Molecular mechanisms of neuronal migration disorders

Abstract

Neuronal migration disorders are characterized by disruption of cortical layer architecture and the appearance of ectopic gray matter or heterotopia. Identification of LIS1 (PAFAH1B1) and DCX revealed that agyria, pachygyria, and band heterotopia form a continuum. ARX, which is involved in interneuron development, causes lissencephaly/agenesis of the corpus callosum due to loss-of-function mutations. In contrast, gain-of-function mutations involving polyalanine tract expansion cause functional disorders, such as epilepsy, intellectual disability, and motor impairment. Onset age and severity increase proportionally to the expansion length of polyalanine residues, which is referred to as interneuronopathy. Tubulinopathies are caused by microtubule abnormalities, and characterized by an indistinct anterior crus of the internal capsule. Channel abnormalities identified in polymicrogyria, as well as in epileptic disorders, have revealed the relationship between structural and functional abnormalities at the molecular level. Thus, mTOR activation causes focal cortical dysplasia and megalencephaly-related disorders, whereas reduced mTOR activity leads to lissencephaly (pachygyria). Molecularly targeted therapies are emerging as potential treatments for functional abnormalities like seizures and intellectual disability in neurodevelopmental disorders such as neuronal migration disorders.