Decoding the Glycan Signature: Unraveling N -Glycosylation Alterations in Glycogen Storage Disease Ia and Ib

Glycogen storage disease (GSD) types Ia and Ib are rare inherited metabolic disorders caused by pathogenic variants in G6PC or SLC37A4 , respectively. These defects disrupt glucose homeostasis and may affect protein glycosylation. We systematically profiled sera N -glycomes from retrospectively collected GSD Ia (n=17), GSD Ib (n=8), and control (n=21) samples. Derived traits analyses revealed distinct, subtype-specific, and shared glycomic alterations, including shifts from α2,3-to α2,6-sialylation in both subtypes. GSD Ia showed enhanced branching and reduced fucosylation, whereas GSD Ib displayed elevated fucosylation, bisection, and reduced branching. In GSD Ia patients with hepatocellular adenoma/carcinoma (HCA/HCC), further enrichment of oligomannosidic and α2,3-sialylation was observed. Several individual N -glycans showed strong discriminatory performance, supporting their potential as biomarkers for GSD I subtyping and HCA/HCC surveillance. This study provides the first comprehensive characterization of systemic N -glycans in GSD Ia and Ib, revealing glycomic remodeling as a potential biomarker of disease subtypes and tumor progression.