Functional characterization of RELN missense mutations involved in recessive and dominant forms of Neuronal Migration Disorders

RELN is a large secreted glycoprotein that acts at multiple steps of cerebral cortex development, including neuronal migration. Only recessive mutations of the Reelin gene (RELN) have been associated with human cortical malformations and none has been functionally characterized. We identified novel missense RELN mutations in both compound and de novo heterozygous patients exhibiting an array of neuronal migration disorders (NMDs) as diverse as pachygyria, polymicrogyria and heterotopia. Most mutations caused defective RELN secretion in vitro and, when ectopically expressed in the embryonic mouse cortex, affected neuronal aggregation and/or migration in vivo. We determined the de novo heterozygous mutations acted as dominant negative and demonstrated that RELN mutations mediate not only recessive, but also dominant NMDs. This work assesses for the first time the pathogenicity of RELN mutations showing a strong genotype-phenotype correlation. In particular, the behavior of the mutant proteins in vitro and in vivo predicts the severity of cortical malformations and provides valuable insight into the pathogenesis of these disorders.

Coexistence of Temporo-Occipital Polymicrogyria with Choroidal Fissure Cyst in a Case of Focal Onset Seizures

Focal-onset seizures can be caused by underlying brain lesions including focal lesions such as granulomas, low-grade neoplasms, vascular lesions, or neuronal migration disorders. Polymicrogyria is a congenital abnormality of cortical formation occurring during embryonic life. Choroidal fissure cysts are either arachnoid or neuroepithelial cysts arising at the choroidal fissure, and mostly they are incidental findings having no significant clinical implications. Coexistence of both of these can lead to dilemma in the management decisions. We present a case of focal-onset seizures with an unreported coexistence of polymicrogyria with choroidal fissure cyst.