Rare genetic causes of lissencephaly may implicate microtubule-based transport in the pathogenesis of cortical dysplasias

Excerpt

Disruption of early neural development can cause severe forms of mental retardation and epilepsy, associated with defects in cortical structure. Lissencephaly is a disorder resulting from abnormal neuronal migration. Of the six causative genes for classical lissencephaly, three, LIS1, DCX, and TUBA1A encode for microtubule-related proteins, indicating the importance of this pathway for neuronal migration (Table 1). The lissencephaly 1 (LIS1) protein is an adaptor for dynein, a microtubule motor protein . Doublecortin (DCX ) encodes a microtubule-associated protein (MAP).^, Finally, tubulin α1a (TUBA1A) is a gene that encodes an alpha tubulin subunit that is enriched during brain development.

These lissencephalic syndromes clinically all share a widespread disruption of lamination in the cerebral cortex (Figure 1). Since all three genes appear to regulate microtubule-based transport, their functional relation and regulation during development is an area of active investigation with implications that may be significant for a wider cohort of patients with focal cortical dysplasias. Cortical dysplasias are a common cause of refractory epilepsy and share some of the same histological features of lissencephaly, including the dyslamination and abnormal neuronal morphology. Disruption of microtubule-based pathways may lead to cortical dysplasias and the causative genes for lissencephaly are a starting point for further investigation.