Folate receptor alpha autoimmunity and cerebral folate deficiency in autism spectrum disorders

Abstract

Cerebral folate deficiency (CFD) is a neurometabolic syndrome characterized by low levels of 5-methyltetrahydrofolate (5MTHF) in the brain despite normal systemic folate levels. Notably, CFD represents one of a few progressive neurological disorders that is treatable and potentially reversible. One common cause of CFD is an autoantibody that binds to the folate receptor-α (FRα) making it non-functional and blocking the transportation of 5MTHF from the blood into the central nervous system. Cow's milk contains soluble FRα antigen, which is 91% similar to human FRα. Autoantibodies to the FRα cross-react with the soluble FRα antigen in cow's milk, increasing the concentration of autoantibodies and resulting in worsen of CFD, while elimination of cow's milk lowers the autoantibody concentration and improves CFD symptoms. Notably, some cases of CFD are due to mitochondrial disease (MD). To date, three studies have reported an association between CFD and Rett syndrome, seven studies have reported that CFD is associated with autism spectrum disorders (ASD) in some children, and five studies have reported FRα autoantibodies in children with ASD, some of whom also had CFD. One study of 93 children with ASD reported that FRα autoantibodies were found in 75.3%. From these studies of children with concomitant ASD and CFD, treatment with oral folinic acid (leucovorin, 0.5 to 2 mg/kg/day) resulted in various improvements ranging from partial improvements in communication, social interaction, attention and stereotypical behavior to complete recovery of both neurological and ASD symptoms. Notably, an overlap between ASD, MD and CFD is found in some children with ASD, and therefore we recommend testing for MD and CFD/FRα autoantibodies in all individuals with ASD. Further studies examining FRα autoantibodies and CFD in children with ASD are warranted.