Genotype-phenotype relationship in various degrees of arylsulfatase A deficiency |
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Authors: | Joachim Kappler Peter Leinekugel Ernst Conzelmann Wim J Kleijer Alfried Kohlschütter Tønne Tønnesen Michael Rochel F Freycon Peter Propping |
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Institution: | (1) Institut für Humangenetik der Universität, Wilhelmstrasse 31 W-5300, Bonn 1, Federal Republic of Germany;(2) Institut für Organische Chemie und Biochemie der Universität, Gerhard-Domagk-Strasse 1 W-5300, Bonn 1, Federal Republic of Germany;(3) Physiologisch-Chemisches Institut, Biozentrum der Universität, Am Hubland W-8700, Würzburg, Federal Republic of Germany;(4) Department of Clinical Genetics, University Hospital, Erasmus University, Rotterdam, The Netherlands;(5) Universitätskinderklinik, Martinistrasse 52 W-2000, Hamburg 20, Federal Republic of Germany;(6) John F. Kennedy Institute, Gl. Landevej 7, DK-2600 Glostrup, Denmark;(7) Taunusklinik, Neuropädiatrie, Debusweg 4 W-6240, Königstein 2, Federal Republic of Germany;(8) Pediatrie A Hôpital Nord, Saint Priest en Jarez, France;(9) Present address: Biochemie II der Universität, Gosslerstrasse 12d W-3400, Göttingen, Federal Republic of Germany |
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Abstract: | Summary Arylsulfatase A (ASA) is a lysosomal enzyme that hydrolyzes sulfatide. Absence of ASA activity leads to metachromatic leukodystrophy (MLD). The clinical outcome resulting from ASA deficiency is highly variable with respect to age of onset and symptoms. So far the causes for the variability are poorly understood. We have studied the relationship between the ASA genotype and the clinical phenotype. Fibroblasts from a total of 34 subjects with low ASA activity were examined with immunoblotting, a sensitive ASA assay, and the sulfatide loading test in order to characterize low ASA activity further. By these methods, three different classes of ASA deficiency can be defined: homozygosity for the pseudodeficiency allele (ASAP), compound heterozygosity for the ASAP and MLD (ASA–) alleles, and ASA–/ ASA– genotypes. These genotypes exhibit different levels of ASA residual activity. Only ASA–/ASA– genotypes are associated with MLD. For diagnostic purposes, however, the differentiation of the various ASA genotypes is essential. |
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