Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a condition that affects brain development and function. Individuals with this condition have an enlarged brain (megalencephaly) and an abnormality of the white matter in the brain (leukoencephalopathy). White matter consists of nerve fibers covered by a fatty substance called myelin that promotes the rapid transmission of nerve impulses. In MLC, the myelin is swollen and contains numerous fluid-filled pockets (vacuoles). Over time, the swelling decreases and the myelin begins to waste away (atrophy). Leukoencephalopathy can lead to abnormal muscle tensing (spasticity), difficulty coordinating movements (ataxia), cysts in the brain (subcortical cysts), abnormal muscle tone (dystonia), swallowing difficulties, mild to moderate intellectual disabilities, speech difficulties, seizures, and difficulties walking. There are three types of MLC, which are distinguished by their signs and symptoms and genetic cause. Type 1 is caused by mutations in the MLC1 gene. Types 2A and 2B are caused by mutations in the HEPACAM gene. MLC types 1 and 2A are inherited in an autosomal recessive manner, while type 2B is inherited in an autosomal dominant manner. In approximately 5% of individuals with MLC, the cause is unknown.  Although there is no specific treatment or cure for MLC, there are ways to manage the symptoms, such as use of antiepileptic drugs, physical therapy, and speech therapy. Management additionally includes avoiding injury to the head, which can temporarily worsen symptoms. A team of doctors or specialists is often needed to figure out the treatment options for each person.

The majority of individuals with MLC have mutations in the MLC1 gene. Mutations within this gene account for approximately 75% of all cases. The MLC1 gene provides instructions for making a protein found primarily in astroglial cells in the brain. Astroglial cells are a specialized type of glial cell, which are cells that protect and maintain nerve cells. The role of the MLC1 protein is not fully understood; however, it is suspected to be involved in the control of fluids into cells or the strength of cells' attachment to one another.  Approximately 20% of individuals with MLC have mutations in the HEPACAM gene. The HEPACAM gene provides instructions for making a protein called GlialCAM, which primarily functions in the brain, particularly in glial cells. GlialCAM attaches to other GlialCAM proteins or to the MLC1 protein and guides them to the space between cells (cell junctions). The function of GlialCAM at the cell junction is unclear. About 5% of individuals with MLC do not have identifiable mutations in either the MLC1 or HEPACAM gene. In these individuals, the cause of MLC is not known.