Beyond Neurodegeneration: White Matter Vacuolation as a Primary Myelin Defect

Spongiform degeneration, or status spongiosis, is characterized by vacuoles within the central nervous system. It appears in numerous neurological diseases, including transmissible spongiform encephalopathies, mitochondrial disorders, and lysosomal storage diseases. Traditionally considered secondary to neurodegeneration, vacuolar changes frequently involve white matter and form within the myelin sheath. This review examines the evidence from various diseases and genetic models that exhibit this pathology to support the hypothesis that white matter vacuolation represents a myelin defect and explores potential causative mechanisms. Our findings suggest that spongiform change in white matter represents a common endpoint of pathway disruptions that lead to metabolic or ionic dyshomeostasis, causing an osmotic imbalance and vacuole formation within myelin. We advocate for further research into myelin-preserving pathways as potential therapeutic avenues to treat conditions exhibiting this pathology.