SGSH encodes N-sulfoglucosamine sulfohydrolase (also called heparan N-sulfatase), a lysosomal enzyme that catalyzes hydrolysis of N-linked sulfate groups from the nonreducing terminal glucosaminide residue of heparan sulfate during its degradation 1. This enzyme is unique among lysosomal sulfatases involved in glycosaminoglycan (GAG) degradation as an N-sulphatase, whereas others are O-sulphatases 1. Loss-of-function mutations in SGSH cause Mucopolysaccharidosis Type IIIA (MPS IIIA, Sanfilippo syndrome type A), an autosomal recessive lysosomal storage disorder characterized by progressive accumulation of heparan sulfate in lysosomes and extracellular spaces 2 3. MPS IIIA manifests as early-onset neurodegenerative disease with severe cognitive decline, behavioral disturbances, and hyperactivity, with relatively mild somatic features 4. SGSH mutations account for one of four genetic subtypes of Sanfilippo syndrome, with 19 novel mutations identified in molecular characterization studies 5. Recent studies in Sgsh knockout mice reveal that SGSH deficiency triggers dramatic microglia activation and dysregulation of genes associated with lysosomal function and immune signaling, driving neuroinflammatory pathways that contribute to neurodegeneration 6. Currently, no approved therapy exists, though clinical trials are ongoing for enzyme replacement therapy, gene therapy, and substrate reduction therapy 7.