Test Id : ARSU

See Lysosomal Storage Disorders Diagnostic Algorithm, Part 2

The preferred test to rule-out metachromatic leukodystrophy is ARSAW / Arylsulfatase A, Leukocytes.

Specimen must be received at least 1 day prior to assay day for processing.

24-Hour volume is required.

Supplies: Urine Tubes, 10 mL (T068)

Container/Tube: Plastic, 10-mL tube

Specimen Volume: 6 mL

Collection Instructions:

1. Collect a 24-hour urine specimen.

2. No preservative.

3. Refrigerate specimen during collection.

Additional Information: See Urine Preservatives-Collection and Transportation for 24-Hour Urine Specimens for multiple collections.

• Urine Preservatives-Collection and Transportation for 24-Hour Urine Specimens
• Informed Consent for Genetic Testing
• Biochemical Genetics Patient Information
• Informed Consent for Genetic Testing (Spanish)
• Lysosomal Storage Disorders Diagnostic Algorithm, Part 2

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.

Note: The addition of preservative or application of temperature controls must occur within 4 hours of completion of the collection.

2.5 mL

Detection of arylsulfatase A deficiency using urine specimens

This test is not suitable for carrier detection.

Metachromatic leukodystrophy (MLD) is caused by deficient activity of arylsulfatase A (ARSA) enzyme and is characterized by progressive neurologic changes and leukodystrophy with variable age of onset.

Pseudodeficiency of arylsulfatase A (ARSA) enzyme has been recognized with increasing frequency among patients with other apparently unrelated neurologic conditions as well as among the general population.

This test is not suitable for carrier detection.

Leukocytes are the preferred screening specimen for metachromatic leukodystrophy.

Additional studies, such as molecular genetic testing of ARSA (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify ARSA Gene List ID: IEMCP-WHFH2K ), urinary excretion of sulfatides (CTSA / Ceramide Trihexosides and Sulfatides, Urine), and histological analysis for metachromatic lipid deposits in nervous system tissue are recommended to confirm a diagnosis.

See Lysosomal Storage Disorders Diagnostic Algorithm, Part 2

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by a deficiency of the arylsulfatase A (ARSA) enzyme, which leads to the accumulation of sulfatides (both galactosyl and lactosyl sulfatide) in the white matter of the central nervous system, the peripheral nervous system, and to a lesser extent, in visceral organs including the kidney and gallbladder. Cells that produce myelin are especially affected causing the characteristic leukodystrophy seen in MLD. Patients with MLD excrete excessive amounts of sulfatides in their urine.

The 3 clinical forms of MLD are late-infantile, juvenile, and adult, depending on age of onset. All forms result in progressive neurologic changes and leukodystrophy demonstrated on magnetic resonance imaging. Late-infantile MLD is the most common (50%-60% of cases) and usually presents before 30 months of age with hypotonia, clumsiness, diminished reflexes, and slurred speech. Progressive neurodegeneration occurs and, unless successfully treated, most patients do not survive past childhood. Juvenile MLD (20%-30% of cases) is characterized by onset between 30 months to 16 years. Presenting features are behavior problems, declining school performance, clumsiness, and slurred speech. Neurodegeneration occurs at a somewhat slower and more variable rate than the late-infantile form. Adult MLD (15%-20% of cases) has an onset after puberty and can be as late as the fourth or fifth decade. Presenting features are often behavior and personality changes, including psychiatric symptoms. Clumsiness, neurologic symptoms, and seizures are also common. The disease course has variable progression and may occur over 2 to 3 decades. The disease prevalence is estimated to be approximately 1 in 100,000.

MLD is an autosomal recessive disorder and is caused by variants in the ARSA gene coding for the ARSA enzyme. This disorder is distinct from conditions caused by deficiencies of arylsulfatase B (Maroteaux-Lamy disease) and arylsulfatase C (steroid sulfatase deficiency). Saposin B deficiency is a rare autosomal recessive disorder with symptoms that mimic MLD; however, the ARSA enzyme level is normal. Like MLD, patients with saposin B deficiency can also excrete excessive amounts of sulfatides in their urine. Individuals with multiple sulfatase deficiency, which is clinically distinct from MLD, will also have deficiency of arylsulfatase A, however, other sulfatase enzymes will also be deficient.

Individuals with "pseudodeficiency" of ARSA have very low levels of ARSA activity but are otherwise healthy. Pseudodeficiency is being recognized with increasing frequency among patients with other apparently unrelated neurologic conditions as well as among the general population, therefore a diagnosis of MLD cannot be based upon reduced ARSA activity alone To confirm a diagnosis, additional studies, such as molecular genetic testing of ARSA (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify Gene List ID: IEMCP-WHFH2K), urinary excretion of sulfatides (CTSA / Ceramide Trihexosides and Sulfatides, Urine), and/or histological analysis for metachromatic lipid deposits in nervous system tissue are recommended.

Current treatment options for MLD are focused on managing disease manifestations such as seizures, decline in mobility and cognitive ability, and feeding difficulties. Hematopoietic stem cell transplantation is an option but outcomes are dependent on the clinical stage and the presence of neurologic symptoms.

> or =19 nmol/h/mL

Note: Results from this assay may not reflect carrier status because of individual variation of arylsulfatase A enzyme levels. Low normal values may be due to the presence of pseudodeficiency or carrier alleles. Patients with these depressed levels may be phenotypically normal.

Reduced levels of arylsulfatase A are seen in patients with metachromatic leukodystrophy (MLD).

Individuals with pseudodeficiency of arylsulfatase A can have results in the affected range but are otherwise unaffected with MLD.

Abnormal results should be confirmed using CTSA / Ceramide Trihexosides and Sulfatides, Urine. If molecular confirmation is desired, consider molecular genetic testing of ARSA (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify Gene List ID: IEMCP-WHFH2K).

Arylsulfatase A is also deficient in individuals with multiple sulfatase deficiency.

This test is not reliable in identifying carriers due both to analytical variation and unusual genetic variants.

This disorder is distinct from conditions caused by deficiencies of arylsulfatase B (Maroteaux-Lamy disease) and arylsulfatase C (steroid sulfatase deficiency).

1. Gieselmann V, Ingeborg KM: Metachromatic leukodystrophy. In: Valle D, Antonarakis S, Ballabio A, Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed March 29, 2021. Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225546629

2. Gomez-Ospina N: Arylsulfatase A deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; Updated April 30, 2020. Accessed March 29, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1130/

3. Fumagalli F, Zambon AA, Rancoita PMV, et al. Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients. J Inherit Metab Dis. 2021 Sep;44(5):1151-1164. doi: 10.1002/jimd.12388.

4. van Rappard DF, Boelens JJ, Wolf NI: Metachromatic leukodystrophy: Disease spectrum and approaches for treatment. Best Pract Res Clin Endocrinol Metab. 2015 Mar;29(2):261-273. doi: 10.1016/j.beem.2014.10.001

• Urine Preservatives-Collection and Transportation for 24-Hour Urine Specimens
• Informed Consent for Genetic Testing
• Biochemical Genetics Patient Information
• Informed Consent for Genetic Testing (Spanish)
• Lysosomal Storage Disorders Diagnostic Algorithm, Part 2

Dialyzed urine is mixed with the artificial substrate p-nitrocatechol sulfate. As sulfate is released, the freed p-nitrocatechol is measured in alkaline solution at 515 nm.(Baum H, Dodgson KS, Spencer B: The assay of arylsulfatases A and B in human urine. Clin Chim Acta 1959;4:453-455; Cowan T, Pasquali M: Laboratory investigations of inborn errors of metabolism. In: Sarafoglou K, Hoffman GF, Roth KD, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. 2nd ed. McGraw-Hill; 2017:1139-1158)

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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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