Test Id : ARSAW

For more information see the following:

-Lysosomal Disorders Diagnostic Algorithm, Part 2

-Newborn Screen Follow-up for Metachromatic Leukodystrophy

For optimal isolation of leukocytes, it is recommended the specimen arrive refrigerated within 6 days of collection to be stabilized. Collect specimen only Monday through Thursday 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 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 Disorders Diagnostic Algorithm, Part 2
• Newborn Screen Follow-up For Metachromatic Leukodystrophy

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

Preferred enzymatic test for detection of arylsulfatase A deficiency

This test is not suitable for carrier detection.

This is the preferred test to rule-out metachromatic leukodystrophy.

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

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

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 (CTSU / Ceramide Trihexosides and Sulfatides, Random, Urine), or histological analysis for metachromatic lipid deposits in nervous system tissue are recommended to confirm a diagnosis.

For more information see the following:

-Lysosomal Disorders Diagnostic Algorithm, Part 2

-Newborn Screen Follow-up for Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA), 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 old. 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.

Metachromatic leukodystrophy is an autosomal recessive disorder caused by disease-causing variants in the ARSA gene. 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 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 has been found among patients with other 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 (CTSU / Ceramide Trihexosides and Sulfatides, Random, Urine), or, less commonly, histological analysis for metachromatic lipid deposits in nervous system tissue are recommended.

Current treatment options for MLD depend on the clinical stage and presence of neurologic symptoms. Early diagnosis is extremely important to improve clinical outcomes. Allogenic hematopoietic stem cell transplant (HSCT) can treat symptoms related to the central nervous system in pre- and very early-symptomatic juvenile- or adult-onset MLD. Recently, autologous hematopoietic stem cell-based gene therapy has been approved in the United States and elsewhere for individuals with presymptomatic late-infantile MLD, presymptomatic juvenile MLD, or early-symptomatic juvenile MLD with maintained ability to walk and before the onset of cognitive decline.

> or =62 nmol/h/mg

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), however some patients with MLD may have normal results by this method.

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

Abnormal results and/or clinical suspicion should be confirmed using CTSU / Ceramide Trihexosides and Sulfatides, Random, 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).

This test is not reliable in identifying carriers.

Some patients with metachromatic leukodystrophy will not be detected by this method.

Arylsulfatase A is also deficient in individuals with multiple sulfatase deficiency and possibly in saposin B deficiency.

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 June 9, 2025. Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225546629

2. Gomez-Ospina N. Arylsulfatase A deficiency. In: Adam MP, Feldman J, Mirzaa GM, et al, eds. GeneReviews[Internet]. University of Washington, Seattle; 2006.Updated April 25,2024. Accessed June 9, 2025. 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;44(5):1151-1164. doi:10.1002/jimd.12388

4. Laugwitz L, Mechtler TP, Janzen N, et al. Newborn screening and presymptomatic treatment of metachromatic leukodystrophy. N Engl J Med. 2024; 391(13): 1256-1258. doi:10.1056/NEJMc2407165

p-Nitrocatechol sulfate (2-hydroxy-5-nitrophenyl sulfate) is used as an analog to the natural substrate. The reaction yields p-nitrocatechol, which is measured at 515 nm.(Shapira E, Blitzer MG, Africk DK, et al: Enzyme assays: arylsulfatase A activity. In: Biochemical Genetics: A Laboratory Manual. Oxford University Press; 1989:41-42; 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)

Preanalytical processing: Monday through Saturday

Assay 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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