Congenital Disorders of Glycosylation

At a glance

Congenital disorders of glycosylation (CDG) refers to a group of multisystemic disorders characterized by dysmorphism, coagulation disorders, and psychomotor retardation. Multiple subtypes exist, of which type Ia is by far the most common.

Synonym

Carbohydrate-Deficient Glycoprotein Syndromes (former name).

Classification

There are basically two types of protein glycosylation:

• N-glycosylation: Comprises an assembly pathway (in the cytosol and the endoplasmic reticulum) and a processing pathway (in the endoplasmic reticulum and the Golgi complex).

• O-glycosylation: More complex that the former one but lacks a processing pathway. Of the 16 known defects, 12 affect N-glycosylation (eight are assembly defects [CDG Ia-Ih] and four are processing defects [CDG IIa-IId]) and four affect the O-glycosylation.

Incidence

Approximately 350 patients with CDG Type Ia (by far the most common type) have been reported worldwide. Half of these cases are estimated to have occurred in Scandinavia. For the other types of CDG, the number of reported patients varies between one and 30 for each type of CDG Type I and II.

Genetic inheritance

Autosomal recessive, except for the multiple exostoses syndrome, which is autosomal dominant inherited.

Pathophysiology

CDG are due to defects in the synthesis of the glycan moiety of glycoproteins and other glycoconjugates. It results in a defective attachment of carbohydrates to proteins due to mutations affecting the N-glycosylation or O-glycosylation. In CDG Type I, lipid-linked oligosaccharide assembly and transfer is affected. In CDG Type II, trimming of the protein-bound oligosaccharide or the sugar attachment to it is affected.

Diagnosis

Clinical findings and electrophoretic patterns of serum transferrin (serum transferring isoelectrofocusing) is the gold standard for N-glycosylation defects. The lack of negatively charged sialic acid (a component of transferring) results in a cathodal shift in the electrophoresis, which is considered diagnostic, although a normal pattern does not exclude CDG. Multiple subtypes exist (see Table C-4), of which CDG Type Ia is the most common. Depending on the subtype, coagulation disorders may result in a prothrombotic or bleeding tendency.