In a patient with juvenile-onset metachromatic leukodystrophy (250100), Fluharty et al. (1991) identified a T-to-G transversion at nucleotide 799, resulting in a change from isoleucine to serine in exon 3. They designated this mutation E3P799 according to the following scheme: location in the gene, e.g., E3 = exon 3 or its immediately adjacent splice-recognition sequence; type of alteration, e.g., P = point mutation leading to amino acid substitution, or S = mutation in splice recognition sequence; and number of initial nucleotide in the altered sequence, e.g., 799 = 799th nucleotide beyond start of initiation codon.
Lugowska et al. (2002) pointed out that this mutation, designated I179S in the accepted terminology, had been described in 15 of 130 MLD patients in the literature. All of them were found to have been heterozygous for this mutation. Lugowska et al. (2002) stated that, according to the Hardy-Weinberg law for 2 alleles, 1 homozygote I179S/I179S among 12 late juveniles and adults studied by them should have been found. Thus, they speculated that the residual ARSA activity in an I179S homozygote might be similar to that found in an individual homozygous for the ARSA pseudodeficiency allele (607574.0001) who does not present with clinical symptoms of classic MLD.
In 2 Italian patients with metachromatic leukodystrophy, one with adult onset and the other with juvenile onset, Gomez-Lira et al. (1998) identified compound heterozygosity for mutations in the ARSA gene. Both carried the I179S mutation (607574.0008); the patient with juvenile onset had the common 459+1G-A (607574.0003) mutation, and the patient with adult onset had a pro135-to-leu mutation (607574.0042).
