Test Id : PMMIL

For more information see Congenital Disorders of Glycosylation: Screening Algorithm.

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.

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.

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.

• Informed Consent for Genetic Testing
• Biochemical Genetics Patient Information
• Informed Consent for Genetic Testing (Spanish)
• Congenital Disorders of Glycosylation: Screening Algorithm

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.

3 mL

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.

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).

For more information see Congenital Disorders of Glycosylation: Screening Algorithm.

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.

PHOSPHOMANNOMUTASE

Normal >350 nmol/h/mg protein

PHOSPHOMANNOSE ISOMERASE

Normal >1,300 nmol/h/mg protein

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.

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.

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

• Informed Consent for Genetic Testing
• Biochemical Genetics Patient Information
• Informed Consent for Genetic Testing (Spanish)
• Congenital Disorders of Glycosylation: Screening Algorithm

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)

Preanalytical processing: Monday through Saturday

Assay performed: Twice per month

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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.

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