Affiliations: Rossignol Medical Center, Irvine, CA, USA | Arkansas Children's Hospital Research Institute,
Department of Pediatrics, University of Arkansas for Medical Sciences, Little
Rock, AR, USA
Note: [] Corresponding author: Daniel A. Rossignol, Rossignol Medical
Center, 16251 Laguna Canyon Road Suite 175, Irvine, CA 92618, USA. Tel.: +1 949
428 8878; E-mail: [email protected]
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.
