Van Allen M I, Kalousek D K, Chernoff G F, Juriloff D, Harris M, McGillivray B C, Yong S L, Langlois S, MacLeod P M, Chitayat D
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Am J Med Genet. 1993 Oct 1;47(5):723-43. doi: 10.1002/ajmg.1320470528.
Four separate initiation sites for neural tube (NT) fusion have been demonstrated recently in mice and other experimental animals. We evaluated the question of whether the multisite model vs. the traditional single-site model of NT closure provided the best explanation for neural tube defects (NTDs) in humans. Evidence for segmental vs. continuous NT closure was obtained by review of our recent clinical cases of NTDs and previous medical literature. With the multi-site NT closure model, we find that the majority of NTDs can be explained by failure of fusion of one of the closures or their contiguous neuropores. We hypothesize that: Anencephaly results from failure of closure 2 for meroacranium and closures 2 and 4 for holoacranium. Spina-bifida cystica results from failure of rostral and/or caudal closure 1 fusion. Craniorachischisis results from failure of closures 2, 4, and 1. Closure 3 non-fusion is rare, presenting as a midfacial cleft extending from the upper lip through the frontal area ("facioschisis"). Frontal and parietal cephaloceles occur at the sites of the junctions of the cranial closures 3-2 and 2-4 (the prosencephalic and mesencephalic neuropores). Occipital cephaloceles result from incomplete membrane fusion of closure 4. In humans, the most caudal NT may have a 5th closure site involving L2 to S2. Closure below S2 is by secondary neurulation. Evidence for multi-site NT closure is apparent in clinical cases of NTDs, as well as in previous epidemiological studies, empiric recurrence risk studies, and pathological studies. Genetic variations of NT closures sites occur in mice and are evident in humans, e.g., familial NTDs with Sikh heritage (closure 4 and rostral 1), Meckel-Gruber syndrome (closure 4), and Walker-Warburg syndrome (2-4 neuropore, closure 4). Environmental and teratogenic exposures frequently affect specific closure sites, e.g., folate deficiency (closures 2, 4, and caudal 1) and valproic acid (closure 5 and canalization). Classification of NTDs by closure site is recommended for all studies of NTDs in humans.(ABSTRACT TRUNCATED AT 400 WORDS)
最近在小鼠和其他实验动物中已证实神经管（NT）融合有四个独立的起始位点。我们评估了NT闭合的多部位模型与传统单部位模型相比，是否能为人类神经管缺陷（NTDs）提供最佳解释这一问题。通过回顾我们最近的NTD临床病例和既往医学文献，获得了关于节段性与连续性NT闭合的证据。采用多部位NT闭合模型，我们发现大多数NTDs可解释为其中一个闭合处或其相邻神经孔融合失败。我们推测：无脑畸形是由于半头畸形时闭合2失败，以及全头畸形时闭合2和4失败所致。脊柱裂囊肿是由于头侧和/或尾侧闭合1融合失败所致。颅脊柱裂是由于闭合2、4和1失败所致。闭合3不融合很少见，表现为从中唇延伸至额部区域的面裂（“面裂”）。额部和顶部脑膨出发生在颅闭合3 - 2和2 - 4的交界处（前脑和中脑神经孔）。枕部脑膨出是由于闭合4的膜融合不完全所致。在人类中，最尾侧的NT可能有一个涉及L2至S2的第5个闭合位点。S2以下的闭合是通过继发性神经形成。NTD临床病例以及既往流行病学研究、经验性复发风险研究和病理学研究中，多部位NT闭合的证据很明显。NT闭合位点的基因变异在小鼠中出现，在人类中也很明显，例如具有锡克族遗传背景的家族性NTDs（闭合4和头侧1）、梅克尔 - 格鲁伯综合征（闭合4）和沃克 - 沃尔堡综合征（2 - 4神经孔，闭合4）。环境和致畸物暴露经常影响特定的闭合位点，例如叶酸缺乏（闭合2、4和尾侧1）和丙戊酸（闭合5和管道形成）。建议在所有人类NTD研究中按闭合位点对NTDs进行分类。（摘要截于400字）
