Malformations of the Cerebral Cortex as a Cause of Mental Retardation and Epilepsy: Anatomoclinical and Genetic Spectrum*

The malformations of the cerebral cortex represent a major cause of developmental disabilities, severe epilepsy and reproductive disadvantage. The advent of high resolution MRI techniques has facilitated the in vivo identification of a large group of cortical malformation phenotypes. Several malformation syndromes caused by abnormal cortical development have been recognized and specific causative gene defects have been identified. Periventricular nodular heterotopia is a malformation of neuronal migration in which a subset of neurons fails to migrate into the developing cerebral cortex. X-linked Periventricular Nodular Heterotopia (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. A rare recessive form of PNH due ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay and early seizures. Lissencephaly-pachygyria and subcortical band heterotopia 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 subcortical band heterotopia owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominant lissencephaly in males and subcortical band heterotopia in female patients. Mutations of DCX have also been found in male patients with anterior subcortical band heterotopia 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.