Underlying pathology

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 MacrophageGaucher cell
Normal macrophageGaucher cell
No accumulation in the lysosomesMacrophage with accumulated glucosylceramide in the lysosomes

Images courtesy Prof. J.A. Barranger and M. Judith Peterschmitt