Interpretive Handbook

Test 61259 :
ARSA Gene, Full Gene Analysis

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive condition caused by mutations in the arylsulfatase A (ARSA) gene. The incidence of MLD is approximately 1:40,000 to 1:160,000, and the estimated carrier frequency in the general population is 1:100 to 1:200. MLD is characterized by the accumulation of cerebroside sulfate, which causes progressive demyelination and the loss of white matter.  


There is a variable age of onset. In the early onset form, symptoms appear in the first 1 to 2 years of life and include deterioration of skills such as walking and speaking. In the juvenile form, symptoms can appear between 4 years of age and the age of sexual maturity, and can include a decline in school performance and behavioral problems. Adults can present with a decline in school or job performance, substance abuse, and emotional lability. The diagnosis is suspected in individuals with progressive neurologic dysfunction and molecular resonance imaging evidence of leukodystrophy.


The ARSA gene is located on chromosome 22 and has 8 exons. The following 4 mutations, c.459+1G>A, c.1204+1G>A, p.Pro426Leu, and p.Ile179Ser, account for 25% to 50% of mutations in the central and western European populations. The presence of 2 of these mutations within the ARSA gene confirms a diagnosis of metachromatic leukodystrophy.


The recommended first-tier tests to screen for MLD are biochemical tests that measure arylsulfatase A enzyme activity in leukocytes and urine: ARST / Arylsulfatase A, Leukocytes and ARSU / Arylsulfatase A, 24 Hour, Urine. Individuals with decreased enzyme activity are more likely to have 2 mutations in the ARSA gene identifiable by molecular gene testing. However, arylsulfatase A enzyme assays cannot distinguish between MLD and ARSA pseudodeficiency, a clinically benign condition that leads to low in vitro ARSA levels, but it is found in 5% to 20% of the normal population. Thus, the diagnosis of MLD must be confirmed by molecular analysis of the ARSA gene.

Useful For Suggests clinical disorders or settings where the test may be helpful

Second-tier test for confirming a diagnosis of metachromatic leukodystrophy (MLD) based on clinical findings and low ARSA activity levels.


Carrier testing when there is a family history of MLD, but disease-causing mutations have not been previously identified

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A small percentage of individuals who are carriers or have a diagnosis of metachromatic leukodystrophy (MLD) may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of MLD. The preferred approach to carrier testing is to first document the presence of an ARSA gene mutation in an affected family member.


In some cases, DNA alterations of undetermined significance may be identified.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.


Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Biffi A, Cesani M, Fumagalli F, et al: Metachromatic leukodystrophy-mutation analysis provides further evidence of genotype-phenotype correlation. Clin Genet 2008 Oct;74(4):349-357

2. Gieselmann V, Krageloh-Mann I: Metachromatic leukodystrophy-an update. Neuropediatrics 2010 Feb;41(1):1-6, Epub 2010 Jun 22

3. Kreysing J, von Figura K, Gieselmann V: Structure of the arylsulfatase A gene. Eur J Biochem 1990 Aug 17;191(3):627-631

4. Polten A, Fluharty AL, Fluharty CB, et al: Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med 1991 Jan 3;324(1):18-22