Cerebral Folate Deficiency Syndromes in Childhood

Abstract

Folate is a B vitamin essential for brain metabolism. It participates in the de novo synthesis of purines and thymidine and, together with cobalamin, represents an important cofactor for homocysteine remethylation and S-adenosylmethionine production by the brain. As with other vitamin deficiency states, folate deficiency may be the consequence of acquired or inherited disorders. Several inborn errors of metabolism can lead to defective folate transport or impaired metabolism, resulting in systemic folate deficiency and, obligatorily, 5-methyltetrahydrofolate (5-MTHF) depletion in the nervous system detectable by assay of cerebrospinal fluid (CSF) levels.¹ Cerebral folate deficiency (CFD), however, is characterized by decreased concentrations of 5-MTHF in the CSF in the context of normal systemic folate metabolism.² The principal mechanistic hypothesis put forth for this condition implies defective transport of folate across the blood-CSF or blood-brain barriers.^3,4 Indeed, mutations in the FOLR1 gene (OMIM 136430), encoding the folate receptor α (FRα), can cause brain-specific folate transport deficiency leading to neurodegeneration in early childhood.⁵ In other patients with CFD, blocking autoantibodies against FRs may also play a pathogenic role.⁴