The Role of Folate Receptor Antibodies in Autism and PANS/PANDAS

Written by: Dr Tim Trodd (Functional Medicine)

Folate and Folate Receptors

Folate plays a crucial role in cellular growth, DNA synthesis, attention, energy production and repair. Folate's active form, 5-Methyltetrahydrofolate (5-MTHF), is essential for numerous biochemical processes, particularly in the brain. Folate receptors, notably folate receptor alpha (FRα), facilitate the transport of folate across cell membranes, ensuring adequate folate levels within cells.

Folate Receptor Antibodies (FRAs)

FRAs are autoantibodies that target folate receptors. When these antibodies bind to the receptors, they can impede the normal transport of folate into the cells. This interference can lead to Cerebral Folate Deficiency, even if plasma folate levels is normal.

Autism Spectrum Disorder (ASD)

A study published in 2013 revealed that maternal antibodies against the folate receptor during pregnancy were associated with an increased risk of autism in offspring. Another study in 2016 identified FRAs in children with autism, suggesting a potential biomarker for early diagnosis and intervention.

Treatment

Treatment of methylation disorders requires using activated B vitamins. The usual supplements Cyanocobalamin for Vitamin B12 and Pteroyl Glutamate for Folate do not occur in nature and may block receptors. Therefore we use Methyl Cobalamin (by injection or liposomal spray) and 5 Formyl THF or 5 Methylene THF for folate. There is a commercially available high dose form of 5 Formyl THF, Leucovorin, which is used to rescue patients from chemotherapy. Leucovorin has been used to treat patients with ASD and positive for FRA’s. In addition, stopping all dairy products is beneficial for individuals with ASD and FRAs, meta-analysis found improvements with Leucovorin treatment in overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%). Significant adverse effects across studies were generally mild but the most common were aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%). A trial of treatment will not cause long lasting side effects PANS/PANDAS.

PANS and PANDAS are characterized by sudden onset of neuropsychiatric symptoms, including obsessive-compulsive behaviours and motor or vocal tics, often following an infectious illness such as streptococcal infection or Mycoplasma Pneumoniae. The infection causes autoimmunity leading to inflammation of the basal ganglia in the brain. A study of 47 children with PANS/PANDAS found that 63% had FRAs. This suggests that autoimmunity and folate receptor dysfunction might be significant contributors and normalisation of Methylation biochemistry will be helpful. Of course IVIG and other PANS/PANDAS treatments will also help lower FRA’s.

Conclusion

The research on FRAs underscores their potential impact on neurological disorders such as ASD and PANS/PANDAS, and provide an opportunity to develop additional treatments. 

Related Blogs

• Hong Kong Child Health: An Investigation into PANS and PANDAS, and the Causes of Tics and OCD in Children
• Understanding PANS and PANDAS: Sudden-Onset Neuropsychiatric Disorders in Children

References

1.  Ramaekers, V. T., et al. (2013). “Folate receptor autoimmunity and autism spectrum disorders.” Molecular Psychiatry, 18(3), 307-315.
2.  Quadros, E. V., et al. (2016). “Autoantibodies to folate receptors in the cerebral folate deficiency syndrome.” Neurology, 86(14), 1223-1230.
3. Swedo, S. E., et al. (2017). “Clinical management of pediatric acute neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).” Journal of Child and Adolescent Psychopharmacology, 27(7), 562-573. 
4. Daniel A Rossignol (2021) “Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis 2021”. 6 May 2025 Retrieved from https://pubmed.ncbi.nlm.nih.gov/34834493/. 
5. 2024 Folate Receptor Alpha Autoantibodies in the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Population.  6 May 2025 Retrieved from https://pubmed.ncbi.nlm.nih.gov/38392599/. 
6. 2004 Dr Jill James Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. 6 May 2025 Retrieved from https://pubmed.ncbi.nlm.nih.gov/15585776/. 
7. 2004 BMJ Is folic acid the ultimate functional food component for disease prevention? 6 May 2025 Retrieved from https://pubmed.ncbi.nlm.nih.gov/14739191/.