What are folate receptor antibodies?

Folate Receptor Antibodies: Understanding Their Role in Disease

Folate receptor antibodies (FRAs) are autoantibodies that bind to folate receptor alpha (FRα) proteins, blocking folate transport across cellular barriers and potentially causing cerebral folate deficiency even when serum folate levels appear normal.

What Are Folate Receptor Antibodies?

Folate receptor antibodies are autoantibodies that target the folate receptor alpha (FRα) protein, which is responsible for transporting folate across cellular membranes, particularly at the blood-brain barrier and placenta. There are two main types of these antibodies:

1. Blocking antibodies: These directly interfere with folate binding to its receptor, preventing folate transport
2. Binding antibodies: These bind to the receptor and may trigger inflammatory responses or receptor internalization

These antibodies can be of different immunoglobulin classes, with IgG1 and IgG2 predominating in women with neural tube defect pregnancies, and IgG1 and IgG4 in children with cerebral folate deficiency 1.

Clinical Significance and Associated Conditions

Folate receptor antibodies have been implicated in several neurological and developmental disorders:

• Autism Spectrum Disorders (ASD): Present in approximately 70% of children with ASD 2
• Cerebral Folate Deficiency (CFD): A neurological syndrome characterized by low cerebrospinal fluid folate levels despite normal serum folate 1
• Neural Tube Defects: Associated with pregnancy complications and abnormal fetal development 2
• Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)/PANDAS: Recently found in 63.8% of patients with these conditions 3

Pathophysiological Mechanisms

The presence of these antibodies can lead to pathology through several mechanisms:

1. Blocking folate transport: FRAs can prevent folate from crossing the blood-brain barrier, leading to cerebral folate deficiency despite normal serum folate levels 4
2. Placental transport disruption: During pregnancy, these antibodies can block folate transport to the developing fetus 2
3. Inflammatory response: Binding antibodies may trigger inflammation through antigen-antibody interactions 1

Diagnostic Testing

Testing for folate receptor antibodies involves specialized assays that can detect both blocking and binding antibodies in serum. These tests are not routinely available in all laboratories but can be performed at specialized centers 1.

It's important to note that standard serum folate measurements may appear normal even in the presence of cerebral folate deficiency caused by these antibodies, making specific testing for the antibodies necessary for diagnosis 1.

Treatment Approaches

Treatment strategies for conditions associated with folate receptor antibodies include:

• Folinic acid (leucovorin): High-dose folinic acid supplementation has shown clinical improvement in core ASD deficits in children with folate receptor antibodies 2
• Levofolinate: In animal studies, this form of folate showed superior brain distribution even in the presence of folate receptor antibodies 4
• Dexamethasone: In animal models, this has been shown to help prevent behavioral deficits when used alongside folinic acid 5

Prevention Strategies

For women with identified folate receptor antibodies who are planning pregnancy:

• High-dose folinic acid: May help prevent developmental deficits in offspring 5
• Interventions to lower antibody titers: Could potentially reduce the risk of having a child with developmental disorders 5

Clinical Implications

The discovery of folate receptor antibodies provides important insights into conditions previously not well understood. Early detection and intervention with appropriate folate supplementation may help prevent or mitigate neurological and developmental disorders associated with these antibodies.

For clinicians, it's important to consider testing for these antibodies in patients with unexplained neurological symptoms, developmental disorders, or a history of pregnancy complications, particularly when standard folate levels appear normal.