Megalencephalic leukoencephalopathy with subcortical cysts-3 (MLC3) is a neurodegenerative disorder characterized by increased head circumference in infancy followed by progressive motor and cognitive decline in early childhood. Affected individuals either do not achieve walking or lose independent ambulation in the first or second decades. Cognitive impairment is variable and accompanied by poor speech and dysarthria. Most patients have early-onset seizures, which may be mild or refractory. Brain imaging shows unremitting megalencephalic leukoencephalopathy with subcortical cysts and swelling of the cerebral white matter (Passchier et al., 2023). For a discussion of genetic heterogeneity of megalencephalic leukoencephalopathy with subcortical cysts, see MLC1 (604004).

Remitting megalencephalic leukoencephalopathy with subcortical cysts-4 (MLC4) is an autosomal recessive neurologic disorder characterized by macrocephaly in infancy associated with developmental delay, delayed walking, variable cognitive decline, behavioral abnormalities, and early-onset seizures. The severity of neurologic dysfunction is variable, even within a family, but tends to show improvement with time. Brain imaging shows swelling of the cerebral white matter and subcortical cysts in the anterior temporal region, consistent with MLC. Brain imaging abnormalities also tend to improve with time, indicating a remitting disease course (Passchier et al., 2023). For a discussion of genetic heterogeneity of megalencephalic leukoencephalopathy with subcortical cysts, see MLC1 (604004).