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Subcortical band heterotopia (double cortex) and X-linked lissencephaly development, possible pathophysiological mechanism

Cortex development is divided into 3 stages. The preplate stage is marked by the appearance of an early population of neurons (PP) located superficial to the dividing neurons in the ventricular zone (VZ). The cortical plate stage is marked by the appearance of cortical plate cells (CP) underneath the marginal zone (MZ). Cortical neurons migrate along radial glia cells (tan), which form a supporting scaffold, positioning themselves in the developing cortical plate. The adult stage is marked by the disappearance of the majority of marginal zone cells and the maturation of the cortical plate into a 6-layered cortex. In subcortical band heterotopia, proliferating neurons are mosaic for normal doublecortin (green cells) and abnormal doublecortin (blue cells) because of random X-inactivation in females. Actin and the microtubules cytoskeleton are destabilized and the scaffold disrupted, such that neurons migrate away from the ventricular zone, but the mutant cells are unable to complete their migration, depositing in the subcortical white matter as a band of heterotopic neurons (BH) (Fitzgerald et al 2011; Cappello et al 2012). In experiments using mice, the ablation of afadin, a membrane scaffolding protein, results in double cortex, apparently the result of faulty development of radial glial scaffolding and neuronal migration (Yamamoto et al 2015). In patients with subcortical band heterotopia, the defects can be both widespread and symmetric (Emsley et al 2011). Normal neurons complete their migration and establish a normal 6-layered cortical plate. In X-linked lissencephaly, all neurons are mutant for doublecortin and unable to complete their migration, resulting in a strikingly abnormal cortex with 4 rudimentary levels. (Contributed by Dr. Joseph Gleeson.)

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Associated Disorders

  • Developmental delay
  • Epilepsy
  • Mental retardation