ARSA – Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by deficient activity of the arylsulfatase A (ARSA) enzyme PMID:1670590. Biallelic loss-of-function and missense mutations in ARSA impair degradation of sulfatides, leading to progressive demyelination of central and peripheral white matter.

Extensive case series and pedigree analyses have identified over 200 distinct pathogenic ARSA variants across more than 100 unrelated families, including compound heterozygotes and consanguineous kindreds (PMID:1676699; PMID:7833949). Segregation of recessive alleles with MLD phenotype has been confirmed in multiple sibships and extended families, supporting autosomal recessive inheritance.

The variant spectrum comprises premature stop codons, frameshifts, splice-site mutations (e.g., c.854+1G>T/A), deep intronic alleles, and missense substitutions affecting conserved residues (e.g., c.1232C>T (p.Thr411Ile)). Population-specific founder alleles such as I179S and P426L have been recurrently observed in European and Ashkenazi cohorts. Allele frequencies in affected populations exceed those expected under Hardy–Weinberg equilibrium, enabling targeted carrier screening.

Functional studies demonstrate that missense mutants often show rapid degradation in early biosynthetic compartments or severely reduced catalytic activity in transient expression assays (PMID:8723680). ARSA–/– mouse models recapitulate sulfatide accumulation and neurologic deficits; enzyme replacement and stem cell gene therapies partially normalize biochemical markers but highlight immunologic tolerance considerations (PMID:11399225).

Pseudodeficiency alleles (c.*96A>G and c.1055A>G) cause partial ARSA activity loss without clinical disease, complicating biochemical diagnosis. Distinction from true MLD alleles requires combined molecular and enzyme assays, including electrophoretic separation and allele-specific PCR (PMID:1357970).

In summary, the ARSA–MLD association is definitive: classic AR inheritance, extensive genetic heterogeneity, and concordant functional data confirm ARSA as a diagnostic and therapeutic target. Early molecular screening and enzymatic testing are essential for family counseling and timely intervention.

References

• The New England journal of medicine • 1991 • Molecular basis of different forms of metachromatic leukodystrophy. PMID:1670590
• Human Genetics • 1991 • An 11-bp deletion in the arylsulfatase A gene of a patient with late infantile metachromatic leukodystrophy. PMID:1676699
• Human Mutation • 1994 • Metachromatic leukodystrophy in the Navajo Indian population: a splice site mutation in intron 4 of the arylsulfatase A gene. PMID:7833949
• Human Mutation • 1996 • Characterization of two arylsulfatase A missense mutations D335V and T274M causing late infantile metachromatic leukodystrophy. PMID:8723680
• American Journal of Medical Genetics • 1992 • Diagnosis of arylsulfatase A deficiency. PMID:1357970
• Human Gene Therapy • 2001 • Bone marrow stem cell gene therapy of arylsulfatase A-deficient mice, using an arylsulfatase A mutant that is hypersecreted from retrovirally transduced donor-type cells. PMID:11399225

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