NAGLU (N-acetyl-alpha-glucosaminidase) is a lysosomal enzyme responsible for degrading heparan sulfate, a glycosaminoglycan critical for cellular homeostasis 1. The enzyme functions within lysosomes to catalyze the sequential breakdown of heparan sulfate proteoglycans, enabling their catabolism 2. Deficiency of NAGLU function leads to accumulation of partially degraded heparan sulfate within lysosomes, causing Mucopolysaccharidosis type IIIB (Sanfilippo syndrome), characterized by progressive cognitive decline, severe neurological manifestations, and hyperactivity 1. Recent evidence indicates NAGLU mutations also associate with Charcot-Marie-Tooth disease, axonal type 2V 3. At the mechanistic level, NAGLU deficiency triggers lysosomal dysfunction and impaired autophagy, with downstream effects on vesicle transport and synaptic function affecting nervous system development 4. Clinical significance extends beyond lysosomal storage disease; heterozygous loss-of-function NAGLU mutations are enriched in Alzheimer's disease patients and promote amyloid-β plaque formation in mouse models through gene-dosage effects 5. NAGLU polymorphisms (p.Ser141Ser and p.Arg737Gly) do not appear to constitute true pseudodeficiency alleles based on enzyme activity analysis 6. Current therapeutic approaches include enzyme replacement therapy and gene therapy for MPSIIIB 1.