CDGS is a group of disorders with clinical and biochemical heterogeneity, presenting in infancy with developmental delay, multisystemic involvement and abnormal serum glycoproteins. Clear evidence exists that defects both in the earliest part of the N-linked oligosaccharide synthetic pathway, dolichol-linked oligosaccharide (DLO) synthesis, and more distal steps, processing the protein-linked oligosaccharide (PLO), result in the Type I phenotype. However, despite similar clinical presentation and diagnostic testing, not all Type 1 CDGS patients have the same biochemical defect. Fibroblasts from a subpopulation of Type 1 CDGS patients have been shown to have phosphomannomutase deficiency (FEBS Letters 377:318, 1995). We now report that 3 biochemical subtypes can be dissected from the Type I CDGS population using fibroblast metabolic labelling.

Fibroblasts from Type I CDGS patients were metabolically labelled with[3H]mannose to ascertain cellular uptake and incorporation into DLOs and PLOs. Two siblings, as previously reported, have 30% of normal [3H]mannose uptake by the cells, DLO incorporation of 50% and PLO incorporation of 40% of that seen in normal fibroblasts (Glycobiology 5(5):503, 1995). A second subgroup, with 2 unrelated patients, shows decreased [3H]mannose uptake (50-70% normal) and slow but eventually normal incorporation into DLO. The [3H]mannose incorporation into PLO was 50-70% of normal. This would suggest a possible defect within the DLO synthetic pathway. The third subgroup, 2 sibs and an unrelated patient, shows normal uptake into cells, normal incorporation into DLO and 50-70% of normal [3H]mannose incorporation into PLO implicating an abnormality in the most distal part of the pathway, the processing of the PLO to its final complex form. Biochemical/phenotypic correlation appears to be limited.