Early onset of lysosomal storage disease in a murine model of mucopolysaccharidosis type VII: undegraded substrate accumulates in many tissues in the fetus and very young MPS VII mouse.

摘要

Lysosomal storage diseases (LSDs), due to deficiency of a lysosomal enzyme, are inherited, progressive disorders that are often fatal during childhood. The mucopolysaccharidoses (MPS) are LSDs caused by deficiency of a lysosomal enzyme needed for the stepwise degradation of glycosaminoglycans. A murine model of MPS VII shares many clinical, biochemical, and pathologic features with human MPS and has proved valuable for the study of the pathophysiology of MPS and for evaluation of therapies for LSDs. Early therapy of MPS VII mice, initiated in the first weeks of life, is much more effective in decreasing clinical and morphologic evidence of disease than treatment begun in mature animals. Whether such early therapy decreases existing storage or prevents its accumulation is incompletely investigated. We performed an analysis of storage in very young MPS VII mice to define the extent of disease at and before the time of initiation of early treatments. MPS VII pups from 12 days postcoitus (dpc) to 31 days postnatal (dpn) were studied. Storage accumulated in fixed tissue macrophages in the liver and cartilage as soon as 12 dpc and was present in central nervous system glia, leptomeninges, and perivascular cells by 15 dpc. Osteoblast and primitive neocortical cell storage was apparent at 18 to 19 dpc. At 2 dpn, lysosomal distention appeared in circulating leukocytes. Abundant lysosomal storage was present in many sites by 14 dpn. Secondary accumulation of beta-hexosaminidase paralleled increasing glycosaminoglycan storage. These results confirm the presence of widespread storage even in utero and in the very young MPS VII mouse and highlight the importance of early treatment to prevent storage accumulation.