Disorders of Neuronal Migration

  • Neuronal migration involves precise orchestration of extracellular signals and transcription factors.
  • Disturbances may arise from genetic or acquired events, varying based on mechanism, timing, and severity.

Classification of Neuronal Migration Defects

  • Focal/Multifocal Neuronal Migration Defects:
    • Schizencephaly
    • Mild subcortical band heterotopia
    • Nodular heterotopia
  • Diffuse Neuronal Migration Defects:
    • Agyria-pachygyria spectrum (Lissencephaly type 1)
    • Severe subcortical band heterotopia
    • Cobblestone lissencephaly complex (Lissencephaly type 2)

Categorization Based on Migration Stage

  • Before/At onset: Schizencephaly, periventricular nodular heterotopia.
  • During migration: Agyria-pachygyria spectrum.
  • Failed penetration of subplate: Lissencephaly with cerebellar hypoplasia.
  • End of migration (overmigration): Type 2, cobblestone complex.

Genetic and Molecular Signalling Defects

  • Filamin 1 (FLN1): Cellular locomotion disruption leading to periventricular nodular heterotopia.
  • Doublecortin (DCX):
    • X-linked mutations causing band heterotopia in females and lissencephaly in males.
  • LIS1 gene mutations:
    • Causes lissencephaly and subcortical laminar heterotopia.
    • Accounts for 40–75% of Type 1 lissencephalies.
  • Reelin (RELN):
    • Secreted by Cajal-Retzius cells.
    • Critical for neuronal migration, cortical lamination, and positioning.

Specific Disorders and Genetic Causes

  • Lissencephaly (Smooth Brain):
    • Classic Type 1 (Miller-Dieker syndrome): LIS1 gene (17p13.3 deletion) or DCX mutations.
    • Associated genes: TUBA1A, DYNC1H1, KIF2A, TUBG1, NDE1.
    • RELN gene: Lissencephaly with cerebellar hypoplasia (Norman-Roberts syndrome).
  • Cobblestone Lissencephaly (Type 2):
    • Genes: POMT1/2, FKRP, SRD5A3, ATP6V0A2, GPR56.
    • Associated conditions: Walker–Warburg syndrome, Muscle-eye-brain disease, Fukuyama congenital muscular dystrophy.
  • Polymicrogyria:
    • PIK3R2B mutations causing bilateral perisylvian polymicrogyria (BPP) or polymicrogyria-polydactyly-hydrocephalus (MPPH).
    • Associated conditions: Joubert syndrome, Aicardi syndrome, Zellweger syndrome.
    • Genes: TUBA8, β-tubulins.
  • Schizencephaly:
    • Typically non-genetic, linked to CMV infection or vascular events.
    • Genetic association: CoL4A1 mutations.
Information
Published:01 May 2025
Modified: 01 May 2025