Abstract
Neuronal migration disorders are human (or animal) diseases that result from a disruption in the normal movement of neurons from their original birth site to their final destination during early development. As a consequence, the neurons remain somewhere along their migratory route, their location depending on the pathological mechanism and its severity. The neurons form characteristic abnormalities, which are morphologically classified into several types, such as lissencephaly, heterotopia, and cobblestone dysplasia. Polymicrogyria is classified as a group of malformations that appear secondary to post-migration development; however, recent findings of the underlying molecular mechanisms reveal overlapping processes in the neuronal migration and post-migration development stages. Mutations of many genes are involved in neuronal migration disorders, such as LIS1 and DCX in classical lissencephaly spectrum, TUBA1A in microlissencephaly with agenesis of the corpus callosum, and RELN and VLDLR in lissencephaly with cerebellar hypoplasia. ARX is of particular interest from basic and clinical perspectives because it is critically involved in tangential migration of GABAergic interneurons in the forebrain and its mutations cause a variety of phenotypes ranging from hydranencephaly or lissencephaly to early-onset epileptic encephalopathies, including Ohtahara syndrome and infantile spasms or intellectual disability with no brain malformations. The recent advances in gene and genome analysis technologies will enable the genetic basis of neuronal migration disorders to be unraveled, which, in turn, will facilitate genotype-phenotype correlations to be determined.
Highlights
The characteristic six-layered neocortex in the human brain is formed by two types of neuron, projection neurons and interneurons, which migrate from their birth places, such as the ventricular zone and ganglionic eminence, respectively
Classical lissencephaly caused by LIS1 or DCX mutations usually exist in isolated forms and only show cortical dysplasia on brain magnetic resonance imaging (MRI)
Rare variant forms of lissencephaly are associated with congenital microcephaly, cerebellar hypoplasia, or agenesis of the corpus callosum
Summary
The characteristic six-layered neocortex in the human brain is formed by two types of neuron, projection neurons and interneurons, which migrate from their birth places, such as the ventricular zone and ganglionic eminence, respectively. Is classified as a spectrum of disorders caused by widespread abnormal transmantle migration, ranging from classical lissencephaly (agyria or pachygyria) to subcortical band heterotopia or double-cortex syndrome (Barkovich et al, 2012). Mutations in LIS1, located on chromosome 17p13.3, or DCX on Xq23 are the main cause for classical lissencephaly (Table 1) (Kato and Dobyns, 2003). Mutations in DCX are causative for classical lissencephaly in male individuals and subcortical band heterotopia in female individuals. Subcortical band heterotopia in male patients is caused by somatic mosaic DCX mutations or LIS1 mutations (Gleeson et al, 2000; Kato et al, 2001; D’agostino et al, 2002; Poolos et al, 2002).
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