A congenital disorder of glycosylation (previously called carbohydrate-deficient glycoprotein syndrome) is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. Congenital disorders of glycosylation are sometimes known as CDG syndromes. They often cause serious, sometimes fatal, malfunction of several different organ systems (especially the nervous system, muscles, and intestines) in affected infants.^[1] The most common sub-type is PMM2-CDG (formerly known as CDG-Ia) where the genetic defect leads to the loss of phosphomannomutase 2 (PMM2), the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate.^[2]

Clinical features depend on the molecular pathology of the particular CDG subtype. Common manifestations include ataxia; seizures; retinopathy; liver disease; coagulopathies; failure to thrive (FTT); dysmorphic features (e.g., inverted nipples and subcutaneous fat pads); pericardial effusion, skeletal abnormalities, and hypotonia. If an MRI is obtained, cerebellar hypoplasia is a common finding.^[3] Some CDG subtypes, like SSR4-CDG 1y, have been classified as connective tissue disorders.^[4]

Ocular abnormalities of PMM2-CDG include: myopia, infantile esotropia, delayed visual maturation, peripheral neuropathy (PN), strabismus, nystagmus, optic disc pallor, and reduced rod function on electroretinography.^[5] Three CDG subtypes PMM2-CDG, PMI-CDG, ALG6-CDG can cause congenital hyperinsulinism with hyperinsulinemic hypoglycemia in infancy.^[6] Because glycoproteins are involved in many central nervous system processes important during early development, intellectual disability and developmental delays are also common in CDG ^[7]

A biologically very important group of carbohydrates is the asparagine (Asn)-linked, or N-linked, oligosaccharides. Their biosynthetic pathway is very complex and involves a hundred or more glycosyltransferases, glycosidases, transporters and synthases. This plethora allows for the formation of a multitude of different final oligosaccharide structures, involved in protein folding, intracellular transport/localization, protein activity, and degradation/half-life. A vast amount of carbohydrate binding molecules (lectins) depend on correct glycosylation for appropriate binding; the selectins, involved in leukocyte extravasation, is a prime example. Their binding depends on a correct fucosylation of cell surface glycoproteins. Lack thereof leads to leukocytosis and increased sensitivity to infections as seen in SLC35C1-CDG(CDG-IIc); caused by a GDP-fucose (Fuc) transporter deficiency.^[8] All N-linked oligosaccharides originate from a common lipid-linked oligosaccharide (LLO) precursor, synthesized in the ER on a dolichol-phosphate (Dol-P) anchor. The mature LLO is transferred co-translationally to consensus sequence Asn residues in the nascent protein, and is further modified by trimming and re-building in the Golgi.^[9]

Deficiencies in the genes involved in N-linked glycosylation constitute the molecular background of most CDGs.^[10]

• Type I defects involve the synthesis and transfer of the LLO
• Type II defects impair the modification process of protein-bound oligosaccharides.

No treatment is available for most of these disorders. Mannose supplementation relieves the symptoms in MPI-CDG for the most part,^[39] even though the hepatic fibrosis may persist.^[40] Fucose supplementation has had a partial effect on some SLC35C1-CDG patients.^[41]

The first CDG patients (twin sisters) were described in 1980 by Jaeken et al.^[42] Their main features were psychomotor retardation, cerebral and cerebellar atrophy and fluctuating hormone levels (e.g.prolactin, FSH and GH). During the next 15 years the underlying defect remained unknown but since the plasmaprotein transferrin was underglycosylated (as shown by e.g. isoelectric focusing), the new syndrome was named carbohydrate-deficient glycoprotein syndrome (CDGS)^[1] Its "classic" phenotype included psychomotor retardation, ataxia, strabismus, anomalies (fat pads and inverted nipples) and coagulopathy.

In 1994, a new phenotype was described and named CDGS-II.^[43] In 1995, Van Schaftingen and Jaeken showed that CDGS-I (now PMM2-CDG) was caused by the deficiency of the enzyme phosphomannomutase. This enzyme is responsible for the interconversion of mannose-6-phosphate and mannose-1-phosphate, and its deficiency leads to a shortage in GDP-mannose and dolichol (Dol)-mannose (Man), two donors required for the synthesis of the lipid-linked oligosaccharide precursor of N-linked glycosylation.^[44]

In 1998, Niehues described a new CDG syndrome, MPI-CDG, which is caused by mutations in the enzyme metabolically upstream of PMM2, phosphomannose isomerase (PMI).^[25] A functional therapy for MPI-CDG, alimentary mannose was also described.^[25]

The characterization of new defects took increased and several new Type I and Type II defects were delineated.^[45]

In 2012, Need described the first case of a congenital disorder of deglycosylation, NGLY1 deficiency.^[46] A 2014 study of NGLY1 deficient patients found similarities with traditional congenital disorders of glycosylation.^[47]

• Inborn error of metabolism
• Leukocyte adhesion deficiency
• PMM2 deficiency