NAGPA (N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase), also known as the 'uncovering enzyme,' catalyzes the critical second step in mannose-6-phosphate (M6P) targeting signal formation on lysosomal enzymes by removing N-acetylglucosamine (GlcNAc) residues from GlcNAc-alpha-P-mannose intermediates 1. This enzymatic activity is essential for proper trafficking of over 60 soluble lysosomal hydrolases to their destination compartments 2. NAGPA mutations reduce cellular enzyme activity by approximately 50% and impair intracellular processing and trafficking, leading to reduced protein half-life 3. Functionally, NAGPA is central to the lysosomal enzyme-targeting pathway alongside GNPTAB and GNPTG 4. Clinically, NAGPA mutations have been associated with persistent developmental stuttering in multiple populations 45, with evidence suggesting these mutations may also contribute to dyslexia 5. Notably, individuals carrying NAGPA mutations show reduced responsiveness to stuttering therapy compared to non-carriers 6. While NAGPA mutations themselves do not cause severe lysosomal storage disorders like mucolipidosis, their role in speech disorders suggests that partial deficits in M6P pathway function can produce specific neurological effects 3. The crystal structure reveals a globular catalytic domain with a flexible C-terminal stem extending from the Golgi membrane 1.