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Pathochemistry, pathogenesis and enzyme replacement in multiple-sulfatase deficiency
Y Eto1, I Gomibuchi, F Umezawa
1Department of Pediatrics, Tokyo Jikei University School of Medicine, Japan.
Abstract:
Multiple-sulfatase deficiency (MSD) is now considered to be heterogeneous and could be classified into three or four clinical phenotypes according to the onset of the disease: neonatal, late infantile, juvenile and possibly adult type. Neonatal-type MSD shows severe clinical involvement and practically no arylsulfatase A, B and C activities in cultured skin fibroblasts. Furthermore, arylsulfatase A activity in neonatal-type MSD was not enhanced by the addition of thiosulfate. Therefore, it is distinct from late infantile-type MSD. The degradation of 14C-sulfatide can occur in MSD-cultured skin fibroblasts and was much higher than in late infantile-type MLD. The addition of thiol protease such as leupeptin to cultured MSD skin fibroblasts enhanced arylsulfatase A activity as well as the degradation of 14C-sulfatide. This suggests that the decreased activities of arylsulfatase A is due to an acceleration of the enzyme degradation. Enzyme replacement by the addition of arylsulfatases of different sources (human liver, brain, fungus) was carried out in cultured MSD skin fibroblasts. Human enzymes of arylsulfatase A and B were mostly taken up by MSD cells rather than those of fungus origin. By the exposure to leukocytes to cultured skin fibroblasts, MSD cells corrected arylsulfatase A and B activities.
Insights
Multiple-sulfatase deficiency (MSD) is a heterogeneous disorder. In neonatal MSD, decreased arylsulfatase A activity stems from accelerated enzyme degradation, distinct from other forms.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Multiple-sulfatase deficiency (MSD) presents with heterogeneous clinical phenotypes.
- Neonatal MSD exhibits severe symptoms and minimal arylsulfatase A, B, and C activity in fibroblasts.
- Neonatal MSD is distinguished from late infantile-type MSD by lack of thiosulfate enhancement of arylsulfatase A activity.
Purpose of the Study:
- To investigate the underlying mechanisms of arylsulfatase A deficiency in neonatal MSD.
- To explore potential therapeutic strategies for MSD using enzyme replacement and cell-based therapies.
Main Methods:
- Cultured skin fibroblasts from MSD patients were used.
- Enzyme activities (arylsulfatase A, B, C) and 14C-sulfatide degradation were measured.
- Enzyme replacement therapy with human and fungal arylsulfatases was performed.
- Leukocyte co-culture was utilized to assess therapeutic potential.
Main Results:
- Degradation of 14C-sulfatide was significantly higher in MSD fibroblasts compared to late infantile-type MLD.
- Leupeptin treatment enhanced arylsulfatase A activity and 14C-sulfatide degradation in MSD fibroblasts, suggesting accelerated enzyme degradation.
- Human-derived arylsulfatases A and B were effectively taken up by MSD cells.
- Co-culture with leukocytes corrected arylsulfatase A and B activities in MSD fibroblasts.
Conclusions:
- Accelerated degradation of arylsulfatase A is a key factor in neonatal MSD.
- Enzyme replacement with human arylsulfatases and leukocyte-based therapy show promise for treating MSD.