Megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts (MLC), also known as van der Knaap disease, is a rare inherited disorder affecting the brain's white matter (leukodystrophy). It is characterized by early-onset macrocephaly (abnormally large head), typically evident within the first year of life, along with progressive deterioration of motor functions, mild cognitive decline, and epileptic seizures. Brain MRI reveals diffuse swelling and signal abnormality of the cerebral white matter along with the presence of subcortical cysts, predominantly in the anterior temporal and frontoparietal regions. The disease is caused by mutations in the MLC1 gene (most common, accounting for approximately 75% of cases) or the GLIALCAM (HEPACAM) gene. These genes encode proteins involved in the regulation of brain water and ion homeostasis, particularly in astrocytes. Dysfunction of these proteins leads to chronic white matter edema (vacuolation), which underlies the macrocephaly and progressive neurological deterioration. Notably, mutations in GLIALCAM can cause either a classic progressive form (autosomal recessive) or a remitting form (autosomal dominant or recessive) in which clinical and MRI features may improve over time. Clinical progression is typically slow. Most affected children develop motor difficulties including spasticity, ataxia, and eventual loss of ambulation, though the rate of decline varies considerably. Cognitive function is relatively preserved early in the disease but may decline over time. Seizures occur in the majority of patients and are generally well-controlled with antiepileptic medications. There is currently no cure or disease-modifying treatment for MLC. Management is supportive and symptomatic, including physical therapy, occupational therapy, seizure management, and monitoring for complications. The disease is more prevalent in certain populations with higher rates of consanguinity, including the Agarwal community in India and Turkish populations.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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