Definition and Symptoms of Gaucher’s Disease
Gaucher’s Disease is the most common autosomal recessive lysosomal storage disorder. It is defined by abnormally high quantities of glucocerebroside (GlcCer) in cells of various organ systems, but most commonly in phagocytic cells such as macrophages (Brady et al. 1965). The accumulation of GlcCer is due to an inherited mutation in the GBA gene that results in a defective glucocerebrosidase (GlcCerase), which catalyzes the breakdown of GlcCer into glucose and ceramide. Symptoms of Gaucher’s Disease include anemia, swollen abdomen, hepatosphenomegaly (enlarged liver and spleen), and abnormal bone manifestations (Goldblatt 1988). The rate of symptom progression usually depends on when symptoms first appear, meaning that symptoms are more likely to progress rapidly if they begin early in life. Epidemiologically, Gaucher’s Disease is most frequently diagnosed in the Ashkenazi Jewish population with a carrier frequency of 8.9% and a birth incidence of 1:450 (Zimran 1991).
Means of Identification/Diagnosis
The diagnosis of Gaucher’s Disease may be a difficult task because the symptoms of the disease overlap with the symptoms of many other diseases (Daniels LB and Glew RH 1982). Gaucher’s Disease may be diagnosed through a low red blood cell or platelet count, which may allow it to be confused for other hematological diseases. Additionally, an enlarged or swollen abdomen could be attributed to a physical injury, and bone/joint pains could be attributed to arthritis or other bone diseases (Daniels LB and Glew RH 1982).
The definitive way to diagnose Gaucher’s Disease is through a blood test that measures GlcCerase activity. GlcCerase activity in white blood cells (ie. macrophages) will be much lower in patients with Gaucher’s Disease than in other individuals (Kampine 1967). A fluorescent substrate analogous to GlcCer is often utilized to assess the activity of GlcCerase in lymphocytes and fibroblasts (Beutler E and Kuhl W 1970). Physicians may also suggest that a CT scan or MRI be taken so that the liver and spleen may be assessed. DNA testing for the four common mutations in the GBA gene that manifest in defective GlcCerase can also be employed for patients that present with Gaucher symptoms. Additionally, samples of fibroblasts or white blood cells can be collected and examined histologically for the presence of Gaucher cells (Goldblatt 1988).
The Quest Toward Discovering Gaucher’s Disease
Gaucher’s Disease was first identified in 1882 by the French physician Phillipe Gaucher. While undertaking his doctorate thesis, he identified a woman with an enlarged spleen thought to be the result of splenetic cancer (Gaucher 1882). However, this patient did not present with malignancy in the spleen, which allowed Gaucher to investigate other causative agents of the enlarged spleen.
The biochemical nature of Gaucher’s Disease was not identified until 1965. In between the initial discovery and biochemical identification, however, physicians diagnosed Gaucher’s Disease in several patients and reported on them. For example, in 1905 Dr. Brill reported on the appearance of Gaucher-associated splenomegaly present in multiple members of the same family and synthesized another report in 1909 including additional cases discovered between 1905 and 1909 (Brill 1909). In the cases discovered by Dr. Brill, no characteristics of malignancy were noted, attributing the sphenomegaly to Gaucher’s Disease, and large cells with small nuclei were detected histologically. Other organs, such as the liver, lymph nodes, and bone marrow were affected in the same histological way as the spleen (Brill 1909). These cells were named Gaucher cells, and the presence of Gaucher cells is one of the primary means of identifying Gaucher’s Disease.
The molecular underpinning of Gaucher’s Disease was reported in 1965 by the Brady lab. It had been well documented that GlcCer accumulation was the cause of Gaucher’s Disease (Brady 1965). To investigate whether the GlcCer accumulation was related to glucocerebroside catabolism, Brady et al. labeled GlcCer with C-14 in order to determine the enzyme that was involved in glucocerebroside metabolism (Brady 1965). This study used spleen tissue from patients in order to deduce the hydrolysis activity of the cerebroside-cleaving enzyme, and measured the activity in radioactive counts per minute (Brady 1965). Brady et al. proposed that the accumulation of GlcCerase is due to a deficiency in GlcCerase.
Following the discovery of the molecular details surrounding Gaucher’s Disease, future experimentation focused on the diagnosis (explained above), molecular basis, and treatment of the disease. Further explanations of each of these points are also discussed on this website (see tabs attached to title page).
Deficiency in GlcCerase wreaks havoc for the metabolism of sphingolipids in the body. Sphingolipids contain an eighteen-carbon amino alcohol structure and are synthesized in the endoplasmic reticulum from nonsphingolipid precursors (National Institute of Health 2010). They are membrane-bound and perform a variety of functions, including cell-cell anchoring, signal transduction, and cell cycle arrest (National Institute of Health 2010). Modifications of the basic structure of sphingolipids bring about various classes of sphingolipids.
The class of sphingolipids that is specific to Gaucher’s Disease is glucosphingolipids. Glucosphingolipids are catabolized as part of normal intracellular turnover. The catabolism of glucosphingolipids is very important because they are difficult to excrete due to their highly hydrophobic nature (National Institute of Health 2010). An inability for a cell to catabolize glucosphingolipids makes the cell highly sensitive to glucosphingolipid accumulation.
GlcCer is the glucosphingolipid that is the result of synthesis between glucose and ceramide. Cells of the immune system contain a high concentration of GlcCer (National Institute of Health 2010). Macrophages engulf leukocytes as part of normal recycling and under normal cellular conditions, the macrophages can catabolize GlcCer (National Institute of Health 2010). Its catabolism involves a hydrolysis reaction that produces glucose and ceramide (National Institute of Health 2010). Glucose metabolism is commonly known and involves the pathways of glycolysis, the TCA Cycle, and oxidative phosphorylation. Ceramide catabolism involves the acetylation of ceramide to form sphingosine, which can be utilized by the cell to produce other types of sphingolipids (National Institute of Health 2010).
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