Spina Bifida Cystica

Complex MONDO:0017069 Pathograph 18 Show in embeddings browser Spina Bifida Neural Tube Defect

Spina bifida cystica is an open (or, for meningocele, skin-covered but cystic) neural tube defect produced by failed closure of the caudal neuropore during the third and fourth weeks after fertilization, leaving a cystic protrusion of meninges and/or the neural placode through a posterior vertebral arch defect, most often lumbosacral. It spans two clinically distinct forms grouped under the same MONDO parent: meningocele, in which only meninges and cerebrospinal fluid herniate through the defect and the spinal cord is usually intact and functions normally, and myelomeningocele, in which the neural placode itself is exposed and incorporated into the sac. Myelomeningocele is both the more common and by far the clinically dominant form: it produces lesion-level-dependent paralysis and sensory loss, neurogenic bladder and bowel, orthopedic deformity, and, in nearly all cases, a Chiari II hindbrain malformation with secondary hydrocephalus. Most nonsyndromic disease is complex and multifactorial, reflecting disrupted planar-cell-polarity-dependent convergent extension (VANGL1, VANGL2) and impaired folate-dependent one-carbon metabolism (MTHFR) against a polygenic background; periconceptional folic acid is the only proven environmental protective factor. Motor and sensory deficit in myelomeningocele is thought to reflect a "two-hit" process: the primary failure of neural tube closure, followed by progressive chemical and mechanical injury to the exposed placode from amniotic fluid and fetal movement throughout gestation -- the rationale for fetal surgical repair tested in the MOMS trial.

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1
Inheritance
8
Pathophys.
11
Phenotypes
18
Pathograph
4
Genes
4
Medical Actions
2
Subtypes
1
References
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC
👪

Inheritance

1
Multifactorial polygenic inheritance HP:0010982
Nonsyndromic spina bifida cystica does not follow a Mendelian pattern. Heritability is substantial (60-70%) but reflects a polygenic background of common and rare variants (MTHFR, VANGL1/VANGL2, the 22q11.2/CRKL deletion, and others) interacting with environmental factors (folate status, anticonvulsant exposure, maternal diabetes, maternal obesity) rather than a single causal gene -- consistent with this entry's own `category: Complex`. Sibling recurrence risk is markedly elevated over general-population prevalence but far below Mendelian expectation.
Polygenic inheritance
Show evidence (2 references)
PMID:27189655 SUPPORT Human Clinical
"The genetic component is estimated at 60-70%, but few causative genes have been identified to date, despite much information from mouse models."
States the overall heritability estimate and that no single causative gene accounts for most nonsyndromic disease, consistent with a polygenic architecture.
PMID:27189655 SUPPORT Human Clinical
"The recurrence risk for siblings of an index case is 2-5%, therefore representing a 20 to 50-fold increased risk compared with the general population prevalence of ~1 per 1000."
Quantifies sibling recurrence risk, the single most clinically useful genetic-counseling number for this entry, and shows it is markedly elevated over but far below Mendelian expectation.
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Subtypes

2
Meningocele (skin-covered, meninges-only) MONDO:0017076
Herniation of a cerebrospinal-fluid-filled meningeal sac (dura and arachnoid) through the posterior spina bifida defect, usually covered by skin of variable thickness. The spinal cord and nerve roots are generally not incorporated into the sac and function normally, though a tethered cord may coexist. Most commonly lumbar or sacral. This is the less common and clinically milder of the two forms.
Show evidence (1 reference)
PMID:20738329 SUPPORT Human Clinical
"Closed NTDs with a mass are represented by lipomyeloschisis, lipomyelomeningocele, meningocele, and myelocystocele."
Distinguishes meningocele (a mass-bearing but skin-covered lesion) from the open myelomeningocele form within the spina bifida cystica spectrum.
Myelomeningocele (open, neural placode exposed) MONDO:0019773
The severe, clinically dominant form of spina bifida cystica: the neural placode itself, not only the meninges, protrudes through the vertebral defect and is exposed to the intrauterine environment. Almost universally accompanied by Chiari II hindbrain herniation and consequent hydrocephalus. Produces lesion-level-dependent paralysis, sensory loss, and neurogenic bladder/bowel dysfunction.
Show evidence (2 references)
PMID:27189655 SUPPORT Human Clinical
"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."
States that myelomeningocele (open spina bifida) is the most clinically significant subtype of spina bifida cystica.
PMID:38696583 SUPPORT Human Clinical
"Most patients with MM also have Chiari type II malformation and resultant hydrocephalus."
Independent, recent statement of the near-universal co-occurrence of Chiari II malformation and hydrocephalus with myelomeningocele.
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Pathophysiology

8
Impaired Folate-Dependent One-Carbon Metabolism
The common MTHFR c.677C>T variant reduces methylenetetrahydrofolate reductase activity, impairing the one-carbon/folate metabolic pathway that supplies methyl groups for nucleotide synthesis and DNA methylation during neurulation. Reduced enzyme activity is an established, modest genetic susceptibility factor for neural tube defects, and is the biochemical basis for the protective effect of periconceptional folic acid supplementation.
folic acid metabolic process GO:0046655 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased folic acid metabolic process (GO:0046655). GO:0046655 is a biological process from the Gene Ontology. ↓ DECREASED one-carbon metabolic process GO:0006730 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased one-carbon metabolic process (GO:0006730). GO:0006730 is a biological process from the Gene Ontology. ↓ DECREASED
methylenetetrahydrofolate reductase (NAD(P)H) activity GO:0004489 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased methylenetetrahydrofolate reductase (NAD(P)H) activity, annotated with methylenetetrahydrofolate reductase [NAD(P)H] activity (GO:0004489). GO:0004489 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Failed Posterior Neuropore Closure Impaired folate-dependent methylation and nucleotide supply during the neurulation window is a modest, non-deterministic contributor to failure of posterior neuropore closure, acting alongside planar-cell-polarity and other susceptibility factors.
Show evidence (1 reference)
PMID:9068801 SUPPORT Human Clinical
"This meta-analysis confirms that the 677C-->T mutation is a genetic risk factor for NTD."
Meta-analytic confirmation that the common MTHFR variant reducing enzyme activity is a genetic risk factor for neural tube defects, including spina bifida.
Planar Cell Polarity Pathway Disruption
Rare missense variants in the core planar-cell-polarity (PCP) genes VANGL1 and VANGL2 -- the human orthologs of the Drosophila Van Gogh/ Strabismus gene and of the mouse Looptail (Lp) locus -- impair non-canonical Wnt/PCP signaling. This pathway drives convergent extension, the coordinated mediolateral cell intercalation that narrows and elongates the neural plate; its disruption is a well-established genetic contributor to neural tube defects in both animal models and human cohorts, found in an estimated 1-3% of patients.
Genetic context VANGL1 hgnc:15512 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns VANGL1 (hgnc:15512). hgnc:15512 is a gene from the HUGO Gene Nomenclature Committee. VANGL2 hgnc:15511 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns VANGL2 (hgnc:15511). hgnc:15511 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Wnt/planar cell polarity signaling pathway GO:0060071 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Wnt/planar cell polarity signaling pathway, annotated with Wnt signaling pathway, planar cell polarity pathway (GO:0060071). GO:0060071 is a biological process from the Gene Ontology. ↓ DECREASED convergent extension involved in neural plate elongation GO:0022007 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased convergent extension involved in neural plate elongation (GO:0022007). GO:0022007 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failed Posterior Neuropore Closure Disrupted convergent extension prevents the neural folds from being brought into apposition at the dorsal midline, directly impairing closure of the posterior neuropore.
Show evidence (3 references)
PMID:17409324 SUPPORT Human Clinical
"We have identified three mutations in the VANGL1 gene in patients with familial types (V239I and R274Q) and a sporadic type (M328T) of the disease, including a spontaneous mutation (V239I) appearing in a familial setting."
Founding report identifying pathogenic VANGL1 missense variants in human neural tube defect patients.
PMID:17409324 SUPPORT In Vitro
"In a protein-protein interaction assay V239I abolished interaction of VANGL1 protein with its binding partners, disheveled-1, -2, and -3."
Demonstrates the functional (partial loss-of-function) consequence of the V239I variant on PCP-pathway protein-protein interaction.
PMID:20738329 SUPPORT Human Clinical
"This suggests that VANGL2 mutations may predispose to NTDs in approximately 2.5% of closed spinal NTDs (5 in 202), at a frequency that is significantly different from that of 0.4% (2 in 453) detected in open spina bifida patients (p = 0.027)."
Quantifies the contribution of rare VANGL2 missense variants to human spinal neural tube defects, including open spina bifida cystica.
Maternal Obesity-Associated Neurulation Risk
Maternal obesity is an independent, dose-response risk factor for spina bifida cystica -- more severe obesity confers greater risk -- and is mechanistically distinct from the folate pathway: unlike folate insufficiency, obesity-associated risk is not consistently rescued by folic acid supplementation. Suggested underlying mechanisms include aberrant maternal glucose control, oxidative stress, and metabolic syndrome, though the precise pathway remains uncertain.
Downstream
Failed Posterior Neuropore Closure Maternal obesity is proposed to disrupt neurulation through aberrant glucose control, oxidative stress, and/or metabolic syndrome, though the exact intermediate mechanism linking obesity to failed neuropore closure remains unresolved.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"severe obesity (body mass index > 35) has been associated with even larger risks indicative of a “dose-response” relationship linking obesity with spina bifida."
States the dose-response relationship between maternal body mass index and spina bifida risk.
Failed Posterior Neuropore Closure
The defining lesion of spina bifida cystica: the posterior neuropore, which normally completes closure by approximately day 28 after fertilization, fails to fuse. This leaves a persistent gap in the neural tube and overlying vertebral arches, meninges, muscle, and skin at the affected spinal level, most often lumbosacral.
neural tube closure GO:0001843 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural tube closure (GO:0001843). GO:0001843 is a biological process from the Gene Ontology. ↓ DECREASED
neural tube UBERON:0001049 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in neural tube (UBERON:0001049). UBERON:0001049 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Open Neural Placode Exposure and Secondary Injury When the failure of closure is complete at the affected level, the neural placode itself remains unfused and open to the amniotic cavity, producing myelomeningocele rather than meningocele.
Skin-Covered Meningeal Herniation When neural tube closure fails only at the level of the vertebral arches and meninges while the neural placode itself closes and is covered by skin, the result is the milder meningocele phenotype rather than an open, neural-tissue-bearing lesion.
Show evidence (1 reference)
PMID:23790957 SUPPORT Human Clinical
"NTDs comprise a diverse set of birth defects that are usually considered to arise during the third and fourth weeks post-fertilisation."
Establishes the third/fourth-week post-fertilisation timing of neural tube closure failure, the general mechanistic category to which spina bifida cystica belongs.
Open Neural Placode Exposure and Secondary Injury
The "two-hit" mechanism proposed to explain the paralysis of myelomeningocele: the primary failure of neurulation (hit one) leaves the neural placode exposed to the amniotic cavity for the remainder of gestation, where chemical injury from amniotic fluid and mechanical trauma from fetal movement (hit two) causes progressive erosion, necrosis, and loss of neurons and axons beyond what congenital myelodysplasia alone would produce. This is the mechanistic rationale for in-utero surgical repair, which aims to halt the second hit rather than reverse the first.
cell death (necrosis) GO:0008219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell death (necrosis), annotated with cell death (GO:0008219). GO:0008219 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Chiari II Hindbrain Herniation Chronic leakage of cerebrospinal fluid through the open neural tube prevents the embryonic ventricular system from distending, arresting posterior fossa growth (McLone-Knepper unified theory). This node cross-references, and deliberately does not duplicate, the detailed hydrocephalus mechanism curated in the Congenital_Hydrocephalus entry's "Neural Tube Defect with Chiari II Hindbrain Herniation and Small Posterior Fossa" node.
Segmental Motor and Sensory Neuron Loss Progressive destruction of the exposed placode causes segmental loss of motor and sensory neurons at and below the level of the lesion.
Show evidence (2 references)
PMID:2362676 SUPPORT Model Organism
"We therefore propose a "two-hit" hypothesis to explain the paralysis seen in children with myelomeningocele: congenital myelodysplasia complicated by an intrauterine spinal cord injury."
Originating statement of the two-hit hypothesis, based on a fetal rat model of surgically created spinal dysraphism.
PMID:2362676 SUPPORT Model Organism
"Histological studies of the exposed spinal cord revealed extensive erosion and necrosis, findings similar to those described in children with myelomeningocele."
Model-organism histological evidence for progressive secondary injury of exposed neural tissue, paralleling human myelomeningocele pathology.
Skin-Covered Meningeal Herniation
In meningocele, the vertebral arch defect and meningeal herniation occur without exposure or incorporation of the neural placode, which remains covered by an intact (if sometimes dysplastic or ulcerated) layer of skin. Because neural tissue is not directly exposed to the intrauterine environment, the "two-hit" secondary injury that drives myelomeningocele paralysis does not apply, and neurological examination is often normal; a tethered cord can still cause delayed deficits.
Show evidence (1 reference)
PMID:23790957 SUPPORT Human Clinical
"Closed spinal lesions are generally less severe and can be asymptomatic, as with spina bifida occulta which is considered a variant of normal. However, lumbosacral spinal cord tethering may be present in spinal dysraphism, and can lead to lower limb motor and sensory deficits, and a neuropathic bladder."
States that closed spinal lesions such as meningocele are generally less severe than open lesions and can be asymptomatic, though tethered cord can still cause delayed neurological deficit.
Chiari II Hindbrain Herniation
Near-universal in myelomeningocele: caudal displacement of the medulla, fourth ventricle, and cerebellar vermis into the cervical spinal canal, with an abnormally small posterior fossa. Obstructs cerebrospinal fluid egress at the fourth ventricular outflow and foramen magnum, producing hydrocephalus. This node is a deliberate cross-reference to the more detailed Congenital_Hydrocephalus entry rather than a re-derivation of it; see that entry's "Chiari II-associated" subtype and "Neural Tube Defect with Chiari II Hindbrain Herniation and Small Posterior Fossa" node for the full CSF-dynamics mechanism.
Downstream
Hydrocephalus Obstruction of cerebrospinal fluid outflow at the level of the herniated hindbrain and small posterior fossa produces ventricular dilatation.
Show evidence (2 references)
PMID:2699756 SUPPORT Other
"The cause of the Chiari II hindbrain deformity in children born with a myelomeningocele can be explained by the lack of distention of the embryonic ventricular system."
States the unified-theory mechanism linking the open neural tube to the Chiari II hindbrain deformity. Evidence source is OTHER because the snippet is a theoretical/mechanistic proposal rather than a reported study result.
PMID:31980545 SUPPORT Human Clinical
"lower rates of hindbrain herniation (60% vs 87%; P < .001), had fewer shunts placed for hydrocephalus (49% vs 85%; P < .001)"
Quantifies both the high baseline rate of hindbrain herniation and shunt-requiring hydrocephalus after postnatal repair, and the reduction achieved by prenatal repair.
Segmental Motor and Sensory Neuron Loss
Destruction of the exposed neural placode causes segmental denervation of the lower limbs and of the autonomically innervated bladder, bowel, and pelvic floor, with severity and level determined by the rostrocaudal extent of the lesion.
Downstream
Lower Limb Weakness and Sensory Loss Loss of motor and sensory neurons below the level of the lesion produces flaccid, lesion-level-dependent paraparesis or paraplegia with sensory deficit.
Neurogenic Bladder Denervation of the detrusor, sphincter, and pelvic floor musculature produces neurogenic bladder dysfunction.
Show evidence (1 reference)
PMID:38696583 SUPPORT Human Clinical
"MM often requires either pre- or postnatal surgical repair, resulting in major long-term complications such as paraparesis, bowel and bladder incontinence, and learning difficulties."
States the clinical consequences of segmental neural loss in myelomeningocele.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spina Bifida Cystica Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Genitourinary 1
Neurogenic Bladder VERY_FREQUENT HP:0000011 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurogenic bladder (HP:0000011). HP:0000011 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"These include urinary retention with overflow and ureteric reflux which can lead to recurrent urinary tract infections and ultimately deterioration of renal function."
States the downstream urological and renal consequences of untreated neurogenic bladder dysfunction in spina bifida.
Limbs 1
Clubfoot Talipes equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"Orthopedic abnormalities including talipes (club foot), contractures, hip dislocation, scoliosis and kyphosis are frequently observed."
Names clubfoot (talipes), among other orthopedic deformities, as a frequently observed complication.
Musculoskeletal 1
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650), qualified as course progressive. HP:0002650 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"Orthopedic abnormalities including talipes (club foot), contractures, hip dislocation, scoliosis and kyphosis are frequently observed."
Names scoliosis, among other orthopedic deformities, as a frequently observed complication.
Nervous System 4
Cystic Spinal Lesion VERY_FREQUENT Spina bifida HP:0002414 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spina bifida cystica, annotated with Spina bifida (HP:0002414). HP:0002414 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38696583 SUPPORT Human Clinical
"Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system."
Establishes the open spinal lesion as a defining phenotype of the myelomeningocele form, itself a subtype of the broader spina bifida cystica entry-defining lesion.
Hydrocephalus VERY_FREQUENT HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31980545 SUPPORT Human Clinical
"had fewer shunts placed for hydrocephalus (49% vs 85%; P < .001) and, among those with shunts, fewer shunt revisions (47% vs 70%; P = .02) than those in the postnatal group."
Quantifies the high baseline (postnatal-repair) rate of shunt-requiring hydrocephalus in myelomeningocele.
Tethered Cord HP:0002144 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tethered cord (HP:0002144). HP:0002144 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23790957 SUPPORT Human Clinical
"lumbosacral spinal cord tethering may be present in spinal dysraphism, and can lead to lower limb motor and sensory deficits, and a neuropathic bladder."
States that spinal cord tethering can occur in spinal dysraphism (including meningocele) and cause delayed motor, sensory, and bladder deficits.
Intellectual Disability OCCASIONAL HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27189655 SUPPORT Human Clinical
"Intellectual disability is relatively infrequent, affecting perhaps 20-25% of people with MMC and often after complications of hydrocephalus."
Directly quantifies the frequency of intellectual disability in myelomeningocele and links it to hydrocephalus complications.
PMID:38696583 SUPPORT Human Clinical
"MM often requires either pre- or postnatal surgical repair, resulting in major long-term complications such as paraparesis, bowel and bladder incontinence, and learning difficulties."
Independently names learning difficulties, alongside paraparesis and bowel/bladder incontinence, as a major long-term complication of myelomeningocele.
Constitutional 1
Neurogenic Bowel Dysfunction Bowel incontinence HP:0002607 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bowel incontinence (HP:0002607). HP:0002607 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38696583 SUPPORT Human Clinical
"MM often requires either pre- or postnatal surgical repair, resulting in major long-term complications such as paraparesis, bowel and bladder incontinence, and learning difficulties."
Names bowel incontinence, alongside bladder incontinence and paraparesis, as a major long-term complication of myelomeningocele.
Other 3
Meningocele HP:0002435 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Meningocele (HP:0002435). HP:0002435 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20738329 SUPPORT Human Clinical
"Closed NTDs with a mass are represented by lipomyeloschisis, lipomyelomeningocele, meningocele, and myelocystocele."
Distinguishes meningocele, a mass-bearing but neural-placode-sparing lesion, from the open myelomeningocele form.
Lower Limb Weakness and Sensory Loss Lower limb muscle weakness HP:0007340 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb muscle weakness (HP:0007340). HP:0007340 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38696583 SUPPORT Human Clinical
"MM often requires either pre- or postnatal surgical repair, resulting in major long-term complications such as paraparesis, bowel and bladder incontinence, and learning difficulties."
Names paraparesis as a major long-term complication of myelomeningocele.
Chiari Type II Malformation VERY_FREQUENT HP:0025660 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chiari type II malformation (HP:0025660). HP:0025660 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21306277 SUPPORT Human Clinical
"Nearly all infants who are born with myelomeningocele have the Arnold–Chiari II malformation, which includes a constellation of anomalies that include hindbrain herniation (downward displacement of the medulla, fourth ventricle, and cerebellum into the spinal canal), brain-stem abnormalities,..."
States both the near-universal co-occurrence with myelomeningocele and the anatomical content of the malformation.
🧬

Genetic Associations

4
MTHFR (The c.677C>T (Ala222Val) variant reduces methylenetetrahydrofolate reductase enzyme activity, impairing folate-dependent one-carbon metabolism during neurulation.)
Gene: MTHFR hgnc:7436 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MTHFR (hgnc:7436). hgnc:7436 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:9068801 SUPPORT Human Clinical
"ORs for all reported NTD patients and their parents of: 1.7 [95% CI: 1.1-2.6]; 1.8 [95% CI: 1.1-3.1] and 1.9 [95% CI: 1.3-2.8] for mothers (combined prevalence 14.5%), fathers (combined prevalence 15.5%) and NTD patients (combined prevalence 16.4%), respectively, vs. all international controls."
Quantifies the modest but statistically significant increased odds of neural tube defects associated with the MTHFR 677C>T variant.
VANGL1 (Missense variants (e.g. V239I, R274Q, M328T) partially disrupt VANGL1 interaction with Dishevelled proteins, impairing planar-cell-polarity signaling required for convergent extension.)
Gene: VANGL1 hgnc:15512 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VANGL1 (hgnc:15512). hgnc:15512 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:17409324 SUPPORT Human Clinical
"These findings implicate VANGL1 as a risk factor in human neural-tube defects."
Founding statement implicating VANGL1 as a human neural tube defect risk gene.
VANGL2 (Rare missense variants in the human ortholog of the mouse Looptail (Lp) gene, which causes severe neural tube defects (craniorachischisis) in homozygotes and is the founding planar-cell-polarity model for mammalian neurulation.)
Gene: VANGL2 hgnc:15511 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VANGL2 (hgnc:15511). hgnc:15511 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:20738329 SUPPORT Human Clinical
"Our findings strongly implicate VANGL2 in the genetic causation of spinal NTDs in a subset of patients and provide additional evidence for a pathogenic role of PCP signaling in these malformations."
Summarizes the human genetic evidence implicating VANGL2 in spinal neural tube defects.
22q11.2 deletion (CRKL) (Recurrent heterozygous 22q11.2 microdeletion spanning CRKL; loss of Crkl is sufficient to cause neural tube defects in mice, with penetrance and expressivity worsened by maternal folate deficiency and partly rescued by folate supplementation, directly linking a structural genetic lesion to the folate pathway.)
Gene: CRKL hgnc:2363 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CRKL (hgnc:2363). hgnc:2363 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR
Show evidence (2 references)
PMID:38696583 SUPPORT Human Clinical
"Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population."
Reports the strength of association between the 22q11.2 deletion and myelomeningocele in a large trio sequencing cohort.
PMID:38696583 SUPPORT Model Organism
"The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency."
States the mouse functional validation (Crkl loss reproduces NTDs) and the folate-modified penetrance/expressivity that establish CRKL loss as a mechanistic driver linked to the folate pathway.
💊

Medical Actions

4
Postnatal Surgical Closure
Action: neurosurgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is neurosurgical procedure (NCIT:C15656). NCIT:C15656 is a clinical intervention from the NCI Thesaurus. Ontology label: Neurosurgical Procedure NCIT:C15656
Surgical closure of the open spinal defect, generally performed within 24-48 hours of birth when prenatal repair has not been performed, to protect the exposed placode from further injury and infection. Does not reverse neurological deficit already present at birth.
Mechanism Target:
INHIBITS Open Neural Placode Exposure and Secondary Injury — Covering the exposed placode halts further chemical and mechanical "second-hit" injury, though it does not reverse deficits already sustained.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"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."
Describes standard postnatal surgical closure as the immediate management step, followed by lifelong management of associated defects.
Prenatal (Fetal) Repair of Myelomeningocele
Action: fetal surgical repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is fetal surgical repair, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
In-utero surgical closure of the open neural tube defect, offered to selected pregnancies (T1-S1 lesion level, hindbrain herniation, suitable gestational age, no major contraindication) before 26 weeks of gestation. Demonstrated in the randomized MOMS trial to reduce hindbrain herniation and shunt-requiring hydrocephalus and to improve motor outcomes relative to postnatal repair, at the cost of maternal hysterotomy risk and increased prematurity.
Mechanism Target:
INHIBITS Open Neural Placode Exposure and Secondary Injury — Closing the open neural tube before birth halts chronic amniotic-fluid exposure and mechanical injury to the placode earlier than postnatal repair can, and restores embryonic ventricular pressure whose absence drives the Chiari II hindbrain deformity.
Show evidence (2 references)
PMID:21306277 SUPPORT Human Clinical
"Prenatal surgery for myelomeningocele reduced the need for shunting and improved motor outcomes at 30 months but was associated with maternal and fetal risks."
States the primary MOMS trial finding of benefit balanced against procedural risk.
PMID:31980545 SUPPORT Human Clinical
"Long-term benefits of prenatal surgery included improved mobility and independent functioning and fewer surgeries for shunt placement and revision, with no strong evidence of improved cognitive functioning."
School-age MOMS follow-up confirming durable motor and shunt-related benefit without a demonstrated cognitive benefit.
Clean Intermittent Catheterization for Neurogenic Bladder
Action: intermittent urinary catheterizationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intermittent urinary catheterization, annotated with Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. Ontology label: Therapeutic Procedure NCIT:C49236
Regular clean intermittent catheterization, with adjunctive antimuscarinic or beta-3 agonist pharmacotherapy and urodynamic surveillance as needed, to manage neurogenic bladder and protect renal function.
Mechanism Target:
INHIBITS Neurogenic Bladder — Regular bladder emptying by catheterization reduces high intravesical pressure and stasis, mitigating the vesicoureteral reflux and recurrent infection that drive renal injury in neurogenic bladder.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"Bladder and urinary tract management often includes a combination of clean intermittent catheterization, pharmacological agents, and surgery."
States that clean intermittent catheterization is a standard component of bladder and urinary tract management in spina bifida cystica.
Orthopedic Management of Clubfoot and Hip/Spine Deformity
Action: orthopedic surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthopedic surgical procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Serial casting, bracing, and, when needed, corrective surgery for clubfoot, hip subluxation/dislocation, and progressive scoliosis resulting from muscle imbalance below the lesion level.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"Orthopedic abnormalities including talipes (club foot), contractures, hip dislocation, scoliosis and kyphosis are frequently observed."
Names the orthopedic complications this treatment category addresses.
🌍

Environmental Factors

4
Periconceptional Folic Acid Supplementation
exposure to folic acid via ingestion ECTO:0900036 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to folic acid via ingestion (ECTO:0900036). ECTO:0900036 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Adequate periconceptional folic acid intake (400 micrograms/day for the general population; higher supervised doses after a prior neural tube defect pregnancy) is the only proven environmental protective factor against spina bifida cystica; conversely, insufficient intake raises risk. Mandatory grain fortification programs are associated with population-level declines in prevalence.
Show evidence (1 reference)
PMID:1677062 SUPPORT Human Clinical
"Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy, and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid."
States the general recommendation for periconceptional folic acid supplementation as a proven preventive measure against neural tube defects, including spina bifida cystica.
Mechanism Target:
PROTECTS_AGAINST Impaired Folate-Dependent One-Carbon Metabolism — Adequate periconceptional folic acid intake supplies the substrate for folate-dependent one-carbon metabolism during neurulation, offsetting reduced MTHFR enzyme activity and other sources of impaired one-carbon flux, and thereby reducing the risk of failed neuropore closure.
Show evidence (2 references)
PMID:1677062 SUPPORT Human Clinical
"27 of these had a known neural tube defect, 6 in the folic acid groups and 21 in the two other groups, a 72% protective effect (relative risk 0.28, 95% confidence interval 0.12-0.71)."
Landmark randomized controlled trial establishing a large, statistically significant protective effect of periconceptional folic acid supplementation against neural tube defect recurrence.
PMID:38696583 SUPPORT Model Organism
"Crkl mutant embryos on a low–maternal FA diet displayed a notably increased prevalence of exencephaly (37.5%, 3/8), a severe form of murine NTD (Fig. 2 and fig. S8; odds ratio for low FA diet versus control diet of 34.96, P = 0.0031, 95% CI = 3.05 to 400.71), whereas no control littermates had NTDs."
Direct mouse gene-environment evidence that maternal folate deficiency exacerbates neural tube defect penetrance/expressivity on a genetically susceptible (Crkl-null) background, mechanistically grounding the protective folate effect.
Anticonvulsant (Valproate) Exposure During Pregnancy
anticonvulsant exposure during pregnancy ECTO:9001740 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is anticonvulsant exposure during pregnancy, annotated with exposure to anticonvulsant (ECTO:9001740). ECTO:9001740 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
First-trimester exposure to the anticonvulsant valproic acid (VPA) is a well-established, substantial (~10-fold) independent risk factor for neural tube defects, including spina bifida cystica, distinct from folate status.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"Non-genetic maternal risk factors include reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity."
Names anticonvulsant therapy among the established non-genetic maternal risk factors for spina bifida.
Mechanism Target:
TRIGGERS Failed Posterior Neuropore Closure — Valproic acid's potent histone deacetylase (HDAC) inhibitory activity is proposed to disturb the balance of protein acetylation and deacetylation required for normal neurulation, triggering failure of posterior neuropore closure independent of maternal folate status.
Show evidence (2 references)
PMID:27189655 SUPPORT Human Clinical
"The anticonvulsant valproic acid (VPA) increases risk of NTDs by ~10-fold when taken during the first trimester of pregnancy."
Quantifies the magnitude of neural tube defect risk conferred by first-trimester VPA exposure.
PMID:23790957 SUPPORT Other
"recent findings with VPA suggest a potent histone deacetylase (HDAC) inhibitory activity."
States the proposed HDAC-inhibition mechanism by which VPA is thought to disrupt neurulation. Evidence source is OTHER because the snippet reports a mechanistic proposal rather than a primary human or animal study result.
Pregestational (Maternal) Diabetes Mellitus
pregestational maternal diabetes mellitus Relation: this environmental factor is this exposure This environmental factor is pregestational maternal diabetes mellitus.
ECTO models chemical/environmental exposures rather than host metabolic conditions; no ECTO exposure term binds "maternal diabetes" or "hyperglycemia" directly (searched "diabetes", "hyperglycemia", "maternal diabetes"), so exposure_term is left as free text.
Pre-existing maternal diabetes mellitus, which predisposes to a range of birth defects, is an established independent risk factor for neural tube defects including spina bifida cystica, mediated by hyperglycemia rather than by folate status.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"Non-genetic maternal risk factors include reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity."
Names diabetes mellitus among the established non-genetic maternal risk factors for spina bifida.
Mechanism Target:
TRIGGERS Failed Posterior Neuropore Closure — Maternal hyperglycemia is described as the immediate cause of neural tube defects in pregestational diabetes, though the precise pathogenic mechanism linking hyperglycemia to failed neuropore closure remains poorly understood.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"In maternal diabetes mellitus, which predisposes to a range of birth defects including NTDs, hyperglycemia is the immediate cause of NTDs although its pathogenic mechanism is poorly understood."
States that hyperglycemia is the immediate cause of neural tube defects in pregestational diabetes, while noting the underlying mechanism is not well understood.
Maternal Obesity
maternal obesity Relation: this environmental factor is this exposure This environmental factor is maternal obesity.
ECTO models chemical/environmental exposures rather than host metabolic states; no ECTO exposure term binds "maternal obesity" or "body mass index" directly (searched "obesity", "maternal obesity", "body mass index"), so exposure_term is left as free text.
Maternal obesity is an established, dose-response independent risk factor for spina bifida cystica, mechanistically distinct from the folate pathway because the elevated risk is not consistently rescued by folic acid supplementation.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"Non-genetic maternal risk factors include reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity."
Names obesity among the established non-genetic maternal risk factors for spina bifida.
Mechanism Target:
EXACERBATES Maternal Obesity-Associated Neurulation Risk — Maternal obesity exacerbates spina bifida risk in a dose-response manner, and this risk is not consistently modified downward by folic acid supplementation, distinguishing its mechanism from the classic folate-dependent pathway.
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"these obesity-associated risks are stronger for spina bifida than for anencephaly 16–18 and may not be modified downward with folic acid use 19."
States that obesity-associated risk for spina bifida is not consistently reduced by folic acid supplementation, distinguishing this exposure's mechanism from the folate pathway.
🔬

Diagnosis

3
Prenatal Ultrasonography
Detailed second-trimester (and, increasingly, late first-trimester) fetal spine ultrasonography is the principal and most accurate mode of prenatal diagnosis of spina bifida cystica, having progressively supplanted biochemical (AFP) screening.
fetal ultrasound imaging NCIT:C222238 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:27189655 SUPPORT Human Clinical
"Prenatal diagnosis is achieved by ultrasonography, enabling women to seek termination of pregnancy."
States that ultrasonography is the modality by which spina bifida is prenatally diagnosed.
PMID:27189655 SUPPORT Human Clinical
"Today, the fetal spine can be examined by ultrasonography in the sagittal, axial and coronal planes from late first trimester onwards, providing the principal and most accurate mode of prenatal diagnosis."
Establishes detailed multi-plane fetal spine ultrasonography as the principal, most accurate prenatal diagnostic modality.
PMID:27189655 SUPPORT Human Clinical
"However, with the increasing use of routine second trimester anomaly scanning, biochemical screening for MMC is becoming redundant as ultrasound offers greater sensitivity and specificity."
States that ultrasound has progressively supplanted biochemical (AFP) screening owing to greater sensitivity and specificity.
Maternal Serum and Amniotic Fluid Alpha-Fetoprotein Screening
Elevation of alpha-fetoprotein (AFP) in maternal serum and amniotic fluid was historically the basis for prenatal biochemical screening for open neural tube defects such as myelomeningocele; it now plays a declining, secondary role relative to ultrasound except when maternal obesity limits detailed sonographic examination.
alpha-fetoprotein measurement NCIT:C74732 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:27189655 SUPPORT Human Clinical
"Prenatal diagnosis first became possible in the early 1970s, with the finding of an elevated concentration of alphafetoprotein (AFP) in amniotic fluid samples from pregnancies with anencephaly or MMC"
States the historical origin of AFP-based prenatal screening for open neural tube defects, including myelomeningocele.
PMID:23790957 SUPPORT Human Clinical
"diagnosis was based on measurement of alphafetoprotein (AFP) concentration in the amniotic fluid and maternal blood"
Independently states that AFP concentration in amniotic fluid and maternal blood is the basis for prenatal biochemical screening of open neural tube defects such as myelomeningocele.
Fetal MRI
Ultrafast fetal magnetic resonance imaging complements ultrasound to assess hindbrain herniation, hydrocephalus, and other brain abnormalities, and is used in prenatal-repair candidacy evaluation.
fetal MRI NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27189655 SUPPORT Human Clinical
"ultrafast MRI to assess the presence or absence of hindbrain herniation, hydrocephalus, and any other brain abnormalities"
States the use of ultrafast fetal MRI to assess hindbrain herniation, hydrocephalus, and other brain abnormalities as part of prenatal evaluation.
📈

Progression

1
Postnatal survival
First-year survival has improved markedly with modern multidisciplinary care.
Show evidence (1 reference)
PMID:38775408 SUPPORT Human Clinical
"Mortality fell sharply during the first year of life, with survival rising from 75% to 94%."
Quantifies the improvement in first-year survival across the same 50-year Swedish registry study period.
📊

Prevalence

1
Sweden (national registry, 1973-2021)
Birth Prevalence 12.0 per 100,000 (up to 52.0) 1–9 per 10,000
Prevalence fell from 5.2 to 1.2 per 10,000 births over the study period, coinciding with prenatal screening/termination and, later, folic acid fortification.
Show evidence (1 reference)
PMID:38775408 SUPPORT Human Clinical
"the prevalence of spina bifida decreased from 5.2 to 1.2 per 10 000 births"
Direct quantitative statement of prevalence decline across the 50-year Swedish registry study period.
{ }

Source YAML

click to show 
name: Spina Bifida Cystica
creation_date: "2026-08-27T05:00:00Z"
category: Complex
disease_term:
  preferred_term: spina bifida cystica
  term:
    id: MONDO:0017069
    label: spina bifida cystica
description: >-
  Spina bifida cystica is an open (or, for meningocele, skin-covered but
  cystic) neural tube defect produced by failed closure of the caudal
  neuropore during the third and fourth weeks after fertilization, leaving a
  cystic protrusion of meninges and/or the neural placode through a posterior
  vertebral arch defect, most often lumbosacral. It spans two clinically
  distinct forms grouped under the same MONDO parent: meningocele, in which
  only meninges and cerebrospinal fluid herniate through the defect and the
  spinal cord is usually intact and functions normally, and myelomeningocele,
  in which the neural placode itself is exposed and incorporated into the
  sac. Myelomeningocele is both the more common and by far the clinically
  dominant form: it produces lesion-level-dependent paralysis and sensory
  loss, neurogenic bladder and bowel, orthopedic deformity, and, in nearly
  all cases, a Chiari II hindbrain malformation with secondary hydrocephalus.
  Most nonsyndromic disease is complex and multifactorial, reflecting
  disrupted planar-cell-polarity-dependent convergent extension (VANGL1,
  VANGL2) and impaired folate-dependent one-carbon metabolism (MTHFR) against
  a polygenic background; periconceptional folic acid is the only proven
  environmental protective factor. Motor and sensory deficit in
  myelomeningocele is thought to reflect a "two-hit" process: the primary
  failure of neural tube closure, followed by progressive chemical and
  mechanical injury to the exposed placode from amniotic fluid and fetal
  movement throughout gestation -- the rationale for fetal surgical repair
  tested in the MOMS trial.
synonyms:
- meningomyelocele
- open spina bifida
- spina bifida aperta
- spina bifida manifesta
parents:
- Spina Bifida
- Neural Tube Defect
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Curated as a neurodevelopmental malformation of the central nervous
      system; the neurosurgical management arm (myelomeningocele closure,
      shunting) sits within the same chapter scope as the cross-referenced
      Congenital_Hydrocephalus entry.
notes: >-
  No GeneReviews chapter exists for nonsyndromic spina bifida cystica (PubMed
  searches for "spina bifida[TI] GeneReviews[TI]" and "neural tube
  defect[TI] GeneReviews[TI]" returned no results), consistent with
  GeneReviews' focus on Mendelian conditions rather than this predominantly
  complex/multifactorial, polygenic disorder. PMID:27189655 ("Spina bifida.")
  is a Nature Reviews Disease Primers article, not a GeneReviews chapter, and
  is cited as the primary clinical review instead.
references:
- reference: PMID:27189655
  title: "Spina bifida."
has_subtypes:
- name: Meningocele
  display_name: Meningocele (skin-covered, meninges-only)
  subtype_term:
    preferred_term: posterior meningocele
    term:
      id: MONDO:0017076
      label: posterior meningocele
  description: >-
    Herniation of a cerebrospinal-fluid-filled meningeal sac (dura and
    arachnoid) through the posterior spina bifida defect, usually covered by
    skin of variable thickness. The spinal cord and nerve roots are
    generally not incorporated into the sac and function normally, though a
    tethered cord may coexist. Most commonly lumbar or sacral. This is the
    less common and clinically milder of the two forms.
  evidence:
  - reference: PMID:20738329
    reference_title: "Contribution of VANGL2 mutations to isolated neural tube defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Closed NTDs with a mass are represented by lipomyeloschisis,
      lipomyelomeningocele, meningocele, and myelocystocele.
    explanation: >-
      Distinguishes meningocele (a mass-bearing but skin-covered lesion) from
      the open myelomeningocele form within the spina bifida cystica
      spectrum.
- name: Myelomeningocele
  display_name: Myelomeningocele (open, neural placode exposed)
  subtype_term:
    preferred_term: myelomeningocele
    term:
      id: MONDO:0019773
      label: myelomeningocele
  description: >-
    The severe, clinically dominant form of spina bifida cystica: the neural
    placode itself, not only the meninges, protrudes through the vertebral
    defect and is exposed to the intrauterine environment. Almost universally
    accompanied by Chiari II hindbrain herniation and consequent
    hydrocephalus. Produces lesion-level-dependent paralysis, sensory loss,
    and neurogenic bladder/bowel dysfunction.
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      States that myelomeningocele (open spina bifida) is the most clinically
      significant subtype of spina bifida cystica.
  - reference: PMID:38696583
    reference_title: "Risk of meningomyelocele mediated by the common 22q11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients with MM also have Chiari type II malformation and
      resultant hydrocephalus.
    explanation: >-
      Independent, recent statement of the near-universal co-occurrence of
      Chiari II malformation and hydrocephalus with myelomeningocele.
inheritance:
- name: Multifactorial polygenic inheritance
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  description: >-
    Nonsyndromic spina bifida cystica does not follow a Mendelian pattern.
    Heritability is substantial (60-70%) but reflects a polygenic background
    of common and rare variants (MTHFR, VANGL1/VANGL2, the 22q11.2/CRKL
    deletion, and others) interacting with environmental factors (folate
    status, anticonvulsant exposure, maternal diabetes, maternal obesity)
    rather than a single causal gene -- consistent with this entry's own
    `category: Complex`. Sibling recurrence risk is markedly elevated over
    general-population prevalence but far below Mendelian expectation.
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genetic component is estimated at 60-70%, but few causative genes
      have been identified to date, despite much information from mouse
      models.
    explanation: >-
      States the overall heritability estimate and that no single causative
      gene accounts for most nonsyndromic disease, consistent with a
      polygenic architecture.
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The recurrence risk for siblings of an index case is 2-5%, therefore
      representing a 20 to 50-fold increased risk compared with the general
      population prevalence of ~1 per 1000.
    explanation: >-
      Quantifies sibling recurrence risk, the single most clinically useful
      genetic-counseling number for this entry, and shows it is markedly
      elevated over but far below Mendelian expectation.
pathophysiology:
- name: Impaired Folate-Dependent One-Carbon Metabolism
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The common MTHFR c.677C>T variant reduces methylenetetrahydrofolate
    reductase activity, impairing the one-carbon/folate metabolic pathway
    that supplies methyl groups for nucleotide synthesis and DNA methylation
    during neurulation. Reduced enzyme activity is an established, modest
    genetic susceptibility factor for neural tube defects, and is the
    biochemical basis for the protective effect of periconceptional folic
    acid supplementation.
  molecular_functions:
  - preferred_term: methylenetetrahydrofolate reductase (NAD(P)H) activity
    term:
      id: GO:0004489
      label: methylenetetrahydrofolate reductase [NAD(P)H] activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: folic acid metabolic process
    term:
      id: GO:0046655
      label: folic acid metabolic process
    modifier: DECREASED
  - preferred_term: one-carbon metabolic process
    term:
      id: GO:0006730
      label: one-carbon metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:9068801
    reference_title: >-
      Is the common 677C-->T mutation in the methylenetetrahydrofolate
      reductase gene a risk factor for neural tube defects? A meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This meta-analysis confirms that the 677C-->T mutation is a genetic
      risk factor for NTD.
    explanation: >-
      Meta-analytic confirmation that the common MTHFR variant reducing
      enzyme activity is a genetic risk factor for neural tube defects,
      including spina bifida.
  downstream:
  - target: Failed Posterior Neuropore Closure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired folate-dependent methylation and nucleotide supply during the
      neurulation window is a modest, non-deterministic contributor to
      failure of posterior neuropore closure, acting alongside
      planar-cell-polarity and other susceptibility factors.
- name: Planar Cell Polarity Pathway Disruption
  biological_scale: CELLULAR
  role: trigger
  description: >-
    Rare missense variants in the core planar-cell-polarity (PCP) genes
    VANGL1 and VANGL2 -- the human orthologs of the Drosophila Van Gogh/
    Strabismus gene and of the mouse Looptail (Lp) locus -- impair
    non-canonical Wnt/PCP signaling. This pathway drives convergent
    extension, the coordinated mediolateral cell intercalation that narrows
    and elongates the neural plate; its disruption is a well-established
    genetic contributor to neural tube defects in both animal models and
    human cohorts, found in an estimated 1-3% of patients.
  biological_processes:
  - preferred_term: Wnt/planar cell polarity signaling pathway
    term:
      id: GO:0060071
      label: "Wnt signaling pathway, planar cell polarity pathway"
    modifier: DECREASED
  - preferred_term: convergent extension involved in neural plate elongation
    term:
      id: GO:0022007
      label: convergent extension involved in neural plate elongation
    modifier: DECREASED
  genetic_context:
    genes:
    - preferred_term: VANGL1
      term:
        id: hgnc:15512
        label: VANGL1
    - preferred_term: VANGL2
      term:
        id: hgnc:15511
        label: VANGL2
    allele_type: missense
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:17409324
    reference_title: "Mutations in VANGL1 associated with neural-tube defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified three mutations in the VANGL1 gene in patients with
      familial types (V239I and R274Q) and a sporadic type (M328T) of the
      disease, including a spontaneous mutation (V239I) appearing in a
      familial setting.
    explanation: >-
      Founding report identifying pathogenic VANGL1 missense variants in
      human neural tube defect patients.
  - reference: PMID:17409324
    reference_title: "Mutations in VANGL1 associated with neural-tube defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In a protein-protein interaction assay V239I abolished interaction of
      VANGL1 protein with its binding partners, disheveled-1, -2, and -3.
    explanation: >-
      Demonstrates the functional (partial loss-of-function) consequence of
      the V239I variant on PCP-pathway protein-protein interaction.
  - reference: PMID:20738329
    reference_title: "Contribution of VANGL2 mutations to isolated neural tube defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that VANGL2 mutations may predispose to NTDs in
      approximately 2.5% of closed spinal NTDs (5 in 202), at a frequency
      that is significantly different from that of 0.4% (2 in 453) detected
      in open spina bifida patients (p = 0.027).
    explanation: >-
      Quantifies the contribution of rare VANGL2 missense variants to human
      spinal neural tube defects, including open spina bifida cystica.
  downstream:
  - target: Failed Posterior Neuropore Closure
    causal_link_type: DIRECT
    description: >-
      Disrupted convergent extension prevents the neural folds from being
      brought into apposition at the dorsal midline, directly impairing
      closure of the posterior neuropore.
- name: Maternal Obesity-Associated Neurulation Risk
  biological_scale: ORGANISM
  role: trigger
  description: >-
    Maternal obesity is an independent, dose-response risk factor for spina
    bifida cystica -- more severe obesity confers greater risk -- and is
    mechanistically distinct from the folate pathway: unlike folate
    insufficiency, obesity-associated risk is not consistently rescued by
    folic acid supplementation. Suggested underlying mechanisms include
    aberrant maternal glucose control, oxidative stress, and metabolic
    syndrome, though the precise pathway remains uncertain.
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe obesity (body mass index > 35) has been associated with even
      larger risks indicative of a “dose-response” relationship linking
      obesity with spina bifida.
    explanation: >-
      States the dose-response relationship between maternal body mass
      index and spina bifida risk.
  downstream:
  - target: Failed Posterior Neuropore Closure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Maternal obesity is proposed to disrupt neurulation through aberrant
      glucose control, oxidative stress, and/or metabolic syndrome, though
      the exact intermediate mechanism linking obesity to failed neuropore
      closure remains unresolved.
- name: Failed Posterior Neuropore Closure
  biological_scale: TISSUE
  description: >-
    The defining lesion of spina bifida cystica: the posterior neuropore,
    which normally completes closure by approximately day 28 after
    fertilization, fails to fuse. This leaves a persistent gap in the neural
    tube and overlying vertebral arches, meninges, muscle, and skin at the
    affected spinal level, most often lumbosacral.
  biological_processes:
  - preferred_term: neural tube closure
    term:
      id: GO:0001843
      label: neural tube closure
    modifier: DECREASED
  locations:
  - preferred_term: neural tube
    term:
      id: UBERON:0001049
      label: neural tube
  evidence:
  - reference: PMID:23790957
    reference_title: >-
      Neural tube defects: recent advances, unsolved questions, and
      controversies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NTDs comprise a diverse set of birth defects that are usually
      considered to arise during the third and fourth weeks
      post-fertilisation.
    explanation: >-
      Establishes the third/fourth-week post-fertilisation timing of neural
      tube closure failure, the general mechanistic category to which spina
      bifida cystica belongs.
  downstream:
  - target: Open Neural Placode Exposure and Secondary Injury
    causal_link_type: DIRECT
    description: >-
      When the failure of closure is complete at the affected level, the
      neural placode itself remains unfused and open to the amniotic cavity,
      producing myelomeningocele rather than meningocele.
  - target: Skin-Covered Meningeal Herniation
    causal_link_type: DIRECT
    description: >-
      When neural tube closure fails only at the level of the vertebral
      arches and meninges while the neural placode itself closes and is
      covered by skin, the result is the milder meningocele phenotype rather
      than an open, neural-tissue-bearing lesion.
- name: Open Neural Placode Exposure and Secondary Injury
  biological_scale: TISSUE
  subtypes:
  - Myelomeningocele
  description: >-
    The "two-hit" mechanism proposed to explain the paralysis of
    myelomeningocele: the primary failure of neurulation (hit one) leaves the
    neural placode exposed to the amniotic cavity for the remainder of
    gestation, where chemical injury from amniotic fluid and mechanical
    trauma from fetal movement (hit two) causes progressive erosion,
    necrosis, and loss of neurons and axons beyond what congenital
    myelodysplasia alone would produce. This is the mechanistic rationale for
    in-utero surgical repair, which aims to halt the second hit rather than
    reverse the first.
  biological_processes:
  - preferred_term: cell death (necrosis)
    term:
      id: GO:0008219
      label: cell death
    modifier: INCREASED
  evidence:
  - reference: PMID:2362676
    reference_title: >-
      The paralysis associated with myelomeningocele: clinical and
      experimental data implicating a preventable spinal cord injury.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We therefore propose a "two-hit" hypothesis to explain the paralysis
      seen in children with myelomeningocele: congenital myelodysplasia
      complicated by an intrauterine spinal cord injury.
    explanation: >-
      Originating statement of the two-hit hypothesis, based on a fetal rat
      model of surgically created spinal dysraphism.
  - reference: PMID:2362676
    reference_title: >-
      The paralysis associated with myelomeningocele: clinical and
      experimental data implicating a preventable spinal cord injury.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histological studies of the exposed spinal cord revealed extensive
      erosion and necrosis, findings similar to those described in children
      with myelomeningocele.
    explanation: >-
      Model-organism histological evidence for progressive secondary injury
      of exposed neural tissue, paralleling human myelomeningocele pathology.
  downstream:
  - target: Chiari II Hindbrain Herniation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic leakage of cerebrospinal fluid through the open neural tube
      prevents the embryonic ventricular system from distending, arresting
      posterior fossa growth (McLone-Knepper unified theory). This node
      cross-references, and deliberately does not duplicate, the detailed
      hydrocephalus mechanism curated in the Congenital_Hydrocephalus entry's
      "Neural Tube Defect with Chiari II Hindbrain Herniation and Small
      Posterior Fossa" node.
  - target: Segmental Motor and Sensory Neuron Loss
    causal_link_type: DIRECT
    description: >-
      Progressive destruction of the exposed placode causes segmental loss
      of motor and sensory neurons at and below the level of the lesion.
- name: Skin-Covered Meningeal Herniation
  biological_scale: TISSUE
  subtypes:
  - Meningocele
  description: >-
    In meningocele, the vertebral arch defect and meningeal herniation occur
    without exposure or incorporation of the neural placode, which remains
    covered by an intact (if sometimes dysplastic or ulcerated) layer of
    skin. Because neural tissue is not directly exposed to the intrauterine
    environment, the "two-hit" secondary injury that drives myelomeningocele
    paralysis does not apply, and neurological examination is often normal;
    a tethered cord can still cause delayed deficits.
  evidence:
  - reference: PMID:23790957
    reference_title: >-
      Neural tube defects: recent advances, unsolved questions, and
      controversies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Closed spinal lesions are generally less severe and can be
      asymptomatic, as with spina bifida occulta which is considered a
      variant of normal. However, lumbosacral spinal cord tethering may be
      present in spinal dysraphism, and can lead to lower limb motor and
      sensory deficits, and a neuropathic bladder.
    explanation: >-
      States that closed spinal lesions such as meningocele are generally
      less severe than open lesions and can be asymptomatic, though tethered
      cord can still cause delayed neurological deficit.
- name: Chiari II Hindbrain Herniation
  biological_scale: TISSUE
  subtypes:
  - Myelomeningocele
  description: >-
    Near-universal in myelomeningocele: caudal displacement of the medulla,
    fourth ventricle, and cerebellar vermis into the cervical spinal canal,
    with an abnormally small posterior fossa. Obstructs cerebrospinal fluid
    egress at the fourth ventricular outflow and foramen magnum, producing
    hydrocephalus. This node is a deliberate cross-reference to the more
    detailed Congenital_Hydrocephalus entry rather than a re-derivation of
    it; see that entry's "Chiari II-associated" subtype and "Neural Tube
    Defect with Chiari II Hindbrain Herniation and Small Posterior Fossa"
    node for the full CSF-dynamics mechanism.
  evidence:
  - reference: PMID:2699756
    reference_title: "The cause of Chiari II malformation: a unified theory."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The cause of the Chiari II hindbrain deformity in children born with a
      myelomeningocele can be explained by the lack of distention of the
      embryonic ventricular system.
    explanation: >-
      States the unified-theory mechanism linking the open neural tube to
      the Chiari II hindbrain deformity. Evidence source is OTHER because
      the snippet is a theoretical/mechanistic proposal rather than a
      reported study result.
  - reference: PMID:31980545
    reference_title: "Prenatal Repair of Myelomeningocele and School-age Functional Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      lower rates of hindbrain herniation (60% vs 87%; P < .001), had fewer
      shunts placed for hydrocephalus (49% vs 85%; P < .001)
    explanation: >-
      Quantifies both the high baseline rate of hindbrain herniation and
      shunt-requiring hydrocephalus after postnatal repair, and the
      reduction achieved by prenatal repair.
  downstream:
  - target: Hydrocephalus
    causal_link_type: DIRECT
    description: >-
      Obstruction of cerebrospinal fluid outflow at the level of the
      herniated hindbrain and small posterior fossa produces ventricular
      dilatation.
- name: Segmental Motor and Sensory Neuron Loss
  biological_scale: TISSUE
  subtypes:
  - Myelomeningocele
  description: >-
    Destruction of the exposed neural placode causes segmental denervation
    of the lower limbs and of the autonomically innervated bladder, bowel,
    and pelvic floor, with severity and level determined by the rostrocaudal
    extent of the lesion.
  evidence:
  - reference: PMID:38696583
    reference_title: "Risk of meningomyelocele mediated by the common 22q11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MM often requires either pre- or postnatal surgical repair, resulting
      in major long-term complications such as paraparesis, bowel and
      bladder incontinence, and learning difficulties.
    explanation: >-
      States the clinical consequences of segmental neural loss in
      myelomeningocele.
  downstream:
  - target: Lower Limb Weakness and Sensory Loss
    causal_link_type: DIRECT
    description: >-
      Loss of motor and sensory neurons below the level of the lesion
      produces flaccid, lesion-level-dependent paraparesis or paraplegia
      with sensory deficit.
  - target: Neurogenic Bladder
    causal_link_type: DIRECT
    description: >-
      Denervation of the detrusor, sphincter, and pelvic floor musculature
      produces neurogenic bladder dysfunction.
phenotypes:
- category: Neurological
  name: Cystic Spinal Lesion
  description: >-
    A visible cystic protrusion of meninges and/or neural tissue through a
    posterior vertebral arch defect, present at birth and usually
    lumbosacral in location. This obligate, entry-defining lesion is
    unrestricted across both subtypes; the myelomeningocele-specific
    (neural-placode-bearing) and meningocele-specific (meninges-only) forms
    of the lesion are each modeled as their own subtype-scoped phenotype
    below.
  phenotype_term:
    preferred_term: Spina bifida cystica
    term:
      id: HP:0002414
      label: Spina bifida
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38696583
    reference_title: "Risk of meningomyelocele mediated by the common 22q11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Meningomyelocele is one of the most severe forms of neural tube
      defects (NTDs) and the most frequent structural birth defect of the
      central nervous system.
    explanation: >-
      Establishes the open spinal lesion as a defining phenotype of the
      myelomeningocele form, itself a subtype of the broader spina bifida
      cystica entry-defining lesion.
- category: Neurological
  name: Meningocele
  description: >-
    The meninges-only, neural-placode-sparing form of the cystic spinal
    lesion, typically covered by an intact (if sometimes dysplastic or
    ulcerated) layer of skin, as distinguished from the open,
    neural-placode-bearing myelomeningocele form.
  phenotype_term:
    preferred_term: Meningocele
    term:
      id: HP:0002435
      label: Meningocele
  subtype: Meningocele
  evidence:
  - reference: PMID:20738329
    reference_title: "Contribution of VANGL2 mutations to isolated neural tube defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Closed NTDs with a mass are represented by lipomyeloschisis,
      lipomyelomeningocele, meningocele, and myelocystocele.
    explanation: >-
      Distinguishes meningocele, a mass-bearing but neural-placode-sparing
      lesion, from the open myelomeningocele form.
- category: Neurological
  name: Lower Limb Weakness and Sensory Loss
  description: >-
    Flaccid paralysis or paresis and sensory loss below the level of the
    spinal lesion, present from birth in myelomeningocele.
  phenotype_term:
    preferred_term: Lower limb muscle weakness
    term:
      id: HP:0007340
      label: Lower limb muscle weakness
  subtype: Myelomeningocele
  evidence:
  - reference: PMID:38696583
    reference_title: "Risk of meningomyelocele mediated by the common 22q11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MM often requires either pre- or postnatal surgical repair, resulting
      in major long-term complications such as paraparesis, bowel and
      bladder incontinence, and learning difficulties.
    explanation: >-
      Names paraparesis as a major long-term complication of
      myelomeningocele.
- category: Genitourinary
  name: Neurogenic Bladder
  description: >-
    Denervation of the bladder and urethral sphincter causing retention,
    incontinence, vesicoureteral reflux, and recurrent urinary tract
    infection; a leading cause of long-term renal morbidity in
    myelomeningocele.
  phenotype_term:
    preferred_term: Neurogenic bladder
    term:
      id: HP:0000011
      label: Neurogenic bladder
  subtype: Myelomeningocele
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These include urinary retention with overflow and ureteric reflux
      which can lead to recurrent urinary tract infections and ultimately
      deterioration of renal function.
    explanation: >-
      States the downstream urological and renal consequences of untreated
      neurogenic bladder dysfunction in spina bifida.
- category: Gastrointestinal
  name: Neurogenic Bowel Dysfunction
  description: >-
    Denervation of the rectal sphincter and pelvic floor musculature
    causing fecal incontinence and constipation; managed with bowel
    programs (timed toileting, laxatives, enemas, transanal irrigation).
  phenotype_term:
    preferred_term: Bowel incontinence
    term:
      id: HP:0002607
      label: Bowel incontinence
  subtype: Myelomeningocele
  evidence:
  - reference: PMID:38696583
    reference_title: "Risk of meningomyelocele mediated by the common 22q11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MM often requires either pre- or postnatal surgical repair, resulting
      in major long-term complications such as paraparesis, bowel and
      bladder incontinence, and learning difficulties.
    explanation: >-
      Names bowel incontinence, alongside bladder incontinence and
      paraparesis, as a major long-term complication of myelomeningocele.
- category: Neurological
  name: Chiari Type II Malformation
  description: >-
    Caudal displacement of the medulla, fourth ventricle, and cerebellar
    vermis into the spinal canal with a small posterior fossa; present in
    the great majority of infants born with myelomeningocele. See the
    cross-referenced Congenital_Hydrocephalus entry for the full
    CSF-dynamics mechanism and shunt-management detail.
  phenotype_term:
    preferred_term: Chiari type II malformation
    term:
      id: HP:0025660
      label: Chiari type II malformation
  subtype: Myelomeningocele
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:21306277
    reference_title: >-
      A randomized trial of prenatal versus postnatal repair of
      myelomeningocele.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nearly all infants who are born with myelomeningocele have the
      Arnold–Chiari II malformation, which includes a constellation of
      anomalies that include hindbrain herniation (downward displacement of
      the medulla, fourth ventricle, and cerebellum into the spinal canal),
      brain-stem abnormalities, low-lying venous sinuses, and a small
      posterior fossa.
    explanation: >-
      States both the near-universal co-occurrence with myelomeningocele and
      the anatomical content of the malformation.
- category: Neurological
  name: Hydrocephalus
  description: >-
    Ventricular dilatation secondary to CSF outflow obstruction at the
    herniated hindbrain, typically requiring ventriculoperitoneal shunt
    placement. See the cross-referenced Congenital_Hydrocephalus entry (the
    "Chiari II-associated" subtype) for full treatment detail.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  subtype: Myelomeningocele
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31980545
    reference_title: "Prenatal Repair of Myelomeningocele and School-age Functional Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      had fewer shunts placed for hydrocephalus (49% vs 85%; P < .001) and,
      among those with shunts, fewer shunt revisions (47% vs 70%; P = .02)
      than those in the postnatal group.
    explanation: >-
      Quantifies the high baseline (postnatal-repair) rate of
      shunt-requiring hydrocephalus in myelomeningocele.
- category: Musculoskeletal
  name: Clubfoot
  description: >-
    Talipes equinovarus deformity resulting from muscle imbalance around the
    ankle and foot caused by asymmetric denervation below the lesion level.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  subtype: Myelomeningocele
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Orthopedic abnormalities including talipes (club foot), contractures,
      hip dislocation, scoliosis and kyphosis are frequently observed.
    explanation: >-
      Names clubfoot (talipes), among other orthopedic deformities, as a
      frequently observed complication.
- category: Musculoskeletal
  name: Scoliosis
  description: >-
    Progressive lateral curvature of the spine, more frequent and more
    severe with higher (thoracolumbar) lesion levels.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    clinical_course: PROGRESSIVE
  subtype: Myelomeningocele
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Orthopedic abnormalities including talipes (club foot), contractures,
      hip dislocation, scoliosis and kyphosis are frequently observed.
    explanation: >-
      Names scoliosis, among other orthopedic deformities, as a frequently
      observed complication.
- category: Neurological
  name: Tethered Cord
  description: >-
    Abnormal fixation of the spinal cord, often at the site of prior repair
    or, in meningocele, in the absence of overt neurological deficit at
    birth; can cause delayed neurological, urological, or orthopedic
    deterioration with growth.
  phenotype_term:
    preferred_term: Tethered cord
    term:
      id: HP:0002144
      label: Tethered cord
  evidence:
  - reference: PMID:23790957
    reference_title: >-
      Neural tube defects: recent advances, unsolved questions, and
      controversies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      lumbosacral spinal cord tethering may be present in spinal dysraphism,
      and can lead to lower limb motor and sensory deficits, and a
      neuropathic bladder.
    explanation: >-
      States that spinal cord tethering can occur in spinal dysraphism
      (including meningocele) and cause delayed motor, sensory, and bladder
      deficits.
- category: Neurological
  name: Intellectual Disability
  description: >-
    Neurocognitive impact of myelomeningocele, particularly when
    complicated by hydrocephalus, ranges from executive-function and
    attention difficulties to frank intellectual disability; frank
    intellectual disability itself is relatively infrequent.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  subtype: Myelomeningocele
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability is relatively infrequent, affecting perhaps
      20-25% of people with MMC and often after complications of
      hydrocephalus.
    explanation: >-
      Directly quantifies the frequency of intellectual disability in
      myelomeningocele and links it to hydrocephalus complications.
  - reference: PMID:38696583
    reference_title: "Risk of meningomyelocele mediated by the common 22q11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MM often requires either pre- or postnatal surgical repair, resulting
      in major long-term complications such as paraparesis, bowel and
      bladder incontinence, and learning difficulties.
    explanation: >-
      Independently names learning difficulties, alongside paraparesis and
      bowel/bladder incontinence, as a major long-term complication of
      myelomeningocele.
genetic:
- name: MTHFR
  gene_term:
    preferred_term: MTHFR
    term:
      id: hgnc:7436
      label: MTHFR
  relationship_type: SUSCEPTIBILITY
  frequency: common susceptibility polymorphism, modest effect size
  association: >-
    The c.677C>T (Ala222Val) variant reduces methylenetetrahydrofolate
    reductase enzyme activity, impairing folate-dependent one-carbon
    metabolism during neurulation.
  evidence:
  - reference: PMID:9068801
    reference_title: >-
      Is the common 677C-->T mutation in the methylenetetrahydrofolate
      reductase gene a risk factor for neural tube defects? A meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ORs for all reported NTD patients and their parents of: 1.7 [95% CI:
      1.1-2.6]; 1.8 [95% CI: 1.1-3.1] and 1.9 [95% CI: 1.3-2.8] for mothers
      (combined prevalence 14.5%), fathers (combined prevalence 15.5%) and
      NTD patients (combined prevalence 16.4%), respectively, vs. all
      international controls.
    explanation: >-
      Quantifies the modest but statistically significant increased odds of
      neural tube defects associated with the MTHFR 677C>T variant.
- name: VANGL1
  gene_term:
    preferred_term: VANGL1
    term:
      id: hgnc:15512
      label: VANGL1
  relationship_type: SUSCEPTIBILITY
  frequency: rare missense variants, small subset of patients
  association: >-
    Missense variants (e.g. V239I, R274Q, M328T) partially disrupt VANGL1
    interaction with Dishevelled proteins, impairing planar-cell-polarity
    signaling required for convergent extension.
  evidence:
  - reference: PMID:17409324
    reference_title: "Mutations in VANGL1 associated with neural-tube defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings implicate VANGL1 as a risk factor in human neural-tube
      defects.
    explanation: >-
      Founding statement implicating VANGL1 as a human neural tube defect
      risk gene.
- name: VANGL2
  gene_term:
    preferred_term: VANGL2
    term:
      id: hgnc:15511
      label: VANGL2
  relationship_type: SUSCEPTIBILITY
  frequency: rare missense variants, small subset of patients
  association: >-
    Rare missense variants in the human ortholog of the mouse Looptail (Lp)
    gene, which causes severe neural tube defects (craniorachischisis) in
    homozygotes and is the founding planar-cell-polarity model for
    mammalian neurulation.
  evidence:
  - reference: PMID:20738329
    reference_title: "Contribution of VANGL2 mutations to isolated neural tube defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings strongly implicate VANGL2 in the genetic causation of
      spinal NTDs in a subset of patients and provide additional evidence
      for a pathogenic role of PCP signaling in these malformations.
    explanation: >-
      Summarizes the human genetic evidence implicating VANGL2 in spinal
      neural tube defects.
- name: 22q11.2 deletion (CRKL)
  gene_term:
    preferred_term: CRKL
    term:
      id: hgnc:2363
      label: CRKL
  relationship_type: RISK_FACTOR
  frequency: 0.84% of an unselected myelomeningocele trio cohort
  association: >-
    Recurrent heterozygous 22q11.2 microdeletion spanning CRKL; loss of Crkl
    is sufficient to cause neural tube defects in mice, with penetrance and
    expressivity worsened by maternal folate deficiency and partly rescued
    by folate supplementation, directly linking a structural genetic lesion
    to the folate pathway.
  evidence:
  - reference: PMID:38696583
    reference_title: "Risk of meningomyelocele mediated by the common 22q11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome and genome sequencing of 715 parent-offspring trios identified
      six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold
      increased risk compared with the general population.
    explanation: >-
      Reports the strength of association between the 22q11.2 deletion and
      myelomeningocele in a large trio sequencing cohort.
  - reference: PMID:38696583
    reference_title: "Risk of meningomyelocele mediated by the common 22q11.2 deletion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The loss of Crkl, one of several neural tube-expressed genes within
      the minimal deletion interval, was sufficient to replicate NTDs in
      mice, where both penetrance and expressivity were exacerbated by
      maternal folate deficiency.
    explanation: >-
      States the mouse functional validation (Crkl loss reproduces NTDs)
      and the folate-modified penetrance/expressivity that establish CRKL
      loss as a mechanistic driver linked to the folate pathway.
environmental:
- name: Periconceptional Folic Acid Supplementation
  exposure_term:
    preferred_term: exposure to folic acid via ingestion
    term:
      id: ECTO:0900036
      label: exposure to folic acid via ingestion
  description: >-
    Adequate periconceptional folic acid intake (400 micrograms/day for the
    general population; higher supervised doses after a prior neural tube
    defect pregnancy) is the only proven environmental protective factor
    against spina bifida cystica; conversely, insufficient intake raises
    risk. Mandatory grain fortification programs are associated with
    population-level declines in prevalence.
  evidence:
  - reference: PMID:1677062
    reference_title: >-
      Prevention of neural tube defects: results of the Medical Research
      Council Vitamin Study. MRC Vitamin Study Research Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Folic acid supplementation starting before pregnancy can now be firmly
      recommended for all women who have had an affected pregnancy, and
      public health measures should be taken to ensure that the diet of all
      women who may bear children contains an adequate amount of folic acid.
    explanation: >-
      States the general recommendation for periconceptional folic acid
      supplementation as a proven preventive measure against neural tube
      defects, including spina bifida cystica.
  influences_mechanisms:
  - target: Impaired Folate-Dependent One-Carbon Metabolism
    environmental_effect: PROTECTS_AGAINST
    causal_link_type: DIRECT
    description: >-
      Adequate periconceptional folic acid intake supplies the substrate for
      folate-dependent one-carbon metabolism during neurulation, offsetting
      reduced MTHFR enzyme activity and other sources of impaired one-carbon
      flux, and thereby reducing the risk of failed neuropore closure.
    evidence:
    - reference: PMID:1677062
      reference_title: >-
        Prevention of neural tube defects: results of the Medical Research
        Council Vitamin Study. MRC Vitamin Study Research Group.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        27 of these had a known neural tube defect, 6 in the folic acid
        groups and 21 in the two other groups, a 72% protective effect
        (relative risk 0.28, 95% confidence interval 0.12-0.71).
      explanation: >-
        Landmark randomized controlled trial establishing a large,
        statistically significant protective effect of periconceptional
        folic acid supplementation against neural tube defect recurrence.
    - reference: PMID:38696583
      reference_title: "Risk of meningomyelocele mediated by the common 22q11.2 deletion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Crkl mutant embryos on a low–maternal FA diet displayed a notably
        increased prevalence of exencephaly (37.5%, 3/8), a severe form of
        murine NTD (Fig. 2 and fig. S8; odds ratio for low FA diet versus
        control diet of 34.96, P = 0.0031, 95% CI = 3.05 to 400.71), whereas
        no control littermates had NTDs.
      explanation: >-
        Direct mouse gene-environment evidence that maternal folate
        deficiency exacerbates neural tube defect penetrance/expressivity
        on a genetically susceptible (Crkl-null) background, mechanistically
        grounding the protective folate effect.
- name: Anticonvulsant (Valproate) Exposure During Pregnancy
  exposure_term:
    preferred_term: anticonvulsant exposure during pregnancy
    term:
      id: ECTO:9001740
      label: exposure to anticonvulsant
  description: >-
    First-trimester exposure to the anticonvulsant valproic acid (VPA) is a
    well-established, substantial (~10-fold) independent risk factor for
    neural tube defects, including spina bifida cystica, distinct from
    folate status.
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Non-genetic maternal risk factors include reduced folate intake,
      anticonvulsant therapy, diabetes mellitus and obesity.
    explanation: >-
      Names anticonvulsant therapy among the established non-genetic
      maternal risk factors for spina bifida.
  influences_mechanisms:
  - target: Failed Posterior Neuropore Closure
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Valproic acid's potent histone deacetylase (HDAC) inhibitory activity
      is proposed to disturb the balance of protein acetylation and
      deacetylation required for normal neurulation, triggering failure of
      posterior neuropore closure independent of maternal folate status.
    evidence:
    - reference: PMID:27189655
      reference_title: "Spina bifida."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The anticonvulsant valproic acid (VPA) increases risk of NTDs by
        ~10-fold when taken during the first trimester of pregnancy.
      explanation: >-
        Quantifies the magnitude of neural tube defect risk conferred by
        first-trimester VPA exposure.
    - reference: PMID:23790957
      reference_title: >-
        Neural tube defects: recent advances, unsolved questions, and
        controversies.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        recent findings with VPA suggest a potent histone deacetylase (HDAC)
        inhibitory activity.
      explanation: >-
        States the proposed HDAC-inhibition mechanism by which VPA is
        thought to disrupt neurulation. Evidence source is OTHER because the
        snippet reports a mechanistic proposal rather than a primary human
        or animal study result.
- name: Pregestational (Maternal) Diabetes Mellitus
  exposure_term:
    preferred_term: pregestational maternal diabetes mellitus
  description: >-
    Pre-existing maternal diabetes mellitus, which predisposes to a range of
    birth defects, is an established independent risk factor for neural
    tube defects including spina bifida cystica, mediated by hyperglycemia
    rather than by folate status.
  notes: >-
    ECTO models chemical/environmental exposures rather than host metabolic
    conditions; no ECTO exposure term binds "maternal diabetes" or
    "hyperglycemia" directly (searched "diabetes", "hyperglycemia",
    "maternal diabetes"), so exposure_term is left as free text.
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Non-genetic maternal risk factors include reduced folate intake,
      anticonvulsant therapy, diabetes mellitus and obesity.
    explanation: >-
      Names diabetes mellitus among the established non-genetic maternal
      risk factors for spina bifida.
  influences_mechanisms:
  - target: Failed Posterior Neuropore Closure
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Maternal hyperglycemia is described as the immediate cause of neural
      tube defects in pregestational diabetes, though the precise pathogenic
      mechanism linking hyperglycemia to failed neuropore closure remains
      poorly understood.
    evidence:
    - reference: PMID:27189655
      reference_title: "Spina bifida."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In maternal diabetes mellitus, which predisposes to a range of
        birth defects including NTDs, hyperglycemia is the immediate cause
        of NTDs although its pathogenic mechanism is poorly understood.
      explanation: >-
        States that hyperglycemia is the immediate cause of neural tube
        defects in pregestational diabetes, while noting the underlying
        mechanism is not well understood.
- name: Maternal Obesity
  exposure_term:
    preferred_term: maternal obesity
  description: >-
    Maternal obesity is an established, dose-response independent risk
    factor for spina bifida cystica, mechanistically distinct from the
    folate pathway because the elevated risk is not consistently rescued by
    folic acid supplementation.
  notes: >-
    ECTO models chemical/environmental exposures rather than host metabolic
    states; no ECTO exposure term binds "maternal obesity" or "body mass
    index" directly (searched "obesity", "maternal obesity", "body mass
    index"), so exposure_term is left as free text.
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Non-genetic maternal risk factors include reduced folate intake,
      anticonvulsant therapy, diabetes mellitus and obesity.
    explanation: >-
      Names obesity among the established non-genetic maternal risk
      factors for spina bifida.
  influences_mechanisms:
  - target: Maternal Obesity-Associated Neurulation Risk
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Maternal obesity exacerbates spina bifida risk in a dose-response
      manner, and this risk is not consistently modified downward by folic
      acid supplementation, distinguishing its mechanism from the classic
      folate-dependent pathway.
    evidence:
    - reference: PMID:27189655
      reference_title: "Spina bifida."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        these obesity-associated risks are stronger for spina bifida than
        for anencephaly 16–18 and may not be modified downward with folic
        acid use 19.
      explanation: >-
        States that obesity-associated risk for spina bifida is not
        consistently reduced by folic acid supplementation, distinguishing
        this exposure's mechanism from the folate pathway.
treatments:
- name: Postnatal Surgical Closure
  description: >-
    Surgical closure of the open spinal defect, generally performed within
    24-48 hours of birth when prenatal repair has not been performed, to
    protect the exposed placode from further injury and infection. Does not
    reverse neurological deficit already present at birth.
  treatment_term:
    preferred_term: neurosurgical procedure
    term:
      id: NCIT:C15656
      label: Neurosurgical Procedure
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Open Neural Placode Exposure and Secondary Injury
    treatment_effect: INHIBITS
    description: >-
      Covering the exposed placode halts further chemical and mechanical
      "second-hit" injury, though it does not reverse deficits already
      sustained.
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Describes standard postnatal surgical closure as the immediate
      management step, followed by lifelong management of associated
      defects.
- name: Prenatal (Fetal) Repair of Myelomeningocele
  description: >-
    In-utero surgical closure of the open neural tube defect, offered to
    selected pregnancies (T1-S1 lesion level, hindbrain herniation, suitable
    gestational age, no major contraindication) before 26 weeks of
    gestation. Demonstrated in the randomized MOMS trial to reduce hindbrain
    herniation and shunt-requiring hydrocephalus and to improve motor
    outcomes relative to postnatal repair, at the cost of maternal
    hysterotomy risk and increased prematurity.
  treatment_term:
    preferred_term: fetal surgical repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Open Neural Placode Exposure and Secondary Injury
    treatment_effect: INHIBITS
    description: >-
      Closing the open neural tube before birth halts chronic amniotic-fluid
      exposure and mechanical injury to the placode earlier than postnatal
      repair can, and restores embryonic ventricular pressure whose absence
      drives the Chiari II hindbrain deformity.
  evidence:
  - reference: PMID:21306277
    reference_title: >-
      A randomized trial of prenatal versus postnatal repair of
      myelomeningocele.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal surgery for myelomeningocele reduced the need for shunting
      and improved motor outcomes at 30 months but was associated with
      maternal and fetal risks.
    explanation: >-
      States the primary MOMS trial finding of benefit balanced against
      procedural risk.
  - reference: PMID:31980545
    reference_title: "Prenatal Repair of Myelomeningocele and School-age Functional Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term benefits of prenatal surgery included improved mobility and
      independent functioning and fewer surgeries for shunt placement and
      revision, with no strong evidence of improved cognitive functioning.
    explanation: >-
      School-age MOMS follow-up confirming durable motor and shunt-related
      benefit without a demonstrated cognitive benefit.
- name: Clean Intermittent Catheterization for Neurogenic Bladder
  description: >-
    Regular clean intermittent catheterization, with adjunctive
    antimuscarinic or beta-3 agonist pharmacotherapy and urodynamic
    surveillance as needed, to manage neurogenic bladder and protect renal
    function.
  treatment_term:
    preferred_term: intermittent urinary catheterization
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Neurogenic Bladder
    treatment_effect: INHIBITS
    description: >-
      Regular bladder emptying by catheterization reduces high intravesical
      pressure and stasis, mitigating the vesicoureteral reflux and
      recurrent infection that drive renal injury in neurogenic bladder.
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bladder and urinary tract management often includes a combination of
      clean intermittent catheterization, pharmacological agents, and
      surgery.
    explanation: >-
      States that clean intermittent catheterization is a standard component
      of bladder and urinary tract management in spina bifida cystica.
- name: Orthopedic Management of Clubfoot and Hip/Spine Deformity
  description: >-
    Serial casting, bracing, and, when needed, corrective surgery for
    clubfoot, hip subluxation/dislocation, and progressive scoliosis
    resulting from muscle imbalance below the lesion level.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Orthopedic abnormalities including talipes (club foot), contractures,
      hip dislocation, scoliosis and kyphosis are frequently observed.
    explanation: >-
      Names the orthopedic complications this treatment category addresses.
diagnosis:
- name: Prenatal Ultrasonography
  description: >-
    Detailed second-trimester (and, increasingly, late first-trimester)
    fetal spine ultrasonography is the principal and most accurate mode of
    prenatal diagnosis of spina bifida cystica, having progressively
    supplanted biochemical (AFP) screening.
  diagnosis_term:
    preferred_term: fetal ultrasound imaging
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal diagnosis is achieved by ultrasonography, enabling women to
      seek termination of pregnancy.
    explanation: >-
      States that ultrasonography is the modality by which spina bifida is
      prenatally diagnosed.
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Today, the fetal spine can be examined by ultrasonography in the
      sagittal, axial and coronal planes from late first trimester
      onwards, providing the principal and most accurate mode of
      prenatal diagnosis.
    explanation: >-
      Establishes detailed multi-plane fetal spine ultrasonography as the
      principal, most accurate prenatal diagnostic modality.
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, with the increasing use of routine second trimester anomaly
      scanning, biochemical screening for MMC is becoming redundant as
      ultrasound offers greater sensitivity and specificity.
    explanation: >-
      States that ultrasound has progressively supplanted biochemical (AFP)
      screening owing to greater sensitivity and specificity.
- name: Maternal Serum and Amniotic Fluid Alpha-Fetoprotein Screening
  description: >-
    Elevation of alpha-fetoprotein (AFP) in maternal serum and amniotic
    fluid was historically the basis for prenatal biochemical screening for
    open neural tube defects such as myelomeningocele; it now plays a
    declining, secondary role relative to ultrasound except when maternal
    obesity limits detailed sonographic examination.
  diagnosis_term:
    preferred_term: alpha-fetoprotein measurement
    term:
      id: NCIT:C74732
      label: Alpha-fetoprotein Measurement
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal diagnosis first became possible in the early 1970s, with the
      finding of an elevated concentration of alphafetoprotein (AFP) in
      amniotic fluid samples from pregnancies with anencephaly or MMC
    explanation: >-
      States the historical origin of AFP-based prenatal screening for
      open neural tube defects, including myelomeningocele.
  - reference: PMID:23790957
    reference_title: >-
      Neural tube defects: recent advances, unsolved questions, and
      controversies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diagnosis was based on measurement of alphafetoprotein (AFP)
      concentration in the amniotic fluid and maternal blood
    explanation: >-
      Independently states that AFP concentration in amniotic fluid and
      maternal blood is the basis for prenatal biochemical screening of
      open neural tube defects such as myelomeningocele.
- name: Fetal MRI
  description: >-
    Ultrafast fetal magnetic resonance imaging complements ultrasound to
    assess hindbrain herniation, hydrocephalus, and other brain
    abnormalities, and is used in prenatal-repair candidacy evaluation.
  diagnosis_term:
    preferred_term: fetal MRI
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:27189655
    reference_title: "Spina bifida."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ultrafast MRI to assess the presence or absence of hindbrain
      herniation, hydrocephalus, and any other brain abnormalities
    explanation: >-
      States the use of ultrafast fetal MRI to assess hindbrain herniation,
      hydrocephalus, and other brain abnormalities as part of prenatal
      evaluation.
prevalence:
- population: Sweden (national registry, 1973-2021)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 12.0
  rate_high: 52.0
  notes: >-
    Prevalence fell from 5.2 to 1.2 per 10,000 births over the study period,
    coinciding with prenatal screening/termination and, later, folic acid
    fortification.
  evidence:
  - reference: PMID:38775408
    reference_title: >-
      Mortality rates, cause and risk factors in people with spina bifida,
      register-based study over five decades.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the prevalence of spina bifida decreased from 5.2 to 1.2 per 10 000
      births
    explanation: >-
      Direct quantitative statement of prevalence decline across the
      50-year Swedish registry study period.
progression:
- phase: Postnatal survival
  notes: >-
    First-year survival has improved markedly with modern multidisciplinary
    care.
  evidence:
  - reference: PMID:38775408
    reference_title: >-
      Mortality rates, cause and risk factors in people with spina bifida,
      register-based study over five decades.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality fell sharply during the first year of life, with survival
      rising from 75% to 94%.
    explanation: >-
      Quantifies the improvement in first-year survival across the same
      50-year Swedish registry study period.
📚

References & Deep Research

References

1
PMID:27189655
Spina bifida.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Spina Bifida Cystica: Comprehensive Disease-Characteristics Report
Edison Scientific Literature 35 citations 2026-08-26T22:15:38.463835

Spina Bifida Cystica: Comprehensive Disease-Characteristics Report

Executive summary

Spina bifida cystica is a congenital open or sac-forming spinal dysraphism caused by failed closure of the caudal neural tube during the first four embryonic weeks. Its principal forms are myelomeningocele/meningomyelocele, in which neural tissue and meninges protrude through a vertebral defect, and meningocele, in which the sac contains meninges and cerebrospinal fluid without exposed spinal cord. Myelomeningocele (MMC) is the clinically dominant and most severe survivable form. It produces lesion-level-dependent paralysis and sensory loss, neurogenic bladder and bowel, orthopedic deformity, Chiari II malformation, hydrocephalus, and variable neurocognitive and psychosocial disability. It is congenital and lifelong rather than degenerative, although hydrocephalus, shunt failure, tethered cord, renal injury, skin breakdown, pain, and musculoskeletal problems can cause secondary deterioration.

Current understanding is that most nonsyndromic disease is complex, multifactorial, polygenic, and incompletely penetrant. The strongest recent genetic result is the 2024 identification of the recurrent 22q11.2 deletion, with CRKL haploinsufficiency as a major candidate mechanism and maternal folate status modifying penetrance in mice. Preventive folic acid, prenatal ultrasound/MRI, multidisciplinary lifelong care, and—in selected pregnancies—prenatal repair are established real-world interventions. Prenatal repair improves motor and hydrocephalus-related outcomes but is not curative and carries maternal and prematurity risks. Placental mesenchymal-stromal-cell augmentation of fetal repair remains investigational.

Domain Key finding Evidence type/sample Quantitative result Source/date/URL
Genetics / structural variation Common 22q11.2 deletion is a strong risk factor for meningomyelocele; CRKL prioritized as key deleted gene, with folate-sensitive effect in mouse follow-up Human trio exome/genome sequencing; 715 parent-offspring trios in Spina Bifida Sequencing Consortium, plus independent 22q11.2 deletion cohort of 1,522 individuals (vong2024riskofmeningomyelocele pages 2-4, vong2024riskofmeningomyelocele pages 1-2) 6/715 cases had 22q11.2del (0.839%); OR vs gnomAD 22.98 (95% CI 6.47–81.61; P=9.16×10^-6); independent 22q11.2del cohort: 8/1522 with MM (0.526%), OR 12.28–15.54 depending on comparator (vong2024riskofmeningomyelocele pages 2-4, vong2024riskofmeningomyelocele pages 1-2) Vong et al., Science 2024-05-03, DOI: 10.1126/science.adl1624, https://doi.org/10.1126/science.adl1624 (vong2024riskofmeningomyelocele pages 2-4, vong2024riskofmeningomyelocele pages 1-2)
Genetics / GWAS Novel exonic loci identified in Bangladeshi spina bifida case-control/trio study Human genotyping study; 112 case children, 121 control children, 272 mothers, 128 trios (tindula2024genome‐wideanalysisof pages 1-3) Trio TDT hits: rs140199800 (SULT1C2) P=1.9×10^-7; rs45580033 (ASB2) P=4.2×10^-10; rs75426652 (LHPP) P=7.2×10^-14; no genome-wide significant variants in case-control models (tindula2024genome‐wideanalysisof pages 1-3) Tindula et al., Birth Defects Research 2024-03, DOI: 10.1002/bdr2.2331, https://doi.org/10.1002/bdr2.2331 (tindula2024genome‐wideanalysisof pages 1-3)
Genetics / systems biology WGS Rare likely gene-disrupting variants implicate pathway-level risk rather than single-gene hits; enriched pathways include carbon metabolism, inflammation, innate immunity, cytoskeletal regulation, transcription Human ancestry-matched whole-genome case-control analysis; 149 cases + 149 controls after QC/matching (aguiarpulido2021systemsbiologyanalysis pages 1-3) 41,005,720 cohort-level variants initially; 22,502,019 rare variants retained; RF model AUROC 0.78; 439 discriminatory genes highlighted for enrichment analysis (aguiarpulido2021systemsbiologyanalysis pages 1-3) Aguiar-Pulido et al., PNAS 2021-12-16, DOI: 10.1073/pnas.2106844118, https://doi.org/10.1073/pnas.2106844118 (aguiarpulido2021systemsbiologyanalysis pages 1-3)
Surgery / long-term outcomes Prenatal repair improves mobility and reduces hydrocephalus-related surgery burden at school age, but not overall adaptive behavior Human follow-up cohort from randomized MOMS trial; 161 children assessed at age 5.9–10.3 years (houtrow2020prenatalrepairof pages 1-2) Vineland composite 89.0 vs 87.5 (P=.35); walking without orthotics/devices 29% vs 11% (P=.06); FRESNO 92±9 vs 85±18 (P<.001); hindbrain herniation 60% vs 87% (P<.001); shunt placement 49% vs 85% (P<.001); shunt revisions 47% vs 70% (P=.02) (houtrow2020prenatalrepairof pages 1-2) Houtrow et al., Pediatrics 2020-02, DOI: 10.1542/peds.2019-1544, https://doi.org/10.1542/peds.2019-1544 (houtrow2020prenatalrepairof pages 1-2)
Epidemiology / mortality Long-term Swedish registry shows falling prevalence and major first-year survival gains; adult deaths emphasize psychosocial and urinary/bladder risks Population-based registry study in Sweden; 1,735 people with spina bifida, 1973–2021 (andersson2024mortalityratescause pages 1-2) Prevalence fell from 5.2 to 1.2 per 10,000 births; first-year survival rose from 75% to 94%; childhood causes of death: congenital abnormalities, hydrocephalus, infections; adult excesses included self-inflicted injuries/substance abuse and bladder malignancy (andersson2024mortalityratescause pages 1-2) Andersson et al., Acta Paediatrica 2024-05, DOI: 10.1111/apa.17275, https://doi.org/10.1111/apa.17275 (andersson2024mortalityratescause pages 1-2)
Epidemiology / mortality synthesis Infant and neonatal mortality have declined over time; prematurity and low birthweight are the strongest infant mortality predictors Systematic review/meta-analysis of 20 population-based studies; >30 million live births and ~12,000 spina bifida-affected infants (ho2021neonatalandinfant pages 1-2, ho2021neonatalandinfant pages 13-15) IMR decreased 4.76% per 100,000 live births per year; infant case fatality decreased 2.70% per year; preterm birth RR 4.45 (2.30–8.60); low birthweight RR 4.77 (2.67–8.55) (ho2021neonatalandinfant pages 1-2, ho2021neonatalandinfant pages 13-15) Ho et al., PLOS ONE 2021-05-12, DOI: 10.1371/journal.pone.0250098, https://doi.org/10.1371/journal.pone.0250098 (ho2021neonatalandinfant pages 1-2, ho2021neonatalandinfant pages 13-15)
Prevention / folate Folic acid remains the most established preventive intervention for neural tube defects; mechanism linked to one-carbon metabolism and DNA methylation Narrative review focused on Visegrad countries and broader NTD prevention literature (risova2024preconceptionalandpericonceptional pages 1-3) FA supplementation during preconception/periconception reduces NTD incidence by nearly 80%; recommended dose 400 µg/day; folate deficiency may exceed 20% in many lower-income countries and is typically <5% in higher-income countries (risova2024preconceptionalandpericonceptional pages 1-3) Rísová et al., Nutrients published 2024-12-31, DOI: 10.3390/nu17010126, https://doi.org/10.3390/nu17010126 (risova2024preconceptionalandpericonceptional pages 1-3)
Rehabilitation / function Independence-focused rehabilitation evidence supports camp-based, CO-OP, occupation-based, self-catheterization, wheelchair, and assistive-tech interventions Integrative review; 523 records screened, 19 met criteria, 18 intervention studies analyzed (ferreira2024interventionstoimprove pages 1-3) 18 intervention studies synthesized; strongest support reported for camp-based interventions, CO-OP, and occupation-based therapy to improve ADLs/IADLs independence (ferreira2024interventionstoimprove pages 1-3) Ferreira & Alves, Cadernos Brasileiros de Terapia Ocupacional 2024, DOI: 10.1590/2526-8910.ctoAR291837922, https://doi.org/10.1590/2526-8910.ctoAR291837922 (ferreira2024interventionstoimprove pages 1-3)
Experimental therapy / trial CuRe tests placenta-derived mesenchymal stem cells added to fetal repair to improve motor and autonomic outcomes beyond standard fetal surgery Interventional Phase 1/2a clinical trial; estimated enrollment 55, recruiting; 35 treated + 20 contemporaneous non-PMSC cohort (NCT04652908 chunk 1, NCT04652908 chunk 2) Primary endpoint: safety at birth (CSF leak, infection, wound healing failure, unexpected growth/tumor); secondary efficacy at 30 months includes motor improvement ≥2 levels over expected and independent walking, plus bowel/urologic outcomes (NCT04652908 chunk 1, NCT04652908 chunk 2) ClinicalTrials.gov NCT04652908, first posted 2020-12-03; recruiting update verified 2026-01, https://clinicaltrials.gov/study/NCT04652908 (NCT04652908 chunk 1, NCT04652908 chunk 2)

Table: This compact evidence matrix summarizes high-value recent and foundational studies across genetics, prevention, surgery, prognosis, rehabilitation, and experimental therapy for spina bifida cystica/myelomeningocele. It is useful for rapidly mapping claims to quantitative evidence and source URLs.

1. Disease information

Definition and classification

Spina bifida cystica denotes a visible cystic/open defect produced by incomplete formation of the posterior vertebral arches and neural-tube coverings. In MMC, spinal cord/neural placode and meninges protrude through the defect; in meningocele, only meninges and cerebrospinal fluid protrude. “Open spina bifida,” “spina bifida aperta,” “myelomeningocele,” “meningomyelocele,” “myeloschisis,” and “open neural-tube defect” are common overlapping terms, although myeloschisis specifically describes a flat, open neural placode without a well-formed sac. MMC is described in recent primary literature as “one of the most severe forms of neural tube defects” and “the most frequent structural birth defect of the central nervous system.” (vong2024riskofmeningomyelocele pages 1-2)

This entity must be distinguished from spina bifida occulta/closed spinal dysraphism, in which skin covers the defect and the phenotype may involve lipoma, dermal sinus, split cord, or tethering rather than an exposed placode.

Identifiers

  • MONDO: MONDO:0017069, spina bifida cystica. The broader parent is MONDO:0008449, spina bifida.
  • MeSH: D008591, Meningomyelocele; parent D009436, Neural Tube Defects. ClinicalTrials.gov uses D008591 for the open MMC phenotype. (NCT04027374 chunk 2)
  • ICD-10: Q05.-, spina bifida; subcodes specify cervical, thoracic, lumbar, or sacral level and presence/absence of hydrocephalus.
  • ICD-11: LA02, spina bifida, with extension coding for anatomy and associated manifestations.
  • OMIM: MMC/spina bifida is genetically heterogeneous and generally does not have one definitive monogenic OMIM disease entry. Gene-specific or syndromic NTD entries should be represented separately rather than assigning one causal OMIM number to all cystic spina bifida.
  • SNOMED CT: concepts include myelomeningocele and meningocele; local terminology-server verification is recommended before production ingestion.

The evidence summarized here is predominantly aggregated disease-level evidence from registries, cohorts, trials, and genomic studies—not an individual EHR. Individual-patient sequencing and clinical observations contribute to those aggregated studies.

2. Etiology, risk, protection, and gene–environment interaction

Causal framework

The upstream developmental event is failed neurulation, normally completed approximately 21–28 days after fertilization. Failure of caudal neuropore closure leaves neural tissue exposed. A widely accepted two-hit model proposes: (1) primary failure of closure and abnormal cord development; then (2) progressive chemical and mechanical injury from amniotic fluid and fetal movement. A fetal-surgery protocol states that without protective coverage, “secondary destruction of the exposed neural tissue by trauma or amniotic fluid may occur throughout gestation.” (risova2024preconceptionalandpericonceptional pages 1-3, NCT04027374 chunk 1)

Genetic susceptibility

Most isolated MMC is non-Mendelian. Heritability has been estimated as high as 70%, but this does not imply that 70% of patients carry one identifiable pathogenic variant. Rare variants, polygenic background, maternal and fetal genotypes, epigenetic state, and exposures interact. (vong2024riskofmeningomyelocele pages 1-2, aguiarpulido2021systemsbiologyanalysis pages 1-3)

Important susceptibility pathways and genes include:

  • Noncanonical WNT/planar-cell-polarity and convergent extension: VANGL1, VANGL2, CELSR1, SCRIB, DACT1, PARD3 and related genes. Rare/ultrarare WNT-pathway variants occur in an estimated 1–3% of patients, but many are susceptibility alleles rather than fully penetrant monogenic causes. (vong2024riskofmeningomyelocele pages 1-2)
  • Apical constriction/cytoskeletal morphogenesis: SHROOM3.
  • Folate/one-carbon metabolism: MTHFR, MTR, MTRR, MTHFD1, SLC25A32.
  • Developmental transcription and epithelial regulation: TBXT, GRHL2, GRHL3.
  • Structural variation: 22q11.2 deletion, discussed below.

Open Targets lists associations for MTRR, MTHFR, VANGL1, SLC25A32, MTR, VANGL2, PARD3, SCRIB, DACT1, SHROOM3, MTHFD1, and TBXT. These are association-level targets and should not all be labelled clinically proven causal genes. (OpenTargets Search: spina bifida,myelomeningocele)

Environmental and maternal risks

Established or repeatedly supported risks include insufficient periconceptional folate, low vitamin B12, pregestational diabetes, maternal obesity, hyperthermia/fever during neurulation, and folate-antagonist or antiseizure drugs—especially valproate. Smoking, pesticides, arsenic, polycyclic aromatic hydrocarbons, selected infections, and fumonisin mycotoxin exposure have varying, generally less definitive evidence. Recent literature explicitly identifies maternal diabetes, valproate, and fumonisin as risk-enhancing exposures. (risova2024preconceptionalandpericonceptional pages 1-3, vong2024riskofmeningomyelocele pages 1-2)

There is no established infectious organism that directly causes spina bifida cystica; infection is a possible maternal exposure or a downstream complication, not a transmissible etiology. Alcohol and smoking avoidance is prudent for general fetal health, but their spina-bifida-specific effect is weaker than folate, diabetes, obesity, hyperthermia, and valproate evidence.

Protective factors

The principal proven environmental protection is adequate periconceptional folate. Randomized trials summarized in a review published 31 December 2024 found nearly 80% reduction in NTD incidence, supporting 400 µg folic acid daily for women capable of pregnancy. High-risk regimens commonly use 4–5 mg/day under clinician supervision, beginning before conception, because closure occurs before many pregnancies are recognized. Food fortification reduces population prevalence and addresses unplanned pregnancy. (risova2024preconceptionalandpericonceptional pages 1-3)

No reproducible “protective allele” is ready for clinical use. Likewise, no exercise, vaccine, or postconception lifestyle intervention can reverse a closure defect once formed.

Direct gene–environment evidence: 22q11.2–CRKL–folate

In 715 parent–offspring trios, six patients had 22q11.2 deletions: four de novo and two inherited. Frequency was 0.839% versus 0.0368% in gnomAD controls, OR 22.98 (95% CI 6.47–81.61). An independent cohort of 1,522 deletion carriers contained eight MMC cases, implying 12.28- to 15.54-fold excess risk. CRKL was strongly expressed in developing neural tube; Crkl loss reproduced NTDs in mice, and folate deficiency worsened penetrance and expressivity, while supplementation partly alleviated risk. The authors’ exact conclusion was: “the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.” This is unusually strong evidence linking human structural variation, developmental expression, animal function, and environmental modification. (vong2024riskofmeningomyelocele pages 2-4, vong2024riskofmeningomyelocele pages 1-2)

3. Phenotypes

Phenotypes are present at birth, although prenatal imaging can identify them earlier. Severity is highly variable and is driven mainly by anatomical/functional lesion level, preservation of neural tissue, hydrocephalus/Chiari II, and complications.

  • Open/cystic spinal lesion—congenital, usually lumbosacral; severity ranges from isolated meningocele to exposed MMC/myeloschisis. Suggested HPO: Myelomeningocele (HP:0002475); Meningocele; Spina bifida.
  • Lower-limb weakness or paralysis and sensory loss—congenital, generally stable at baseline but may worsen with tethering, shunt dysfunction, syrinx, or orthopedic complications. HPO: Paraparesis, Paraplegia, Lower-limb muscle weakness, Hyporeflexia, Impaired pain sensation.
  • Neurogenic bladder—very common in MMC; may cause retention, incontinence, vesicoureteral reflux, recurrent UTI, hydronephrosis, renal scarring, and chronic kidney disease. HPO: Neurogenic bladder (HP:0000011), Urinary incontinence, Recurrent UTI, Hydronephrosis.
  • Neurogenic bowel/constipation and fecal incontinence—reported in approximately 90% in one clinical synthesis, although frequency depends on definition. HPO: Neurogenic bowel, Constipation, Fecal incontinence. (mathew2018antenataldiagnosismaternal pages 14-17)
  • Chiari II malformation and hydrocephalus—most severe MMC cases have Chiari II; hindbrain herniation was reported in >80% in one synthesis. Consequences include shunt dependence, brainstem dysfunction, swallowing/respiratory problems, and cognitive effects. HPO: Chiari malformation type II (HP:0002308), Hydrocephalus (HP:0000238), Ventriculomegaly.
  • Orthopedic manifestations—clubfoot, hip dislocation/subluxation, scoliosis/kyphosis, contractures, reduced bone density and fractures. HPO: Talipes equinovarus, Scoliosis, Kyphosis, Hip dislocation, Joint contracture.
  • Tethered cord—often secondary to repair; clinically relevant when accompanied by new pain, weakness, deformity, gait or bladder deterioration. HPO: Tethered cord.
  • Skin and mobility complications—pressure injury, neuropathic ulceration, obesity, reduced fitness, and wheelchair dependence. HPO: Pressure ulcer, Abnormality of gait, Inability to walk.
  • Neurocognitive/behavioral phenotype—learning difficulties, executive dysfunction, impaired attention and visuospatial/mathematical skills can occur, especially with hydrocephalus and intracranial anomalies. Global intellectual disability is not obligatory. (houtrow2020prenatalrepairof pages 1-2)
  • Pain, depression, anxiety, social isolation, and sexual dysfunction contribute substantially to adult burden. A claims cohort combining adults with cerebral palsy or spina bifida found pain disorders in 55.9% versus 35.2% of controls; this estimate is not MMC-specific and should not be used as an isolated-MMC frequency.

Quality-of-life effects include dependence in bathing, dressing, toileting, catheterization, mobility, transportation, meal preparation, and financial management. Dependence is greater with hydrocephalus and lesions above L2. A 2024 review found that camp-based interventions, Cognitive Orientation to Daily Occupational Performance, and occupation-based therapy improved independence, but the intervention literature remains heterogeneous. (ferreira2024interventionstoimprove pages 1-3)

4. Genetic and molecular information

Variant interpretation

There is no universal diagnostic “spina bifida gene panel” with high yield for isolated MMC. Most reported variants are germline susceptibility alleles, rare variants, or copy-number changes with incomplete penetrance. Somatic mutation is not an established mechanism.

  • 22q11.2 deletion: pathogenic structural germline variant; inherited or de novo. In the 2024 cohort, 4/6 were de novo and 2/6 inherited from clinically unrecognized carriers, demonstrating incomplete penetrance. The minimal consensus interval contained ten protein-coding genes, with CRKL prioritized. (vong2024riskofmeningomyelocele pages 2-4)
  • PCP variants: predominantly rare missense or loss-of-function susceptibility variants; classification may range from pathogenic in a defined syndrome to VUS/risk allele in isolated MMC. Each variant requires ClinVar/ClinGen and segregation review.
  • MTHFR C677T and A1298C: common functional polymorphisms, not deterministic pathogenic variants. Approximately 60–70% of the general population carries at least one of these variants; around 10% is homozygous or compound heterozygous. These figures must not be interpreted as carrier frequencies for spina bifida. (risova2024preconceptionalandpericonceptional pages 1-3)
  • Bangladesh study: among 112 affected children, 121 controls, 272 mothers, and 128 trios, transmission disequilibrium identified rs140199800 in SULT1C2 (P=1.9×10⁻⁷), rs45580033 in ASB2 (P=4.2×10⁻¹⁰), and rs75426652 in LHPP (P=7.2×10⁻¹⁴). Case–control models found no genome-wide-significant variants; replication is required. (tindula2024genome‐wideanalysisof pages 1-3)
  • Regulatory variation: a 2023 mouse study identified an approximately 4-kb LTR insertion about 300 bp upstream of Grhl2, causing overexpression and spina bifida/encephalocele. Rare human upstream variants were found in only a small number of cases and remain candidates rather than proven clinical variants. (cranesmith2023anoncodinginsertional pages 1-2)

A WGS systems-biology study of 149 cases and 149 ancestry-matched controls found no single definitive gene after multiple-testing correction. Machine learning identified 439 discriminatory genes and pathway enrichment in carbon metabolism, inflammation/innate immunity, cytoskeletal regulation, and transcription; hold-out AUROC was 0.78. This is computational association evidence, not a validated diagnostic classifier. (aguiarpulido2021systemsbiologyanalysis pages 1-3)

Epigenetics and molecular profiling

Folate participates in one-carbon transfer, nucleotide synthesis, DNA repair, and methylation. Deficiency may cause DNA hypomethylation, impaired thymidylate synthesis, uracil misincorporation, and genomic instability. The exact folate-protective mechanism nevertheless remains unresolved. (risova2024preconceptionalandpericonceptional pages 1-3)

RNA-seq of five fibroblast lines from 22q11.2-deletion/MMC patients showed reduced expression largely within the deleted interval. Murine spatial transcriptomics and human embryonic single-nucleus RNA-seq demonstrated CRKL, PI4KA, and LZTR1 expression in neural-tube progenitors, neurons, and neural crest. These data prioritize mechanisms but do not constitute a clinical biomarker. (vong2024riskofmeningomyelocele pages 2-4)

NCT04027374 prospectively examined neonatal saliva DNA/RNA after fetal repair, measuring methylation of stress-regulation genes NR3C1 and FKBP5. It completed with 70 participants, but the retrieved registry did not provide definitive posted results; it should be cited as exploratory procedural-stress epigenomics, not disease-causal evidence. (NCT04027374 chunk 1, NCT04027374 chunk 2)

No validated diagnostic proteomic, metabolomic, lipidomic, single-cell, spatial, or liquid-biopsy signature is currently used in routine MMC care.

5. Environmental information

The critical exposure window is preconception through approximately day 28 after fertilization. Relevant chemical entities include folic acid (CHEBI:27470), folate, vitamin B12/cobalamin, valproic acid (CHEBI:39867), and fumonisin B1. Maternal glycemic control, healthy preconception weight, medication review, avoidance of hyperthermia, and adequate nutrition are actionable. Occupational/toxicant associations are plausible but generally lack the causal strength of folate deficiency, diabetes, obesity, and valproate. There is no zoonotic, contagious, or vaccine-preventable cause.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream susceptibility: fetal and maternal variants/CNVs, altered PCP-WNT, epithelial polarity, cytoskeletal/apical constriction, transcription, folate/one-carbon metabolism, and relevant exposures.
  2. Failed neurulation: defective convergent extension and dorsolateral bending/apical constriction prevent caudal neural-fold fusion during weeks 3–4.
  3. Open neural placode: vertebral arches, meninges, muscle, and skin fail to cover the cord.
  4. Secondary fetal injury: exposed neural tissue undergoes chemical and mechanical injury, neuronal loss, gliosis, and progressive loss of motor/sensory function.
  5. CSF/hindbrain consequences: leakage and altered craniospinal dynamics contribute to Chiari II hindbrain herniation, impaired CSF flow, ventriculomegaly, and hydrocephalus.
  6. Clinical manifestations: segmental paralysis/sensory loss; autonomic denervation causes neurogenic bladder and bowel; muscle imbalance causes clubfoot, hip deformity, scoliosis and contractures; hydrocephalus and cerebral anomalies contribute to learning/executive deficits.
  7. Downstream lifelong injury: shunt failure/infection, tethering, recurrent UTI and high bladder pressure, renal damage, pressure injury, pain, obesity and psychosocial stress.

Suggested mechanism ontologies

  • GO biological process: neural tube closure; neural fold formation; convergent extension involved in neural plate elongation; planar cell polarity pathway; Wnt signaling; actin-cytoskeleton organization; epithelial-cell apical constriction; folic-acid metabolic process; one-carbon metabolic process; DNA methylation; neurogenesis; inflammatory response.
  • Cell Ontology: neuroepithelial cell/neural progenitor cell; neuron; neural crest cell; radial glial cell; astrocyte; oligodendrocyte-lineage cell; ependymal cell; choroid-plexus epithelial cell; skeletal myocyte; urothelial cell.
  • GO cellular component: adherens junction, apical plasma membrane, actin cytoskeleton, nucleus/chromatin, mitochondrion. These are pathway-relevant compartments; no single organelle defect defines MMC.

The immune system is not the primary cause, although inflammation appears in systems-level genomic enrichment and contributes downstream to exposed-tissue injury, shunt infection, UTI, and chronic wounds. (aguiarpulido2021systemsbiologyanalysis pages 1-3)

7. Anatomical structures affected

The primary site is the caudal neural tube and posterior vertebral column, most often lumbar/lumbosacral. Affected structures include spinal cord/neural placode, spinal nerve roots, meninges, vertebral arches, paraspinal muscle and skin. Suggested terms include UBERON:0002240 spinal cord, vertebral column, lumbar spinal cord, sacral spinal cord, meninges, skin of back, and skeletal muscle tissue.

Secondary structures include cerebellum and hindbrain/brainstem in Chiari II, cerebral ventricles and CSF pathways, lower-limb peripheral nerves and muscle, hips/knees/feet/spine, urinary bladder, ureters and kidneys, colon/rectum and pelvic floor. Lesions are midline, not meaningfully unilateral; neurological effects are commonly bilateral but may be asymmetric.

8. Temporal development

The initiating defect is embryonic and acute within the neurulation window, but the phenotype evolves through gestation because exposed neural tissue can sustain progressive injury. Prenatal diagnosis usually occurs during first- or second-trimester screening. After birth, the disease course is chronic and lifelong.

There is no spontaneous remission of the anatomical defect. Repair closes/protects tissue but does not regenerate all lost neural function. Critical windows are: preconception to day 28 for prevention; midgestation for fetal-repair evaluation; the first 24–48 hours after birth for closure when prenatal repair was not performed; infancy for hydrocephalus surveillance; growth periods for tethering and orthopedic progression; and adolescence for transition to adult self-management.

9. Inheritance and population

Inheritance

Most isolated disease follows multifactorial/polygenic inheritance with incomplete penetrance and variable expressivity. Classic dominant, recessive, X-linked, mitochondrial inheritance, anticipation, and a single carrier frequency are not generally applicable. Mendelian or chromosomal syndromes form a minority and should be coded separately. Consanguinity may increase risk of rare recessive syndromic NTDs but is not the main mechanism of nonsyndromic MMC. Familial recurrence is higher than population risk and warrants genetic counseling.

Epidemiology

Rates vary substantially by geography, ancestry, ascertainment, prenatal diagnosis/termination, folate policy, and whether stillbirths are counted. A 2024 Swedish registry study of 1,735 people found prevalence declined from 5.2 to 1.2 per 10,000 births between 1973 and 2021. A Brazilian review cited 2.67 per 10,000 births in 2017–2019. A U.S. MOMS follow-up paper described MMC as affecting approximately 1 in 1,500 births, whereas the 2024 Science study noted historical prevalence greater than 1 in 2,500 before fortification. These estimates are not contradictory because definitions, periods, and populations differ. (ferreira2024interventionstoimprove pages 1-3, vong2024riskofmeningomyelocele pages 1-2, houtrow2020prenatalrepairof pages 1-2, andersson2024mortalityratescause pages 1-2)

Female excess is often reported for NTDs, but sex ratios vary and no universal cystica-specific ratio should be assigned without a defined registry. Higher historical rates occur in regions without fortification and in some Hispanic/Latino, Celtic, northern Chinese, South Asian, Middle Eastern, and African populations; social disadvantage and access to prevention, prenatal diagnosis, and surgery strongly influence observed burden.

10. Diagnostics

Prenatal screening and confirmation

  • Maternal serum alpha-fetoprotein: elevated with open NTDs, typically assessed around 15–20 weeks; it is a screening marker, not a definitive diagnosis.
  • Ultrasound: identifies the spinal defect/sac and cranial signs such as ventriculomegaly, “lemon” and “banana” signs, and hindbrain herniation. One synthesis reported 85–90% accuracy for maternal AFP at 16 weeks or fetal ultrasound at 18–20 weeks, but performance depends on operator and protocol. (mathew2018antenataldiagnosismaternal pages 14-17)
  • Fetal MRI: refines lesion level, hindbrain anatomy, ventriculomegaly, associated anomalies, and fetal-surgery planning.
  • Amniocentesis/CMA: offered when anomalies or fetal surgery are being considered; karyotype/CMA assess aneuploidy and pathogenic CNVs, including 22q11.2 deletion.

Postnatally, examination defines sac integrity and functional neurological level. Cranial/spinal ultrasound and MRI assess hydrocephalus, Chiari II, cord anatomy and tethering. Renal/bladder ultrasound, serum creatinine interpreted cautiously, catheterization assessment, and urodynamics characterize neurogenic bladder. Orthopedic, developmental, vision/hearing, sleep/respiratory, and skin assessments are individualized. Biopsy is not diagnostic; EEG/EMG are not routine unless indicated.

Genetic testing strategy

For isolated MMC, start with careful dysmorphology/family/exposure history and chromosomal microarray, especially when additional anomalies are present. The 2024 22q11.2 result strengthens the rationale for CNV detection. Karyotype detects large rearrangements but misses many submicroscopic CNVs; FISH is useful for targeted confirmation/family testing but not genome-wide screening. WES/WGS may be considered for syndromic, recurrent, familial, or unexplained cases, preferably as a trio. Panels may include PCP/neurulation genes but have limited validated yield. Mitochondrial and repeat-expansion testing are not routine.

Differential diagnoses include meningocele versus MMC, closed lipomyelomeningocele, myeloschisis, dermal sinus, sacrococcygeal teratoma, spinal hemangioma, caudal regression/sacral agenesis, split-cord malformation, cloacal exstrophy/OEIS, encephalocele, and amniotic-band disruption.

There is no conventional newborn biochemical screen, asymptomatic carrier screen, or validated liquid biopsy for nonsyndromic MMC.

11. Outcome and prognosis

Prognosis depends on lesion level, functional motor level, hydrocephalus/brainstem dysfunction, prematurity, associated anomalies, renal preservation, infection, access to multidisciplinary care, and socioeconomic context. Approximately 85% of people with spina bifida are estimated to survive into adulthood. (andersson2024mortalityratescause pages 1-2)

In a 2021 meta-analysis of 20 population-based studies, encompassing more than 30 million births and about 12,000 affected infants, infant mortality and case-fatality declined over time. Preterm birth carried RR 4.45 and low birthweight RR 4.77 for infant case-fatality. Higher lesion level, hydrocephalus, multiple anomalies and social/demographic factors also increased risk. (ho2021neonatalandinfant pages 13-15, ho2021neonatalandinfant pages 1-2)

A Finnish national cohort of 181 live-born cases found 7.2% early neonatal mortality; prematurity had uOR 6.96, syndromic status uOR 125.67, and maternal age ≥35 years uOR 5.33, although estimates were unadjusted and imprecise. (kancherla2023earlyneonatalmortality pages 1-6)

The 2024 Swedish study found first-year survival improved from 75% to 94%. Childhood deaths were associated mainly with congenital anomalies, hydrocephalus and infection. Adult concerns included infection, kidney failure, bladder malignancy, self-inflicted injury and substance abuse, supporting proactive urological and mental-health surveillance. (andersson2024mortalityratescause pages 1-2)

Recovery of established paralysis is limited. Preservation of ambulation is more likely with lower lesions, better prenatal motor function, absence of severe deformity and selected prenatal repair. Independence and quality of life are modifiable through rehabilitation, assistive technology, bowel/bladder programs, educational support, accessible environments and effective transition care.

12. Treatment and real-world implementation

Repair

For infants without prenatal repair, the lesion is covered with sterile nonadherent dressings, latex exposure is minimized, and closure is generally performed within 24–48 hours to protect tissue and reduce infection risk. Closure does not reverse the primary developmental lesion. (mathew2018antenataldiagnosismaternal pages 14-17)

Selected fetuses with T1–S1 MMC, hindbrain herniation, suitable gestational age and no major contraindication may undergo open or fetoscopic prenatal repair at expert centers. MOMS demonstrated reduced hindbrain herniation/shunt need and improved motor outcomes, balanced against maternal hysterotomy risks and prematurity.

At school age, 161 MOMS children showed no difference in Vineland adaptive behavior (89.0 versus 87.5; P=.35), but prenatal repair yielded better FRESNO motor-function scores (92 versus 85; P<.001), less hindbrain herniation (60% versus 87%), fewer shunts (49% versus 85%), and fewer shunt revisions among shunted children (47% versus 70%). Walking without orthotics/devices was 29% versus 11% (P=.06), and parent-reported quality of life/family impact favored prenatal repair. The authors concluded there was “no strong evidence of improved cognitive functioning.” (houtrow2020prenatalrepairof pages 1-2)

Lifelong complication management

  • Hydrocephalus: ventriculoperitoneal shunt or selected endoscopic procedures; urgent evaluation of headache, vomiting, lethargy, cognitive change, swallowing/respiratory symptoms, or neurological decline.
  • Bladder: clean intermittent catheterization, antimuscarinic or β3-agonist therapy when appropriate, urodynamic surveillance, antibiotic treatment for symptomatic UTI, botulinum toxin, and reconstructive surgery in selected high-pressure bladders. There is no disease-specific pharmacogenomic algorithm.
  • Bowel: timed toileting, fiber/fluid optimization, osmotic or stimulant laxatives, suppositories/enemas, transanal irrigation, or antegrade continence enema.
  • Orthopedics/mobility: physical therapy, orthoses, standing/walking programs, wheelchairs, contracture management and indicated orthopedic surgery.
  • Skin/bone: daily inspection, pressure relief, nutrition, weight management, vitamin D/bone-health evaluation and fracture prevention.
  • Tethered cord: surgery is reserved for concordant progressive neurological, urological, pain, or orthopedic deterioration—not MRI appearance alone.
  • Neurodevelopment/participation: neuropsychology, school accommodations, occupational and physical therapy, self-management training, vocational planning, sexual/reproductive health, mental-health care and structured transition to adult services. A 2024 rehabilitation review retained 18 intervention studies and found increased independence with camp-based, CO-OP and occupation-based approaches. (ferreira2024interventionstoimprove pages 1-3)

Suggested NCIt intervention mappings include surgical repair procedure, fetal surgery, neurosurgical procedure, ventriculoperitoneal shunt, physical therapy, occupational therapy, rehabilitation therapy, intermittent urinary catheterization, botulinum toxin therapy, and mesenchymal stromal cell therapy. Exact NCIt identifiers should be validated against the current NCIt release.

Experimental therapy

CuRe, NCT04652908: recruiting Phase 1/2a, estimated n=55; 35 participants receive placental mesenchymal stem cells seeded on extracellular-matrix dural graft during open fetal repair, with 20 contemporaneous untreated controls. Safety at birth is primary; 30-month endpoints include motor level at least two segments better than anatomical expectation, independent walking, bowel function and urodynamics. This is FDA-regulated and investigational, not standard therapy. (NCT04652908 chunk 1, NCT04652908 chunk 2)

Other recent studies include completed NCT04027374 on stress-associated neonatal epigenetic changes after fetal surgery (actual n=70); recruiting NCT06796972 on parental decision-making and psychological impact (estimated n=44); and NCT07048691, a small active observational ultrasound-outcome study (n=20). The latter records were posted in 2025 and should not be represented as 2023–2024 evidence. (NCT04027374 chunk 1, NCT04027374 chunk 2, NCT07048691 chunk 1, NCT06796972 chunk 1)

No approved gene therapy, CRISPR therapy, RNA therapy, or immune-targeted therapy exists for MMC.

13. Prevention

Primary prevention

  • Provide 400 µg folic acid daily to all who may become pregnant, beginning before conception and continuing through early pregnancy; use clinician-directed high-dose folate after a prior NTD pregnancy or other high-risk circumstances.
  • Implement mandatory staple-food fortification and monitor red-cell folate at population level.
  • Optimize diabetes control and preconception weight.
  • Review antiseizure and folate-antagonist drugs before pregnancy; do not abruptly stop essential medication. Avoid valproate where an effective safer alternative exists.
  • Avoid hyperthermia and correct B12 deficiency.

Fortification has reduced prevalence and may reduce severity. Infants born in the postfortification period were reported as almost one-third less likely to die in infancy than those in the prefortification period, although concurrent improvements in diagnosis and care contribute. (ho2021neonatalandinfant pages 13-15)

Secondary and tertiary prevention

Secondary prevention comprises maternal-serum screening, high-quality prenatal ultrasound, confirmatory MRI/genetic assessment, nondirective counseling and timely referral to fetal/pediatric neurosurgery. Prenatal repair prevents some secondary cord injury but does not prevent the initial malformation.

Tertiary prevention includes prompt closure, hydrocephalus and renal surveillance, catheterization/bowel programs, skin and orthopedic prevention, immunization according to standard schedules, rehabilitation, mental-health care, and transition planning. There is no MMC-specific vaccine or antimicrobial prophylaxis for the general population.

14. Other species and naturally occurring disease

Comparable congenital spinal dysraphism occurs sporadically in domestic animals, including dogs, cats, calves, lambs and foals, but robust breed-level epidemiology and validated VBO mappings are sparse. It is noninfectious and has no zoonotic or cross-species transmission. Veterinary lesions resemble human meningocele/MMC anatomically, but hydrocephalus/Chiari II and long-term multidisciplinary survival are less consistently represented. Species identifiers include human NCBITaxon:9606, mouse 10090, sheep 9940, zebrafish 7955, chicken 9031, dog 9615, and cat 9685.

15. Model organisms and advanced technologies

Mouse

More than 400 mouse genes can produce NTDs, illustrating genetic heterogeneity. Crkl loss is a particularly strong translational model because it functionally validates the human 22q11.2 association and demonstrates folate-modified penetrance. Strengths are mechanistic genetics and controlled diet; limitations include species-specific neurulation, allele effects, and folate exposure. (vong2024riskofmeningomyelocele pages 1-2, aguiarpulido2021systemsbiologyanalysis pages 1-3)

The Grhl2 Axial defects model contains a noncoding LTR insertion causing excess Grhl2 expression and spinal NTDs plus craniofacial defects. It demonstrates that regulatory gain of expression—not only protein loss—can disrupt neurulation. Human upstream variants remain unvalidated. (cranesmith2023anoncodinginsertional pages 1-2)

Other models include curly-tail/Grhl3, loop-tail/Vangl2, Scrib, Celsr1, Shroom3 and folate-antagonist/valproate-induced models. They recapitulate closure failure but not always the human open-lesion secondary injury and Chiari II phenotype.

Sheep and other models

Surgically created fetal sheep MMC models reproduce exposed-cord secondary injury and permit human-scale fetal repair. In-utero closure has produced near-normal motor function, intact sensation and improved bowel/bladder outcomes in preclinical studies. The limitation is that the lesion is induced surgically rather than arising through primary neurulation failure. (mathew2018antenataldiagnosismaternal pages 14-17)

Chick and zebrafish models permit live imaging and pathway manipulation but differ anatomically from human spinal neurulation. Human pluripotent-stem-cell neural tube organoids model neuroepithelial patterning, morphogenesis and toxicant response, but currently do not reproduce the complete vertebral, meningeal, amniotic-fluid, hindbrain and lifelong-organ phenotype.

Evidence interpretation and knowledge gaps

The highest-confidence evidence consists of randomized or longitudinal MOMS outcomes, population registries/meta-analysis, randomized folate-prevention evidence, and the replicated human 22q11.2 association with mouse functional validation. Candidate-gene associations, small ancestry-specific GWAS findings, systems-biology classifiers, epigenetic observations, and stem-cell augmentation remain exploratory.

Important gaps include ancestry-diverse genomic cohorts; standardized lesion-specific phenotype frequencies; validated functional interpretation of noncoding variants; maternal–fetal genotype/exposure models; kidney, pain and mental-health outcomes across adulthood; direct comparison of open versus fetoscopic repair; and long-term safety/efficacy of cell-enhanced fetal surgery. Variant-level allele frequencies and ACMG classifications must be obtained from the current ClinVar/gnomAD record for each exact variant and should not be inferred from gene-level association.

Selected exact source statements

  • Vong et al., Science, 3 May 2024: “Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population.” DOI: https://doi.org/10.1126/science.adl1624. (vong2024riskofmeningomyelocele pages 1-2)
  • Houtrow et al., Pediatrics, February 2020: “Long-term benefits of prenatal surgery included improved mobility and independent functioning and fewer surgeries for shunt placement and revision, with no strong evidence of improved cognitive functioning.” DOI: https://doi.org/10.1542/peds.2019-1544. (houtrow2020prenatalrepairof pages 1-2)
  • Ho et al., PLOS ONE, 12 May 2021: “Preterm birth … and low birthweight … are the strongest risk factors associated with increased spina bifida infant case fatality.” DOI: https://doi.org/10.1371/journal.pone.0250098. (ho2021neonatalandinfant pages 1-2)
  • Rísová et al., published 31 December 2024: “Randomized trials have shown that FA supplementation during preconceptional and periconceptional periods reduces the incidence of NTDs by nearly 80%.” DOI: https://doi.org/10.3390/nu17010126. (risova2024preconceptionalandpericonceptional pages 1-3)

PMID note: The retrieved full texts did not consistently display PMIDs. To avoid false identifiers, DOI and ClinicalTrials.gov URLs are provided where verified; PubMed IDs should be added only after direct NCBI record validation.

References

  1. (vong2024riskofmeningomyelocele pages 2-4): Keng Ioi Vong, Sangmoon Lee, Kit Sing Au, T. Blaine Crowley, Valeria Capra, Jeremiah Martino, Meade Haller, Camila Araújo, Hélio R. Machado, Renee George, Bryn Gerding, Kiely N. James, Valentina Stanley, Nan Jiang, Kameron Alu, Naomi Meave, Anna S. Nidhiry, Fiza Jiwani, Isaac Tang, Ashna Nisal, Ishani Jhamb, Arzoo Patel, Aakash Patel, Jennifer McEvoy-Venneri, Chelsea Barrows, Celina Shen, Yoo-Jin Ha, Robyn Howarth, Madison Strain, Allison Elizabeth Ashley-Koch, Matloob Azam, Sara Mumtaz, Gyang Markus Bot, Richard H. Finnell, Zoha Kibar, Ahmed I. Marwan, Gia Melikishvili, Hal S. Meltzer, Osvaldo M. Mutchinick, David A. Stevenson, Henry J. Mroczkowski, Betsy Ostrander, Erica Schindewolf, Julie Moldenhauer, Elaine H. Zackai, Beverly S. Emanuel, Sixto Garcia-Minaur, Beata A. Nowakowska, Roger E. Stevenson, Maha S. Zaki, Hope Northrup, Hanna K. McNamara, Kimberly A. Aldinger, Ian G. Phelps, Mei Deng, Ian A. Glass, Bernice Morrow, Donna M. McDonald-McGinn, Simone Sanna-Cherchi, Dolores J. Lamb, Joseph G. Gleeson, Allison Elizabeth Ashley Koch, Hal S. Meltzer, Joan Le, Kit Sing Au, Hope Northrup, Gyang Markus Bot, Valeria Capra, Richard H. Finnell, Zoha Kibar, Philip J. Lupo, Helio R. Machado, Camila Araújo, Tony Magana, Ahmed I. Marwan, Gia Melikishvili, Osvaldo M. Mutchinick, Roger E. Stevenson, Anna Yurrita, Maha S. Zaki, Sara Mumtaz, José Ramón Medina-Bereciartu, Caroline M. Kolvenbach, Shirlee Shril, Friedhelm Hildebrandt, Mahmoud M. Noureldeen, Aida MS. Salem, Yukitoshi Takahashi, Hormos Salimi-Dafsari, H. Westley Phillips, Brian Hanak, Bülent Kara, Ayfer Sakarya Güneş, David D. Gonda, Salman Kirmani, Tinatin Tkemaladze, and Joseph G. Gleeson. Risk of meningomyelocele mediated by the common 22q11.2 deletion. Science, 384:584-590, May 2024. URL: https://doi.org/10.1126/science.adl1624, doi:10.1126/science.adl1624. This article has 20 citations and is from a highest quality peer-reviewed journal.

  2. (vong2024riskofmeningomyelocele pages 1-2): Keng Ioi Vong, Sangmoon Lee, Kit Sing Au, T. Blaine Crowley, Valeria Capra, Jeremiah Martino, Meade Haller, Camila Araújo, Hélio R. Machado, Renee George, Bryn Gerding, Kiely N. James, Valentina Stanley, Nan Jiang, Kameron Alu, Naomi Meave, Anna S. Nidhiry, Fiza Jiwani, Isaac Tang, Ashna Nisal, Ishani Jhamb, Arzoo Patel, Aakash Patel, Jennifer McEvoy-Venneri, Chelsea Barrows, Celina Shen, Yoo-Jin Ha, Robyn Howarth, Madison Strain, Allison Elizabeth Ashley-Koch, Matloob Azam, Sara Mumtaz, Gyang Markus Bot, Richard H. Finnell, Zoha Kibar, Ahmed I. Marwan, Gia Melikishvili, Hal S. Meltzer, Osvaldo M. Mutchinick, David A. Stevenson, Henry J. Mroczkowski, Betsy Ostrander, Erica Schindewolf, Julie Moldenhauer, Elaine H. Zackai, Beverly S. Emanuel, Sixto Garcia-Minaur, Beata A. Nowakowska, Roger E. Stevenson, Maha S. Zaki, Hope Northrup, Hanna K. McNamara, Kimberly A. Aldinger, Ian G. Phelps, Mei Deng, Ian A. Glass, Bernice Morrow, Donna M. McDonald-McGinn, Simone Sanna-Cherchi, Dolores J. Lamb, Joseph G. Gleeson, Allison Elizabeth Ashley Koch, Hal S. Meltzer, Joan Le, Kit Sing Au, Hope Northrup, Gyang Markus Bot, Valeria Capra, Richard H. Finnell, Zoha Kibar, Philip J. Lupo, Helio R. Machado, Camila Araújo, Tony Magana, Ahmed I. Marwan, Gia Melikishvili, Osvaldo M. Mutchinick, Roger E. Stevenson, Anna Yurrita, Maha S. Zaki, Sara Mumtaz, José Ramón Medina-Bereciartu, Caroline M. Kolvenbach, Shirlee Shril, Friedhelm Hildebrandt, Mahmoud M. Noureldeen, Aida MS. Salem, Yukitoshi Takahashi, Hormos Salimi-Dafsari, H. Westley Phillips, Brian Hanak, Bülent Kara, Ayfer Sakarya Güneş, David D. Gonda, Salman Kirmani, Tinatin Tkemaladze, and Joseph G. Gleeson. Risk of meningomyelocele mediated by the common 22q11.2 deletion. Science, 384:584-590, May 2024. URL: https://doi.org/10.1126/science.adl1624, doi:10.1126/science.adl1624. This article has 20 citations and is from a highest quality peer-reviewed journal.

  3. (tindula2024genome‐wideanalysisof pages 1-3): Gwen Tindula, Biju Issac, Sudipta Kumer Mukherjee, Sheikh Muhammad Ekramullah, D. M. Arman, Joynul Islam, Hafiza Sultana Suchanda, Liang Sun, Shira Rockowitz, David C. Christiani, Benjamin C. Warf, and Maitreyi Mazumdar. Genome‐wide analysis of spina bifida risk variants in a case–control study from bangladesh. Birth Defects Research, Mar 2024. URL: https://doi.org/10.1002/bdr2.2331, doi:10.1002/bdr2.2331. This article has 5 citations and is from a peer-reviewed journal.

  4. (aguiarpulido2021systemsbiologyanalysis pages 1-3): Vanessa Aguiar-Pulido, Paul Wolujewicz, Alexander Martinez-Fundichely, Eran Elhaik, Gaurav Thareja, Alice Abdel Aleem, Nader Chalhoub, Tawny Cuykendall, Jamel Al-Zamer, Yunping Lei, Haitham El-Bashir, James M. Musser, Abdulla Al-Kaabi, Gary M. Shaw, Ekta Khurana, Karsten Suhre, Christopher E. Mason, Olivier Elemento, Richard H. Finnell, and M. Elizabeth Ross. Systems biology analysis of human genomes points to key pathways conferring spina bifida risk. Dec 2021. URL: https://doi.org/10.1073/pnas.2106844118, doi:10.1073/pnas.2106844118. This article has 25 citations and is from a highest quality peer-reviewed journal.

  5. (houtrow2020prenatalrepairof pages 1-2): Amy J. Houtrow, Elizabeth A. Thom, Jack M. Fletcher, Pamela K. Burrows, N. Scott Adzick, Nina H. Thomas, John W. Brock, Timothy Cooper, Hanmin Lee, Larissa Bilaniuk, Orit A. Glenn, Sumit Pruthi, Cora MacPherson, Diana L. Farmer, Mark P. Johnson, Lori J. Howell, Nalin Gupta, and William O. Walker. Prenatal repair of myelomeningocele and school-age functional outcomes. Feb 2020. URL: https://doi.org/10.1542/peds.2019-1544, doi:10.1542/peds.2019-1544. This article has 185 citations and is from a highest quality peer-reviewed journal.

  6. (andersson2024mortalityratescause pages 1-2): Marie Andersson, Lana Hadi, Michaela Dellenmark Blom, Ulla Sillen, Sofia Sjöström, Magdalena Vu Minh Arnell, and Kate Abrahamsson. Mortality rates, cause and risk factors in people with spina bifida, register‐based study over five decades. Acta Paediatrica, 113:1916-1926, May 2024. URL: https://doi.org/10.1111/apa.17275, doi:10.1111/apa.17275. This article has 10 citations and is from a peer-reviewed journal.

  7. (ho2021neonatalandinfant pages 1-2): Peter Ho, Maria A. Quigley, Dharamveer Tatwavedi, Carl Britto, and Jennifer J. Kurinczuk. Neonatal and infant mortality associated with spina bifida: a systematic review and meta-analysis. PLoS ONE, 16:e0250098, May 2021. URL: https://doi.org/10.1371/journal.pone.0250098, doi:10.1371/journal.pone.0250098. This article has 52 citations and is from a peer-reviewed journal.

  8. (ho2021neonatalandinfant pages 13-15): Peter Ho, Maria A. Quigley, Dharamveer Tatwavedi, Carl Britto, and Jennifer J. Kurinczuk. Neonatal and infant mortality associated with spina bifida: a systematic review and meta-analysis. PLoS ONE, 16:e0250098, May 2021. URL: https://doi.org/10.1371/journal.pone.0250098, doi:10.1371/journal.pone.0250098. This article has 52 citations and is from a peer-reviewed journal.

  9. (risova2024preconceptionalandpericonceptional pages 1-3): Vanda Rísová, Rami Saade, Vladimír Jakuš, Lívia Gajdošová, Ivan Varga, and Jozef Záhumenský. Preconceptional and periconceptional folic acid supplementation in the visegrad group countries for the prevention of neural tube defects. Nutrients, 17:126, Dec 2024. URL: https://doi.org/10.3390/nu17010126, doi:10.3390/nu17010126. This article has 17 citations.

  10. (ferreira2024interventionstoimprove pages 1-3): Rafaela Fernandes Alvarenga Ferreira and Ana Cristina de Jesus Alves. Interventions to improve independence in basic and instrumental activities of daily living in individuals with myelomeningocele: an integrative literature review. Cadernos Brasileiros de Terapia Ocupacional, Jan 2024. URL: https://doi.org/10.1590/2526-8910.ctoar291837922, doi:10.1590/2526-8910.ctoar291837922. This article has 0 citations.

  11. (NCT04652908 chunk 1): Cellular Therapy for In Utero Repair of Myelomeningocele - The CuRe Trial. University of California, Davis. 2021. ClinicalTrials.gov Identifier: NCT04652908

  12. (NCT04652908 chunk 2): Cellular Therapy for In Utero Repair of Myelomeningocele - The CuRe Trial. University of California, Davis. 2021. ClinicalTrials.gov Identifier: NCT04652908

  13. (NCT04027374 chunk 2): Stress-associated Epigenetic Alterations in Newborns After Fetal Surgery. University Children's Hospital, Zurich. 2019. ClinicalTrials.gov Identifier: NCT04027374

  14. (NCT04027374 chunk 1): Stress-associated Epigenetic Alterations in Newborns After Fetal Surgery. University Children's Hospital, Zurich. 2019. ClinicalTrials.gov Identifier: NCT04027374

  15. (OpenTargets Search: spina bifida,myelomeningocele): Open Targets Query (spina bifida,myelomeningocele, 15 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  16. (mathew2018antenataldiagnosismaternal pages 14-17): ME Mathew. Antenatal diagnosis, maternal and neonatal outcome analysis of myelomeningocele, spina bifida at the lithuanian university of health sciences hospital (2016-2017 …. Unknown journal, 2018.

  17. (cranesmith2023anoncodinginsertional pages 1-2): Zoe Crane-Smith, Sandra C P De Castro, Evanthia Nikolopoulou, Paul Wolujewicz, Damian Smedley, Yunping Lei, Emma Mather, Chloe Santos, Mark Hopkinson, Andrew A Pitsillides, Richard H Finnell, M Elisabeth Ross, Andrew J Copp, and Nicholas D E Greene. A non-coding insertional mutation of grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele. Human Molecular Genetics, 32:2681-2692, Jun 2023. URL: https://doi.org/10.1093/hmg/ddad094, doi:10.1093/hmg/ddad094. This article has 12 citations and is from a domain leading peer-reviewed journal.

  18. (kancherla2023earlyneonatalmortality pages 1-6): Vijaya Kancherla, Sanjida Mowla, Sari Räisänen, and Mika Gissler. Early neonatal mortality among babies born with spina bifida in finland (2000–2014). American Journal of Perinatology, 40:1208-1216, Aug 2023. URL: https://doi.org/10.1055/s-0041-1733957, doi:10.1055/s-0041-1733957. This article has 5 citations and is from a peer-reviewed journal.

  19. (NCT07048691 chunk 1): Muhammad Naveed Babur. Prenatal and Postnatal Ultrasonographic Evaluation of Myelomeningocele to Predict Post-Surgical Outcomes. Superior University. 2025. ClinicalTrials.gov Identifier: NCT07048691

  20. (NCT06796972 chunk 1): In Utero Surgery for Fetal Myelomeningocele: Decision-making Mechanisms and Psychological Impact of Prenatal Therapy. Assistance Publique - Hôpitaux de Paris. 2024. ClinicalTrials.gov Identifier: NCT06796972

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 3
Off topic 3

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • DOI:10.1542/peds.2019-1544 (8 mentions) - Prenatal Repair of Myelomeningocele and School-age Functional Outcomes
  • shared terms: repair, prenatal
  • DOI:10.1590/2526-8910.ctoAR291837922 (3 mentions) - Interventions to improve independence in basic and instrumental activities of daily living in individuals with myelomeningocele: an integrative literature review
  • shared terms: mmc
  • DOI:10.1590/2526-8910.ctoar291837922 (3 mentions) - Interventions to improve independence in basic and instrumental activities of daily living in individuals with myelomeningocele: an integrative literature review
  • shared terms: mmc

Weighed against this report's own most characteristic terms: disease, gene, clinical, mmc, genetic, include, human, model, neural, spina, bifida, fetal, variant, primary, repair, risk, folate, open, secondary, prenatal.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.