Original Article

Molecular Psychiatry (2013) 18, 369–381; doi:10.1038/mp.2011.175; published online 10 January 2012

Cerebral folate receptor autoantibodies in autism spectrum disorder

R E Frye1, J M Sequeira2, E V Quadros2, S J James1 and D A Rossignol3

  1. 1Department of Pediatrics, Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
  2. 2Department of Medicine, State University of New York—Downstate Medical Center, Brooklyn, NY, USA
  3. 3International Child Development Resource Center, Melbourne, FL, USA

Correspondence: Dr RE Frye, MD, PhD, Department of Pediatrics, Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. E-mail: REFrye@uams.edu

Received 4 August 2011; Revised 3 November 2011; Accepted 7 November 2011
Advance online publication 10 January 2012



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 (ASDs) 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. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2mgkg−1 per day; maximum 50mg per day). Treatment response was measured and compared with a wait-list control group. Compared with 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. 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.


autism spectrum disorders; cerebral folate deficiency; folate receptor autoantibody; folinic acid; leucovorin calcium