Megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts is a progressive condition that affects brain development and function. Individuals with this condition typically have an enlarged brain (megalencephaly) that is evident at birth or within the first year of life. Megalencephaly progressively increases the size of the head. Affected people also have leukoencephalopathy, an abnormality of the brain's white matter. White matter consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates nerve fibers and promotes the rapid transmission of nerve impulses. In megalencephalic leukoencephalopathy with subcortical cysts, the myelin is swollen and stippled with fluid-filled pockets (vacuoles). Over time, the swelling decreases and the myelin begins to waste away (atrophy). Individuals affected with this condition may develop subcortical cysts below an area of the brain called the cerebral cortex. These cysts can grow in size and number.

People with megalencephalic leukoencephalopathy with subcortical cysts typically experience abnormal tensing of the muscles (spasticity) and difficulty coordinating movements (ataxia). Walking ability varies greatly among those affected. Some people lose the ability to walk early in life and need wheelchair assistance, while others are able to walk unassisted well into adulthood. Affected individuals may also develop abnormal muscle tone (dystonia), involuntary writhing movements of the limbs (athetosis), difficulty swallowing (dysphagia), and impaired speech (dysarthria). Despite the widespread brain abnormalities, people with this condition typically have only mild to moderate intellectual impairment. More than half of all people with this condition have recurrent seizures (epilepsy). Seizures can occur without warning or may follow minor head trauma. Additionally, minor head trauma can further impair movements and may lead to coma.

Megalencephalic leukoencephalopathy with subcortical cysts is a rare condition; at least 150 cases have been reported.

Mutations in the MLC1 gene cause most cases of megalencephalic leukoencephalopathy with subcortical cysts. The MLC1 gene provides instructions for producing a protein that is found in the brain, spleen, and white blood cells (leukocytes). Within the brain, the MLC1 protein is found in specialized cells called astroglial cells, which support and nourish other cells. Research suggests that astroglial cells play an important role in the long-term maintenance of myelin. The precise function of the MLC1 protein in astroglial cells, the spleen, and leukocytes is unknown.

MLC1 gene mutations inhibit the production of functional MLC1 protein. Most mutations probably alter the structure of the MLC1 protein or prevent the cell from producing any of this protein. It is unknown how a lack of functional MLC1 protein impairs brain development and function, causing the signs and symptoms of megalencephalic leukoencephalopathy with subcortical cysts.

Approximately 25 percent of people with megalencephalic leukoencephalopathy with subcortical cysts do not have identified mutations in the MLC1 gene. In these individuals, the cause of the disorder is unknown. Mutations in one or more as-yet unidentified genes may be responsible for the disorder in these cases.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.