Cerebral Folate Receptor Autoantibodies in Autism Spectrum Disorder

Background: Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASD) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA positive children has not been systematically investigated.

Objectives: First, to determine the prevalence of FRAs in a group of children with ASD.  Second, to determine the correlation between FRAs and cerebrospinal (CSF) concentrations of 5-methyltetrahydrofolate (5MTHF). Finally, to examine the effects of folinic acid treatment on ASD behaviors.

Methods: In this study, serum FRA concentrations were measured in 93 children with ASD. A subset of FRA positive children underwent a lumbar puncture to determine CSF concentrations of 5MTHF. Children with FRAs were treated with oral leucovorin calcium (2 mg/kg/day; maximum 50 mg/day). Treatment response was measured and compared to a wait-list control group.

Results: A high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with the CSF fluid 5MTHF concentrations which were below the normative mean in every case. Compared to controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low.

Conclusions: This study suggests that FRAs may be important in ASD and that FRA positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.