Research progress on the etiology and pathogenesis of spina bifida_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHU Haiyan ,  WANG Linlin ,  REN Aiguo

Institute of Reproductive Health, National Health Commission Key Laboratory of Reproductive Health, Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, 100191, P.R.China;

Corresponding author：

WANG Linlin, Email: linlinwang@bjmu.edu.cn; REN Aiguo, Email: renag@bjmu.edu.cn

Keywords：

Spina bifida; neural tube defects; pathogenesis

DOI：

10.7507/1002-1892.202106052

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To review the research progress on etiology and pathogenesis of spina bifida. Methods By consulting relevant domestic and foreign research literature on spina bifida, the classification, epidemic trend, pathogenesis, etiology, prevention and treatment of it were analyzed and summarized. Results Spina bifida, a common phenotype of neural tube defects, is classified based on the degree and pattern of malformation associated with neuroectodermal involvement and is due to the disturbance of neural tube closure 28 days before embryonic development. The prevalence of spina bifida varies greatly among different ethnic groups and regions, and its etiology is complex. Currently, some spina bifida patients can be prevented by folic acid supplements, and with the improvement of treatment technology, the short-term and long-term survival rate of children with spina bifida has improved. Conclusion The research on the pathogenesis of spina bifida will be based on the refined individual information on exposure, genetics, and complex phenotype, and will provide a theoretical basis for improving prevention and treatment strategies through multidisciplinary cooperation.

Citation： ZHU Haiyan, WANG Linlin, REN Aiguo. Research progress on the etiology and pathogenesis of spina bifida. Chinese Journal of Reparative and Reconstructive Surgery, 2021, 35(11): 1368-1373. doi: 10.7507/1002-1892.202106052 Copy

1.	McComb JG. A practical clinical classification of spinal neural tube defects. Childs Nerv Syst, 2015, 31(10): 1641-1657.
2.	Tortori-Donati P, Rossi A, Cama A. Spinal dysraphism: a review of neuroradiological features with embryological correlations and proposal for a new classification. Neuroradiology, 2000, 42(7): 471-491.
3.	顾莉莉, 李胜利. 胎儿脊柱裂的产前诊断进展. 中华医学超声杂志 (电子版), 2012, 9(3): 201-204.
4.	Atta CA, Fiest KM, Frolkis AD, et al. Global birth prevalence of spina bifida by folic acid fortification status: A systematic review and meta-analysis. Am J Public Health, 2016, 106(1): e24-34.
5.	Copp AJ, Adzick NS, Chitty LS, et al. Spina bifida. Nat Rev Dis Primers, 2015, 1: 15007. doi: 10.1038/nrdp.2015.7.
6.	Canfield MA, Ramadhani TA, Shaw GM, et al. Anencephaly and spina bifida among Hispanics: maternal, sociodemographic, and acculturation factors in the National Birth Defects Prevention Study. Birth Defects Res A Clin Mol Teratol, 2009, 85(7): 637-646.
7.	Cragan JD, Roberts HE, Edmonds LD, et al. Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis-United States, 1985-1994. MMWR CDC Surveill Summ, 1995, 44(4): 1-13.
8.	马瑞新, 杨燕芬, 刘辉, 等. 2006—2012 年北京市房山区神经管缺陷流行特征. 中国生育健康杂志, 2015, (4): 316-319, 323.
9.	孙洪亚, 徐燕军, 郁静茹, 等. 2006—2012 年北京市顺义区神经管缺陷流行特征. 中国儿童保健杂志, 2016, 24(2): 180-182.
10.	Velie EM, Shaw GM. Impact of prenatal diagnosis and elective termination on prevalence and risk estimates of neural tube defects in California, 1989-1991. Am J Epidemiol, 1996, 144(5): 473-479.
11.	Liu J, Zhang L, Li Z, et al. Prevalence and trend of neural tube defects in five counties in Shanxi province of Northern China, 2000 to 2014. Birth Defects Res A Clin Mol Teratol, 2016, 106(4): 267-274.
12.	Copp AJ, Greene ND. Neural tube defects-disorders of neurulation and related embryonic processes. Wiley Interdiscip Rev Dev Biol, 2013, 2(2): 213-227.
13.	Copp AJ, Stanier P, Greene ND. Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurol, 2013, 12(8): 799-810.
14.	Greene ND, Copp AJ. Neural tube defects. Annu Rev Neurosci, 2014, 37: 221-242.
15.	Copp AJ, Greene ND, Murdoch JN. The genetic basis of mammalian neurulation. Nat Rev Genet, 2003, 4(10): 784-793.
16.	O’Rahilly R, Müller F. The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology, 2002, 65(4): 162-170.
17.	van Straaten HW, Copp AJ. Curly tail: a 50-year history of the mouse spina bifida model. Anat Embryol (Berl), 2001, 203(4): 225-237.
18.	Mitchell LE, Adzick NS, Melchionne J, et al. Spina bifida. Lancet, 2004, 364(9448): 1885-1895.
19.	徐琳, 王建华, 牛勃. Shh 信号通路与神经管畸形. 中国优生与遗传杂志, 2015, 23(3): 1-3, 11.
20.	Greene ND, Copp AJ. Development of the vertebrate central nervous system: formation of the neural tube. Prenat Diagn, 2009, 29(4): 303-311.
21.	Wu Y, Peng S, Finnell RH, et al. Organoids as a new model system to study neural tube defects. FASEB J, 2021, 35(4): e21545. doi: 10.1096/fj.202002348R.
22.	Kibar Z, Underhill DA, Canonne-Hergaux F, et al. Identification of a new chemically induced allele (Lp(m1Jus)) at the loop-tail locus: morphology, histology, and genetic mapping. Genomics, 2001, 72(3): 331-337.
23.	De Marco P, Merello E, Consales A, et al. Genetic analysis of disheveled 2 and disheveled 3 in human neural tube defects. J Mol Neurosci, 2013, 49(3): 582-588.
24.	Lei YP, Zhang T, Li H, et al. VANGL2 mutations in human cranial neural-tube defects. N Engl J Med, 2010, 362(23): 2232-2235.
25.	Robinson A, Escuin S, Doudney K, et al. Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis. Hum Mutat, 2012, 33(2): 440-447.
26.	Tian T, Cao X, Chen Y, et al. Somatic and de novo germline variants of MEDs in human neural tube defects. Front Cell Dev Biol, 2021, 9: 641831. doi: 10.3389/fcell.2021.641831.
27.	Tian T, Lei Y, Chen Y, et al. Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects. Hum Genet, 2020, 139(10): 1299-1314.
28.	Murdoch JN, Copp AJ. The relationship between sonic Hedgehog signaling, cilia, and neural tube defects. Birth Defects Res A Clin Mol Teratol, 2010, 88(8): 633-652.
29.	Wang L, Lin S, Yi D, et al. Apoptosis, expression of PAX3 and P53, and Caspase signal in fetuses with neural tube defects. Birth Defects Res, 2017, 109(19): 1596-1604.
30.	Wang L, Lin S, Zhang J, et al. Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects: A genome-wide DNA methylation analysis. Epigenetics, 2017, 12(2): 157-165.
31.	Tian T, Lai X, Xiang K, et al. Hypermethylation of PI3K-AKT signalling pathway genes is associated with human neural tube defects. Epigenetics, 2021. doi: 10.1080/15592294.2021.1878725.
32.	Trinidad MC, Wick M. Practice Bulletin No. 187:Neural tube defects. Obstetrics and Gynecology, 2017, 130(6): e279-e290.
33.	Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA, 1993, 269(10): 1257-1261.
34.	Blencowe H, Cousens S, Modell B, et al. Folic acid to reduce neonatal mortality from neural tube disorders. Int J Epidemiol, 2010, 39 Suppl 1(Suppl 1): i110-121.
35.	Finnell RH, Caiaffa CD, Kim SE, et al. Gene environment interactions in the etiology of neural tube defects. Front Genet, 2021, 12: 659612. doi: 10.3389/fgene.2021.659612.
36.	Facchinetti F, Cavalli P, Copp AJ, et al. An update on the use of inositols in preventing gestational diabetes mellitus (GDM) and neural tube defects (NTDs). Expert Opin Drug Metab Toxicol, 2020, 16(12): 1187-1198.
37.	Greene ND, Copp AJ. Inositol prevents folate-resistant neural tube defects in the mouse. Nat Med, 1997, 3(1): 60-66.
38.	D’Souza SW, Copp AJ, Greene NDE, et al. Maternal inositol status and neural tube defects: A role for the human yolk sac in embryonic inositol delivery? Adv Nutr, 2021, 12(1): 212-222.
39.	Desrosiers TA, Siega-Riz AM, Mosley BS, et al. Low carbohydrate diets may increase risk of neural tube defects. Birth Defects Res, 2018, 110(11): 901-909.
40.	Hiramatsu Y, Sekiguchi N, Hayashi M, et al. Diacylglycerol production and protein kinase C activity are increased in a mouse model of diabetic embryopathy. Diabetes, 2002, 51(9): 2804-2810.
41.	McLeod L, Ray JG. Prevention and detection of diabetic embryopathy. Community Genet, 2002, 5(1): 33-39.
42.	Zhao Z, Cao L, Hernández-Ochoa E, et al. Disturbed intracellular calcium homeostasis in neural tube defects in diabetic embryopathy. Biochem Biophys Res Commun, 2019, 514(3): 960-966.
43.	Milunsky A, Ulcickas M, Rothman KJ, et al. Maternal heat exposure and neural tube defects. JAMA, 1992, 268(7): 882-885.
44.	Zash R, Makhema J, Shapiro RL. Neural-tube defects with dolutegravir treatment from the time of conception. N Engl J Med, 2018, 379(10): 979-981.
45.	Zash R, Holmes L, Diseko M, et al. Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. N Engl J Med, 2019, 381(9): 827-840.
46.	Ren A, Qiu X, Jin L, et al. Association of selected persistent organic pollutants in the placenta with the risk of neural tube defects. Proc Natl Acad Sci U S A, 2011, 108(31): 12770-12775.
47.	Wang C, Pi X, Chen Y, et al. Prenatal exposure to barium and the occurrence of neural tube defects in offspring. Sci Total Environ, 2021, 764: 144245. doi: 10.1016/j.scitotenv.2020.144245.
48.	Jin L, Zhang L, Li Z, et al. Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population. Reprod Toxicol, 2013, 35: 25-31.
49.	Ross MM, Piorczynski TB, Harvey J, et al. Ceramide: a novel inducer for neural tube defects. Dev Dyn, 2019, 248(10): 979-996.
50.	修波. 脊柱裂研究进展. 中华神经外科疾病研究杂志, 2017, 16(2): 97-100.

1. McComb JG. A practical clinical classification of spinal neural tube defects. Childs Nerv Syst, 2015, 31(10): 1641-1657.
2. Tortori-Donati P, Rossi A, Cama A. Spinal dysraphism: a review of neuroradiological features with embryological correlations and proposal for a new classification. Neuroradiology, 2000, 42(7): 471-491.
3. 顾莉莉, 李胜利. 胎儿脊柱裂的产前诊断进展. 中华医学超声杂志 (电子版), 2012, 9(3): 201-204.
4. Atta CA, Fiest KM, Frolkis AD, et al. Global birth prevalence of spina bifida by folic acid fortification status: A systematic review and meta-analysis. Am J Public Health, 2016, 106(1): e24-34.
5. Copp AJ, Adzick NS, Chitty LS, et al. Spina bifida. Nat Rev Dis Primers, 2015, 1: 15007. doi: 10.1038/nrdp.2015.7.
6. Canfield MA, Ramadhani TA, Shaw GM, et al. Anencephaly and spina bifida among Hispanics: maternal, sociodemographic, and acculturation factors in the National Birth Defects Prevention Study. Birth Defects Res A Clin Mol Teratol, 2009, 85(7): 637-646.
7. Cragan JD, Roberts HE, Edmonds LD, et al. Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis-United States, 1985-1994. MMWR CDC Surveill Summ, 1995, 44(4): 1-13.
8. 马瑞新, 杨燕芬, 刘辉, 等. 2006—2012 年北京市房山区神经管缺陷流行特征. 中国生育健康杂志, 2015, (4): 316-319, 323.
9. 孙洪亚, 徐燕军, 郁静茹, 等. 2006—2012 年北京市顺义区神经管缺陷流行特征. 中国儿童保健杂志, 2016, 24(2): 180-182.
10. Velie EM, Shaw GM. Impact of prenatal diagnosis and elective termination on prevalence and risk estimates of neural tube defects in California, 1989-1991. Am J Epidemiol, 1996, 144(5): 473-479.
11. Liu J, Zhang L, Li Z, et al. Prevalence and trend of neural tube defects in five counties in Shanxi province of Northern China, 2000 to 2014. Birth Defects Res A Clin Mol Teratol, 2016, 106(4): 267-274.
12. Copp AJ, Greene ND. Neural tube defects-disorders of neurulation and related embryonic processes. Wiley Interdiscip Rev Dev Biol, 2013, 2(2): 213-227.
13. Copp AJ, Stanier P, Greene ND. Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurol, 2013, 12(8): 799-810.
14. Greene ND, Copp AJ. Neural tube defects. Annu Rev Neurosci, 2014, 37: 221-242.
15. Copp AJ, Greene ND, Murdoch JN. The genetic basis of mammalian neurulation. Nat Rev Genet, 2003, 4(10): 784-793.
16. O’Rahilly R, Müller F. The two sites of fusion of the neural folds and the two neuropores in the human embryo. Teratology, 2002, 65(4): 162-170.
17. van Straaten HW, Copp AJ. Curly tail: a 50-year history of the mouse spina bifida model. Anat Embryol (Berl), 2001, 203(4): 225-237.
18. Mitchell LE, Adzick NS, Melchionne J, et al. Spina bifida. Lancet, 2004, 364(9448): 1885-1895.
19. 徐琳, 王建华, 牛勃. Shh 信号通路与神经管畸形. 中国优生与遗传杂志, 2015, 23(3): 1-3, 11.
20. Greene ND, Copp AJ. Development of the vertebrate central nervous system: formation of the neural tube. Prenat Diagn, 2009, 29(4): 303-311.
21. Wu Y, Peng S, Finnell RH, et al. Organoids as a new model system to study neural tube defects. FASEB J, 2021, 35(4): e21545. doi: 10.1096/fj.202002348R.
22. Kibar Z, Underhill DA, Canonne-Hergaux F, et al. Identification of a new chemically induced allele (Lp(m1Jus)) at the loop-tail locus: morphology, histology, and genetic mapping. Genomics, 2001, 72(3): 331-337.
23. De Marco P, Merello E, Consales A, et al. Genetic analysis of disheveled 2 and disheveled 3 in human neural tube defects. J Mol Neurosci, 2013, 49(3): 582-588.
24. Lei YP, Zhang T, Li H, et al. VANGL2 mutations in human cranial neural-tube defects. N Engl J Med, 2010, 362(23): 2232-2235.
25. Robinson A, Escuin S, Doudney K, et al. Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis. Hum Mutat, 2012, 33(2): 440-447.
26. Tian T, Cao X, Chen Y, et al. Somatic and de novo germline variants of MEDs in human neural tube defects. Front Cell Dev Biol, 2021, 9: 641831. doi: 10.3389/fcell.2021.641831.
27. Tian T, Lei Y, Chen Y, et al. Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects. Hum Genet, 2020, 139(10): 1299-1314.
28. Murdoch JN, Copp AJ. The relationship between sonic Hedgehog signaling, cilia, and neural tube defects. Birth Defects Res A Clin Mol Teratol, 2010, 88(8): 633-652.
29. Wang L, Lin S, Yi D, et al. Apoptosis, expression of PAX3 and P53, and Caspase signal in fetuses with neural tube defects. Birth Defects Res, 2017, 109(19): 1596-1604.
30. Wang L, Lin S, Zhang J, et al. Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects: A genome-wide DNA methylation analysis. Epigenetics, 2017, 12(2): 157-165.
31. Tian T, Lai X, Xiang K, et al. Hypermethylation of PI3K-AKT signalling pathway genes is associated with human neural tube defects. Epigenetics, 2021. doi: 10.1080/15592294.2021.1878725.
32. Trinidad MC, Wick M. Practice Bulletin No. 187:Neural tube defects. Obstetrics and Gynecology, 2017, 130(6): e279-e290.
33. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA, 1993, 269(10): 1257-1261.
34. Blencowe H, Cousens S, Modell B, et al. Folic acid to reduce neonatal mortality from neural tube disorders. Int J Epidemiol, 2010, 39 Suppl 1(Suppl 1): i110-121.
35. Finnell RH, Caiaffa CD, Kim SE, et al. Gene environment interactions in the etiology of neural tube defects. Front Genet, 2021, 12: 659612. doi: 10.3389/fgene.2021.659612.
36. Facchinetti F, Cavalli P, Copp AJ, et al. An update on the use of inositols in preventing gestational diabetes mellitus (GDM) and neural tube defects (NTDs). Expert Opin Drug Metab Toxicol, 2020, 16(12): 1187-1198.
37. Greene ND, Copp AJ. Inositol prevents folate-resistant neural tube defects in the mouse. Nat Med, 1997, 3(1): 60-66.
38. D’Souza SW, Copp AJ, Greene NDE, et al. Maternal inositol status and neural tube defects: A role for the human yolk sac in embryonic inositol delivery? Adv Nutr, 2021, 12(1): 212-222.
39. Desrosiers TA, Siega-Riz AM, Mosley BS, et al. Low carbohydrate diets may increase risk of neural tube defects. Birth Defects Res, 2018, 110(11): 901-909.
40. Hiramatsu Y, Sekiguchi N, Hayashi M, et al. Diacylglycerol production and protein kinase C activity are increased in a mouse model of diabetic embryopathy. Diabetes, 2002, 51(9): 2804-2810.
41. McLeod L, Ray JG. Prevention and detection of diabetic embryopathy. Community Genet, 2002, 5(1): 33-39.
42. Zhao Z, Cao L, Hernández-Ochoa E, et al. Disturbed intracellular calcium homeostasis in neural tube defects in diabetic embryopathy. Biochem Biophys Res Commun, 2019, 514(3): 960-966.
43. Milunsky A, Ulcickas M, Rothman KJ, et al. Maternal heat exposure and neural tube defects. JAMA, 1992, 268(7): 882-885.
44. Zash R, Makhema J, Shapiro RL. Neural-tube defects with dolutegravir treatment from the time of conception. N Engl J Med, 2018, 379(10): 979-981.
45. Zash R, Holmes L, Diseko M, et al. Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. N Engl J Med, 2019, 381(9): 827-840.
46. Ren A, Qiu X, Jin L, et al. Association of selected persistent organic pollutants in the placenta with the risk of neural tube defects. Proc Natl Acad Sci U S A, 2011, 108(31): 12770-12775.
47. Wang C, Pi X, Chen Y, et al. Prenatal exposure to barium and the occurrence of neural tube defects in offspring. Sci Total Environ, 2021, 764: 144245. doi: 10.1016/j.scitotenv.2020.144245.
48. Jin L, Zhang L, Li Z, et al. Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population. Reprod Toxicol, 2013, 35: 25-31.
49. Ross MM, Piorczynski TB, Harvey J, et al. Ceramide: a novel inducer for neural tube defects. Dev Dyn, 2019, 248(10): 979-996.
50. 修波. 脊柱裂研究进展. 中华神经外科疾病研究杂志, 2017, 16(2): 97-100.

Chinese Journal of Reparative and Reconstructive Surgery

Research progress on the etiology and pathogenesis of spina bifida

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content