Interpretive Handbook

Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndrome, are a group of inherited metabolic diseases that affect 1 of the steps of the pathway involved in glycosylation. CDGs typically present as multisystemic disorders with developmental delay, hypotonia, abnormal magnetic resonance imaging (MRI) 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 (Ib, in particular) intelligence is not compromised.

Phosphomannomutase-2 deficiency (CDG-Ia or PMM2-CDG) is an autosomal recessive glycosylation disorder resulting from reduced or absent activity of the enzyme phosphomannomutase-2, encoded by the PMM2 gene. Over 700 individuals have been described to date, making it the most common congenital disorder CDG worldwide. All patients with CDG-Ia have a neurological manifestation of disease with variable involvement of other organ systems. Individuals with this disorder typically present in the neonatal period with failure to thrive, developmental delay, abnormal subcutaneous fat distribution, elevated liver transaminases, and abnormal MRI findings. Currently, there is no cure and treatment remains primarily supportive and symptomatic.

Phosphomannose isomerase deficiency (CDG-Ib or 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 subtype of CDG is unique in that there is little to no involvement of the central nervous system. The primary clinical manifestations are a result of aberrant gastrointestinal function. In particular, individuals with CDG-Ib may present with failure to thrive, hypoglycemia, chronic diarrhea, and protein-losing enteropathy. Although CDG-Ib can be life threatening,  it can be effectively treated with mannose supplementation.

Diagnosis of congenital disorders of glycosylation Ia (phosphomannomutase-2 deficiency [CDG-Ia or PMM2-CDG]) and Ib (phosphomannose isomerase deficiency [CDG-Ib or MPI-CDG]) as measured in fibroblasts

A follow-up test for patients with an abnormal transferrin isoform profile as determined by isoelectric focusing or liquid chromatography-mass spectrometry (eg, CDG/89891 Carbohydrate Deficient Transferrin for Congenital Disorders of Glycosylation, Serum)

Normal results are not consistent with either phosphomannomutase-2 deficiency (CDG-Ia or PMM2-CDG) or phosphomannose isomerase deficiency (CDG-Ib or MPI-CDG). 

Markedly reduced activity of phosphomannomutase is consistent with a diagnosis of CDG-Ia. Markedly reduced activity of phosphomannose isomerase is consistent with a diagnosis of CDG-Ib.

Mild to moderately reduced enzyme activities will be interpreted in the context of clinical and other laboratory test information submitted with the specimen.

This test is not appropriate for carrier testing.

The initial screening test for congenital disorders of glycosylation is transferrin isoform analysis (CDG/89891 Carbohydrate Deficient Transferrin for Congenital Disorders of Glycosylation, Serum). The results of the transferrin isoform analysis should be correlated with the clinical presentation to determine the most appropriate testing strategy.

PMM

Normal >700 nmol/h/mg Prot

PMI

Normal >1,500 nmol/h/mg Prot

1. Jaeken J: Congenital Disorders of Glycosylation. Ann N Y Acad Sci 2010;1214:190-198

2. Jaeken J, Matthijs: Congenital Disorders of Glycosylation: A Rapidly Expanding Disease Family. Annu Rev Genomics Hum Genet 2007;8:261-278

3. Marquardt T, Denecke J: Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 2003 Jun;162(6):359-379