Clinical signs and treatment of cerebral folate transport deficiency, a novel inherited disorder of folate metabolism

Background: Folates are essential cofactors for important metabolic pathways such as synthesis of amino acids, DNA and lipophilic substances. The main folate compound 5-methyltetrahydofolate (5MTHF) is actively transported across the blood- cerebrospinal fluid (CSF)-barrier to supply the brain. Cellular uptake of folates is mediated by the proton-coupled intestinal transporter, the reduced folate carrier, and by two GPI-anchored receptors, folate receptor α (FRa) and β (FRa). At least five distinct inherited disorders of folate transport and metabolism are presently. An inherited disorder of folate transport into brain has not been described yet.

Methods: We studied a group of pediatric patients with progressive movement disturbance, psychomotor decline and epilepsy as well as severely reduced folate concentrations in the CSF. Brain MRI showed profound hypomyelination and in vivo MR spectroscopy a combined loss of white matter choline and inositol. A candidate gene approach was used to identify the primary genetic defect and was confirmed by rescue of folate binding by retroviral gene transfer into patient cells.

Results: In three patients we identified mutations in the FOLR1 gene coding for the FRa to cause an autosomal-recessive inherited, brain-specific folate transport defect. Folinic acid therapy could restore CSF folate concentrations, reverse white matter choline and inositol depletion and consecutively improve clinical symptoms.

Conclusions: Mutations in the FOLR1 gene coding for FRa are responsible for inherited cerebral folate transport deficiency with manifestation in early childhood. Our results characterize a novel severe, but treatable neurodegenerative disorder and provide new insights into the folate metabolic pathways involved in myelin formation and human brain function.