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Grant Abstract: Folic Acid Prevention Pathways for ASD in High Risk Families

Grant Number: 5R01ES025574-04
PI Name: Schmidt
Project Title: Folic Acid Prevention Pathways for ASD in High Risk Families

Abstract: Autism spectrum disorders (ASD) are a growing concern, with more than 1 in every 68 children affected in the US by the age of eight years. Complex interactions between genes and environmental factors are thought to contribute to ASD risk. Evidence is accumulating for a potentially large role in ASD etiology and symptom severity for the early in-utero environment, including gestational nutrition. Maternal folic acid is one of the first modifiable factors identified to date with the potential to reduce the incidence of ASD by ~40%. In addition to being essential for neurodevelopment, folate is critical for preventing apoptosis, and is involved in nuclear and mitochondrial DNA synthesis and repair. Folic acid is associated with reduced ASD risk at a time in early pregnancy when impaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment. In addition, our work was first to show that children with ASD are more likely to have mitochondrial dysfunction (MD), mtDNA overreplication, and mtDNA deletions than typically developing children (TD). To this end, we propose to extend the current R01ES025574, “Folic Acid Prevention Pathways for ASD in High Risk Families,” and leverage data and samples from mother-child pairs in a large NIH-funded cohort study to examine critical steps within the folate pathway against deficits in bioenergetics and DNA damage in lymphoblasts from children with ASD and in placenta samples from Markers of Autism Risk in Babies: Learning Early Signs (MARBLES) mothers as a potential pathway for ASD prevention through maternal supplemental folic acid intake. Delivery biospecimens have been obtained from the MARBLES study of ~350 mothers who have a child with confirmed ASD and became pregnant with another child who is then followed until 36 months when they are clinically assessed, in order to understand what influences the neurodevelopmental outcome of the younger sibling and to identify early markers of ASD. This is a significant advantage given that samples and data on demographic, lifestyle, health, interpregnancy interval, dietary, and other potentially relevant factors have been prospectively collected in this study since 2006. By following up two different lines of research that pointed towards a deficit of mitochondrial methenyltetrahydrofolate cyclohydrolase (MTHFD2), we aim to explore mitochondrial mechanisms behind the potential protection observed in epidemiological ASD studies in order to identify biomarkers of folate insufficiencies and ASD.

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