Megalencephalic leukoencephalopathy with subcortical cysts: A personal biochemical retrospective

Eur J Med Genet. 2018 Jan;61(1):50-60. doi: 10.1016/j.ejmg.2017.10.013. Epub 2017 Oct 25.


Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy characterized by dysfunction of the role of glial cells in controlling brain fluid and ion homeostasis. Patients affected by MLC present macrocephaly, cysts and white matter vacuolation, which lead to motor and cognitive impairments. To date, there is no treatment for MLC, only supportive care. MLC is caused by mutations in the MLC1 and GLIALCAM genes. MLC1 is a membrane protein with low identity to the Kv1.1 potassium channel and GlialCAM belongs to an adhesion molecule family. Both proteins form a complex with an as-yet-unknown function that is expressed mainly in the astrocytes surrounding the blood-brain barrier and in Bergmann glia. GlialCAM also acts as an auxiliary subunit of the chloride channel ClC-2, thus regulating its localization at cell-cell junctions and modifying its functional properties by affecting the common gate of ClC-2. Recent studies in Mlc1-, GlialCAM- and Clcn2-knockout mice or Mlc1-knockout zebrafish have provided fresh insight into the pathophysiology of MLC and further details about the molecular interactions between these three proteins. Additional studies have shown that GlialCAM/MLC1 also regulates other ion channels (TRPV4, VRAC) or transporters (Na+/K+-ATPase) in a not-understood manner. Furthermore, it has been shown that GlialCAM/MLC1 may influence signal transduction mechanisms, thereby affecting other proteins not related with transport such as the EGF receptor. Here, we offer a personal biochemical retrospective of the work that has been performed to gain knowledge of the pathophysiology of MLC, and we discuss future strategies that may be used to identify therapeutic solutions for MLC patients.

Keywords: Astrocyte; ClC-2; GlialCAM; Leukodystrophy; MLC1.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain / metabolism
  • Cell Cycle Proteins
  • Cysts / genetics*
  • Cysts / pathology
  • Hereditary Central Nervous System Demyelinating Diseases / genetics*
  • Hereditary Central Nervous System Demyelinating Diseases / pathology
  • Humans
  • Membrane Proteins / metabolism
  • Protein Binding
  • Proteins / chemistry
  • Proteins / genetics*
  • Proteins / metabolism


  • Cell Cycle Proteins
  • HEPACAM protein, human
  • MLC1 protein, human
  • Membrane Proteins
  • Proteins

Supplementary concepts

  • Megalencephalic leukoencephalopathy with subcortical cysts