OCCURRENCE, DISTRIBUTION, AND PHENOTYPE OF ARYLSULFATASE A MUTATIONS IN PATIENTS WITH METACHROMATIC LEUKODYSTROPHY

Occurrence, distribution, and phenotype of arylsulfatase A (ASA) mutat ions were investigated in 27 patients with metachromatic leukodystroph y (MLD) from Central Europe, mainly from Austria (n = 15) and Poland ( n = 9). Genomic DNA from leukocytes, fibroblasts, or paraffin-embedded , formalin-fixed brain or nerve tissue, respectively, was tested by na tural or mutated primer-modulated PCR restriction, fragment length pol ymorphism for the eight most common European mutations: R84Q, S96F, 45 9+1G>A, I179S, A212V, 1204+1G>A, P426L, and 1401del11bp. The overall i dentification rate of unrelated MLD alleles was the highest, in adult (90%), medium in juvenile (50%), and lowest in late infantile (36%) ML D patients. The two common alleles, 459+1G>A and P426L, together accou nted for 42% of all 50 unrelated MLD alleles investigated; I179S was o bserved in 6 of 50 MLD alleles (12%). Thus, I179S was far more frequen t than hitherto thought and appears to be a third common mutation in E urope. Moreover, a different allelic distribution between Austrian and Polish juvenile patients was disclosed, indicating genetic heterogene ity of MLD even within Central Europe. The genotype-phenotype correlat ion suggested by Polten et al. [N Engl J Med 324:18-22, 1991] was not followed by all of our MLD patients. Moreover, some MLD patients with identical ASA mutations presented with different phenotypes. This may be due, at least in some cases, to the presence of an additional mutat ion on individual mutant alleles. Therefore, prediction of the clinica l course from single mutation analysis is not possible. (C) 1997 Wiley -Liss, Inc.