title: Heterogeneity in late-onset metachromatic leukodystrophy. Effect of inhibitors of cysteine proteinases.
abstract: The synthesis of arylsulfatase A polypeptides was followed in fibroblasts from 11 patients with late-onset forms of metachromatic leukodystrophy. In 10 cell lines, the apparent rate of synthesis was 20%-70% as measured by the amount of [35S]arylsulfatase A secreted in the presence of 10 mM NH4Cl. The specific activity of the secreted arylsulfatase A was normal. The residual activity of arylsulfatase A was below 10% except for one cell line in which it was 20%. The activity of arylsulfatase A and the degradation of sulfatides was partially restored in these fibroblast lines by treatment with irreversible (peptidyl diazomethyl ketones) or competitive (leupeptin) inhibitors of cysteine proteinases. Thus, the mutation(s) in these cell lines led to the synthesis of arylsulfatase. A polypeptides with increased susceptibility to cysteine proteinases. Multiple allelic mutations within this group of late-onset metachromatic leukodystrophy were suggested by the clinical heterogeneity, the variability of the residual activity, and in the response to inhibitors of cysteine proteinases. In fibroblasts from one patient, the apparent rate of synthesis of arylsulfatase A was less than 5%. Furthermore, inhibitors of cysteine proteinases were without effect, suggesting that the mutation in this patient is different from the others.
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000096:biosynthesis* / Q000172:deficiency; D002648:Child; D002675:Child, Preschool; D015853:Cysteine Proteinase Inhibitors; D004795:Enzyme Stability; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000201:enzymology / Q000235:genetics*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D011480:Protease Inhibitors; D011506:Proteins; D002553:Cerebroside-Sulfatase