Research Progress of Pathological Mechanism in Megalencephalic Leukoencephalopathy With Subcortical Cysts

Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is a degenerative disease of the central nervous system caused by mutations in MLC1 or GlialCAM, characterized with astrocyte swelling and vesicle formation of myelin. MLC/GlialCAM and ClC-2 co-localize at the end feet of astrocytes. Previous studies discovered that MLC1/GlialCAM mutation affects the conductivity of ClC-2 channels, resulting in the imbalance of water and ion homeostasis in astrocytes, while in the GlialCAM homozygous knockout mouse, the phenotype cannot be rescued by crossing with transgenic mice that selectively open ClC-2. Recent study showed that mutated MLC1 promotes the internalization of Connexin43 and reduced the formation of gap junctions at the cell membrane, affected the efficiency of intercellular communication, and interrupted normal glial syncytial function, which led to MLC with astrocyte edema and the vesicle formation of myelin. It indicated that the abnormal function of glial syncytia composed of astrocytes, oligodendrocytes and connexins needs further investigation.