Cerebral folate deficiency and ASD

 

     Autism spectrum disorder (ASD) has been associated with abnormalities in folate metabolism. Cerebral folate deficiency (CFD) is defined as any neuropsychiatric or developmental disorder characterized by decreased 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF) in the presence of normal folate metabolism outside the nervous system. The main cause of FCD is the presence of autoantibodies to the folate receptor alpha (FRα) also known as FOLR1 or folate binding protein, impairing the transportof folate through the choroid plexus to the brain. These autoantibodies are highly prevalent in children with ASD. In some cases of FCD, mitochondrial diseases, inborn errors of metabolism and loss of functional mutations of the FRα gene (FOLR1) are identified. Vitamin D deficiency occurs commonly and will reduce expression of the RFC1 gene, which provides the alternative pathway for high plasma folate concentrations, allowing reduced folate (folinic acid) to bypass the blood-brain barriers. Therefore, it is essential to correct vitamin D deficiency in combination with folinic acid treatment for FCD. For an accurate diagnosis of FCD, it is necessary to measure MTHF in spinal fluid because blood folate and metabolite status do not reflect CNS folate deficiency. Folinic acid supplementation for FCD carriers during the preconception and gestational periods reduces the risk of developing ASD in their offspring.

    Studies show that soluble folate-binding proteins in milk can cross react withproblem even worse for kids with autism by further decreasing folate to thebrain. Conversely, studies show a dairy-free diet can reduce folate receptorautoimmunity in cerebral folate deficiency syndrome.

REFERENCE:

Ramaekers, V.T.; Quadros, E.V. Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies. Nutrients 2022, 14, 3096.

Ramaekers, V.T., Sequeira, J.M., Blau, N. and Quadros, E.V. (2008), A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Developmental Medicine & Child Neurology, 50: 346-352. https://doi.org/10.1111/j.1469- 8749.2008.02053.x

Richard E Frye, John C Slattery, and Edward V Quadros. Folate metabolism abnormalities in autism: potential biomarkers. Biomarkers in medicine 2017 11:8, 687-699.