An arylsulphatase A (ARSA) frameshift mutation (289insG) in metachromatic leukodystrophy (MLD)

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of arylsulphatase A (ARSA) (EC 3.1.6.8). MLD involves progressive demyelination, resulting in a variety of neurological symptoms varying in severity (Kolodny and Fluharty, 1995). The ARSA gene consists of eight exons encoding the 507 amino acid enzyme (Stein et al, 1989). It is transcribed into three mRNA species, a major species of 2.1 kb, and two minor species of 3.7 and 4.8 kb. Over 90 largely missense mutations and polymorphisms have been identified in the ARSA gene (Human Gene Mutation Database). Some healthy individuals, referred to as having pseudodeficiency of arylsulphatase A (ARSA-PD), have very low ARSA activity. The molecular defect responsible for ARSA-PD is characterised by two A to G transitions (Gieselmann et al, 1989), the first of which causes the substitution of a glycosylated asparagine with a serine residue at position 350 (N350S), resulting in about 50% of enzyme being mistargeted. The second results in a non-functional polyadenylylation signal and a deficiency of the major 2.1 kb mRNA species, leading to a 70% reduction of polyadenylylated mRNA (Harvey et al, 1998). As a result of the combined effect of these variants, ARSA-PD homozygotes have only about 10% of normal enzyme activity but this is sufficient to prevent the development of MLD symptoms.