Timing & Key Steps

*Globus pallidus: classically taught as diencephalic; modern developmental data show it derives from the medial ganglionic eminence (telencephalic) but migrates ventrally. The board answer remains diencephalon.

Neural crest cells delaminate from the dorsal neural folds and migrate widely. Major derivatives:

• Peripheral nervous system: all Schwann cells; sensory ganglia (DRG; sensory portions of CN V, VII, IX, X — mixed with placodal contribution)
• Autonomic ganglia: sympathetic (paravertebral, prevertebral) and parasympathetic (including the enteric nervous system — failure of migration to distal colon → Hirschsprung disease)
• Adrenal medulla (chromaffin cells)
• Melanocytes (skin, hair, leptomeninges)
• Odontoblasts; bones & cartilage of pharyngeal arches; mesenchyme of head and face
• Aorticopulmonary septum + tunica media of arch-derived great vessels
• Cranial leptomeninges (forebrain pia/arachnoid); caudal leptomeninges have mesodermal contribution

Spectrum

Holoprosencephaly (HPE) = failure of the prosencephalon to cleave into two cerebral hemispheres. Severity spectrum:

• Alobar HPE — complete failure of cleavage; single ventricle / fused thalami; facial anomalies range up to cyclopia with proboscis; usually lethal
• Semilobar HPE — partial separation posteriorly; intermediate severity; cleft lip/palate, hypotelorism
• Lobar HPE — nearly normal separation with subtle midline fusion; mild facial dysmorphism; survivable
• Middle interhemispheric variant (syntelencephaly) — failure of midline cleavage of posterior frontal/parietal regions only

Causes: sporadic; SHH (sonic hedgehog) pathway mutations (SHH, ZIC2, SIX3, TGIF); trisomy 13 (Patau); maternal diabetes; maternal alcohol use; cholesterol synthesis disorders (Smith-Lemli-Opitz). "Single midline maxillary central incisor" is a subtle marker.

Agenesis of the Corpus Callosum (ACC)

• Failure of midline crossing of commissural fibers; can be complete or partial (posterior usually affected first because the corpus callosum develops front-to-back, EXCEPT for the rostrum which forms last)
• Imaging hallmarks: Probst bundles (longitudinal white-matter tracts running anteroposteriorly along the medial hemispheric walls), colpocephaly (enlarged occipital horns), parallel orientation of lateral ventricles ("racing-car" sign)
• May be isolated (often normal cognition) or syndromic (Aicardi syndrome — almost exclusively females, rare affected males usually 47,XXY; presumed de novo X-linked/male-lethal mechanism, gene unknown; triad = agenesis/dysgenesis of corpus callosum + infantile epileptic spasms + chorioretinal lacunae)

Septo-Optic Dysplasia (de Morsier)

• Triad (any two of three required): optic nerve hypoplasia + absent septum pellucidum + hypothalamic-pituitary insufficiency
• Associations: HESX1, SOX2, SOX3, OTX2 (PAX6 is for aniridia, NOT SOD); GH deficiency, ACTH/cortisol deficiency, central DI

Congenital Aqueductal Stenosis

• Most common cause of congenital obstructive (non-communicating) hydrocephalus in infants — narrowing or web within the cerebral aqueduct of Sylvius prevents 3rd→4th ventricle CSF flow.
• X-linked recessive forms (L1CAM) account for some cases — "HSAS" (hydrocephalus due to stenosis of aqueduct of Sylvius), males more affected. Other causes: in-utero infection (CMV, toxoplasmosis), tectal glioma, post-hemorrhagic gliosis.
• Presentation: macrocephaly, bulging fontanelle, "sun-setting" eyes (Parinaud-like dorsal midbrain compression), developmental delay. Treatment: ETV (endoscopic third ventriculostomy) preferred when feasible, otherwise VP shunt.

Spinal Cord: Basal vs Alar Plate Derivatives

• By week 4–5, the neural tube wall organizes around a sulcus limitans into two longitudinal columns:
• Basal plate (ventral) → motor neurons (anterior horn cells of the cord and motor cranial nerve nuclei).
• Alar plate (dorsal) → sensory interneurons (posterior horn of the cord and sensory cranial nerve nuclei).
• The same alar/basal plate organization persists in the brainstem, where the sulcus limitans separates motor (medial) from sensory (lateral) cranial nerve nuclei in the floor of the 4th ventricle.

Cortical Architecture & Myelination Timing

• Six-layered neocortex (from pia inward): I = molecular (Cajal-Retzius cells); II = external granular; III = external pyramidal; IV = internal granular (main thalamocortical input); V = internal pyramidal (corticospinal/Betz output); VI = multiform (corticothalamic output).
• Migration is "inside-out" — layer VI forms first, layer II last (preplate → Cajal-Retzius/marginal zone + subplate → layers VI→II form sequentially).
• Myelination: begins in the PNS in the first trimester, in the CNS from ~14 weeks; complete in the PNS by ~3–5 years; CNS myelination continues into the third decade (frontal cortex last). Order: caudal→rostral and central→peripheral within the brain; U-fibers myelinate LAST.
• U-fiber rule: in most congenital leukodystrophies (MLD, X-ALD, Krabbe, PKU, MSUD) U-fibers are spared initially; U-fibers are involved early in Canavan disease, Alexander disease, and in acquired demyelinating processes (MS, ADEM, PML) — a board-classic discriminator.
• Full-term infant nerve conduction velocities are ~50% of adult values; reach adult speeds by ~3–5 years (paralleling PNS myelin completion). Slow infant NCS is therefore normal — interpret cautiously against age-matched norms.

Syringomyelia

• CSF-filled cavity (syrinx) within the central spinal cord
• Classic association: Chiari I (~50%); also post-traumatic, post-inflammatory (TM), tumor-associated
• Classic exam: "cape distribution" suspended sensory loss of pain & temperature (decussating spinothalamic fibers crossing the central cord are affected first) with preserved fine touch, vibration, and proprioception (dorsal columns spared); LMN weakness at the level of the syrinx (anterior horn involvement); UMN signs below as the syrinx enlarges and compresses the corticospinal tracts
• MRI shows the syrinx; always image the craniocervical junction to evaluate for Chiari I