Congenital Disorders of Glycosylation ( CDG ): Review

Abstract

Abstract Glycosylation is the most important posttranslational change for proteins. There are more than 100 different types of congenital disorders of glycosylation (CDG). The most frequent is PMM2‐CDG with over 700 patients described. N‐Linked glycosylation starts from the cytoplasm through the endoplasmic reticulum to the Golgi apparatus, leading to CDG‐I and CDG‐II defects, respectively. Secretory N‐glycosylation abnormalities can be demonstrated by transferrin isoelectric focusing (the screening test for most CDG types). There are also congenital O‐linked, combined and lipid‐linked glycosylation defects. Clinically, there is often multisystem involvement or a neurologic phenotype. Multiple abnormalities are usually present by routine laboratory analysis (e.g. increased serum transaminases, decreased coagulation factors and endocrine anomalies). Aetiologic treatment is limited to a handful of CDG (mannose supplementation for MPI‐CDG and galactose for PGM1‐CDG). The mainstay is supportive care. Twenty percent of patients with PMM2‐CDG die within 2 years; once the age of 4 year is reached, chances for survival rise dramatically. Key Concepts Glycosylation is essential for the normal function of glycosylated proteins (and lipids), and plays a role in many biologic processes such as endocrine regulation, coagulation, immunity, cell–cell interaction and organogenesis. From the different types of glycosylation defects, N‐linked glycosylation defects are the most common and lead to an easily detectable, mostly multisystem disease. Serum transferrin isoelectric focusing detects the missing negative charges of sialic acid in almost all secretory N‐linked glycosylation defects. Tissue‐specific O‐linked glycosylation defects and GPI‐anchor‐linked glycosylation defects are mostly recognisable syndromes diagnosed by genetic diagnostic methods. The most common CDG type, PMM2‐CDG, shows a phenotype of inverted nipples, abnormal fat pads, strabismus, hypotonia and feeding difficulties from a few months of age. Congenital anomalies are relatively common in CDG, including cerebellar vermis hypoplasia, eye malformations, cardiac defects, abnormal fat distribution, skeletal dysplasia, arachnodactyly or cleft palate. Specific treatment is only available for PMI‐CDG, namely oral mannose supplementation. Galactose treatment is beneficial for the endocrine, liver and coagulation problems in PGM1‐CDG.