT^® would be highly recommended.

Testing with FRAT^® for folate receptor autoantibodies should be done on a timely basis, and with a sense of urgency. The reasoning for this is that the brain has plasticity, therefore administering a treatment plan earlier than later may have greater benefits.

If FRAT^® is positive for folate receptor autoantibodies, one emerging therapeutic strategy involves administering active folates, such as folinic acid, to help improve folate availability to the neurons. Folinic acid is a type of folate, also known as vitamin B9.

Folates, in general, are types of Vitamin B9 and are necessary for many of our basic systems in the body to function properly. The most commonly known form of folate, folic acid, is an oxidized form, and is found in prenatal vitamins, over-the-counter vitamins and is readily supplied in some of the foods that we eat (breads, cereals, pasta, rice) via mandatory fortification. Because it is in an oxidized form, it requires several steps to be converted into a biological usable form. Folinic acid, also known as leucovorin in some instances, is one of the active forms of folate that can be readily used by the body without the need for conversion and does not require the same enzymatic conversion to become bioactive. This makes folinic acid a more direct and readily available source of folate. In the case of those that have folate receptor autoantibodies, folinic acid can enter the brain via a different channel (reduced folate carrier) and work around the blocked folate receptor alpha.

This approach has been well-documented through various studies. For example, in a 2016 publication by Frye et al. which shows results of a double-blinded placebo-controlled study, the response to folinic acid was several folds better in children with ASD who had autoantibodies to the folate receptor alpha, compared to children who were negative for the autoantibodies. Additional studies have evidenced similar findings. In many cases, children with ASD that have tested positive for folate receptor autoantibodies have improved with folinic acid. As with any medical situation, a physician’s assessment and guidance is necessary.

With the sudden rise of Autism, we see greater efforts by parents to seek more information and guidance. This is certainly needed. Science does move slowly, but significant progress is being made with parents’ support! FRAT^® is now starting to become an integral part of this.

FRAT^® is crucial for diagnosing and managing conditions related to impaired folate metabolism. It helps in understanding the underlying causes of various neurological, developmental, and reproductive health issues, thereby enabling more targeted and effective treatments.