{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAlpha‐N‐acetylglucosaminidase (NAGLU) is a lysosomal enzyme that catalyzes a critical step in the degradation of heparan sulfate. Deficiency of NAGLU—caused by a wide range of inherited mutations such as missense, nonsense, small insertions/deletions, and even large intragenic deletions—leads to the accumulation of heparan sulfate and the development of mucopolysaccharidosis type IIIB (Sanfilippo syndrome type B). Clinically, patients present with progressive central nervous system deterioration and severe neurocognitive decline, underscoring the enzyme’s vital role in maintaining neuronal and lysosomal function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther studies have detailed the extensive allelic heterogeneity of the NAGLU gene across different populations, with mutation screening revealing founder effects and novel variants responsible for disease variability. In parallel, efforts in developing robust enzyme assays—including measurements of cerebrospinal fluid activity and innovative approaches such as engineering recombinant fusion proteins to improve cellular uptake—have reinforced NAGLU’s importance as both a biochemical marker and a direct therapeutic target in enzyme replacement and gene therapy strategies. Notably, investigations have also linked partial loss‐of‐function mutations to later‐onset neuropathies, indicating that even modest deficits in NAGLU activity can disrupt neuronal homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nHigh‐resolution structural studies have unveiled a novel homotrimeric configuration of human NAGLU, with its catalytic (α/β)8 barrel domain and key glutamate residues demarcating the active site. This atomic-level insight has not only provided a mechanistic understanding of how diverse mutations disrupt enzyme function but has also informed therapeutic design efforts. Moreover, emerging evidence suggests that aberrant NAGLU function may contribute to broader neurodegenerative processes—including α‐synuclein aggregation observed in Parkinson’s disease—thereby linking lysosomal dysfunction with later-onset neuropathologies and highlighting the enzyme’s multifaceted role in neural maintenance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "G Yogalingam, J J Hopwood "}, {"type": "b", "children": [{"type": "t", "text": "Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.1189"}], "href": "https://doi.org/10.1002/humu.1189"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11668611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11668611"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Serap Emre, Mugen Terzioglu, Aysegul Tokatli, et al. 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