Human Neural Tube Defects: Developmental Biology, Epidemiology, and Genetics

Neurotoxicology and Teratology 27 (2005) 515–524 www.elsevier.com/locate/neutera Review article Human neural tube defects: Developmental biology, epidemiology, and genetics Eric R. Detraita, Timothy M. Georgeb, Heather C. Etcheversa, John R. Gilbertb, Michel Vekemansa, Marcy C. Speerb,* aHoˆpital Necker, Enfants Malades Unite´ INSERM U393, 149, rue de Se`vres, 75743 Paris Cedex 15, France bCenter for Human Genetics, Duke University Medical Center, Box 3445, Durham, NC 27710, United States Received 16 December 2004; accepted 17 December 2004 Available online 5 March 2005 Abstract Birth defects (congenital anomalies) are the leading cause of death in babies under 1 year of age. Neural tube defects (NTD), with a birth incidence of approximately 1/1000 in American Caucasians, are the second most common type of birth defect after congenital heart defects. The most common presentations of NTD are spina bifida and anencephaly. The etiologies of NTDs are complex, with both genetic and environmental factors implicated. In this manuscript, we review the evidence for genetic etiology and for environmental influences, and we present current views on the developmental processes involved in human neural tube closure. D 2004 Elsevier Inc. All rights reserved. Keywords: Neural tube defect; Genetics; Teratology Contents 1. Formation of the human neural tube .............................................. 516 2. Single site of neural fold fusion ................................................ 518 3. Relationship of human neural tube closure to mouse neural tube closure . ......................... 518 4. Clues from observational data ................................................. 518 5. Evidence for a genetic factor in human neural tube defects .................................. 519 6. If neural tube defects are genetic, how do they present in families? .............................. 519 7. Clues to genes involved in human neural tube defects from mouse models . ......................... 520 8. Environmental factors associated with neural tube defects ................................... 520 9. Synthesizing the data ...................................................... 521 Acknowledgments .......................................................... 521 References .............................................................. 521 Birth defects (congenital anomalies) are the leading cause American Caucasians, are the second most common type of of death in babies under 1 year of age. Neural tube defects birth defect after congenital heart defects. In human, the (NTD), with a birth incidence of approximately 1/1000 in most common NTD are anencephaly and myelomeningocele. Anencephaly results from a failed closure of the rostral end of the neural tube and is characterized by a total or T Corresponding author. Tel.: +1 919 684 2063; fax: +1 919 684 0917. partial absence of the cranial vault and cerebral hemisphere. E-mail address: [email protected] (M.C. Speer). Myelomeningocele is a defective closure of the neural tube 0892-0362/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ntt.2004.12.007 516 E.R. Detrait et al. / Neurotoxicology and Teratology 27 (2005) 515–524 in the vertebral column. Depending on the size and the variety of experimental systems including but not restricted location of the defect, the patient can suffer either no to mouse, zebrafish, and chick. physical handicap or lifelong disabilities [86].These common birth defects vary in frequency depending on the geographical localization. Anencephaly and spina bifida 1. Formation of the human neural tube occur at frequencies ranging from 0.9 in Canada to 7.7 in the United Arab Emirates and 0.7 in central France to 11.7 Neurulation, which is the formation of the neural tube, is in South America per 10,000 births [86]. an important morphogenetic event in human development. The mortality rate for children with spina bifida is increased over the general population risk in the first year of life. The cost of providing for medical care for a child with myelomeningocele has been estimated to be over $70,000 (adjusted to 2001 dollars) annually for the first 20 years of life, including costs associated with an average of 5 surgeries per year [94] in the first 5 years of life (20 year lifetime cost is $1.4 million/case). The phenotypes of the open NTDs include myelomeningocele (spina bifida cystica, open spina bifida) and anencephaly. Anencephaly, an incomplete formation of the brain and skull, is uniformly lethal. The most common form of NTD, myelomeningocele, is an open lesion in the caudal spine and contains dysplastic spinal cord, often resulting in a lack of neural function below the level of the defect. Affected patients usually have reduced ability to walk, or need the use of a wheelchair, have little or no bowel and/or bladder control, and require frequent surgical interventions to minimize the effects of hydrocephalus. The most common presentations, spina bifida and anencephaly, can occur within the same family, raising the question as to whether these phenotypes are related and due to a common underlying gene [29,31,33, 38,65,77]. Defining the phenotype in affected patients is paramount to the evaluation of human neural tube defects. Phenotypic parameters include: location and level of the defect, whether the defect crosses CNS segmental boundaries, and catalogu- ing the variety of anomalies in a patient or family. Open defects such as anencephaly, craniorachischisis, myelomeningocele, and myeloschisis are defined based upon the location and level and are descriptive in nature. Associated anomalies, Chiari II malformation, hydrocephalus, syringo- myelia, polymicrogyria, cortical heterotopias, and agenesis of the corpus callosum further add to and can confuse the phenotypic definitions. NTDs in humans result from the combined effects of genetic and environmental influences, and as such are a classic example of a multifactorial disorder. Identifying the genetic factors is critical for characterizing the interactions Fig. 1. Human embryonic developmental stages during which the neural between genes and the environment, and understanding tube forms. A1 and 2: Carnegie stage 9 (CS 9–20 days) the neural groove is these interactions will provide the basis for designing novel open and anterior neural fold is visible. B1 and 2: CS 10 (22 days). The preventive strategies and for offering accurate reproductive neural folds fuses centrally leaving an open tube in the rostral and caudal risks to couples. The genetic factors will likely involve region. C1, 2 and 3: CS 11 (24 days). The neural tube is closed except for aberrant variations in genes key for the normal closure of the the rostral (C2 and 3) and caudal neuropores. D1 and 2: CS 12 (26 days) the caudal neuropore is closing (C2). E1 and 2: CS 13 (28 days). The neural tube. Neural tube closure is a complex, early neuropores are closed. E1 corresponds to early CS 13 and E2 to a late CS developmental process, informed not only by nascent studies 13. The scale bars represent 1 mm in all photographs except C3 and D2 in human embryos, but by the plethora of investigations in a where they represent 0.5 mm. E.R. Detrait et al. / Neurotoxicology and Teratology 27 (2005) 515–524 517 The neural tube gives rise to the brain and the spinal cord to depends on the highly conserved Wnt-frizzled signal form the central nervous system. Neurulation in mammalian transduction pathways (see Lawrence at al. 2003 [48] embryos occurs in two phases: primary and secondary and Copp et al. 2003 [13] for reviews on convergent neurulation [68]. These two phases occur in distinct areas extension). along the rostro-caudal axis of the embryo. Secondary On day 19 (CS 8.5), the border of the neural plate neurulation is limited to the tail bud, which lies beyond the becomes gradually more pronounced and elevated. The caudal neuropore. In contrast to primary neurulation, neural plate folds longitudinally along the midline of the described in detail below, secondary neurulation occurs by plate from the head toward the tail to form the neural proliferation of stem cells [8], which form a rod-like groove. The folds rise up dorsally, approach each other and condensation that subsequently cavitates. The cavitation ultimately merge together, forming a tube open at both ends transforms the rod into a tube, and the lumen of this tube by day 23 (CS 10.5) (Fig 1A and B). As the neural folds comes into continuity with the lumen of the tube formed fuse, the cells adjacent to the neural plate also fuse across during primary neurulation. In tailless humans, the tail bud the midline to become the overlying epidermis. The rostral does not develop as in tailed animals, and secondary and caudal openings are called neuropores and are best neurulation does not appear to be responsible for open distinguished around day 23 when about 17–19 somites are neural tube defects. For this reason, we will focus on visible (Fig. 1C). The rostral and caudal neuropores close primary neurulation. later, on the 26th (CS 12) and 28th (CS 13) days of Primary neurulation generates the entire neural tube gestation, respectively (Fig. 1D to E). We utilize the rostral to the caudal neuropore. During this process, terminology suggested by O’Rahilly and Mqller [60], who occurring during the third and fourth weeks of development reserve the term bclosureQ for the closing of neuropores, (Carnegie stages (CS) 8 to 13, Fig. 1), the flat layer of while the term bfusionQ is used to designate the merging of ectodermal cells overlying the notochord is transformed into the neural folds and the formation of a tube. a hollow tube. Although there is general agreement on the morphoge- Eighteen days after fertilization (CS 8), the midline netic movements of the first events of neural tube formation, dorsal ectoderm of the embryo thickens and forms the the last event in neural tube formation, the fusion of neural neural plate while cell shape changes. The neural plate first folds, is subject to debate concerning the number of appears at the cranial end of the embryo and differentiates initiation sites of fusion and their location.

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