The Evolving Paradigm of Autism: Folate Receptor Autoimmunity deranging Epigenetic Programming in fetal and postnatal Brain Development

15/10/2026

AI Summary

Folate receptor autoantibodies impair placental and blood-brain barrier folate transport, causing cerebral folate deficiency and deranged foetal and postnatal synaptogenesis and corticogenesis.
FRAb and low cerebrospinal fluid folate are detected in most children with autism and in over one third of asymptomatic parents, indicating familial risk.
Early detection permits high-dose folinic acid therapy; preconception and pregnancy folinic supplementation for FRAb-positive parents may reduce autism risk.

Biochimie. 2026 Oct 14:S0300-9084(26)00256-7. doi: 10.1016/j.biochi.2026.10.019. Online ahead of print.

ABSTRACT

This review on autism provides a summary of the multiple genetic, epigenetic and environmental changes setting the stage for disturbed brain development due to aberrant synaptogenesis and corticogenesis during the prenatal and post-natal periods. The emphasis is placed on nonmendelian transmission driven by epigenetics. Folate deficiency appears to play a critical role in influencing many of the structural changes contributing to developmental deficits. Impaired passage of folate across the placental and the blood-brain barriers to the fetal and postnatal brain because of folate receptor autoantibodies (FRAb) emerges as the major cause. Cerebral folate deficiency with or without autism has been associated with FOLR1 gene defects, a rare disorder. On the other hand, FRAb in association with low CSF folate is present in most children diagnosed with autism. These autoantibodies are present in more than 1/3 of asymptomatic parents of children with autism or are acquired by the child during the first two years of life. Early detection of FRAb amongst autistic children is necessary to enable high dose folinic acid treatment. The use of folinic acid before conception and during pregnancy among mothers or both parents with FRAb, represents a promising strategy to reduce the risk of autism in future offspring. Interventational treatments in parents prior to pregnancy and optimal therapeutic approaches in infants are needed to prevent disordered development of the pre- or post-natal brain.

PMID:42874702 | DOI:10.1016/j.biochi.2026.10.019

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