Northrup H, Volcik K A
Department of Pediatrics, Division of Medical Genetics, University of Texas Medical School, Houston, Texas, USA.
Curr Probl Pediatr. 2000 Nov-Dec;30(10):313-32. doi: 10.1067/mpp.2000.112052.
NTDs, resulting from failure of the neural tube to close during the fourth week of embryogenesis, are the most common severely disabling birth defects in the United States, with a frequency of approximately 1 of every 2000 births. Neural tube malformations involving the spinal cord and vertebral arches are referred to as spina bifida, with severe types of spina bifida involving protrusion of the spinal cord and/or meninges through a defect in the vertebral arch. Depending on the level of the lesion, interruption of the spinal cord at the site of the spina bifida defect causes paralysis of the legs, incontinence of urine and feces, anesthesia of the skin, and abnormalities of the hips, knees, and feet. Two additional abnormalities often seen in children with spina bifida include hydrocephalus and the Arnold-Chiari type II malformation. Despite the physical and particular learning disabilities children with spina bifida must cope with, participation in individualized educational programs can allow these children to develop skills necessary for autonomy in adulthood. Advances in research to uncover the molecular basis of NTDs is enhanced by knowledge of the link between both the environmental and genetic factors involved in the etiology of NTDs. The most recent development in NTD research for disease-causing genes is the discovery of a genetic link to the most well-known environmental cause of neural tube malformation, folate deficiency in pregnant women. Nearly a decade ago, periconceptional folic acid supplementation was proven to decrease both the recurrence and occurrence of NTDs. The study of folate and its association with NTDs is an ongoing endeavor that has led to numerous studies of different genes involved in the folate metabolism pathway, including the most commonly studied thermolabile mutation (C677T) in the MTHFR gene. An additional focus for NTD research involves mouse models that exhibit both naturally occurring NTDs, as well as those created by experimental design. We hope the search for genes involved in the risk and/or development of NTDs will lead to the development of strategies for prevention and treatment. The most recent achievement in treatment of NTDs involves the repair of meningomyelocele through advancements in fetal surgery. Convincing experimental evidence exists that in utero repair preserves neurologic function, as well as resolving the hydrocephalus and Arnold-Chiari malformation that often accompany meningomyelocele defects. However, follow-up is needed to completely evaluate long-term neurologic function and overall improved quality of life. And in the words of Olutoye and Adzick, "until the benefits of fetal [meningomyelocele] repair are carefully elucidated, weighed against maternal and fetal risks, and compared to conventional postnatal therapy, this procedure should be restricted to a few centers that are committed (clinically and experimentally) to investigating these issues."
神经管缺陷（NTDs）是由于胚胎发育第四周神经管闭合失败所致，是美国最常见的严重致残性出生缺陷，发生率约为每2000例出生中有1例。涉及脊髓和椎弓的神经管畸形被称为脊柱裂，严重类型的脊柱裂包括脊髓和/或脑膜通过椎弓缺损突出。根据病变部位，脊柱裂缺损部位的脊髓中断会导致腿部瘫痪、大小便失禁、皮肤感觉缺失以及髋部、膝盖和足部异常。脊柱裂患儿常出现的另外两种异常包括脑积水和II型阿诺德-奇亚里畸形。尽管脊柱裂患儿必须应对身体和特殊学习障碍，但参与个性化教育项目可以使这些儿童培养成年后实现自主所需的技能。了解神经管缺陷病因中环境和遗传因素之间的联系，有助于推动揭示神经管缺陷分子基础的研究进展。神经管缺陷致病基因研究的最新进展是发现了与神经管畸形最著名的环境病因——孕妇叶酸缺乏之间的遗传联系。近十年前，已证实孕前补充叶酸可降低神经管缺陷的复发率和发生率。对叶酸及其与神经管缺陷关联的研究仍在持续进行，这导致了对叶酸代谢途径中不同基因的大量研究，包括甲基四氢叶酸还原酶（MTHFR）基因中最常研究的不耐热突变（C677T）。神经管缺陷研究的另一个重点是既表现出自然发生的神经管缺陷，也包括通过实验设计产生神经管缺陷的小鼠模型。我们希望对涉及神经管缺陷风险和/或发育的基因的研究将促成预防和治疗策略的制定。神经管缺陷治疗的最新成果包括通过胎儿手术的进展来修复脊髓脊膜膨出。有令人信服的实验证据表明，子宫内修复可保留神经功能，并解决脊髓脊膜膨出缺陷常伴随出现的脑积水和阿诺德-奇亚里畸形。然而，需要进行随访以全面评估长期神经功能和整体生活质量的改善情况。用奥卢托耶（Olutoye）和阿齐克（Adzick）的话说，“在胎儿[脊髓脊膜膨出]修复的益处得到仔细阐明、与母婴风险进行权衡并与传统产后治疗进行比较之前，该手术应仅限于少数几个致力于（临床和实验方面）研究这些问题的中心。”
