Neurulation & Neural Tube Defects

Neurulation is the folding of a flat sheet of dorsal ectoderm into the closed neural tube, the precursor to the entire CNS. It happens in two phases over weeks 3–4: the cranial neural tube closes first (anterior neuropore by day 25), then the caudal end (posterior neuropore by day 27). When closure fails, the underlying CNS structures remain exposed and never develop normally; the resulting open or covered defect depends on where and when closure fails. Folate's effect on recurrence risk works because the critical window closes before most patients know they're pregnant, so supplementation must be periconceptional.

• Primary neurulation: folding. The notochord induces overlying ectoderm to thicken into the neural plate (week 3). The plate's lateral edges elevate, fold dorsally, and fuse at the midline like a zipper, beginning at the future cervical spine and extending both rostrally and caudally. The two open ends are the anterior and posterior neuropores.
• Secondary neurulation: cavitation. The most caudal part of the neural tube (lower sacral, coccygeal) forms by hollowing out a solid mesenchymal cord rather than by folding. Failure here gives closed (skin-covered) spinal dysraphisms (tethered cord, lipomyelomeningocele, dermal sinus).

The split matters clinically: open NTDs (anencephaly, myelomeningocele) result from failed primary neurulation and have elevated AFP; closed dysraphisms are skin-covered and do not raise AFP. Some closed forms (tethered cord, lipomyelomeningocele, dermal sinus) reflect failed secondary neurulation, whereas spina bifida occulta is fundamentally a posterior vertebral arch (bony) fusion defect rather than a pure neural-tube closure failure.

These two dates are the most clinically central facts in the chapter; folate dosing and prenatal screening protocols both follow from them. Anencephaly is universally lethal; affected pregnancies often have polyhydramnios (impaired fetal swallowing). Myelomeningocele has been treated by in-utero surgical repair (MOMS trial) with reduced shunt-dependent hydrocephalus and improved motor outcomes.

• Anencephaly: anterior neuropore failure. Open cranial vault, no forebrain. Strong association with elevated maternal serum AFP and acetylcholinesterase in amniotic fluid.
• Encephalocele: posterior or occipital skull defect with brain/meningeal herniation. Often not detected by AFP if covered by skin.
• Myelomeningocele: posterior neuropore failure with spinal cord and meninges in the sac. Clinically defines "spina bifida." Lower-extremity weakness, neurogenic bladder, hindbrain herniation (Chiari II).
• Meningocele: meninges only; cord is anatomically intact. Better prognosis.

• Spina bifida occulta: a vertebral arch defect without neural tissue herniation. Found incidentally in 5–10% of adults; often clinically silent. Cutaneous markers: hairy patch, dimple, lipoma, hemangioma over lumbosacral spine.
• Tethered cord syndrome: abnormal low-lying conus medullaris (below L1–L2) anchored by thick filum or lipoma. Progressive lower-extremity and bladder dysfunction.
• Lipomyelomeningocele / dermal sinus: secondary-neurulation failures. Skin is intact; AFP is not elevated.

• Multifactorial inheritance. Recurrence risk after one affected child is ~3–4%; after two affected children ~10%.
• Folate works. 400 μg/day periconceptionally for the general population; 4 mg/day if a prior affected pregnancy. The critical window is before day 28, so folate must be on board before conception.
• MTHFR (C677T, A1298C) variants modestly increase risk in some populations but routine testing is not recommended; folate prophylaxis is universal.
• Valproate: disrupts folate-dependent methylation and inhibits histone deacetylases; ~1–2% risk of NTD in exposed pregnancies. Switch antiepileptic preconceptionally when possible.
• Diabetes: uncontrolled maternal diabetes increases NTD risk (and many other malformations). HbA1c control is the single biggest preconception lever.
• Single-gene NTDs are rare. VANGL1, VANGL2 (planar cell polarity), and a few others have been implicated but most NTDs are multifactorial.

• Meckel-Gruber syndrome: autosomal recessive, ciliopathy. Triad of occipital encephalocele + cystic dysplastic kidneys + polydactyly. Often lethal in infancy.
• Chiari II malformation: almost universal in myelomeningocele. Posterior fossa is small; cerebellum and medulla herniate caudally; aqueductal stenosis → hydrocephalus requires shunting.
• Walker-Warburg syndrome: α-dystroglycanopathy. Lissencephaly + cerebellar/brainstem malformation + retinal dysplasia + congenital muscular dystrophy. Early-lethal.