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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.

SUBMITTER: Frye RE

PROVIDER: S-EPMC3578948 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency (CFD). CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid). One cause of CFD is an autoantibody that interferes with the function of the FRα. FRα autoantibodies (FRAAs) have been reported in ASD. A systematic review was performed to identify studies reporting FRAAs in association with ASD, or the use of d,l-leucovorin in the treatment of ASD. A meta-analysis examined the prevalence of FRAAs in ASD. The pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38% (with a significant variation across studies due to heterogeneity). The etiology of CFD in ASD was attributed to FRAAs in 83% of the cases (with consistency across studies) and mitochondrial dysfunction in 43%. A significant inverse correlation was found between higher FRAA serum titers and lower 5-MTHF CSF concentrations in two studies. The prevalence of FRAA in ASD was 71% without significant variation across studies. Children with ASD were 19.03-fold more likely to be positive for a FRAA compared to typically developing children without an ASD sibling. For individuals with ASD and CFD, meta-analysis also found improvements with d,l-leucovorin in overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%). Twenty-one studies (including four placebo-controlled and three prospective, controlled) treated individuals with ASD using d,l-leucovorin. d,l-Leucovorin was found to significantly improve communication with medium-to-large effect sizes and have a positive effect on core ASD symptoms and associated behaviors (attention and stereotypy) in individual studies with large effect sizes. 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%). Taken together, d,l-leucovorin is associated with improvements in core and associated symptoms of ASD and appears safe and generally well-tolerated, with the strongest evidence coming from the blinded, placebo-controlled studies. Further studies would be helpful to confirm and expand on these findings.

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Cerebral folate receptor autoantibodies in autism spectrum disorder.

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