Pérez-Dueñas et alArticle postulate that cerebral folate deficiency (CFD) may be amenable to therapeutic supplementation. Diverse metabolic pathways and unrelated processes can lead to cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) depletion, the hallmark of CFD. They set out to study the spectrum and frequency of disorders associated with CFD by measuring cerebrospinal fluid 5-MTHF, biogenic amines, and pterins in 134 individuals free of neurometabolic disease and in 584 patients with several diseases of the central nervous system. Direct sequencing of the FOLR1 transporter gene was also performed in some patients. They report that, of the 2 main forms of CFD identified, mild to moderate 5-MTHF deficiency was most commonly associated with disorders bearing no primary relation to folate metabolism, whereas profound 5-MTHF depletion was associated with specific mitochondrial disorders, metabolic and transporter defects, or cerebral degenerations. The results suggest that 5-MTHF can serve either as the hallmark of inborn disorders of folate transport and metabolism or, more frequently, as an indicator of neurologic dysfunction.