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Metachromatic Leukodystrophy via the ARSA Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
ARSA 81405 81405,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7579ARSA81405 81405,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Renee Bend, PhD

Clinical Features and Genetics

Clinical Features

Metachromatic leukodystrophy (MLD) is a rare neurometabolic disorder caused by progressive loss of myelin in the nervous system. Three forms of the disease have similar clinical features, but are distinguished by age of onset - infantile, juvenile, and adult MLD (Gomez-Ospina. 2017. PubMed ID: 20301309).

Patients with infantile onset MLD have normal initial development, then begin to lose acquired skills between 6 months and 2 years of age. Initial signs often include loss of motor skills, gait abnormalities, seizures, optic atrophy, dysarthria, peripheral neuropathy, slow nerve conduction velocity, hypotonia, and hearing impairment. As the disease progresses, patients slowly lose the ability to voluntarily control their muscles and spasticity becomes prominent. This form of the disease typically progresses to death within five years of symptom onset, but patients can survive into their second decade with intensive medical support. This is the most common form of MLD (Harrington et al. 2019. PubMed ID: 31036045).

Juvenile onset MLD occurs between 2 years of age and puberty. Presenting signs often include a decline in school performance, inattention, behavioral challenges, gait disturbance, ataxia, peripheral neuropathy, and seizures. Rate of progression and severity of symptoms are variable, but tend to be slower than that seen in the infantile form. A majority of individuals die before the third decade (Harrington et al. 2019. PubMed ID: 31036045). This is the second most common form of MLD.

Adult onset MLD presents after sexual maturity, and sometimes as late as the fifth decade. Declining work or school performance, substance abuse, psychosis, dementia, hypotonia, spasticity, incontinence, and peripheral neuropathy are frequent presenting features. The disease course in adult onset cases may last 2-3 decades and can include some periods of stability (Rauschka et al. 2006. PubMed ID: 16966551; Gomez-Ospina. 2017. PubMed ID: 20301309).

In the final stages of every form of the disease, patients are often bedridden, with medical support for all basic life functions. Early molecular diagnosis may be critical for the most effective treatments, as currently the best outcomes have been observed when treatment is received prior to the onset of clinical symptoms (Sessa et al. 2016. PubMed ID: 27289174; Biffi et al. 2008. PubMed ID: 18978739; Gomez-Ospina. 2017. PubMed ID: 20301309).


Bi-allelic pathogenic variants in the ARSA gene cause autosomal recessive metachromatic leukodystrophy (MLD). Over 250 ARSA alterations have been reported as causative, and include missense, nonsense, splice-altering, frameshift, in-frame indel, and gross deletion variants (Cesani et al. 2016. PubMed ID: 26462614; Human Gene Mutation Database). A single alteration (c.459+1G>A) is estimated to account for approximately 20% of MLD in patients of European decent. A different single change (p.Gly99Asp) is predicted to account for ~45% of MLD in Japanese patients (Gomez-Ospina. 2017. PubMed ID: 20301309). At least two variants, called pseudodeficiency alleles, are associated with decreased enzyme activity, but a normal clinical phenotype (Barth et al. 1994. PubMed ID: 7815433).

Pathogenic ARSA variants are classified into two types - those with no enzyme activity (called "I" or "null" alleles), and those with some residual activity ("R" alleles). The biallelic combinations of II, IR, or RR alleles correlates with the age of onset of the clinical phenotype - with individuals with two I alleles typically having infantile-onset disease, one I and one R allele often resulting in juvenile onset disease, and two R alleles typically causing the adult-onset form of MLD. Finally, pathogenic alterations in the PSAP gene cause a second form of metachromatic leukodystrophy, which may be considered in the differential diagnosis (Gomez-Ospina. 2017. PubMed ID: 20301309).

The ARSA gene is on chromosome 22q13.33, contains eight exons, and encodes a 509 amino acid protein. The ARSA gene product is the arylsulfatase A protein, a lysosomal enzyme involved in the metabolism of sulfated glycolipids. These particular glycolipids are a critical component of myelin sheaths (the fatty insulating layer surrounding axons). In the absence of adequate arylsufatase A activity, sulfatide fats accumulate, resulting in slow loss of functional myelin. This progressive demyelination causes the insidious neurological disease observed in MLD patients.

Clinical Sensitivity - Sequencing with CNV PG-Select

Diminished arylsulfatase A enzyme activity, resulting from biallelic pathogenic variants in the ARSA gene, is the most common cause of metachromatic leukodystrophy (MLD). Clinical sensitivity for this test is high (>95%) in cases with demonstrated enzyme deficiency, and clinical features of MLD (Gort et al. 1999. PubMed ID: 10477432; Gomez-Ospina. 2017. PubMed ID: 20301309). Care should be taken, however, for patients with enzyme deficiency but no features of MLD, as this can be caused by pseudodeficiency alleles, which are present in ~1% of the healthy population (Barth et al. 1994. PubMed ID: 7815433). Rarely, pathogenic variants in the prosaposin gene (PSAP) cause metachromatic leukodystrophy, therefore PSAP-associated MLD may be considered in the differential diagnosis (Cesani et al. 2016. PubMed ID: 26462614).

Testing Strategy

This test provides full coverage of all coding exons of the ARSA gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Our test also covers the c.*96A>G SNP.

Indications for Test

This test is suitable for patients with diminished arylsufatase A enzyme activity (<10% of normal values), progressive neurological deterioration, leukodystrophy on MRI, or family members of an individual with a known ARSA variant. Prenatal diagnosis is possible for patients with an established diagnosis in a family member. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ARSA.


Official Gene Symbol OMIM ID
ARSA 607574
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Metachromatic Leukodystrophy AR 250100


  • Barth et al. 1994. PubMed ID: 7815433
  • Biffi et al. 2008. PubMed ID: 18978739
  • Cesani et al. 2016. PubMed ID: 26462614
  • Gomez-Ospina. 2017. PubMed ID: 20301309
  • Gort et al. 1999. PubMed ID: 10477432
  • Harrington et al. 2019. PubMed ID: 31036045
  • Human Gene Mutation Database (Biobase).
  • Rauschka et al. 2006. PubMed ID: 16966551
  • Sessa et al. 2016. PubMed ID: 27289174


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

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2) Select Additional Test Options

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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