Clinical Information

Congenital disorders of glycosylation (CDG) are a group of over 150 inherited metabolic disorders largely affecting N- and O-glycosylation of proteins. CDG typically present as multisystemic disorders and may include developmental delay, hypotonia, abnormal magnetic resonance imaging findings, hypoglycemia, and protein-losing enteropathy. There is considerable variation in the severity of this group of diseases, which can range from hydrops fetalis to a mild presentation in adults. In some subtypes such as phosphomannose isomerase intelligence is not compromised.

Phosphomannomutase-2 deficiency (PMM2-CDG)is an autosomal recessive glycosylation disorder resulting from reduced or absent activity of the enzyme phosphomannomutase-2, encoded by the PMM2 gene. It is the most common CDG worldwide with phenotypic variability ranging from severely affected infants to mildly affected adults. In infancy, patients with PMM2-CDG will typically present with neurological involvement such as axial hypotonia, hyporeflexia, developmental delay, cerebellar hypoplasia, failure to thrive, hepatopathy, and abnormal subcutaneous fat distribution. There is variable involvement of other organ systems including features such as heart defects, epilepsy, strabismus, retinitis pigmentosa, liver dysfunction, endocrine abnormalities such as hypothyroidism and hypoglycemia, and skeletal deformities. Currently, there is no cure and treatment, while becoming more effective, remains primarily supportive and symptomatic.

Phosphomannose isomerase deficiency (MPI-CDG) is an autosomal recessive glycosylation disorder resulting from reduced or absent activity of phosphomannose isomerase, an enzyme encoded by the MPI gene. This CDG subtype is unique in that there is little to no involvement of the central nervous system. It is mainly hepatic-intestinal without dysmorphology, and the primary clinical manifestations are a result of aberrant gastrointestinal function. Individuals with MPI-CDG may present with failure to thrive, hypoglycemia, chronic diarrhea, and protein-losing enteropathy. MPI-CDG is also unique in that it’s effectively treated with mannose supplementation, though can be fatal if left untreated.