• Test code: 06174
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Metachromatic Leukodystrophy Panel

Test description

The Invitae Metachromatic Leukodystrophy Panel analyzes genes associated with metachromatic leukodystrophy. Arylsulfatase A deficiency is the most common cause of metachromatic leukodystrophy (MLD) cases and is due to pathogenic variants in the ARSA gene. A small fraction of cases are due to pathogenic variants in the PSAP gene and individuals with multiple sulfatase deficiency can also have symptoms of MLD.

This test is indicated for any individual in whom a diagnosis of MLD is suspected based on clinical observation, neurologic findings that are consistent with progressive neurologic dysfunction, radiologic evidence of demyelination, or increased urinary sulfatide excretion.

Additionally, any individual with low arylsulfatase A enzyme activity must undergo variant analysis for metachromatic leukodystrophy. ARSA has known pseudodeficiency alleles, and biallelic variants are present in approximately 2% of individuals of European descent. Further, studies have found pseudodeficiency alleles in the heterozygous state in up to 5% of Europeans, 20%–30% of Asians, and up to 40% of individuals of African descent. Pseudodeficiency alleles do NOT cause clinical disease.

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Primary panel (3 genes)
  • metachromatic leukodystrophy (MLD)
    • benign variants causing pseudodeficiency of arylsulfatase A

Metachromatic leukodystrophy (MLD) is a neurodegenerative lipid storage disorder that results in progressive demyelination of the central nervous system and peripheral nerves. The majority of cases are caused by dysfunction of the lysosomal enzyme arylsulfatase A. Arylsulfatase A catabolizes sulfatides, which are the most abundant sphingolipid in myelin and function to maintain myelin. A deficiency of arylsulfatase A results in chronic progressive accumulation of sphingolipids within the lysosome, leading to myelin breakdown (leukodystrophy). A very small number of individuals with MLD have a deficiency of the activator protein saposin B, instead of arylsulfatase A. Saposins are cofactors for the lysosomal enzymes involved in degrading sphingolipids so defects in saposins can also lead to sulfatide accumulation and cause demyelination. Both forms present with similar clinical and neuroradiologic features, but individuals with PSAP variants have normal arylsulfatase A activity and abnormal urine sulfatide excretion. Pathogenic variants in SUMF1 lead to multiple sulfatase deficiency. Since arylsulfatase A is a sulfatase, individuals with multiple sulfatase deficiency have the combined features of MLD as well as mucopolysaccharidosis II, IIIA, IIID, IVA and VI, X-linked ichthyosis, and the X-linked recessive form of chondrodysplasia punctata.

Three primary clinical presentations, based on the age of symptom onset, are generally recognized: late infantile, juvenile, and adult.

The late-infantile presentation, representing 50%–60% of MLD cases, is the most commonly observed. It is due to a complete lack of arylsulfatase A activity and leads to the most severe form of the disease. The late-infantile form typically manifests between one and two years of age with a loss of motor milestones—typically a gait disorder after independent walking has already been achieved. Over the next several years, patients experience a rapid deterioration with muscle wasting, rigidity, strabismus, progressive vision loss, possible seizures, swallowing difficulties, and dementia. Death usually occurs by ten years of age.

The juvenile form represents 20%–30% of cases and is frequently subdivided into early and late-juvenile forms. The early juvenile form manifests between four and six years of age with gait and postural abnormalities, behavioral and emotional problems, vision loss, seizures, and progressive spastic tetraparesis. The late-juvenile form appears from six to sixteen years of age with an insidious progression. Impaired school performance, behavioral problems, and language regression are initially evident, followed by motor difficulties progressing to spastic tetraparesis. Premature death usually occurs between 10 and 20 years of age.

The adult form represents 15%–20% of cases and generally presents after 16 years of age with two main forms, motor and psychiatric, though affected individuals may express both categories of symptoms. The motor form presents with neurologic symptoms such as weakness, incontinence, and loss of coordination progressing to spasticity. Individuals are often misdiagnosed with multiple sclerosis or other neurodegenerative diseases. The psychiatric form presents with behavioral abnormalities such as emotional instability, unusual social interactions, poor decision making, and a progressive mental deterioration. Many patients are often misdiagnosed with schizophrenia or depression. Death usually occurs six to fourteen years after symptom onset and is most commonly due to pneumonia or other infection.

The vast majority of cases of MLD are due to biallelic variants in ARSA. A very small percentage are due to pathogenic variants in PSAP, which encodes the Saposin-B (Sap-B) sphingolipid activator protein or Sulfatase-modifying factor-1 (SUMF1). Variants in SUMF1 cause multiple sulfatase deficiency.

Metachromatic leukodystrophy is inherited in an autosomal recessive manner.

Incidence is estimated at 1 in 40,000–160,000 in various populations. In specific populations, prevalence has been reported to be much higher:

  • 1 in 75 Habbani Jews in Israel
  • 1 in 2,500 Alaskan Eskimos
  • 1 in 6,400 Navajo Indians

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ARSA NM_000487.5
PSAP NM_002778.3
SUMF1 NM_182760.3