Severe central nervous system demyelination in Sanfilippo disease.

Introduction: Chronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC Methods: Brain and spinal cord tissues of human MPS III patients, 6-month-old Results: Analyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or "zebra bodies" consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Discussion: Our findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.