Hunter syndrome (mucopolysaccharidosis type II): Molecular mechanisms, CNS biomarkers, and emerging therapeutic strategies.

Abstract

Hunter syndrome (mucopolysaccharidosis type II, MPS II) is an X-linked lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS), leading to lysosomal accumulation of glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate. Although traditionally viewed as an inherited metabolic disease, increasing evidence indicates that the most severe clinical burden of MPS II arises from central nervous system (CNS) dysfunction driven by convergent neurobiological mechanisms relevant to neuropsychiatric and neurodegenerative disorders. GAGs accumulation disrupts lysosomal integrity, impairs autophagy-lysosome flux, alters mitochondrial homeostasis, and activates innate immune pathways, including NLRP3 inflammasome signaling. These processes promote chronic neuroinflammation, microglial activation, secondary lipid and ganglioside storage, axonal injury, and progressive cognitive and behavioral decline in neuronopathic MPS II. Multimodal biomarkers-including cerebrospinal fluid heparan sulfate, neurofilament light chain, and neuroimaging-link molecular pathology to neuronal injury and provide objective measures of CNS disease burden and therapeutic response. The genetic complexity of the IDS locus contributes to marked phenotypic heterogeneity and informs both diagnosis and prognosis. Advances in newborn screening and molecular diagnostics now enable earlier identification of affected individuals, creating opportunities for timely intervention before irreversible neurodegeneration occurs. Here, we review current insights into lysosomal-immune-neuronal crosstalk in MPS II and discuss emerging CNS-targeted therapeutic strategies, including blood-brain barrier-penetrant enzyme replacement therapies, intracerebroventricular delivery, AAV-mediated gene therapy, genome editing, and adjunctive approaches targeting neuroinflammation and cellular clearance. Collectively, MPS II serves as a model disorder illustrating how lysosomal dysfunction and innate immune activation converge to drive neurodegeneration, with broader implications for translational research in psychiatric and neurodegenerative disease.