The glucocerebrosidase locus in Gaucher's disease: molecular analysis of a lysosomal enzyme.

Gaucher's disease was first described by Phil- lippe Gaucher in 1882, who reported a patient with hepatosplenomegaly in whom the charac- teristic abnormal macrophages were thought to represent a primary neoplasm of the spleen.3 Identification of the stored material as glucocerebroside in 1934 was followed many years later by the finding that glucocerebrosidase activity was markedly reduced in the spleen of patients with Gaucher's disease by Brady et a14 and Patrick5 independently in 1965. Although the enzyme is deficient in most tissues of the body, it is the cellular specificity of the substrate that determines which tissues are principally affected. The substrate, glucocere- broside, is a constituent of complex glycolipids and is released in the breakdown of cell mem- branes, particularly leucocytes and erythro- cytes, by mononuclear phagocytes. Thus, in Gaucher's disease engorged macrophages ac- cumulate throughout the body and cause hepatosplenomegaly, bone marrow infiltration with skeletal disease, and, rarely, involvement of the lungs and brain.