Megalencephalic leukoencephalopathy with subcortical cysts: a third confirmed case with literature review

Area of Science:

• Neurology
• Genetics
• Pathology

Background:

• Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, early-onset neurological disorder characterized by progressive white matter disease, macrocephaly, and cognitive/motor decline.
• Genetic mutations in MLC1 are a known cause of this debilitating condition.

Observation:

• This study details the brain structure of a male patient with confirmed MLC1 mutations.
• Early macrocephaly at 6 months was followed by developmental delay.
• MRI revealed extensive white matter abnormalities and progressive subcortical cysts in the temporal and frontal lobes.

Findings:

• Brain biopsy at 15 months showed normal gray matter but pale subcortical white matter.
• Microscopic examination identified uniform, fine vacuoles (2-4 μm) within the white matter, separating myelinated axons.
• These vacuoles, with single- to triple-unit membranes resembling myelin, contained occasional organelles but lacked intermediate filaments.
• Evidence suggests myelin outer and inner layers formed blebs, potentially contributing to vacuole formation.
• Genetic analysis identified two heterozygous mutations in the MLC1 gene (intron 3: c.322-1 G>A; intron 7: c.597+1G>A), leading to amino acid deletions.

Implications:

• The characteristic fine vacuolation of white matter with axonal separation is a key diagnostic feature of MLC in early childhood.
• Understanding the precise ultrastructural changes aids in diagnosing and potentially managing MLC.
• Further research into the pathomechanisms of myelin vacuolation in MLC is warranted.