congenital disorders of glycosylation

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins.

The Congenital Disorders of Glycosylation (CDG) are a collection of over 20 inherited diseases that impair protein N-glycosylation.

The clinical appearance of CDG patients is quite diverse making it difficult for physicians to recognize them.

A simple blood test of transferrin glycosylation status signals a glycosylation abnormality, but not the specific defect.

An abnormal trasferrin glycosylation pattern suggests that the defect is in either genes that synthesize and add the precursor glycan (Glc(3)Man(9)GlcNAc(2)) to proteins (Type I) or genes that process the protein-bound N-glycans (Type II).

Type I defects create unoccupied glycosylation sites, while Type II defects give fully occupied sites with abnormally processed glycans.

These types are expected to be mutually exclusive, but a group of patients is now emerging who have variable coagulopathy and hypoglycemia together with a combination of Type I and Type II transferrin features.

Classification

 congenital disorder of glycosylation type I (CDG-Is or CDG1s)

• congenital disorder of glycosylation type Ia (CDG-Ia or CDG1A)
• congenital disorder of glycosylation type Ib (CDG-Ib or CDG1B) (MIM.602579) (12872847)

 congenital disorder of glycosylation type II (CDG-IIs or CDG2s)

Type I CDGs (CDG1s) comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin.

References

 Martin PT. Congenital muscular dystrophies involving the O-mannose pathway. Curr Mol Med. 2007 Jun;7(4):417-25. PMID: 17584082

 Rampal R, Luther KB, Haltiwanger RS. Notch signaling in normal and disease States: possible therapies related to glycosylation. Curr Mol Med. 2007 Jun;7(4):427-45. PMID: 17584081

 Schulz BL, Laroy W, Callewaert N. Clinical laboratory testing in human medicine based on the detection of glycoconjugates. Curr Mol Med. 2007 Jun;7(4):397-416. PMID: 17584080

 Freeze HH. Congenital Disorders of Glycosylation: CDG-I, CDG-II, and beyond. Curr Mol Med. 2007 Jun;7(4):389-96. PMID: 17584079

 Freeze HH.Novel perspectives on glycosylation and human disease. Curr Mol Med. 2007 Jun;7(4):387. PMID: 17584078

 Grewal PK, Hewitt JE. Glycosylation defects: a new mechanism for muscular dystrophy? Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R259-64. PMID: 12925572

 Aebi M, Hennet T. Congenital disorders of glycosylation: genetic model systems lead the way. Trends Cell Biol. 2001 Mar;11(3):136-41. PMID: 11306275

 Aebi M, Helenius A, Schenk B, Barone R, Fiumara A, Berger EG, Hennet T, Imbach T, Stutz A, Bjursell C, Uller A, Wahlstrom JG, Briones P, Cardo E, Clayton P, Winchester B, Cormier-Dalre V, de Lonlay P, Cuer M, Dupre T, Seta N, de Koning T, Dorland L, de Loos F, Kupers L, et al. Carbohydrate-deficient glycoprotein syndromes become congenital disorders of glycosylation: an updated nomenclature for CDG. First International Workshop on CDGS. Glycoconj J. 1999 Nov;16(11):669-71. PMID: 11003549