Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy

Abstract

Occurrence, distribution, and phenotype of arylsulfatase A (ASA) mutations were investigated in 27 patients with metachromatic leukodystrophy (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 natural or mutated primer-modulated PCR restriction, fragment length polymorphism for the eight most common European mutations: R84Q, S96F, 459+1G > A, I179S, A212V, 1204+1G > A, P426L, and 1401del11bp. The overall identification rate of unrelated MLD alleles was the highest, in adult (90%), medium in juvenile (50%), and lowest in late infantile (36%) MLD patients. The two common alleles, 459+1G > A and P426L, together accounted for 42% of all 50 unrelated MLD alleles investigated; I179S was observed in 6 of 50 MLD alleles (12%). Thus, I179S was far more frequent than hitherto thought and appears to be a third common mutation in Europe. Moreover, a different allelic distribution between Austrian and Polish juvenile patients was disclosed, indicating genetic heterogeneity of MLD even within Central Europe. The genotype-phenotype correlation 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 mutation on individual mutant alleles. Therefore, prediction of the clinical course from single mutation analysis is not possible.

Defective Oligomerization of Arylsulfatase A as a Cause of Its Instability in Lysosomes and Metachromatic Leukodystrophy

“…Furthermore, the knowledge of the cathepsin L cleavage site makes possible the development of peptide inhibitors that protect the P426L-ASA in the lysosomal environment. Because the P426L-ASA allele accounts for 16 -25% of all ASA alleles in MLD patients (6,27,28), about one-fifth of all MLD patients could benefit from such a therapeutic approach.…”

Sulfatide Storage in Neurons Causes Hyperexcitability and Axonal Degeneration in a Mouse Model of Metachromatic Leukodystrophy

“…Late-onset (adult) MLD is characterized by low residual ASA activity (von Figura et al, 2001). Characteristic symptoms in adult MLD are schizophrenialike behavioral abnormalities [in patients with the I179S mutation (Tylki-Szymanska et al, 1996)] or clumsiness of movement and spastic paresis of arms and legs [in patients with the P426L mutation (Berger et al, 1997)]. In contrast, nerve conduction velocity is sometimes normal, and signs of peripheral neuropathy and demyelination are often absent (Kolodny and Fluharty, 1995).…”

Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy

“…The MLD mutations that have been characterized are functionally divided into two groups: 0 alleles, associated with null or very low enzymatic activity, and R alleles, encoding for ARSA with detectable residual activity. The 0 allele c.459+1G>A and the R alleles c.536T>G and c.1277C>T are the most frequent mutations detected in the Caucasian population (Berger, et al, 1997;Lugowska, et al, 2005;Polten, et al, 1991). All the other described alterations, which account for the majority of the alleles, are rare or private.…”