Mucopolysaccharidoses are rare genetic diseases from the group of lysosomal storage disorders caused by deficiency of enzymes involved in degradation of mucopolysaccharides (glycosaminoglycans, GAGs). Within each mucopolysaccharidosis, there is a continuous spectrum of clinical features from the very severe to the more mildly affected individuals. Surprisingly, in most cases, it is not possible to predict severity and clinical progress (i.e., the natural history) of the disease on the basis of detection of particular mutations or residual activity of the deficient enzyme. In this article, the reasons for such an unexpected difficulty are discussed. A model for the correlation between residual activity of a lysosomal enzyme and the turnover rate of its substrate(s) has been proposed previously by others, however, in that model it was assumed that substrate concentration in the lysosome is not regulated, thus the residual activity of a hydrolase would be the only determinant of the rate of substrate accumulation. On the other hand, both a general model for genetic regulation of turnover of GAGs and results of very recent studies strongly suggest that expression of genes coding for enzymes involved in GAG synthesis is precisely regulated and may vary between individuals. Therefore, we propose that apart from measurement of residual activity of the enzyme involved in degradation of GAGs, the efficiency of synthesis of these compounds should also be estimated. If the hypothesis presented in this article is true, the ratio of the synthesis of glycosaminoglycans to the residual activity of the deficient enzyme should be of considerable prognostic value.