Congenital Disorders of Glycosylation & Cancer

1. CDG Classification

Traditional division:

• CDG-I: defects in dolichol-linked oligosaccharide synthesis, upstream of OST transfer. Leads to ER-side under-glycosylation. Most common: PMM2-CDG (phosphomannomutase 2), MPI-CDG (phosphomannose isomerase, the only treatable CDG by oral mannose), ALG1–13 deficiencies.
• CDG-II: defects in Golgi glycan processing or transport. Examples: MGAT2-CDG, COG complex deficiencies, SLC35A1-CDG (CMP-sialic-acid transporter).

Clinical features span all systems: central nervous system (developmental delay, cerebellar atrophy, stroke-like episodes), coagulation (antithrombin deficiency), endocrine (hypothyroidism), skeletal, hepatic, immune. Transferrin isoelectric focusing was the first-line diagnostic; mass spectrometry and WES now dominate. Treatments are disease-specific — MPI-CDG responds to oral mannose; PMM2-CDG has no disease-modifying therapy, though trials of epalrestat (aldose reductase inhibitor) are ongoing. Substrate-reduction, chaperone, and ASO approaches are in development.

2. COG Complex Disorders

The Conserved Oligomeric Golgi complex (COG, 8 subunits) is a multi-subunit tethering complex at the Golgi. Loss-of-function mutations in any of the eight subunits (COG1–COG8) cause CDG-II-type phenotypes. The mechanism: COG tethers retrograde Golgi vesicles for cisternal-maturation-driven enzyme recycling; loss of tethering mis-localises glycosyltransferases, producing widespread under-glycosylation of N- and O-glycans. COG-CDG is a paradigmatic trafficking-machinery disease.

3. Cancer and Aberrant Glycosylation

Tumour cells routinely display altered surface glycosylation. Common patterns:

• Increased sialyl-Lewis X/A: promotes extravasation via selectin binding — the mechanistic basis of haematogenous metastasis. CA19-9 (sLe^a) is a pancreatic-cancer tumour marker.
• Increased β1,6-branched N-glycans(MGAT5): correlates with metastatic potential; binds galectin-3 on the cell surface and forms a lattice that modulates RTK signalling.
• Truncated O-glycans (Tn, sialyl-Tn antigens): GalNAc-only or sialyl-GalNAc; exposure of normally-masked cryptic epitopes in breast and pancreatic cancer.
• Polysialic acid (PolySia) on NCAM: overexpressed in neuroendocrine tumours, correlates with migration and invasion.

Therapeutic implications: targeting glycan antigens with antibodies (anti-sTn in trials for ovarian cancer) or with CAR-T cells; ST6GAL1 inhibitors for metastasis prevention. Glycan-based biomarkers are standard of care for several cancers.

4. I-Cell Disease & Mucolipidoses

Mucolipidosis II (I-cell disease) andmucolipidosis III result from mutations in GNPTAB or GNPTG (Module 3, M6P pathway). Because M6P tagging fails, lysosomal hydrolases are secreted rather than delivered to lysosomes; lysosomes accumulate undegraded substrates (the characteristic “I-cells” = inclusion cells). Phenotype resembles Hurler syndrome (mucopolysaccharidosis I): coarse facies, skeletal dysplasia, developmental delay. Paradoxically, serum lysosomal enzyme activity is elevated — these enzymes are being secreted. This diagnostic paradox was a key early clue to the M6P pathway.

5. Infection and the Golgi

Many viruses subvert the Golgi. Enveloped viruses acquire their glycoprotein envelope in the Golgi (SARS-CoV-2 S protein, influenza HA, herpes-family GP). Some viruses (polyomaviruses) repurpose the Golgi for replication-complex assembly. Cholera toxin and ricin are retrograde-transported from plasma membrane through Golgi to ER via COPI-related machinery, exploiting the KDEL receptor pathway backward to reach the cytosol. These hijackings have made the Golgi a useful target for broad-spectrum anti-infective development.