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Review
. 2015 Apr 30:1:15007.
doi: 10.1038/nrdp.2015.7.

Spina bifida

Andrew J Copp  1 , N Scott Adzick  2 , Lyn S Chitty  3 , Jack M Fletcher  4 , Grayson N Holmbeck  5 , Gary M Shaw  6
Affiliations
Review

Spina bifida

Andrew J Copp et al. Nat Rev Dis Primers. .

Abstract

Spina bifida is a birth defect in which the vertebral column is open, often with spinal cord involvement. The most clinically significant subtype is myelomeningocele (open spina bifida), which is a condition characterized by failure of the lumbosacral spinal neural tube to close during embryonic development. The exposed neural tissue degenerates in utero, resulting in neurological deficit that varies with the level of the lesion. Occurring in approximately 1 per 1,000 births worldwide, myelomeningocele is one of the most common congenital malformations, but its cause is largely unknown. The genetic component is estimated at 60-70%, but few causative genes have been identified to date, despite much information from mouse models. Non-genetic maternal risk factors include reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity. Primary prevention by periconceptional supplementation with folic acid has been demonstrated in clinical trials, leading to food fortification programmes in many countries. Prenatal diagnosis is achieved by ultrasonography, enabling women to seek termination of pregnancy. Individuals who survive to birth have their lesions closed surgically, with subsequent management of associated defects, including the Chiari II brain malformation, hydrocephalus, and urological and orthopaedic sequelae. Fetal surgical repair of myelomeningocele has been associated with improved early neurological outcome compared with postnatal operation. Myelomeningocele affects quality of life during childhood, adolescence and adulthood, posing a challenge for individuals, families and society as a whole. For an illustrated summary of this Primer, visit: http://go.nature.com/fK9XNa.

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Figures

Figure 1
Figure 1. Overview of neural tube defects.
Schematic representation of several neural tube defects (NTDs). Spina bifida occulta is found in up to 10% of people and usually occurs in the low spinal region. Closed spinal dysraphism has many variants, including lipomyelomeningocele, low-lying conus and thickened filum terminale. CSF, cerebrospinal fluid.
Figure 2
Figure 2. Neurulation and the origin of open and closed spinal bifida.
(a) Schematic transverse sections showing the process of primary neurulation, which involves bending of the neural plate, convergence of the neural folds and closure of the neural tube. (b) A histological section through the open spinal neural folds of an unaffected human embryo (Carnegie stage 12, 26 days post-fertilization), showing the closing neural tube during primary neurulation. (c) Failure of the neural groove to close in the low spinal region in the fourth week after fertilization leads to myelomeningocele (also termed open spina bifida). (d) Schematic sagittal sections showing the process of secondary neurulation, which involves condensation of the caudal eminence, followed by the formation of the lumen (canalization), completion of secondary neurulation and regression of the tail. This process finalizes in the sixth week after fertilization. (e) A histological section through an unaffected human embryo (Carnegie stage 13, 30 days post-fertilization), showing formation of the secondary neural tube (nt) through canalization. (f) Failure of the secondary neural tube to separate from non-neural tissues (tethering) leads to closed spinal dysraphism, in this case with massive lipoma. no, notochord; np, neural plate; so, somite.
Figure 3
Figure 3. MRI appearance of brain dysmorphology in myelomeningocele.
Mid-sagittal MRI images of a typically developing child (parts a, d and g), a child with myelomeningocele and a hypoplastic corpus callosum (parts b, e and h) and a child with myelomeningocele and a hypogenetic corpus callosum (parts c, f and i). T1-weighted MRI images (parts a–c) that reveal a downward shift of the cerebellum (cb) in the children with spina bifida, representing the Chiari II malformation. Also note the tectal beaking (t) and the structural abnormalities in the corpus callosum (cc). Diffusion imaging tractography (parts d–i) showing connectivity emanating from the corpus callosum. This connectivity is divided into anterior (frontal; blue) and posterior (yellow) segments (parts g–i). Note the relative preservation of frontal connectivity in the individuals with spina bifida. There is a greater and more aberrant pattern of connectivity in the child with the hypogenetic corpus callosum. Images courtesy of K. Bradley (University of Houston, Texas, USA) and J. Juranek (University of Texas Health Science Center at Houston, USA).
Figure 4
Figure 4. Myelomeningocele and associated cranial signs on ultrasonography.
Diagnostic ultrasonography images of normally developing fetuses and fetuses with myelomeningocele. Compared with the regular, parallel vertebrae covered with skin in a normal fetus (part a), the spine is protruding from the vertebral column in myelomeningocele (arrow, part b). The low spinal view of a normal fetus (part c) shows the cauda equina within the vertebral canal, whereas in spina bifida, a protruding meningeal cyst is visible (arrow, part d). In a typically developing fetus, the skull has a regular, smooth frontal appearance (part e). By contrast, cranial signs that accompany myelomeningocele include the lemon sign, which is due to scalloping of the frontal bones (arrows, part f). Of note, the size of the anterior horn is also marked in part f. Compared with the dumb-bell shape of the unaffected fetal cerebellum (part g), the banana sign seen in myelomenigocele is characterized by a convex-shaped cerebellum (arrows, part h).
Figure 5
Figure 5. Fetal surgery for spina bifida.
When a human fetus with spina bifida reaches 22 weeks of gestation, the mother and fetus can undergo surgery to repair the fetal spinal lesion. First, a hysterotomy is made in the mother by a uterine stapler, exposing the myelomeningocele lesion and neural placode (part a). This is followed by closure of the myelomeningocele lesion using a dural and myofascial flap (part b).
Figure 6
Figure 6. Quality-of-life concerns across developmental stages in patients with spina bifida.
Schematic representation of the main quality-of-life concerns for individuals with spina bifida.
Figure 7
Figure 7. Folate metabolism and possible interventions.
Maternal supplementation with folic acid prevents many cases of spina bifida, most probably through its regulation of epigenetic modifications (methylation) and/or cell proliferation (through a role in the synthesis of purines and pyrimidines) in the embryo, although the exact mechanism is incompletely understood. However, defects in enzymes involved in these pathways might mean that folic acid supplementation alone is inadequate and point to the need to supplement with other metabolites (green boxes). Thus far, mutations in the genes encoding several enzymes involved in the folate one-carbon metabolism pathway (especially in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR); maternal and fetal mutations) and the glycine cleavage system (which produces formate in the mitochondria; fetal mutations only) have been definitively associated with increased risk of spina bifida. Solid arrows indicate the key metabolic reactions. Dashed arrows indicate metabolic pathways that involve multiple reactions.
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References

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