Neural Tube Defects: Genetics

Abstract

Neural tube defects (NTDs) are malformations of the brain and the spinal cord, resulting from lack of closure of the developing neural tube during embryological development. NTDs are complex birth disorders with a worldwide prevalence from 0.5 to 2.0 per 1000 births. The two most common types of NTD are anencephaly and spina bifida, which involve failure of neural tube closure in the cranial and in the back regions respectively. NTDs are hypothesised to be a result of genetic abnormalities and environmental factors; yet, the aetiology remains undetermined. Research studies over the past decade have indicated that maternal folate deficiency is an extremely important risk factor for an NTD birth, with maternal folate supplementation decreasing risk. However, the role that folate plays in NTD risk is not well defined.

Key Concepts:

  • Neural tube defects (NTDs) are congenital malformations of the brain and spinal cord.

  • The prevalence rates of NTDs vary worldwide.

  • NTDs are complex birth defects composed of both genetic and environmental components.

  • The underlying mechanism remains undetermined.

  • NTDs are classified by whether they are open or closed and by the location of the lesion.

  • Folic acid supplementation ameliorates NTD risk.

  • The majority of NTDs are sporadic and nonsyndromic.

  • To date, association studies in relatively small patient cohorts have been used in an attempt to find causative genes.

  • Future additional approaches will include Genome‐Wide Association Study (GWAS) and high‐throughput sequencing.

Keywords: genetics; neural tube defects; complex disorder; folic acid; candidate genes

References

Alwan S, Reefhuis J, Rasmussen SA, Olney RS and Friedman JM (2007) Use of selective serotonin‐reuptake inhibitors in pregnancy and the risk of birth defects. New England Journal of Medicine 356(26): 2684–2692.

Aqrabawi HE (2005) Incidence of neural tube defects among neonates at King Hussein Medical Centre, Jordan. Eastern Mediterranean Health Journal 11(4): 819–823.

Au KS, Ashley‐Koch A and Northrup H (2010) Epidemiologic and genetic aspects of spina bifida and other neural tube defects. Developmental Disabilities Research Reviews 16(1): 6–15.

Bassuk AG and Kibar Z (2009) Genetic basis of neural tube defects. Seminars in Pediatric Neurology 16(3): 101–110.

Bell KN and Oakley GP Jr (2009) Update on prevention of folic acid‐preventable spina bifida and anencephaly. Birth Defects Research. Part A, Clinical and Molecular Teratology 85(1): 102–107.

Berry RJ, Li Z, Erickson JD et al. (1999) Prevention of neural‐tube defects with folic acid in China. China‐U.S. Collaborative Project for Neural Tube Defect Prevention. New England Journal of Medicine 341(20): 1485–1490.

Blencowe H, Cousens S, Modell B and Lawn J (2010) Folic acid to reduce neonatal mortality from neural tube disorders. International Journal of Epidemiology 39(suppl. 1): i110–i121.

Botto LD, May K, Fernhoff PM et al. (2003) A population‐based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112(1 part 1): 101–107.

Botto LD, Moore CA, Khoury MJ and Erickson JD (1999) Neural‐tube defects. New England Journal of Medicine 341(20): 1509–1519.

Boulet SL, Yang Q, Mai C et al. (2008) Trends in the postfortification prevalence of spina bifida and anencephaly in the United States. Birth Defects Research. Part A, Clinical and Molecular Teratology 82(7): 527–532.

Brough L, Rees GA, Crawford MA and Dorman EK (2009) Social and ethnic differences in folic acid use preconception and during early pregnancy in the UK: effect on maternal folate status. Journal of Human Nutrition and Dietetics 22(2): 100–107.

Canfield MA, Ramadhani TA, Shaw GM et al. (2009) Anencephaly and spina bifida among Hispanics: maternal, sociodemographic, and acculturation factors in the National Birth Defects Prevention Study. Birth Defects Research. Part A, Clinical and Molecular Teratology 85(7): 637–646.

Chen X and Brodland GW (2008) Multi‐scale finite element modeling allows the mechanics of amphibian neurulation to be elucidated. Physical Biology 5(1): 015003.

Cherian A, Seena S, Bullock RK and Antony AC (2005) Incidence of neural tube defects in the least‐developed area of India: a population‐based study. Lancet 366(9489): 930–931.

Christensen B, Arbour L, Tran P et al. (1999) Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. American Journal of Medical Genetics 84(2): 151–157.

Copp AJ and Greene ND (2010) Genetics and development of neural tube defects. Journal of Pathology 220(2): 217–230.

Crider KS, Cleves MA, Reefhuis J et al. (2009) Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Archives of Pediatrics & Adolescent Medicine 163(11): 978–985.

Detrait ER, George TM, Etchevers HC et al. (2005) Human neural tube defects: developmental biology, epidemiology, and genetics. Neurotoxicology and Teratology 27(3): 515–524.

Edwards JH (1969) Inheritance of chronic granulomatous disease. Lancet 2(7625): 850–851.

Fletcher JM, Copeland K, Frederick JA et al. (2005) Spinal lesion level in spina bifida: a source of neural and cognitive heterogeneity. Journal of Neurosurgery 102(3 suppl.): 268–279.

Forrester S, Kovach MJ, Smith RE et al. (2002) Kousseff syndrome caused by deletion of chromosome 22q11‐13. American Journal of Medical Genetics 112(4): 338–342.

Gelineau‐van Waes J, Starr L, Maddox J et al. (2005) Maternal fumonisin exposure and risk for neural tube defects: mechanisms in an in vivo mouse model. Birth Defects Research. Part A, Clinical and Molecular Teratology 73(7): 487–497.

Greene ND and Copp AJ (2009) Development of the vertebrate central nervous system: formation of the neural tube. Prenatal Diagnosis 29(4): 303–311.

Greene ND, Stanier P and Copp AJ (2009) Genetics of human neural tube defects. Human Molecular Genetics 18(R2): R113–129.

Grewal J, Carmichael SL, Song J and Shaw GM (2009) Neural tube defects: an analysis of neighbourhood‐ and individual‐level socio‐economic characteristics. Paediatric and Perinatal Epidemiology 23(2): 116–124.

Harris MJ (2009) Insights into prevention of human neural tube defects by folic acid arising from consideration of mouse mutants. Birth Defects Research. Part A, Clinical and Molecular Teratology 85(4): 331–339.

Harris MJ and Juriloff DM (2010) An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure. Birth Defects Research. Part A, Clinical and Molecular Teratology 88(8): 653–669.

Hendricks K (1999) Fumonisins and neural tube defects in South Texas. Epidemiology 10(2): 198–200.

Li R, Chase M, Jung SK, Smith PJ and Loeken MR (2005) Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress. American Journal of Physiology. Endocrinology and Metabolism 289(4): E591–599.

Loeken MR (2005) Current perspectives on the causes of neural tube defects resulting from diabetic pregnancy. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 135C(1): 77–87.

Marasas WF, Riley RT, Hendricks KA et al. (2004) Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among populations consuming fumonisin‐contaminated maize. Journal of Nutrition 134(4): 711–716.

Martin RA, Fineman RM and Jorde LB (1983) Phenotypic heterogeneity in neural tube defects: a clue to causal heterogeneity. American Journal of Medical Genetics 16(4): 519–525.

Martínez‐Frías ML, Bermejo E, Rodríguez‐Pinilla E, Prieto L and Frías JL (1998) Epidemiological analysis of outcomes of pregnancy in gestational diabetic mothers. American Journal of Medical Genetics 78(2): 140–145.

Matok I, Gorodischer R, Koren G et al. (2009) Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations. British Journal of Clinical Pharmacology 68(6): 956–962.

Moretti ME, Bar‐Oz B, Fried S and Koren G (2005) Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta‐analysis. Epidemiology 16(2): 216–219.

Nickel RE, Pillers DA, Merkens M et al. (1994) Velo‐cardio‐facial syndrome and DiGeorge sequence with meningomyelocele and deletions of the 22q11 region. American Journal of Medical Genetics 52(4): 445–449.

O'Leary VB, Mills JL, Parle‐McDermott A et al. (2005) Screening for new MTHFR polymorphisms and NTD risk. American Journal of Medical Genetics. Part A 138A(2): 99–106.

O'Rahilly R and Muller F (2002) The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology 65(4): 162–170.

O'Reilly GC and Shields LE (2000) Karyotyping for isolated neural tube defects. A report of two cases. Journal of Reproductive Medicine 45(11): 950–952.

van der Put NM, van den Heuvel LP, Steegers‐Theunissen RP et al. (1996) Decreased methylene tetrahydrofolate reductase activity due to the 677C→T mutation in families with spina bifida offspring. Journal of Molecular Medicine 74(11): 691–694.

Rasmussen SA, Chu SY, Kim SY, Schmid CH and Lau J (2008) Maternal obesity and risk of neural tube defects: a metaanalysis. American Journal of Obstetrics and Gynecology 198(6): 611–619.

Ray JG, Wyatt PR, Vermeulen MJ, Meier C and Cole DE (2005) Greater maternal weight and the ongoing risk of neural tube defects after folic acid flour fortification. Obstetrics and Gynecology 105(2): 261–265.

Sadler TW, Merrill AH, Stevens VL et al. (2002) Prevention of fumonisin B1‐induced neural tube defects by folic acid. Teratology 66(4): 169–176.

Saitsu H, Yamada S, Uwabe C, Ishibashi M and Shiota K (2004) Development of the posterior neural tube in human embryos. Anatomy and Embryology 209(2): 107–117.

Shaw GM, Lu W, Zhu H et al. (2009) 118 SNPs of folate‐related genes and risks of spina bifida and conotruncal heart defects. BMC Medical Genetics 10: 49.

Shaw GM, Todoroff K, Velie EM and Lammer EJ (1998) Maternal illness, including fever and medication use as risk factors for neural tube defects. Teratology 57(1): 1–7.

Shurtleff DB (2004) Epidemiology of neural tube defects and folic acid. Cerebrospinal Fluid Research 1(1): 5.

Vieira AR and Castillo Taucher S (2005) [Maternal age and neural tube defects: evidence for a greater effect in spina bifida than in anencephaly]. Revista médica de Chile 133(1): 62–70.

Volcik KA, Blanton SH, Tyerman GH et al. (2000) Methylenetetrahydrofolate reductase and spina bifida: evaluation of level of defect and maternal genotypic risk in Hispanics. American Journal of Medical Genetics 95(1): 21–27.

Williams LJ, Rasmussen SA, Flores A, Kirby RS and Edmonds LD (2005) Decline in the prevalence of spina bifida and anencephaly by race/ethnicity: 1995–2002. Pediatrics 116(3): 580–586.

Yazdy MM, Liu S, Mitchell AA and Werler MM (2010) Maternal dietary glycemic intake and the risk of neural tube defects. American Journal of Epidemiology 171(4): 407–414.

Yerby MS (2003) Management issues for women with epilepsy: neural tube defects and folic acid supplementation. Neurology 61(6 suppl. 2): S23–26.

Further Reading

Czeizel AE and Dudas I (1992) Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. New England Journal of Medicine 327: 1832–1835.

MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the medical research council vitamin study. Lancet 338: 131–137.

Muller F and O'Rahilly R (2001) Human Embryology and Teratology, 3rd edn. New York: Wiley‐Liss.

Wyszynski DF (2006) Neural Tube Defects, From Origin to Treatment. New York, NY: Oxford University Press.

Web Links

International Clearing House for Birth Defects Research: http://www.icbdsr.org/

Morbidity and Mortality Weekly Report: http://www.cdc.gov/mmwr/

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
O'Byrne, Michelle R, Au, Kit Sing, and Northrup, Hope(Nov 2010) Neural Tube Defects: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006233.pub2]