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Test ID: PMMIL Phosphomannomutase and Phosphomannose Isomerase, Leukocytes

Reporting Name

PMM-PMI, Leukocytes

Useful For

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.

Clinical Information

Congenital disorders of glycosylation (CDG) are a group of over 100 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 (MPI)-CDG (CDG-Ib) 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 with phenotypic variability ranging from severely affected infants to mildly affected adults. In infancy, patients with CDG-Ia 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 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.

Interpretation

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.

Report Available

30 to 45 days

Day(s) Performed

Preanalytical processing: Monday through Saturday

Assay performed: Twice per month

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 Feb;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 Jun 11;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 August 12, 2021. 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 Dec;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 Nov;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 July 20, 2021. Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225081470

Method Name

Colorimetric

Specimen Type

Whole Blood ACD


Ordering 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

Reference Values

PHOSPHOMANNOMUTASE

Normal >350 nmol/h/mg protein

 

PHOSPHOMANNOSE ISOMERASE

Normal >1,300 nmol/h/mg protein

Test Classification

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test 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 In Process

 

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

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 an Inborn Errors of Metabolism Test Request (T798) with the specimen.

Mayo Clinic Laboratories | Neurology Catalog Additional Information:

mml-Pediatric, mml-Neurometabolic