Neuronal migration disorders: clinical, neuroradiologic and genetics aspects

Abstract

Disorders of neuronal migration are a heterogeneous group of disorders of nervous system development. One of the most frequent disorders is lissencephaly, characterized by a paucity of normal gyri and sulci resulting in a 'smooth brain'. There are two pathologic subtypes: classical and cobblestone. Six different genes could be responsible for this entity (LIS1, DCX, TUBA1A, VLDLR, ARX, RELN), although co-delection of YWHAE gene with LIS1 could result in Miller-Dieker Syndrome. Heterotopia is defined as a cluster of normal neurons in abnormal locations, and divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia. Genetically, heterotopia is related to Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2) genes mutations. Polymicrogyria is described as an augmentation of small circonvolutions separated by shallow enlarged sulci; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria results in a clinical syndrome manifested by mild mental retardation, epilepsy and pseudobulbar palsy. Gene mutations linked to this disorder are SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1. Schizencephaly, consisting in a cleft of cerebral hemisphere connecting extra-axial subaracnoid spaces and ventricles, is another important disorder of neuronal migration whose clinical characteristics are extremely variable. EMX2 gene could be implicated in its genesis. Focal cortical dysplasia is characterized by three different types of altered cortical laminations, and represents one of most severe cause of epilepsy in children. TSC1 gene could play a role in its etiology. Conclusion: This review reports the main clinical, genetical and neuroradiological aspects of these disorders. It is hoped that accumulating data of the development mechanisms underlying the expanded network formation in the brain will lead to the development of therapeutic options for neuronal migration disorders.

Leading Tip Drives Soma Translocation via Forward F-Actin Flow during Neuronal Migration

“…This suggests that the regulatory signal of reelin on neuronal soma translocation is mainly received by the tip of the leading process in developing cerebral cortex, consistent with our finding of an important role of the GC-like leading tip in soma translocation. Besides mutations in reelin signaling pathway, retardation in neuronal migration happens in many other pathological conditions, including a wide spectrum of developmental neurological disorders in humans (Hatten, 1999;Gleeson, 2001;Spalice et al, 2009). It is of great interest to explore whether migration retardation under these pathological conditions is caused by failure in the generation or transmission of the traction force by the GC-like leading tip in migrating neurons during development.…”

O papel das proteínas do citoesqueleto na fisiologia celular normal e em condições patológicas

“…12 As malformações do córtex cerebral são a principal causa de epilepsia grave na população pediátrica, sendo que 40% das crianças com epilepsia fármaco-resistente apresentam algum tipo de malformação cortical. 44 Estudos em humanos e camundongos têm identificado mutações em genes envolvidos em alguns processos essenciais, como a proliferação, migração e adesão celular, mas principalmente nos processos dinâmicos do citoesqueleto. Mutações nesses genes podem ser cruciais para o surgimento de anormalidades durante o desenvolvimento do córtex cerebral, podendo resultar em graves malformações corticais, como heterotopias e displasias.…”

Epileptogenic malformations of cortical development: when evolution goes awry

“…Therefore, the true impact of MCDs on human pathology is difficult to assess and as the current diagnostics of MCDs relies mainly on neuroimaging studies and sometimes on neuropathological investigations of a surgically resected specimen, even the true prevalence of MCDs is currently unknown. It is supposed that 25% to 40% of intractable childhood epilepsy could be attributable to MCDs (7,13). Better detection rates require specialized MRI protocols (13,14) and with proper neuroimaging the diagnoses of MCDs can sometimes be made before the 24th week of gestation (2) and can help to provide appropriate genetic counselling and testing.…”

“…It is supposed that 25% to 40% of intractable childhood epilepsy could be attributable to MCDs (7,13). Better detection rates require specialized MRI protocols (13,14) and with proper neuroimaging the diagnoses of MCDs can sometimes be made before the 24th week of gestation (2) and can help to provide appropriate genetic counselling and testing.…”