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Key Points

  • Disease summary:

    • Neural tube defects (NTDs) occur in 0.5 to 2/1000 pregnancies worldwide and are the second most common birth defect after congenital heart defects.

    • The neural tube is an embryonic structure that forms from the folding of ectodermal tissue to into a hollow canal. The floor of this canal (neural plate) combined with migrating neural crest cells will give rise to the major structures of the central nervous system.

    • In humans, the cranial and caudal ends of the tube are the last regions to close. Closure of the neural tube is completed within 5 weeks of fertilization.

    • When the neural tube fails to close, the subsequent development of all underlying structures is disrupted. Lack of closure in the cranial region results in failure of the brain to develop (anencephaly). Lack of closure in the caudal region produces damage to the spinal cord (spina bifida; most commonly myelomeningocele, but also includes meningocele and lipomeningocele).

    • Other forms of NTDs include encephalocele, craniorachischisis, and iniencephaly.

  • Differential diagnosis:

    • None.

  • Monogenic forms:

    • NTDs are a feature of several rare inherited syndromes (most notably, Meckel-Gruber syndrome). The vast majority of NTDs occur as isolated defects. Isolated NTDs exhibit hallmarks of a complex disease with multiple environmental and genetic factors.

  • Family history:

    • The risk to siblings is approximately 2% to 5%.

  • Twin studies:

    • In one study, NTD twin concordance was more frequent in monozygotic twins than in dizygotic twins.

  • Environmental factors:

    • Lower levels of folate are observed in mothers with an NTD pregnancy, and periconceptional folic acid supplementation can reduce the risk of an NTD pregnancy by up to 75%. Other risk factors include maternal use of valproic acid (a folate antagonist used to manage migraines, epilepsy, and bipolar disorder), maternal diabetes, and maternal obesity. Antifolate compounds such as methotrexate are known as teratogens. Use of antifolates during pregnancy is contraindicated but exposure to methotrexate during pregnancy has not been associated with NTDs.

  • Genome-wide associations:

    • The research community is forming a consortium to perform a GWAS of NTDs.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria for Neural Tube Defects

Diagnostic evaluation should include at least one of the following

  • Spina bifida occulta (closed defect): The posterior elements of the vertebral arch fail to close. There is an absence of a sac of neural tissue protruding from the back. This defect may or may not include an affected spinal cord. If not, it often goes undetected. Asymptomatic spina bifida occulta is an incidental finding arising from lower back imaging studies.

  • Spina bifida cystica (open defect): Myelomeningocele is the most common and severe subtype. It involves protrusion of the spinal cord, nerve roots, meninges, and cerebrospinal fluid (CSF). Most lesions are lumbar, and higher lesions are associated with more severe clinical outcomes.

  • Anencephaly (open defect): Failure of the neural tube to close at the cranial end results in failure of the brain ...

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