Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Objective Megalencephalic leukoencephalopathy with cysts ( MLC ) is a genetic infantile‐onset disease characterized by macrocephaly and white matter edema due to loss of MLC 1 function. Recessive mutations in either MLC 1 or GLIALCAM cause the disease. MLC 1 is involved in astrocytic volume regulation; Glial CAM ensures the correct membrane localization of MLC 1. Their exact role in brain ion‐water homeostasis is only partly defined. We characterized Glialcam ‐null mice for further studies. Methods We investigated the consequences of loss of Glial CAM in Glialcam ‐null mice and compared Glial CAM developmental expression in mice and men. Results Glialcam ‐null mice had early‐onset megalencephaly and increased brain water content. From 3 weeks, astrocytes were abnormal with swollen processes abutting blood vessels. Concomitantly, progressive white matter vacuolization developed due to intramyelinic edema. Glialcam ‐null astrocytes showed abolished expression of MLC 1, reduced expression of the chloride channel ClC‐2 and increased expression and redistribution of the water channel aquaporin4. Expression of other MLC 1‐interacting proteins and the volume regulated anion channel LRRC 8A was unchanged. In mice, Glial CAM expression increased until 3 weeks and then stabilized. In humans, Glial CAM expression was highest in the first 3 years to then decrease and stabilize from approximately 5 years. Interpretation Glialcam ‐null mice replicate the early stages of the human disease with early‐onset intramyelinic edema. The earliest change is astrocytic swelling, further substantiating that a defect in astrocytic volume regulation is the primary cellular defect in MLC . Glial CAM expression affects expression of MLC 1, ClC‐2 and aquaporin4, indicating that abnormal interplay between these proteins is a disease mechanism in megalencephalic leukoencephalopathy with cysts.