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anomalies of cortical development

Wednesday 30 March 2005

The development of the cerebral cortex progresses through defined stages including neural proliferation, neuroblast migration and neuronal differentiation. Disruptions in each of these developmental stages can lead to characteristic cerebral cortical malformations.

The malformations of the cerebral cortex represent a major cause of developmental disabilities, severe epilepsy and reproductive disadvantage.

Epilepsy is often present in patients with cortical malformations and tends to be severe, although its incidence and type vary in different malformations. It is estimated that up to 40% of children with drug-resistant epilepsy have a cortical malformation. However, the physiopathological mechanisms relating cortical malformations to epilepsy remain elusive.


- anomalies of neural proliferation
- anomalies of neuroblast migration
- anomalies of neuronal differentiation


- Mutations in genes that are involved in neural proliferation give rise to microcephaly (small brain).

  • A rare recessive form of PNH due ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay and early seizures.

- Mutations in genes that direct the onset of neuroblast migration give rise to periventricular cortical heterotopia (clusters of neurons along the ventricles of the brain).

- Periventricular nodular heterotopia (PNH) is a malformation of neuronal migration in which a subset of neurons fails to migrate into the developing cerebral cortex.

  • X-linked PNH is mainly seen in females and is often associated with focal epilepsy. FLNA mutations have been reported in all familial cases and in about 25% of sporadic patients.

- Mutations in genes that are required for neuroblast migration cause type I lissencephaly (smooth brain) and subcortical band heterotopia (smooth brain with a band of neurons beneath the cortex).

- Mutations in genes that direct migratory neurons to arrest in the cortex lead to type II lissencephaly (smooth brain with clusters of neurons along the surface of the brain).

- Lissencephaly-pachygyria and subcortical band heterotopia (SBH) are disorders of neuronal migration and represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes.

  • LIS1 mutations cause a more severe malformation in the posterior brain regions. Most children have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posterior SBH owing to mosaic mutations of LIS1.
  • DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Mutations of DCX have also been found in male patients with anterior SBH and in female relatives with normal brain magnetic resonance imaging.
  • Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin (RELN) gene.
  • X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene. Affected boys have severe delay and seizures with suppression-burst EEG. Early death is frequent. Carrier female patients can have isolated corpus callosum agenesis.

- Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to chromosome Xq28 in some pedigrees, autosomal dominant or recessive inheritance in others, and an association with chromosome 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy.

  • Recessive bilateral frontoparietal polymicrogyria has been associated with mutations of the GPR56 gene.


- Lian G, Sheen V. Cerebral developmental disorders. Curr Opin Pediatr. 2006 Dec;18(6):614-20. PMID: 17099359

- Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res. 2006 Aug;173(2):322-33. PMID: 16724181