The Continuing Challenge of Understanding, Preventing, and Treating Neural Tube Defects

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Science  01 Mar 2013:
Vol. 339, Issue 6123, 1222002
DOI: 10.1126/science.1222002

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Structured Abstract


Neural tube defects (NTDs) are debilitating birth defects involving the central nervous system (CNS). Despite recent advances, NTDs represent the second most common group of human birth defects. These defects arise when the complex process of early CNS development goes awry. Normally, the brain and the spinal cord begin to form as a flat sheet of cells that rolls up and closes to form a hollow neural tube. Failure in this rolling and sealing process results in an NTD, such as spina bifida. From animal models, we know of over 200 genes that regulate this process, with many more still likely to be discovered. Environmental factors also can have a profound influence on neural tube closure, as evidenced by the impact of folic acid on NTD prevalence. However, the mechanisms by which environmental factors affect the process of neural tube closure and their critical interaction with genetic factors remain largely a mystery.

Embedded Image

Successive images showing the progression of neural tube closure in a stylized vertebrate embryo. Initially, the CNS is a flat sheet; paired neural folds elevate along the rostrocaudal axis (rostral = up) and move medially, eventually fusing to enclose the neural tube. Disruption of this process during human embryogenesis results in neural defects, such as spina bifida.


Three major advances from three different directions—genetics, epidemiology, and surgery—have advanced understanding, prevention, and treatment of NTDs. The rapidly expanding knowledge of the genetic causes of NTDs in animal models is poised to inform high-throughput whole-genome studies of human patients. Epidemiological studies have led to the identification of folic acid as a primary prevention strategy for NTDs. Recent advances in in utero surgical repair of spinal NTDs have improved the clinical outcome by comparison with postnatal surgery.


Despite the advances, NTDs remain a very common birth defect and, even with surgical intervention, result in enormous clinical, emotional, financial, and societal costs. The implementation of large-scale genomic studies of human NTD patients is expected to move the field beyond its current focus on individual genetic pathways. Experimental animal systems can complement and extend the information that flows from genomic studies, and animal models can also be exploited to understand the mechanisms by which environmental factors alter the risk for NTDs. The technology exists to create patient-derived stem cells, which may hold a key for understanding this very early developmental process in humans and could provide a platform for screening therapeutic agents. Overall, the key challenge will be to understand the developing neural tube, a complex three-dimensional structure that changes rapidly over time and is dependent on the surrounding tissues for developmental signals and biomechanical forces to drive the dynamic and important process of neural tube closure.

Prevention or Repair

Neural tube defects, such as spina bifida, remain remarkably common, despite widespread efforts to prevent them through supplementing maternal diets with folic acid. Surgery early in development has seen some success, but problems often remain. Wallingford et al. (10.1126/science.1222002) review normal and abnormal neural tube development and suggest that discovering the genetic risk factors for these serious birth defects could provide ways to prevent and treat neural tube defects.


Human birth defects are a major public health burden: The Center for Disease Control estimates that 1 of every 33 United States newborns presents with a birth defect, and worldwide the estimate approaches 6% of all births. Among the most common and debilitating of human birth defects are those affecting the formation of the neural tube, the precursor to the central nervous system. Neural tube defects (NTDs) arise from a complex combination of genetic and environmental interactions. Although substantial advances have been made in the prevention and treatment of these malformations, NTDs remain a substantial public health problem, and we are only now beginning to understand their etiology. Here, we review the process of neural tube development and how defects in this process lead to NTDs, both in humans and in the animal models that serve to inform our understanding of these processes. The insights we are gaining will help generate new intervention strategies to tackle the clinical challenges and to alleviate the personal and societal burdens that accompany these defects.

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