Metachromatic Leukodystrophy via the ARSA Gene

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.

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).

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.