Evidence for multi‐site closure of the neural tube in humans

Abstract

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)

Rudimentary Meningocele: Remnant of a Neural Tube Defect?

“…8,27 A fairly new theory about closure of the neural tube may yield greater insight into the pathologic mechanism of rudimentary meningocele, as it seems to explain some of the clinical findings. 10,11 Traditionally, neural tube closure was believed to begin in the cervical region and to proceed from there in a continuous bidirectional way 11 ( Figure 4A). More recent observations in humans and animals, however, indicate multisite initiation of neural tube closure 10 ( Figure 4B).…”

“…Closure in the occipital area appears to be achieved by a membrane rather than a midline fusion of folds, which explains why such defects may or may not appear in the midline. 10 Another feature of neural tube defects is genetic susceptibility, with a risk of repetitive events in affected families. 10 This suggests that specific genes control individual closure sites.…”

Testing the vulnerability of the phylotypic stage: On modularity and evolutionary conservation

“…For the phylotypic stage in vertebrates there is no lack of intraspecific genetic variation. For instance, numerous anomalies of neural tube closure with a genetic basis exist in mammalian species (e.g., Van Allen et al, 1993;Hume et al, 1996). There is also intraspecific variation in the number of somites which can be deduced from the intraspecific variation in the number of vertebrae that arise from them at a later stage of development (Schulz, 1961;Woolfenden, 1961).…”

Spatial and temporal expression of folate‐binding protein 1 (Fbp1) is closely associated with anterior neural tube closure in mice

“…The lateral edges of the neural plate elevate to form the neural folds and they fuse to form the neural tube. The fusion of the neural folds initiates at several sites in mammalian embryos, although the mode of neural tube closure may be different among species (Van Allen et al, 1993;Juriloff and Harris, 2000;Nakatsu et al, 2000).…”