Improvement of CDG diagnosis by combined examination of several glycoproteins

Abstract

Congenital disorders of glycosylation (CDG) represent a family of genetic diseases with broad clinical presentation. Initial diagnosis is currently mainly based on the identification of hyposialylated serum transferrin (TF) by isoelectric focusing (IEF). To improve the diagnosis of known CDG types and to identify so far unknown CDG cases, additional glycoproteins, alpha1-antitrypsin titrypsin (alpha1-AT) and alpha1-antichymotrypsin (alpha1-ACT), were studied. According to the patterns of transferrin, enzyme assays and mutation analysis, 16 patients with various clinical symptoms suspicious for CDG were divided into three groups: group A (n = 6) with confirmed CDG; group B (n = 4) with clear abnormal TF-IEF patterns of unknown origin (all known CDG types were excluded) and group C (n = 6) with borderline TF-IEF patterns; 164 samples served as a control group. Automated IEF of TF, alpha1-AT and alpha1-ACT was carried out using a PhastSystem. CDG patients with glycosylation defects of known origin (group A) and patients with abnormal TF-IEF patterns due to glycosylation defects of as yet unknown origin (group B) showed abnormal IEF patterns of all three glycoproteins. These results confirmed generalized defects of glycosylation. Furthermore, the IEF pattern of alpha1-ACT seems to allow a differentiation between CDG Ia and CDG Ic. However, patients with borderline TF-IEF pattern (group C) showed a normal alpha1-AT-IEF pattern. Four of these six patients also showed a normal alpha1-ACT-IEF pattern; this constellation suggests that CDG can most likely be excluded. In the two remaining patients of group C with a borderline TF-IEF pattern an abnormal pattern of alpha1-ACT-IEF was obtained which needs further investigations. We conclude that the combined investigation of three glycoproteins provides additional information in the diagnostic work-up of patients with possible CDG. The suspicion of CDG in patients with apparent glycosylation defects of unknown origin or borderline TF-IEF pattern can be either substantiated or weakened.