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Test Catalog

Test ID: PMMIL    
Phosphomannomutase and Phosphomannose Isomerase, Leukocytes

Useful For Suggests clinical disorders or settings where the test may be helpful

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 leukocytes

 

Follow-up testing for patients with an abnormal transferrin isoform profile

 

This test is not useful for carrier testing.

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

Congenital disorders of glycosylation (CDG) are a large and growing group of inborn errors of glycan metabolism that are clinically diverse, but most often present during infancy or childhood.

 

A diagnostic workup for a CDG should begin with transferrin analysis by liquid chromatography-mass spectrometry (CDG / Carbohydrate Deficient Transferrin for Congenital Disorders of Glycosylation, Serum).

 

Follow-up testing of an abnormal transferrin isoform profile may include enzymatic analysis for the diagnosis of phosphomannomutase-2 deficiency (PMM2-CDG or CDG-Ia) and phosphomannose isomerase deficiency (MPI-CDG or CDG-Ib).

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 one of the steps of the pathway involved in glycosylation. CDG 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 (PMM2-CDG or CDG-Ia) 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. Patients with CDG-Ia have moderate to severe neurological disease, more or less typical dysmorphology, and variable involvement of other organ systems. Severely affected individuals with CDG-Ia usually present in the neonatal period with failure to thrive, developmental delay, abnormal subcutaneous fat distribution, elevated liver transaminases, and abnormal MRI findings. Later presenting individuals can have clinical features that include ataxia, significantly delayed motor and language development, seizures, stroke-like episodes, retinitis pigmentosa, joint contractures and skeletal deformities. An adult form has also been described. Currently, there is no cure and treatment remains primarily supportive and symptomatic.

 

Phosphomannose isomerase deficiency (MPI-CDG or CDG-Ib) 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. In particular, individuals with CDG-Ib may present with failure to thrive, hypoglycemia, chronic diarrhea, and protein-losing enteropathy. CDG-Ib is also unique in that it can be effectively treated with mannose supplementation, though can be fatal if left untreated.

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.

PHOSPHOMANNOMUTASE

Normal >350 nmol/h/mg protein

 

PHOSPHOMANNOSE ISOMERASE

Normal >1,300 nmol/h/mg protein

Interpretation Provides information to assist in interpretation of the test results

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

 

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

There are some known carriers of PMM2 who have reduced enzyme activity that falls in the range of affected patients with PMM2-CDG. However, white blood cell enzyme activity is still more reliable than fibroblast testing for PMM2-CDG.(1,2) The PMM2 enzyme result should be considered along with CDG transferrin, clinical phenotype, and genotype when determining a diagnosis.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Grunewald S, Schollen E, Van Schaftingen E, Jaeken J, Matthijs G: High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). Am J Hum Genet. 2001 Feb;68(2):347-354

2. Pirard M, Matthijs G, Heykants L, Schollen E, Grunewald S, Jaeken J, van Schaftingen E: Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of phosphomannomutase 2. FEBS Lett. 1999 Jun 11;452(3):319-322

3. Sparks SE, Krasnewich DM: Congenital disorders of N-linked glycosylation pathway overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2005. Updated January 30, 2014. Accessed July 30, 2020. Available at www.ncbi.nlm.nih.gov/books/NBK1332/

4. Sparks SE, Krasnewich DM: PMM2-CDG (CDG-Ia) In: Adam MP. Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2005. Updated October 29, 2015. Accessed July 30, 2020. Available at www.ncbi.nlm.nih.gov/books/NBK1110/

5. 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.

6. Jaeken J, Matthijs G, Carchon H, Van Schaftingen E: Defects of N-glycan synthesis. In: Valle D, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed July 30, 2020. Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225081470

Special Instructions Library of PDFs including pertinent information and forms related to the test