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.The exact mechanism of neurotoxicity is not understood, but it is thought to involve a reaction to glucosylsphingosine.Different mutations in the GBA (beta-glucosidase) gene determine the remaining activity of the enzyme. In type I, there is some residual activity of the enzyme, accounting for the lack of neuropathology in this type. Although there is some correlation between genotype and phenotype, neither the amount of stored lipids, nor the residual enzyme activity correlates well with disease symptoms. This circumstance has called for alternative explanations accounting for disease symptoms including

jamming of the endo/lysosomal system
ER stress
altered lipid composition of membranes throughout the cell, including the plasma membrane, and consequent changes in the dynamic and signaling properties of the cell membrane
inflammation caused by cytokine secretion as a result of sphingolipid accumulation, and neurodegeneration caused by the accumulation of glucosylsphingosine, a neurotoxinHeterozygotes for particular acid beta-glucosidase mutations carry about a five-fold risk of developing Parkinsons disease, making this the most common known genetic risk factor for Parkinsons.Cancer risk may be increased, particularly myeloma. This is thought to be due to accumulation of glucosylceramide and complex glycosphingolipids.The role of inflammatory processes in Gaucher disease is poorly elucidated. However, sphingolipids are known to participate in inflammation and apoptosis, and markers of macrophage activation are elevated in people with Gaucher disease.
These markers include angiotensin-converting enzyme, cathepsin S, chitotriosidase, and CCL18 in the blood plasma; and tumor necrosis factor alpha in splenic Gaucher cells (engorged macrophages). Diagnosis
Gaucher disease is suggested based on the overall clinical picture. Initial laboratory testing may include enzyme testing. As a result, lower than 15% of mean normal activity is considered to be diagnostic. Decreased enzyme levels will often be confirmed by genetic testing. Numerous different mutations occur; sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available and is useful when a known genetic risk factor is present.A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme, and immunoglobulin levels, or by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gauchers disease activity in response to treatment, and may reflect the severity of the disease

Classification
Gauchers disease (GD) has three common clinical subtypes. These subtypes have come under some criticism for not taking account of the full spectrum of observable symptoms (the phenotypes). Also, compound heterozygous variations occur which considerably increase the complexity of predicting disease course. GD type I (non-neuropathic) is the most common and least severe form of the disease. Symptoms may begin early in life or in adulthood and mainly affect the liver, spleen, and bone.