Phosphomannomutase (PMM) and Phosphomannose Isomerase (PMI), Fibroblasts
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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 and may include 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 CDG worldwide. All patients with CDG-Ia have neurological manifestations 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 CDG subtype 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.
Diagnosing 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
Follow-up testing for patients with an abnormal transferrin isoform profile as determined by isoelectric focusing or liquid chromatography-mass spectrometry (eg, CDG / 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.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test is not appropriate for carrier testing.
The initial screening test for congenital disorders of glycosylation is transferrin isoform analysis (CDG / 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.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Normal >700 nmol/h/mg protein
Normal >1,500 nmol/h/mg protein
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Sparks SE, Krasnewich DM: Congenital Disorders of N-linked Glycosylation Pathway Overview. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle; 1993-2016. Updated 2014 Jan 30. Available at www.ncbi.nlm.nih.gov/books/NBK1332/
2. Scott K, Gadomski T, Kozicz T, Morava E: Congenital disorders of glycosylation: new defects and still counting. J Inherit Metab Dis 2014 Jul; 37(4):609-617