Overview
This lecture discusses the genetic and environmental causes of neural tube defects (NTDs), focusing on the role of folate metabolism, epigenetic regulation, and epidemiologic evidence for folate dose-dependency in NTD prevention.
Causes of Neural Tube Defects (NTDs)
- NTDs have both genetic and environmental (epigenetic) risk factors.
- Genetic mutations and environmental influences impact neural tube closure during embryonic development.
- Many NTDs involve defects in the folate metabolic pathway.
Folate Pathway and Its Importance
- Folate is essential for the synthesis of purines and pyrimidines, the building blocks of nucleotides.
- Folate provides methyl groups needed for methylation of DNA and other macromolecules.
- DNA methylation, influenced by folate, regulates gene expression critical to neural tube formation.
Molecular Pathways Linked to NTDs
- The planar cell polarity pathway (studied in mice) is crucial for proper folic acid metabolism and neural tube closure.
- Transmembrane and cytosolic proteins facilitate normal folic acid metabolism in embryonic cells.
- Failure of neuroectoderm and cutaneous ectoderm dissociation leads to NTDs, usually around day 25–26 of embryonic development.
Epidemiological Evidence: Folate and NTD Risk
- Studies show a dose-dependent relationship between maternal red blood cell folate levels and NTD incidence.
- Higher maternal folate levels correspond to lower rates of NTDs in offspring.
- Krista Kreider (CDC) conducted large population studies in Asia demonstrating this linear relationship.
Key Terms & Definitions
- Neural Tube Defect (NTD) — Birth defect arising from incomplete closure of the neural tube during embryogenesis.
- Folate — A B-vitamin (B9) vital for DNA synthesis and methylation processes.
- Methylation — Addition of a methyl group to DNA or other molecules, affecting gene regulation.
- Planar Cell Polarity Pathway — A molecular signaling pathway involved in coordinating cell orientation and folic acid metabolism.
- Dose Dependency — The relationship where the effect changes as the dose of a substance (e.g., folate) increases or decreases.
Action Items / Next Steps
- Review embryology of neural tube formation and failure points.
- Study the folate metabolic pathway and its role in DNA synthesis.
- Read Krista Kreider’s epidemiologic paper on maternal folate and NTD risk.