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HelpTest Code PMMIL Phosphomannomutase and Phosphomannose Isomerase, Leukocytes
Reporting Name
PMM-PMI, LeukocytesUseful For
Diagnosing congenital disorders of glycosylation Ia (phosphomannomutase-2 deficiency: PMM2-CDG) and Ib (phosphomannose isomerase deficiency: MPI-CDG) as measured in leukocytes
Follow-up testing for patients with an abnormal type I CDG transferrin isoform profile
This test is not useful for carrier testing.
Performing Laboratory
Mayo Clinic Laboratories in Rochester
Specimen Type
Whole Blood ACDOrdering Guidance
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, which may include this test.
Shipping Instructions
For optimal isolation of leukocytes, it is recommended the specimen arrive refrigerated within 6 days of collection to be stabilized. Collect specimen Monday through Thursday only and not the day before a holiday. Specimen should be collected and packaged as close to shipping time as possible.
Specimen Required
Container/Tube:
Preferred: Yellow top (ACD solution B)
Acceptable: Yellow top (ACD solution A)
Specimen Volume: 6 mL
Collection Instructions: Send specimen in original tube. Do not aliquot.
Specimen Minimum Volume
3 mL
Specimen Stability Information
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Whole Blood ACD | Refrigerated (preferred) | 6 days | YELLOW TOP/ACD |
| Ambient | 6 days | YELLOW TOP/ACD |
Special Instructions
Reference Values
PHOSPHOMANNOMUTASE
Normal >350 nmol/h/mg protein
PHOSPHOMANNOSE ISOMERASE
Normal >1,300 nmol/h/mg protein
Day(s) Performed
Preanalytical processing: Monday through Saturday
Assay performed: Twice per month
Test Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
82657
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| PMMIL | PMM-PMI, Leukocytes | 100735-0 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 50836 | Specimen | 31208-2 |
| 50837 | Specimen ID | 57723-9 |
| 50838 | Source | 31208-2 |
| 50839 | Order Date | 82785-7 |
| 50840 | Reason For Referral | 42349-1 |
| 50841 | Method | 85069-3 |
| 50842 | Phosphomannomutase, Leuko | 78970-1 |
| 50843 | Phosphomannose Isomerase, Leuko | 78963-6 |
| 50844 | Interpretation | 59462-2 |
| 50845 | Amendment | 48767-8 |
| 50846 | Reviewed By | 18771-6 |
| 50847 | Release Date | 82772-5 |
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.
Interpretation
Normal results are not consistent with either phosphomannomutase-2 deficiency (PMM2-CDG) or phosphomannose isomerase deficiency (MPI-CDG).
Markedly reduced activity of phosphomannomutase is consistent with a diagnosis of PMM2-CDG. Markedly reduced activity of phosphomannose isomerase is consistent with a diagnosis of MPI-CDG.
Mild to moderately reduced enzyme activities will be interpreted in the context of clinical and other laboratory test information submitted with the specimen.
Cautions
There are some known carriers of phosphomannomutase-2 deficiency (PMM2) who have reduced enzyme activity that falls in the range of affected patients with PMM2-congenital disorders of glycosylation (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
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;68(2):347-354
2. Pirard M, Matthijs G, Heykants L, et al. Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of phosphomannomutase 2. FEBS Lett. 1999;452(3):319-322
3. Lam C, Krasnewich DM. PMM2-CDG. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2005. Updated May 20, 2021. Accessed January 19, 2024. Available at: www.ncbi.nlm.nih.gov/books/NBK1110/
4. Schiff M, Roda C, Monin ML, et al. Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature. J Med Genet. 2017;54(12):843-851
5. Girard M, Douillard C, Debray D, et al. Long term outcome of MPI-CDG patients on D-mannose therapy. J Inherit Metab Dis. 2020;43(6):1360-1369
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 January 19, 2024. Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225081470
Method Description
Leukocytes are harvested from one 7-mL tube of ACD-treated blood and the resulting leukocyte cell pellet is subjected to 1 freeze-thaw cycle. The lysate is collected and the enzymatic activity for both phosphomannomutase and phosphomannose isomerase is measured by a colorimetric assay.(Personal communication. Dr. Otto van Diggelen, Erasmus University, Rotterdam, The Netherlands 2008; Cowan T, Pasquali M. Laboratory investigations of inborn errors of metabolism. In: Sarafoglou K, Hoffman GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. 2nd ed. McGraw Hill Education; 2017:1139-1158)
Report Available
30 to 45 daysSpecimen Retention Time
WBC homogenate: 1 monthReject Due To
| Gross hemolysis | Reject |
Method Name
Colorimetric
Forms
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing-Spanish (T826)
2. Biochemical Genetics Patient Information (T602) in Special Instructions
3. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.
Secondary ID
89656Genetics Test Information
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 type 1 CDG transferrin isoform profile may include enzymatic analysis for the diagnosis of phosphomannomutase-2 deficiency (PMM2-CDG) and phosphomannose isomerase deficiency (MPI-CDG).
Testing Algorithm
For more information see Congenital Disorders of Glycosylation: Screening Algorithm.