Invitae Metachromatic Leukodystrophy Test


Test description

The Invitae Metachromatic Leukodystrophy Test analyzes ARSA, the only gene known to cause arylsulfatase A deficiency and the one most commonly associated with metachromatic leukodystrophy (MLD). MLD is also referred to as arylsulfatase A deficiency.

This test is indicated for any individual in whom a diagnosis of MLD is suspected based on clinical observation, neurologic findings that consistent with progressive neurologic dysfunction, or 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 result in 5%–20% of normal enzyme activity but do NOT cause clinical disease.

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Primary panel (1 gene)


Add-on generalized leukodystrophies genes (4 genes)

Phenotypic features of MLD can overlap with generalized leukodystrophies. Given the significant phenotypic overlap between MLD, Canavan disease, Krabbe disease, Tay Sachs, and Sandhoff disease, analyzing the genes associated with these disorders may be appropriate. These genes can be included at no additional charge.


GALC: Analysis includes the large (30 kb) deletion for Krabbe Disease.

  • 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. It is 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).

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). These variants 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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ARSA NM_000487.5
ASPA NM_000049.2
GALC* NM_000153.3
HEXA NM_000520.4
HEXB NM_000521.3

GALC: Analysis includes the large (30 kb) deletion for Krabbe Disease.