CDGS is a group of disorders presenting in infancy with developmental delay, multisystemic involvement and abnormal serum glycoproteins. No specific enzyme deficiencies have been defined in patients with Type 1 CDGS, who show a distinct serum transferrin isoelectric focusing pattern and comprise the majority of CDGS patients. Analysis of the N-linked glycosylation of α-1 antitrypsin from Type I CDGS patients has provided evidence for subgroups with different metabolic defects in the N-linked oligosaccharide synthetic pathway, i.e., early in dolichol-linked oligosaccharide (DLO) synthesis, and later in processing of the protein-linked oligosaccharide(PLO). Patient fibroblast metabolic labelling studies support the existence of 3 biochemical subtypes in Type I CDGS. Cells from Type I CDGS patients were labelled with [3H]mannose to ascertain: 1) cellular uptake, 2) incorporation into DLO and 3)incorporation into PLO. Two siblings were previously reported to have 30% of normal[3H]mannose uptake by the cells with DLO incorporation of 50% and PLO incorporation of 40% of normal (Glycobiology 5(5):503, 1995). These patients appear to have a defect in DLO synthesis, probably due to reduced availability of mannose substrate. A second subgroup shows decreased [3H]mannose uptake into cells (50-70% normal) and delayed incorporation into DLO. The [3H]mannose incorporation into PLO was 50-70% of normal; suggesting a defect within the DLO synthetic pathway. A third subgroup has normal uptake into cells, normal DLO incorporation and 50-70% of normal [3H]mannose incorporation into PLO implicating abnormal late PLO processing. These data suggest that the clinically homogenous group of Type I CDGS patients have different defects in N-linked glycan synthesis.