Pathophysiology
The disease is caused by a defect in housekeeping gene lysosomal glucocerebrosidase (also known as beta-glucosidase, EC 3.2.1.45, PDB 1OGS) on the first chromosome (1q21). The enzyme is a 55.6 KD, 497 amino acids long protein that catalyses the breakdown of glucosylceramide, a cell membrane constituent of red and white blood cells. The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into Gaucher cells, which appear on light microscopy to resemble crumpled-up paper.
In the brain (type II and III), glucosylceramidase accumulates due to the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves.
Different mutations in the beta-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype.
Heterozygotes for particular acid beta-glucosidase mutations carry about a fivefold risk of developing Parkinson's disease, making this the most common known genetic risk-factor for Parkinson's. A study of 1525 Gaucher patients in the United States suggested that while cancer risk is not elevated, particular malignancies (non-Hodgkin lymphoma, melanoma and pancreatic cancer) occurred at a 2-3 times higher rate.
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