Medical treatment of autism spectrum disorder in children: Current evidence, controversies, and clinical challenges

Figure 3 Folate transport and metabolism pathway targeted by folinic acid in autism spectrum disorder. This figure illustrates the biological mechanism underlying cerebral folate deficiency in a subset of children with autism spectrum disorder. It provides the mechanistic rationale for targeted treatment with high-dose folinic acid (leucovorin). Under normal conditions, active folate (5-methyltetrahydrofolate) is transported across the blood-brain barrier by the folate receptor alpha. In children with cerebral folate deficiency, circulating folate receptor alpha autoantibodies bind and block the folate receptor alpha receptor, impairing folate transport into the central nervous system despite normal peripheral serum folate levels. This blockade reduces cerebral folate availability and disrupts downstream metabolism in the folate cycle. Folinic acid, a reduced folate derivative, bypasses the folate receptor alpha-dependent transport mechanism because it can enter the brain via alternative, non-folate receptor alpha transporters. Once inside the central nervous system, folinic acid is converted to 5-methyltetrahydrofolate, restoring folate cycle function and improving neurological and behavioral outcomes in biomarker-positive children. This figure highlights the translational precision-medicine link, showing that folate receptor alpha autoantibodies are predictive biomarkers of clinical responsiveness to folinic acid therapy. 5-MTHF: 5-methyltetrahydrofolate.