Approximately 50% of all proteins and 80% of those in blood are glycosylated and need appropriate sugar moieties added to function properly. A broad class of monogenic disease is the congenital disorders of glycosylation (CDGs), involving over 160 different genes (Fig. 1): most are autosomal recessive and a few are X-linked. They usually present in infancy with multisystem problems, including failure to thrive, liver disease, hypotonia, intestinal disease (often protein-losing enteropathy), developmental delay, eye and skeletal anomalies, immunologic abnormalities, and may or may not include brain and/or neurodevelopmental abnormalities. CDGs are divided into two main groups: type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (llO) chain and its transfer to the nascent protein; type II CDGs are due to defects in the processing of the protein-bound glycans either late in the endoplasmic reticulum or in the Golgi apparatus. Screening for N-linked glycosylation disorders can be achieved by isoelectric focusing of transferrin, a heavily glycosylated plasma protein. Decrease in the proportion of tetrasialo-transferrin with increases of asialo- or di- or trisialotransferrin, suggest the diagnosis, which then needs molecular confirmation. Because the multipathway, or type II, CDGs require sequencing and the manifestations are so variable, increasingly the diagnosis is established by direct genome-wide investigation through either exome or genome sequencing.
Fig1. A schematic of the N-linked pathway highlighting those genes required for both the initial steps of lipid-linked oligosaccharide synthesis and several key components for glycan processing within the Golgi. These genes highlighted in red represent known loci for glycosylation disorders. The blue arrow indicates MPI. Supplementation with pharmacologic doses of mannose can drive this reaction to create extra mannose-6-phosphate. (Adapted from Ng BG, Freeze HH: Perspectives on glycosylation and its congenital disorders, Trends Genet 34(6):466–476, 2018. https://doi.org/10.1016/j.tig.2018.03.002.)
One example is CDG due to pathogenic variants in MPI, called MPI-CDG or CDG1b. This condition spares cognitive development but manifests in infancy with severe failure to thrive, protein-losing enteropathy, hypoglycemia, and coagulation defects. Treatment with high-dose mannose (1 g/kg body weight) results in elimination of hypoglycemia, protein-losing enteropathy, and coagulation defects. Despite treatment, some patients have manifested liver fibrosis in adulthood, so long-term follow-up is essential.
