General description

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by macrocephaly, developmental delays, ataxia, spasticity, and epilepsy. It can follow autosomal dominant or recessive inheritance patterns, depending on the causative gene mutation. MLC is categorized into classic (progressive) and improving (remitting) forms. Recently, new genetic subtypes, MLC3 (GPRC5B mutations) and MLC4 (AQP4 mutations), have been identified, with MLC3 being a classic type and MLC4 a remitting type.

• Classic MLC (MLC1, MLC2A, MLC3): The most common form, usually caused by mutations in the MLC1, GLIALCAM (MLC2A), or GPRC5B genes. Symptoms typically begin with macrocephaly within the first year of life, followed by progressive neurological symptoms such as ataxia, spasticity, developmental delays, and epilepsy. Motor function often deteriorates, and many patients require a wheelchair by adolescence, although disease progression and severity can vary widely.
• Improving MLC (MLC2B, MLC4): Caused by dominant GLIALCAM or AQP4 mutations, this form presents similarly with macrocephaly and developmental delays but shows a more favorable course. Neurological symptoms may improve or stabilize, and MRI abnormalities can normalize. Some individuals remain clumsy or hypotonic, and epilepsy is less common.

MLC is the first human disease known to be caused by genetic abnormalities in astrocytes, affecting the brain's ion and water homeostasis. It manifests as chronic white matter edema, with excessive water accumulating in the myelin sheath's vacuoles and astrocytic end-feet near blood vessels.

Symptom severity and progression vary. While some individuals lose independent mobility within a few years, others may continue walking into their fifth decade. The disease can worsen following triggers like head trauma or fever. However, without such triggers, some patients may experience stable periods without progression.

Radiographic features

Imaging studies reveal diffuse swelling of the cerebrum, with T2WI showing widespread hyperintensity in the cerebral white matter, occasionally sparing the occipital lobe. FLAIR images demonstrate a lower signal in the white matter compared to the gray matter, indicating significant water accumulation. Both DWI and ADC show hyperintensity.

Cysts are consistently present in the anterior temporal lobe in all cases and may also appear in the frontal and parietal lobes.

In typical cases, the posterior limb of the internal capsule is partially affected, displaying T2WI hyperintensity.