Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: Haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients

Arylsulfatase A (ARSA) deficiency is the main cause of metachromatic leukod ystrophy (MLD), a lysosomal disorder with no specific treatment. In view of the importance of genetic counseling, analyses of mutations and polymorphi sms, including the ARSA pseudodeficiency allele, were carried out in 18 unr elated Spanish MLD patients, A systematic search allowed us to identify 100 % of the alleles involving 17 different mutations, 12 of which are novel: G 32S, L68P, R84W, P94A, G99V, P136S, W193X, H227Y, R288H, G308D, T327I, and IVS6-12C-->G. Two new polymorphisms, 2033C>T and 2059C>T, were identified i n intron 6 which, in combination with two polymorphisms previously describe d (2161C>G and 2213C>G), gave rise to four different haplotypes in the cont rol population. In addition, we also studied polymorphism 842G>T. Linkage d isequilibrium was detected between mutations IVS2 + 1G-->A, D255H, and T327 I and specific haplotypes, suggesting a unique origin for these mutations. Moreover, mutation T327I was always associated with the T allele of the new rare variant A210A (893C>T). The distribution of mutation D255H (frequency 19.4%) among patients with different MLD clinical presentation revealed a clear genotype-phenotype correlation paralleling that reported for mutation IVS2 + 1G-->A (frequency 25%). Among the novel mutations, only P136S and R 288H occurred on a background of the ARSA pseudodeficiency allele. Screenin g 182 normal chromosomes identified a frequency of 8.8% of this allele; mor eover, we identified two unrelated subjects with the polyA- mutation in the absence of the N350S mutation, and this infrequent haplotype reinforced th e heterogeneity of conditions with ARSA deficiency. Hum Mutat 14:240-248, 1 999. (C) 1999 Wiley-Liss, Inc.