What are Folate Receptor Autoantibodies?

Folate receptor autoantibodies (FRAAs or sometimes folate receptor antibodies (FRAbs)) are immune system proteins that attack the folate receptor alpha (FRα), the protein that transports folate into cells and across the blood-brain barrier. FRAAs bind to folate receptors and prevent folate from being transported from the cerebrospinal fluid to the central nervous system. This can lead to cerebral folate deficiency. 

The two types of autoantibodies that have been identified are either blocking or binding. Blocking antibodies attach to the folate-binding site on FRα and stop folate from attaching, while binding antibodies attach to other areas of the receptor and can reduce its function.¹

FRAAs have also been implicated in the development of neural tube defects and behavioral disorders such as autism.² Low levels of folate have also been associated with a higher risk of major depressive disorder (MDD) and other mood disorders.³

The Folate Receptor Autoantibody Test (FRAT) is a blood test used to detect autoantibodies against FRα. It is usually suggested for people with suspected cerebral folate deficiency, autism spectrum disorder, developmental delays or certain neurological symptoms.

The gold standard for diagnosing cerebral folate deficiency (CFD) is a lumbar puncture, which is used to measure cerebrospinal fluid (CSF) folate.

Some research has suggested that MTHFR genetic mutations may be associated with folate receptor autoantibodies.

The MTHFR mutation impairs the body’s ability to metabolize folic acid, which can lead to lower levels of active folate and higher levels of homocysteine. People with variants of the MTHFR mutation may have a higher risk of developing cardiovascular disease and mood disorders such as depression. Pregnant women with MTHFR are at higher risk of having children with neural tube defects.

A small 2018 study reported higher FRAA levels in pregnant women with the MTHFR C677T mutation. However, more recent studies have not confirmed a consistent relationship. It has been suggested that MTHFR mutations and FRAA may be independent factors.⁴

Further research is required to understand if the MTHFR polymorphisms and FRAA status are related, and how.⁵

Dihydrofolate reductase (DHFR) converts dihydrofolate (DHF) into tetrahydrofolate (THF) after folate has entered the cell. When FRAAs are present, folate transport into the brain may be impaired, which then reduces the amount that can be converted into THF.

This impairment may be linked to cerebral folate deficiency, but research is limited.

Several recent studies have linked folate receptor alpha autoantibodies (FRAAs) with cerebral folate deficiency (CFD) and autism spectrum disorder (ASD).

Folate abnormalities are known to play a role in the development and presentation of autism.

A 2021 systematic review and meta-analysis involving 21 studies found that the prevalence of CFD in children with autism was 38%, with 83% attributed to FRAAs. Overall, the prevalence of FRAAs in children with autism was 71%. The study also found a high prevalence of FRAAs in families, suggesting they may be inherited. However, environmental factors may also contribute. The most effective treatment for CFD appears to be Leucovorin (folinic acid) which can enter the brain via the reduced folate carrier pathway (RFC). High doses of Leucovorin have been shown to compensate for the poor efficiency of this pathway, and are effective in restoring folate levels in the CSF.⁶

However, a 2024 study from China found that boys with autism had lower binding-FRAA levels than in typically developing boys, and also that FRAA levels declined with age. 

The study authors suggested that this result may be due to frequent exposure to milk folate receptor proteins, which has been indicated to reduce binding-type responses in some children. This cross-reactivity is not common.⁷