BRAIN HISTOPATHOLOGY IN LEUKOENCEPHALOPATHY DUE TO MLC1 GENE MUTATION

Objectives: Megaloencephalic leukoencephalopathy with subcortical cysts (MLC) is a childhood white matter disease. The diagnosis is mainly MRI-based and 60–70% of the patients harbor MLC1 gene mutations. We present the histopathologic and spectrometric findings in a patient with typical clinical and imaging characteristics of the disease and MLC1 mutations.

Methods: A small biopsy, including cortex and subcortical white matter, was obtained at the age of 15 months from the right frontal gyrus. Tissue was prepared for light and electron microscopy. Serial brain proton MR Spectroscopy and sequencing analysis of the MLC1 gene were performed.

Results: There was diffuse fine and uniform microvacuolation of the white matter. Oligodendrocytes exhibited expanded vacuolated cytoplasm. White matter myelination was poor with occasional hypomyelinated axons. The number of myelinated axons (neurofilament) was moderately reduced. Electron microscopy confirmed markedly reduced packing density of myelinated axons that were widely separated by cytoplasmic mainly empty vacuoles. Some vacuoles were in close contact with the myelin and appeared to be arising from the outer layer of myelin sheath. Hypomyelinated axons typically had only 4–5 myelin layers. Some axons were normal and the others were degenerated or absent. Complex vacuolated membranous material was located mainly in cytoplasm of the oligodendrocytes. A decreasing over time NAA was found on the spectra. Patient was found compound heterozygous for the mutations IVS3–1G>A and pISV7+1G>A.

Conclusion: The findings demonstrate that the leukoencephalopathy due to mutations of MLC1 gene is a vacuolating myelinopathy with evidence of axonal degeneration. The myelin sheaths are thin with a tendency to peripheral separation of myelin and vacuole formation. The etiology of the vacuolization is unknown but an abnormal interaction between astrocytes and oligodendrocytes is speculated. The axonal degeneration could be an epiphenomenon, but a primary axonopathy should be considered since MLC1 protein is expressed in astroglial processes and also in axonal tracts.