MAN2B1 encodes a lysosomal alpha-mannosidase that hydrolyzes terminal alpha-mannosidic linkages (alpha 1,2-, alpha 1,3-, and alpha 1,6-linked) on mannose residues within oligosaccharides generated during N-glycoprotein degradation 1. The enzyme is localized to lysosomes, extracellular exosomes, and azurophil granule lumens, functioning in glycoprotein catabolism 2. Biallelic MAN2B1 mutations cause alpha-mannosidosis, an autosomal recessive lysosomal storage disorder characterized by mannose-rich oligosaccharide accumulation 3. Clinical manifestations include immune deficiency with recurrent infections, skeletal abnormalities (dysostosis multiplex, scoliosis), sensorineural hearing loss, intellectual disability, motor dysfunction, and facial coarsening 1. Disease severity correlates with mutation type and mutant protein subcellular localization; mutations preventing lysosomal targeting cause more severe phenotypes than those allowing partial lysosomal localization 4. Beyond alpha-mannosidosis, MAN2B1 dysregulation associates with neurodegenerative and immune-related pathologies. CSF MAN2B1 levels are altered in Parkinson's disease patients and correlate with clinical scores 5. MAN2B1 appears as a crosstalk gene linking systemic lupus erythematosus and moyamoya disease pathogenesis 6. Recently approved enzyme replacement therapy (velmanase alfa) improves non-neurological manifestations but cannot cross the blood-brain barrier, highlighting the critical importance of early diagnosis for therapeutic intervention 3.