Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare and still incurable genetic leukodystrophy characterised by a slowly progressive course leading to motor and cognitive deficits as well as epilepsy. The clinical condition of patients is often worsened after trauma or certain infections. Patient care requires intensive parental, educational and social support.

About 80% of people with MLC carry mutations in the MLC1 gene encoding a protein whose function is not yet fully understood; a minority of patients (around 15%) have mutations in the Hepacam / Glialcam gene which encodes a cell adhesion molecule.

These two proteins are very strongly expressed in a population of brain cells called astrocytes. Astrocytes are essential for homeostasis and brain function, including maintaining water and ion balance. Studies by our research group and others suggest that MLC1 may regulate the exchange of ions and water. We recently began to study the role of MLC1 in the intracellular processes controlling the response of astrocytes to stress conditions (osmotic, inflammatory and oxidative stress). The results obtained will provide us with fundamental knowledge to study how mutations in MLC1 alter the functionality of astrocytes and lead to brain damage.

For this, we obtained inducible pluripotent stem cells from skin fibroblasts of people suffering from MLC and we are currently in the process of differentiating them into astrocytes carrying pathological mutations of MLC. This model should allow us to gain new insights into molecules and pathways that may become pharmacological targets to restore astrocyte function(s) and ultimately correct neurological deficits, which would pave the way for the development of treatments that can cure MLC or improve the quality of life of people with it.