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neural tube defects

Wednesday 15 October 2003

Definition: Neural tube defects (NTDs) are a group of severe congenital abnormalities resulting from the failure of neurulation. The pattern of inheritance of these complex defects is multifactorial, making it difficult to identify the underlying causes.

Neural tube defects (NTDs) are a group of birth anomalies resulting from failure of fusion of the neural tube around the 28th day after conception, at a time when most women do not know they are pregnant.

NTDs are known to occur in 1 out every 1,000 pregnancies in the United States, with varying rates reported among the world’s populations [1]. The estimated recurrence risk in siblings is 2–5%, representing up a 50-fold increased risk over that observed in general population.

The most common NTDs is anencephaly, which results from failure of fusion of the cranial neural tube, and myelomeningocele (commonly called spina bifida), which results from the failure of fusion in the spinal region of the neural tube.

Failure of closure that involves the entire body axis is known as craniorachischisis, which is an additional, relatively rare, form of dysraphism.

Anencephaly and myelomeningocele are referred as “open” NTDs because the affected region is exposed to the body surface. There are also a number of closed or skin-covered conditions that involve the neural tube, including: encephalocele, meningocele, lipomeningocele, also referred to as spina bifida occulta, and sacral agenesis.

All infants with anencephaly are stillborn or die shortly after birth, whereas many infants with spina bifida survive, usually as a result of extensive medical and surgical care.

Crucial mechanisms of neurulation include the planar cell polarity pathway, which is essential for the initiation of neural tube closure, and the sonic hedgehog signaling pathway, which regulates neural plate bending.


- cranial NTDs

  • exencephaly
  • anencephaly
  • cranial meningocele/myelomeningocele
  • encephalocele (myeloencephalocele)
  • spinal meningocele

- spinal NTDs (spinal dysraphism)

  • spina bifida occulta
  • lumbra dermal sinus
  • spina bifida aperta (spina bifida cystica) +/- posterior meningocele or myelomeningocele
  • rachischisis
  • anterior meningocele/myelomeningocele
  • lateral meningocele/myelomeningocele
  • iniencephaly

- craniospinal NTDs

  • craniospinal rachischisis


- open NTDs (open dysraphisms)

  • anencephaly
  • myelomeningocele (spina bifida)
  • myeloschisis
  • hemimyelomeningocele
  • hemimyelocele
  • craniorachischis

- closed NTDs (closed dysraphisms or skin-covered NTDs)

  • lipomyeloschisis
  • lipomyelomeningocele
  • meningocele
  • myelocystocele

Etiological forms

- non-syndromal NTDs

  • non-syndromal sporadic NTDs
  • non-syndromal familial NTDs

- syndromal NTDs

- VANGL1-associated neural tube defects


Several open dysraphisms (including myeloschisis, hemimyelomeningocele, and hemimyelocele) are sometimes associated with a Chiari II malformation.

A number of skin-covered neural-tube defects (closed dysraphisms) are categorized clinically depending on the presence of a subcutaneous mass (lipomyeloschisis, lipomyelomeningocele, meningocele, and myelocystocele) or the absence of such a mass (complex dysraphic states, including split cord malformations, dermal sinus, caudal regression, and segmental spinal dysgenesis).


Population- and family-based studies indicate a complex multigenic cause of neural-tube defects. Only one causative gene (VANGL1) has been identified in humans.

Polymorphic variants in genes of the folate and homocysteine pathways have been associated with an increased risk of neural-tube defects, including a common variant (C677T) in the MTHFR gene (5,10-methylene tetrahydrofolate reductase).

Association studies conducted in NTDs suggest that variations in folate-related genes might increase the risk for NTDs through gene–gene and gene–environment interaction and via either the maternal or embryonic genotype. Additional studies are needed to further elucidate the role of folate pathway gene variants and their interaction with the environment in increasing the risk for NTDs.

- chromosomal anomalies

  • trisomy 13
  • trisomy 18
  • trisomy 21

- malformative syndromes

  • Meckel syndrome
  • Walker-Warburg syndrome

- associated malformations

- gene mutations

  • VANGL1 germline mutations (VANGL1-associated neural tube defects)(17409324)


Maternal periconceptional supplementation of folic acid reduces the incidence of neural-tube defects by 50 to 70%.

Animal models

Animal studies, conducted mainly in mouse models, represent a powerful tool for identifying genes involved in normal and abnormal neurulation. To date, as many as 190 naturally occurring or experimentally induced mouse mutants with NTDs have been described.

Identification and characterization of faulty genes in these mutants would present strong candidates that contribute to the human disease. These genes are involved in a wide range of functions at all steps of neurulation from neural induction to closure of the neural tube and a few are implicated in essential cellular functions such as genome stability and DNA repair.

Mutated Vangl2 is present in the Loop-tail (Lp) mouse mutant with a severe defect known as craniorachischisis.

  • Vangl2 is the mammalian homologue of the drosophila (fly) gene Stbm/Vang, which is required for establishing planar cell polarity in the developing eye, wing, and leg tissues.

VANGL1 mutations in humans underscore the critical role of core planar-cell-polarity genes (Vangl2, Celsr1, Dvl, and Fz) in controlling convergent extension, a process necessary for neural-tube closure.

Moreover, it was shown that mutations in Ptk7 interact genetically with Vangl2 in mice that are heterozygous for both mutations and consequently develop neural-tube defects.


- Kibar Z, Torban E, McDearmid JR, Reynolds A, Berghout J, Mathieu M, Kirillova I, De Marco P, Merello E, Hayes JM, Wallingford JB, Drapeau P, Capra V, Gros P. Mutations in VANGL1 associated with neural-tube defects. N Engl J Med. 2007 Apr 5;356(14):1432-7. PMID: 17409324

- De Marco P, Merello E, Mascelli S, Capra V. Current perspectives on the genetic causes of neural tube defects. Neurogenetics. 2006 Nov;7(4):201-21. PMID: 16941185

- Katsanis N. Ciliary proteins and exencephaly. Nat Genet. 2006 Feb;38(2):135-6. PMID: 16444248

- Zohn IE, Chesnutt CR, Niswander L. Cell polarity pathways converge and extend to regulate neural tube closure. Trends Cell Biol. 2003 Sep;13(9):451-4. PMID: 12946622

- Juriloff DM, Harris MJ. Mouse models for neural tube closure defects. Hum Mol Genet. 2000 Apr 12;9(6):993-1000. PMID: 10767323