Protein glycosylation is an essential post-translational modification of various proteins, affecting their folding, sorting, and function. Inborn defects in the assembly and processing of glycans on glycoproteins are known as congenital disorders of glycosylation (CDG) and can affect both N- and O-glycosylation (for reviews see Marquardt and Denecke,¹ Jaeken,² and Grunewald et al³). N-glycosylation defects and especially defects in the assembly of the dolichol linked N-glycan precursor in the endoplasmic reticulum (ER) (CDG-I) result in hypoglycosylation of many kinds of (serum) glycoproteins. CDG-I is therefore a group of multisystemic disorders.

The assembly of the N-glycan precursor in the ER is a highly ordered process involving at least 30 known gene products. Mutations in 11 of these (PMM2, MPI, ALG6, DPM1, ALG3, MPDU1, ALG12, ALG8, ALG2, DPAGT1, and ALG1) have been shown to cause CDG type I (CDG-Ia to CDG-Ik).^2,4–10 Although it remains difficult to define a characteristic clinical phenotype for each type of CDG, mainly because only a limited number of patients have been assigned to most types, they generally share hypotonia and different degrees of mental retardation. Central nervous system defects are absent in CDG-Ib patients (with a deficiency of phosphomannose isomerase, MPI) and in the recently published CDG-Ih patient (with a deficiency of dolichyl-P-Glc: Glc₁Man₉GlcNAc₂-PP-dolichyl α1, 3-glucosyltransferase, ALG8).⁴ CDG-Ib patients present mainly with hypoglycaemia, coagulopathy, hepatomegaly, protein-losing enteropathy, hepatic fibrosis, cyclic vomiting, and diarrhoea.^11–14 It is the only type with an efficient therapy because dietary mannose can be used via an alternative pathway to generate mannose-6-phosphate that is normally produced from fructose-6-phosphate by the action of MPI.

The only CDG-Ih patient described so far shares this relatively mild presentation with severe diarrhoea and moderate hepatomegaly.⁴

Our cohort of unsolved CDG patients included …