Therapeutic approaches in Congenital Disorders of Glycosylation (CDG) involving N-linked glycosylation: an update

Abstract

Congenital disorders of glycosylation (CDG) are a group of clinically and genetically heterogeneous metabolic disorders. Over 150 CDG types have been described. Most CDG types are ultrarare disorders. CDG types affecting N-glycosylation are the most common type of CDG with emerging therapeutic possibilities. This review is an update on the available therapies for disorders affecting the N-linked glycosylation pathway. In the first part of the review, we highlight the clinical presentation, general principles of management, and disease-specific therapies for N-linked glycosylation CDG types, organized by organ system. The second part of the review focuses on the therapeutic strategies currently available and under development. We summarize the successful (pre-) clinical application of nutritional therapies, transplantation, activated sugars, gene therapy, and pharmacological chaperones and outline the anticipated expansion of the therapeutic possibilities in CDG. We aim to provide a comprehensive update on the treatable aspects of CDG types involving N-linked glycosylation, with particular emphasis on disease-specific treatment options for the involved organ systems; call for natural history studies; and present current and future therapeutic strategies for CDG.

Keywords: CDG; congenital disorders of glycosylation; dietary interventions; monosaccharide supplementation; therapy.

Fig. 1. Overview of involved organ systems in disorders of N-linked glycosylation for which therapies are available.

Affected systems are depicted with common involvement in congenital disorders of glycosylation (CDG). VSD ventricular septal defect.

Fig. 2. Therapeutic mechanisms of monosaccharide supplementation in N-linked glycosylation.

Man supplementation in MPI-CDG bypasses disrupted MPI enzyme activity by providing exogenous Man for synthesis of mannose-6-phosphate, which is ultimately converted to GDP-Man and incorporated into the growing N-glycans on the endoplasmic reticulum (ER) membrane. Gal supplementation in PGM1-CDG restores levels of activated sugar UDP-GLU and UDP-Gal for incorporation into N-glycans in the Golgi, effectively redirecting cellular sugar metabolism to PGM1-independent pathways. Fucose supplementation in SLC35C1-CDG increases fucose availability in the Golgi (54).