Neural Tube Defects: Genetics, Environment, and the Critical Role of Folate

Abstract

Neural tube defects (NTDs) are serious congenital malformations caused by defective neural tube closure during embryogenesis. Genetic and environmental factors play a role in the etiology of NTDs, highlighting the significance of gene-gene and gene-environment interactions in their occurrence and recurrence risk. Multiple genetic researches in humans and animal models have also pointed out the functions of aberrant genes in the developmental vulnerability of NTDs, with implications for cellular and morphological events in embryogenesis. Other than genetic factors, non-genetic factors such as maternal nutrition, environmental pollutants, and folic acid deficiency also play important roles in NTD risk. Significantly, folate supplementation has long been known for its preventive effects, although mechanisms are still the subject of active research. In this review, current knowledge of the genetic and non-genetic factors influencing NTDs, including major signaling pathways, adhesion molecules, and the involvement of folate in neural tube closure, are brought together. Knowledge of these mechanisms is important for the planning of effective prevention and treatment approaches to reduce the global burden of NTDs.

Introduction

Neural tube defects (NTDs) are among the most prevalent congenital malformations of the central nervous system, occurring in about 1 in 1,000 live births globally. NTDs are caused by the defective closure of the neural tube during early embryogenesis, which leads to anencephaly, spina bifida, and encephalocele. NTDs are caused by a combination of genetic predispositions and environmental factors.

Comprehending the intricate interplay of genetic and non-genetic elements is important in deciphering the pathogenesis of NTDs and establishing targeted preventive interventions. The current review delves into the genetic basis, gene-environment interaction, and protective effect of folate during neural tube formation.

Genetic Factors in Neural Tube Defects

1. Key Genetic Pathways Involved in Neural Tube Development

Genetic studies have identified several key pathways essential for proper neural tube closure. These include:

• Wnt Signaling Pathway: Plays a critical role in regulating cell proliferation and differentiation during neural tube formation. Mutations in Wnt genes have been linked to NTDs.

• Sonic Hedgehog (Shh) Pathway: Important for dorsal-ventral patterning in neural tube closure, with mutations in Shh-related genes contributing to NTDs.

• Bone Morphogenetic Protein (BMP) Pathway: Involved in neural crest differentiation, and disruptions in BMP signaling can lead to defective neural tube closure.

• Planar Cell Polarity (PCP) Pathway: Regulates the coordinated movements of cells necessary for neural tube closure. Mutations in PCP genes such as VANGL1 and CELSR1 have been implicated in NTDs.

2. Candidate Genes Associated with NTDs

Several genes have been identified in association with NTDs, including:

• MTHFR (Methylenetetrahydrofolate Reductase): Plays a role in folate metabolism, and polymorphisms in MTHFR (such as C677T and A1298C) are linked to an increased risk of NTDs.

• PAX3: Important for neural crest cell development, with mutations resulting in spina bifida and other NTDs.

• GRHL3: Regulates neural tube closure, and mutations have been reported in human NTD cases.

• SHROOM3: Involved in cytoskeletal remodeling, essential for neural fold fusion.

Gene-Environment Interactions in NTDs

1. Maternal Nutrition and Folate Deficiency

One of the most firmly established environmental risk factors for NTDs is maternal folate deficiency. Folate is important in DNA synthesis, repair, and methylation. Inadequate folic acid levels during early pregnancy cause defective closure of the neural tube, resulting in NTDs. Genetic polymorphisms, including those in MTHFR, enhance this risk by impairing folate metabolism.

2. Environmental Toxins and Teratogens

Exposure to certain environmental agents increases the likelihood of NTDs. These include:

• Heavy Metals (e.g., Lead, Arsenic): Disrupt normal embryonic development and increase oxidative stress.

• Medications (e.g., Valproic Acid, Retinoids): Known teratogens that interfere with folate metabolism and neural tube closure.

• Maternal Hyperthermia: Increased core body temperature during early pregnancy (e.g., due to fever or excessive sauna use) has been linked to NTDs.

3. Epigenetic Modifications

Epigenetic changes, such as DNA methylation and histone modifications, influence gene expression without altering the DNA sequence. Abnormal epigenetic regulation has been implicated in NTDs, particularly in genes associated with neural tube closure.

Folate and its Role in Preventing NTDs

1. Mechanisms of Folate Action

Folate is essential for cellular division and DNA methylation, both critical for embryonic development. The primary mechanisms through which folate prevents NTDs include:

• Providing Methyl Donors for DNA and RNA Synthesis: Essential for proper neural tube development.

• Regulating Homocysteine Levels: Elevated homocysteine levels, due to folate deficiency, are associated with increased NTD risk.

• Enhancing Cell Proliferation and Differentiation: Required for neural crest cell migration and closure of the neural tube.

2. Evidence from Epidemiological Studies

Studies have demonstrated a significant reduction in NTD incidence following mandatory folic acid fortification programs worldwide.

• United States and Canada: After folic acid fortification, NTD rates declined by 20-50%.

• China and Europe: Supplementation programs showed similar declines, reinforcing the protective role of folate.

3. Recommended Folate Intake

The CDC and WHO recommend that women of reproductive age consume at least 400 micrograms of folic acid daily to reduce NTD risk. Women with a history of NTD-affected pregnancies are advised to take higher doses (4 mg daily).

Cell Adhesion Molecules (CAMs) and Neural Tube Closure

Cell adhesion molecules play a crucial role in neural tube development by facilitating cellular interactions necessary for tube closure.

• Cadherins (e.g., N-Cadherin, E-Cadherin): Mediate cell-cell adhesion in neuroepithelial tissues.

• Integrins: Regulate cell-extracellular matrix interactions essential for tissue remodeling.

• Neural Cell Adhesion Molecule (NCAM): Implicated in neurodevelopmental processes, with mutations contributing to NTDs.

Mutations or dysregulation in these adhesion molecules disrupt normal neural tube fusion, leading to congenital defects.

Conclusion

Neural tube defects result from a multifaceted interaction between genetic, epigenetic, and environmental determinants. Genetic signaling pathways like Wnt, Shh, BMP, and PCP are crucial to neural tube closure, and maternal nutrition, specifically folate consumption, plays a significant role in modulating the susceptibility to NTDs. Gene-environment interactions, such as those of folate metabolic genes like MTHFR, highlight the importance of individualized prevention. Discovery of the molecular mechanisms of neural tube closure will lead to novel interventions and enhanced public health measures for lessening the load of NTDs globally.

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