An unusual arylsulfatase A pseudodeficiency allele carrying a splice site mutation in a metachromatic leukodystrophy patient

A late infantile metachromatic leukodystrophy patient was found to be heterozygous for the arylsulfatase A (ARSA) pseudodeficiency (pd) polyadenylation site variant (*96A > G) in the absence of the commonly associated N-glycosylation site variant (N350S). ARSA alleles were sequenced and the genotype completely defined. Six sequence variations were identified, among which two resulted as severe disease-causing mutations, both leading to the loss of the reading frame: a splice acceptor site mutation in intron 4 (849-1G > A), located on the *96A > G allele and a mononucleotide deletion (258delC) in exon 2, located on the other allele. The altered splicing caused by the 849-1G > A mutation was shown by in vitro expression of a recombinant gene containing the genomic region surrounding the mutation. Haplotype analysis of the unusual pd allele was performed in order to investigate its possible origin.