An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA; EC 3.1.6.8). The 8 ARSA exons and adjacent intron boundaries from a patient with late-infantile metachromatic leukodystrophy were polymerase chain reaction (PCR) amplified in seven discrete reactions. Amplified ARSA exons were analysed for the presence of sequence alterations by single-strand conformation polymorphism analysis, followed by direct sequencing of PCR products. The patient was found to be homozygous for a C-->T transition in exon IV that results in the substitution of a highly conserved threonine residue at amino acid 274 with a methionine (T274M). Analysis of a further 29 MLD patients revealed the presence of five additional homozygotes for T274M. All 6 T274M homozygotes (representing four families) were of Lebanese descent, and all were known to be the result of consanguineous marriages. The altered amino acid is rigidly conserved among 10 sulfatases from Escherichia coli to humans; therefore, it is most likely that the resultant mutant protein will have little or no enzyme activity. This is consistent with the very low ARSA activity measured in these patients and their uniformly severe clinical presentation.