Cellular and Physiological Nutrition/Metabolism
Clinical and Translational Nutrition
Joanna Fiddler, PhD (she/her/hers)
Assistant Professor
University of Arkansas
Fayetteville, Arkansas, United States
Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.
Eric Ciappio, PhD, RD (he/him/his)
Nutrition Science
Balchem Human Nutrition & Health
Surfside Beach, South Carolina, United States
Disclosure(s): Balchem: Employee (Ongoing); Stock Shareholder (excluding mutual funds) (Ongoing)
Martha Field, PhD (she/her/hers)
Associate Professor
Nutritional Sciences
Cornell University
Ithaca, New York, United States
Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.
Kevin Klatt, PhD, RD (he/him/his)
Assistant Professor
University of Toronto
Toronto, Ontario, Canada
Disclosure(s): American Society for Nutrition (ASN): Advisory Committee/Board Member (Ongoing)
Gates Foundation: Consultant (Ongoing)
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition characterized by a broad range of behavioral and cognitive features, with contributions from both genetic and environmental factors. Folate is an essential micronutrient needed for neurodevelopment. Inadequate maternal folate during pregnancy is a well-established risk factor for neural tube defects, and folate's central role in one-carbon metabolism, DNA synthesis, and methylation underscores its importance in brain development more broadly. Emerging evidence suggests that abnormalities in folate transport, particularly involving folate receptor alpha (FRa) autoantibodies, may contribute to reduced cerebral folate availability in a subset of individuals with ASD. Folinic acid (leucovorin), a reduced form of folate that bypasses some transport barriers, is currently approved as a treatment for the reduction of side effects from high-dose chemotherapy with methotrexate. The rationale for leucovorin use as a treatment for ASD stems from its ability to restore folate-dependent metabolic pathways, potentially improving methylation, neurotransmitter synthesis, and mitochondrial function. Small clinical studies and open-label trials have suggested improvements in language, social communication, and adaptive behaviors with leucovorin supplementation. However, larger randomized controlled trials are limited, and results remain inconsistent, leaving uncertainty about the generalizability and robustness of these findings.