Submission Details

ARSA was first reported in relation to metachromatic leukodystrophy (MLD), an autosomal recessive lysosomal disease, in 1991 (Polten et al, PMID: 1670590). ARSA encodes arylsufatase A, a lysosomal enzyme that breaks down cerebroside-3-sulfate (sulfatide) in the presence of its sphingolipid activator protein, SaposinB (Sap-B, enoded by PSAP). When arylsufatase A activity is deficient, sulfatides accumulate in the lysosomes of all cell types and are also excreted in the urine. Sulfatide accumulation results in progressive demyelination and dysfunction of the central and peripheral nervous systems, with progressive motor and cognitive deficiency. Symptoms include ataxia, gait disturbance, seizures, spasticity, vision and hearing loss, and behavioral and psychiatric issues in later onset patients. The age of onset and severity of clinical course determined by the residual ARSA activity. There are 3 subtypes. In the late infantile form, onset is usually between 1-2 years of age; in the juvenile form, onset is between 4-14 years; while the adult onset form presents after puberty and as late as the 4th or 5th decade of life (Cesani et al, 2016, PMID: 26462614; Gomez-Ospina et al, 2020, PMID: 20301309; Shaimardanova et al, 2020, PMID: 33195324).

MLD is one of the most common leukodystrophies. The prevalence is 1 in 40,000–160,000 worldwide, but is much higher in some isolated populations, including Habbanite Jews (1 in 75), Navajo ( 1 in 2500), and Israel Arab groups (1 in 8,000) (Cesani et al, 2016, PMID: 26462614; Gomez-Ospina et al, 2020, PMID: 20301309). Over 150 ARSA variants have been identified in patients with MLD (Shaimardanova et al, 2020, PMID: 33195324). Four variants (c.465+1G>A, c.1210+1G>A, p.Pro428Leu, and p.Ile181Ser) account for 25%-50% of ARSA variants in patients with MLD of central and western European ancestry (Gomez-Ospina et al, 2020, PMID: 20301309).

The ARSA-pseudodeficiency (Pd) allele decreases ARSA activity but does not result in clinical symptoms because the residual enzymatic activity is sufficient for sulfatide break down. The ARSA-pseudodeficiency (Pd) allele is characterized by two variants in cis; c.1055A>G (p.Asn352Ser) (old nomenclature 1049A>G, Asn350Ser), which affects N-glycosylation position and leads to a partial enzyme mistargeting, and ∗96A>G transition, which occurs in the first functional polyadenylation signal, and results a reduction in ARSA mRNA (Cesani et al, 2016, PMID: 26462614; Gomez-Ospina et al, 2020, PMID: 20301309). In addition, the older literature (published before the adoption of HGVS nomenclature) names variants based on the amino acid positions of the processed mature protein, which differs from the translated protein in six nucleotides at the 5’ end cDNA sequence and by two amino acids at the N-terminus (Cesani et al, 2016, PMID: 26462614). Therefore, care must be taken to ensure that the correct variant is being assessed.

In this curation, data on 14 variants (nonsense, frameshift, splice site, missense) in 13 patients from 5 publications were collected (Fluharty et al, 1991, PMID: 1684088; Grossi et al, 2008, PMID: 1670590; Amr et al, 2021; PMID: 33185815; Santhanakumaran et al, 2022, PMID: 36240581; Wang et al, 2022, PMID: 36324388). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function.

This gene-disease relationship is also supported by experimental evidence including the biochemical functional of arylsufatase A, which is consistent with the clinical and biochemical features observed in patients with MLD (Mehl and Jatzkewitz, 1968, PMID: 5646041; Shaimardanova et al, 2020, PMID: 33195324), the features of an Arsa knock out mouse model (Hess et al, 1996, PMID: 8962139), and the results of a cell-gene therapy clinical trial (Fumagalli et al, 2022, PMID: 35065785). More evidence is available in the literature, but the maximum score for experimental evidence (6 points) has been reached. In summary, ARSA is definitely associated with autosomal recessive metachromatic leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Classification approved by the ClinGen Lysosomal Diseases GCEP on June 15, 2023 (SOP v9).