Secondary Storage of Dermatan Sulfate in Sanfilippo Disease

Abstract

Mucopolysaccharidoses are a group of genetically inherited disorders that result from the defective activity of lysosomal enzymes involved in glycosaminoglycan catabolism, causing their intralysosomal accumulation. Sanfilippo disease describes a subset of mucopolysaccharidoses resulting from defects in heparan sulfate catabolism. Sanfilippo disorders cause severe neuropathology in affected children. The reason for such extensive central nervous system dysfunction is unresolved, but it may be associated with the secondary accumulation of metabolites such as gangliosides. In this article, we describe the accumulation of dermatan sulfate as a novel secondary metabolite in Sanfilippo. Based on chondroitinase ABC digestion, chondroitin/dermatan sulfate levels in fibroblasts from Sanfilippo patients were elevated 2-5-fold above wild-type dermal fibroblasts. Lysosomal turnover of chondroitin/dermatan sulfate in these cell lines was significantly impaired but could be normalized by reducing heparan sulfate storage using enzyme replacement therapy. Examination of chondroitin/dermatan sulfate catabolic enzymes showed that heparan sulfate and heparin can inhibit iduronate 2-sulfatase. Analysis of the chondroitin/dermatan sulfate fraction by chondroitinase ACII digestion showed dermatan sulfate storage, consistent with inhibition of iduronate 2-sulfatase. The discovery of a novel storage metabolite in Sanfilippo patients may have important implications for diagnosis and understanding disease pathology.

Arylsulfatase G inactivation causes loss of heparan sulfate 3- O -sulfatase activity and mucopolysaccharidosis in mice

“…Chondroitin/dermatan sulfate was low in all tissues and did not accumulate except for a twofold increase in the liver of the knockouts (Fig. 2H), which may reflect secondary storage induced by heparan sulfate accumulation, as reported for fibroblasts derived from MPS IIIA, IIIB, IIIC, and IIID patients (11).…”

Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy

“…Urinary CS excretion has been studied semiquantitatively in studies on the DS:CS ratio as potential biomarkers, but no absolute levels have been reported [21]. Secondary accumulation of metabolites other than the primary storage material has been reported in several lysosomal storage disorders, and include GAGs and complex lipids [39,40]. In these studies general lysosomal dysfunction and direct effect of storage material on activity of some other lysosomal enzymes have been proposed as underlying mechanism.…”

Cardiac disease as the presenting feature of mucopolysaccharidosis type IIIA: A case report

“…We do not know whether severe cardiac involvement in MPS III-A is rare or simply underdiagnosed. However, the finding that MPS III is also associated with secondary storage of dermatan sulfate [18] suggests that other organs, in addition to those of the nervous central system, can be severely affected by this disorder. Furthermore, the rapidly lethal course of cardiomyopathy may hinder diagnostic investigation of MPS in affected patients.…”