Gaucher disease is a lysosomal storage disorder caused by a mutation in the gene responsible for the production of the enzyme acid-β glucosidase. More than 300 mutant alleles have now been identified. Mistry PK, Weinthal JA, Weinreb NJ. Disease state awareness in Gaucher disease: a Q&A expert roundtable discussion. Clin Adv Hematol Oncol. 2012;10:1-16.
The disease was first described by the French medical student Phillipe Gaucher in 1882 on observing a young woman with an enlarged spleen and characteristic engorged cells. Brady RO. Gaucher’s disease: past, present and future. Bailleres Clin Haematol 1997;10(4):621-34. Just over 50 years later, Aghion reported that patients with this condition accumulated a sphingolipid called glucosylceramide. But it was not until 1965 that Brady and colleagues showed that Gaucher disease was caused by reduced activity of acid-β glucosidase. Brady RO. Gaucher’s disease: past, present and future. Bailleres Clin Haematol 1997;10(4):621-34.
Acid β-glucosidase normally breaks down glycosphingolipids derived from physiological turn-over of membranes, particularly of blood cells. Genetic mutation reduces acid-β glucosidase activity, which then becomes insufficient to prevent accumulation of a glycosphingolipid called glucosylceramide in the lysosomes of cells, mainly in macrophages. Glucosylceramide-engorged macrophages, called Gaucher cells, accumulate in organs. Gaucher cell storage leads to a further cascade of pathophysiological events, including the production of a chronic inflammatory and hypermetabolic state. Grabowski G. Gaucher disease and other storage disorders. Hematology Am Soc Hematol Educ Program 2012;1:13-18 (doi: 10.1182/asheducation-2012.1.13)
This is a multi-system disease that has significant variation in its clinical manifestations, severity and course. Partial deficiency of acid-β glucosidase is associated with disease of the liver, spleen, bone marrow and lung. Severe deficiency of the enzyme is also associated with neurological manifestations. Cox TM, Schofield JP. Gaucher’s disease: clinical features and natural history. Bailleres Clin Haematol 1997;10(4):657-689.
A Gaucher cell swollen with glucosylceramide
|Normal Macrophage||Gaucher cell|
|No accumulation in the lysosomes||Macrophage with accumulated glucosylceramide in the lysosomes|
Images courtesy Prof. J.A. Barranger and M. Judith Peterschmitt