Molecular basis

In normal individuals, glucocerebrosidase breaks down glucocerebroside, a glycolipid arising from the membranes of worn-out red and white blood cells, within the lysosomes of cells of the monocyte/macrophage lineage.^{[1, 2]} In individuals with Gaucher disease, this catalytic breakdown is insufficient, leading to the storage of large quantities of substrate within the monocytes/macrophages. These lipid-engorged cells are referred to as Gaucher cells and take on a distinctive appearance. Their cytoplasm resembles “wrinkled tissue paper” as a result of filling with fibrils and “rope-like” deposits of glucocerebroside.^[3] Gaucher cells are very enlarged, long-lived and possibly immortal.^[2,4] These aberrant tissue-bound macrophages accumulate progressively and in enormous numbers in the liver, spleen (Figure 1), bone marrow and other organs. This accumulation disturbs and inhibits the normal function of these organs and tissues which may lead to irreparable damage. Studies suggest that the stored Gaucher cells may stimulate increased release of cytokines such as interleukin (IL)-6, IL-10 and tumor necrosis factor-alpha which, in turn, may contribute to the pathogenesis of the disease.^[5,6]

Gaucher cells in spleen and liver biopsies

References

1 Barton NW, Brady RO, Dambrosia JM, et al: Replacement therapy for inherited enzyme deficiency — macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 324:1464-1470, 1991

2 Mankin HJ: Indications for and complications of skeletal surgery in patients with Gaucher disease. Gaucher Clinical Perspectives 4(1):7-11, 1996

3 Barranger JA, Rice E: An overview of Gaucher disease. Gaucher Clinical Perspectives 1(1):1-5, 1993

4. Fallet S, Grace ME, Sibille A, et al: Enzyme augmentation in moderate to life-threatening Gaucher disease. Pediatric Research 31(5):496-502, 1992

5 Michelakakis H, Spanou C, Kondyli A, et al: Plasma tumor necrosis factor-a levels in Gaucher disease. Biochimica Biophysica Acta 1317:219-222, 1996

6 Allen MJ, Myer BJ, Khokher AM, et al: Pro-inflammatory cytokines and the pathogenesis of Gaucher’s disease: increased release of interleukin-6 and interleukin-10. Q J Med 90:19-25, 1997