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Evidence for multi-site closure of the neural tube in humans
M I Van Allen1, D K Kalousek, G F Chernoff
1Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
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)
Insights
Neural tube defects (NTDs) in humans are better explained by a multisite model of neural tube (NT) closure, rather than a single-site model. This approach helps classify NTDs based on specific closure site failures.
Area of Science:
- Developmental biology
- Human embryology
- Teratology
Background:
- The traditional single-site model of neural tube (NT) closure has been challenged by recent findings in animal models.
- Understanding the precise mechanisms of NT closure is crucial for explaining neural tube defects (NTDs).
Observation:
- Recent research in animal models identified four distinct initiation sites for neural tube (NT) fusion.
- Clinical cases of human NTDs and existing medical literature were reviewed to assess closure patterns.
Findings:
- The multisite model effectively explains the majority of human NTDs as failures of specific closure sites or their adjacent neuropores.
- Specific NTDs are hypothesized to arise from failures at particular closure sites: anencephaly (closures 2, 4), spina bifida cystica (closure 1), craniorachischisis (closures 1, 2, 4), and cephaloceles (closure junctions or closure 4).
- Closure 3 non-fusion is rare, presenting as midfacial clefts, while caudal NT closure may involve a fifth site.
Implications:
- Classifying NTDs by their specific closure site failure offers a more comprehensive understanding of their etiology.
- This model aids in identifying genetic and environmental factors affecting distinct closure sites, potentially leading to targeted prevention and treatment strategies.
- Recognizing multisite closure is vital for future research, clinical classification, and understanding the pathogenesis of NTDs.