PMM2 (phosphomannomutase 2) catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, a critical step in synthesizing GDP-mannose and dolichol-phosphate-mannose required for protein N-linked glycosylation 1. These nucleotide-activated sugars are essential substrates for mannosyl transfer reactions throughout the cell 2. PMM2 deficiency causes phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG), the most common N-glycosylation disorder, characterized by impaired protein glycosylation with primarily neurological manifestations 1. Recent studies in PMM2-deficient neural models demonstrate aberrant neural activity, widespread decreases in protein glycosylation, impaired mitochondrial structure, and abnormal glucose metabolism, with enzyme activity correlating directly to neurological symptom severity 3. Beyond neurological involvement, PMM2 mutations have been identified in congenital hyperinsulinism 4 and primary ovarian insufficiency 5. Cardiac complications also occur in PMM2-CDG patients 6. Emerging therapeutic approaches targeting mannose metabolism show promise; mannose supplementation normalizes protein glycosylation and reduces inflammatory pathways in intestinal disease models 7. Current treatments remain primarily preventive and symptomatic, though pharmacological approaches targeting PMM2 activity or mannose metabolism pathways are under investigation 2.