Test Id : MPS4W

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.

1. Patient's age is required.

2. Reason for testing is required.

Container/Tube:

Preferred: Yellow top (ACD solution B)

Acceptable: Yellow top (ACD solution A) or lavender top (EDTA)

Specimen Volume: 6 mL

Collection Instructions: Send whole blood specimen in original tube. Do not aliquot.

• Informed Consent for Genetic Testing
• Biochemical Genetics Patient Information
• Informed Consent for Genetic Testing (Spanish)
• Lysosomal Storage Disorders Diagnostic Algorithm, Part 1

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:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Biochemical Genetics Patient Information (T602)

3. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.

5 mL

Supporting the biochemical diagnosis of mucopolysaccharidosis type IVA and IVB in whole blood specimens

This test is not useful for carrier detection.

This test provides diagnostic testing for individuals with clinical signs and symptoms suspicious for mucopolysaccharidosis type IVA or IVB. If an enzyme deficiency is detected by this test, additional biochemical or molecular testing is required to confirm a diagnosis.

Mucopolysaccharidosis IVA, (MPS IVA; Morquio A syndrome) is caused by reduced or absent N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme activity. The glycosaminoglycans, keratan and chondroitin sulfate, accumulate in multiple tissues but mainly bone, cartilage, heart valves, and cornea. Clinical features and severity of symptoms of MPS IVA are widely variable affecting multiple body systems, in particular the skeletal system. Other clinical features may include short stature, dental anomalies, corneal clouding, respiratory insufficiency, and cardiac disease. Intelligence is usually normal.

Mucopolysaccharidosis type IVB (MPS IVB or Morquio syndrome B) is caused by reduced or absent beta-galactosidase activity leading to the accumulation of glycosaminoglycans, particularly keratan sulfate. MPS IVB typically manifests as a systemic skeletal disorder with variable severity ranging from early severe disease to a later onset attenuated form. Virtually all patients have dysostosis multiplex and short stature along with other symptoms that may include coarse facies, hepatosplenomegaly, hoarse voice, stiff joints, cardiac disease, but no neurological involvement.

GM1 gangliosidosis is also caused by reduced or absent beta-galactosidase activity, however the clinical features include neurological involvement in addition to the skeletal and other systemic findings associated with MPS IVB. The disorder can be classified into 3 subtypes that vary with respect to age of onset and clinical presentation.

Galactosialidosis is associated with a combined deficiency of beta-galactosidase and neuraminidase secondary to a defect in the cathepsin A protein. The disorder can be classified into 3 subtypes that vary with respect to age of onset and clinical presentation. Typical clinical presentation is coarse facial features, cherry-red spots, and skeletal dysplasia. The early infantile form is associated with fetal hydrops, skeletal dysplasia, and early death, while the late infantile form is characterized by short stature, dysostosis multiplex, coarse facial features, corneal clouding, hepatosplenomegaly, and heart valve problems.

A diagnostic workup for MPS also includes glycosaminoglycan (GAG) determination in urine (MPSQU / Mucopolysaccharides Quantitative, Random, Urine) or blood (MPSBS / Mucopolysaccharidosis, Blood Spot or MPSER / Mucopolysaccharidosis Quantitative, Serum) and molecular genetic analysis of the relevant gene. For MPS IVA, molecular analysis of the GALNS gene (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify Gene List ID: IEMCP-JUFPRX) and for MPS IVB and GM1 gangliosidosis, molecular analysis of the GLB1 gene (CGPH; specify Gene List ID: IEMCP-D5F3YS) allows for detection of disease-causing variants in affected patients and subsequent carrier detection in relatives.

A diagnostic workup for galactosialidosis traditionally includes determination of beta-galactosidase enzyme activity in leukocytes or fibroblasts and neuraminidase activity in fibroblasts followed by molecular analysis of CTSA (CGPH; specify Gene List ID: IEMCP-D1J7U5). Analysis of urine mucopolysaccharides, oligosaccharides, ceramide trihexoside, and sulfatides (LSDS / Lysosomal Storage Disorders Screen, Random, Urine) can help differentiate between galactosialidosis, MPS IVA, and MPS IVB/GM1 to guide physicians in choosing the best confirmatory molecular testing option. See Lysosomal Storage Disorders Diagnostic Algorithm, Part 1.

N-acetylgalactosamine-6-sulfatase: >1.60 nmol/hour/mg protein

Beta-galactosidase: >0.28 nmol/hour/mg protein

An interpretive report will be provided.

Abnormal results are not sufficient to establish a diagnosis of a particular disease. To verify a preliminary diagnosis based on this assay, additional biochemical or molecular genetic analyses are required.

When abnormal results are detected, a detailed interpretation is given, including an overview of the results and of their significance, a correlation to available clinical information, elements of differential diagnosis, recommendations for additional biochemical testing, and in vitro, confirmatory studies (enzyme assay, molecular analysis), and a phone number to reach one of the laboratory directors in case the referring physician has additional questions.

Beta-galactosidase is also reduced in patients with galactosialidosis. Those patients will also demonstrate deficient activity of neuraminidase which is not evaluated on this panel. If there is clinical suspicion of galactosialidosis, please order follow up testing to include test OLIGU / Oligosaccharide Screen, Random, Urine

Individuals with pseudodeficiency alleles can show reduced enzyme activity.

Carrier status (heterozygosity) for these conditions cannot be reliably detected.

Enzyme levels may be normal in individuals receiving enzyme replacement therapy or who have undergone hematopoietic stem cell transplant.

1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; Accessed July 14, 2023. https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225544161

2. Hopwood JJ, Ballabio A. Multiple sulfatase deficiency and the nature of the sulfatase family. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; Accessed July 14, 2023. https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225546905

Leukocytes are incubated with four cocktail mixes: 1) substrate and internal standard (IS) for iduronate 2-sulfatase, heparan N-sulfatase, alpha-N-acetylglucosaminidase, N-acetylgalactosamine-sulfate, beta-galactosidase, arylsulfatase B, beta-glucuronidase, and tripeptidyl peptidase 1; 2) substrate and IS for acetyl-CoA:alpha-glucosaminide N-acetyltransferase; 3) substrate and IS for N-acetylglucosamine-6-sulfatase; and 4) substrate and IS for palmitoyl-protein thioesterase 1 in 96-well plates. Following overnight incubation, the plates are combined and purified by liquid-liquid extraction. The extracts are evaporated, reconstituted with mobile phase, and analyzed by tandem mass spectrometry.(Unpublished Mayo method)

Preanalytical processing: Monday through Saturday

Testing performed: Tuesday

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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.

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