Cerebral folate receptor autoantibodies in autism spectrum disorder

Abstract

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 (2 mg kg(-1) per day; maximum 50 mg 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.

Figures

Figure 1

The prevalence of blocking and binding folate receptor autoantibodies in ASD. (a) The prevalence of children with ASD for negative, low, medium and high titers of the folate receptor-blocking autoantibody. (b) The prevalence of children with ASD for negative, low, medium and high titers of the folate receptor-binding autoantibody. (c) The prevalence of being negative for both the binding and the blocking autoantibodies, being positive for only the blocking or the binding autoantibody and being positive for both the binding and the blocking autoantibodies. (d) The blocking folate receptor autoantibody titer was found to significantly decrease with age. ASD, autism spectrum disorder.

Figure 2

The relationship between cerebrospinal fluid 5-methyltetrahydrofolate concentrations and blocking folate receptor autoantibody titers. Lower cerebrospinal fluid 5-methyltetrahydrofolate concentrations are associated with higher blocking folate receptor autoantibody titers.

Figure 3

Improvement ratings for nine cognitive-behavioral dimensions for children treated with leucovorin calcium compared with the no-treatment group (a-i). Improvement is rated on a 7-point scale ranging from much worse (−3) to much better (+3). For each cognitive-behavioral dimension, we provide the score for each child treated with leucovorin on the right of each graph (filled circles), and the score for each control child who did not undergo treatment (unfilled circles). The median for each group is given by a thick line, and the mean for each group is provided by diamonds. The P-value for the Mann–Whitney U-test is provided at the middle bottom of each graph and the P-value for the t-test is provided at the middle top of each graph.

Figure 4

The relationship between improvement ratings in verbal communication (a, b) and expressive language (c, d) and age for children with (b, d) and without (a, c) binding folate receptor autoantibody. (a, c) For children without the binding autoantibody, improvements in verbal communication and expressive language are higher for older children than for younger children. (b, d) For children with the binding autoantibody, improvements in verbal communication and expressive language are higher for younger children than for older children. Correlation coefficients are provided for the relationship between improvement and age for each graph; hence, the P-value for these correlations are not provided.