History and Metabolic Context

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).

This image depicts a ten year old child with splenomegaly, one of the common symptoms associated with Gaucher's Disease. Source:
This image depicts a ten year old child with splenomegaly, one of the common symptoms associated with Gaucher’s Disease. Source: Goldblatt 1988.

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).

Source: National Human Genome Research Institute

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.

Phillipe Gaucher, 1854-1918. Source: Google Images
Phillipe Gaucher, 1854-1918. Source: Google Images

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).

Sphingolipid Metabolism

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.

GlcCerase hydrolysis mechanism. Source: Dvir et al. 2003
GlcCerase hydrolysis reaction. Source: Dvir et al. 2003

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).

To learn more about Gaucher’s Disease, visit the following pages:

Molecular Basis of Disease

Treatments and Disease Management

Conclusions and Proposals for Future Work

4 Replies to “History and Metabolic Context”

  1. This was a great summary of the history and metabolic context. I just had a few questions that I was wondering as I read. You mentioned that you could use Red blood cell counts and platelet counts to help diagnose Gauchers, however I was not able to directly see how this disease would manifest these symptoms. I believe you I am just wondering how.

    In regards to the blood test that measures GlcCerase activity, I think it would be useful to demonstrate what the results of the test would say about the prognosis. I am guessing a normal individual would see a loss in fluorescent signal upon cleavage of the analogous substrate, while a patient with Gaucher would see no drop in fluorescence.

    I really liked the history of the disease section very interesting, clear and informative. I think it might be useful explaining the link between the observed enlarged spleen and how that relates to histology. Are the “large cells with small nuclei” large because accumulation of unhydrolyzed GlcCer?

    How did Brady et al. come to the conclusion from the results of the radioactivity experiment. What data lead to their conclusions? I feel like this is the big finding that changed the view of the disease, more curious than anything (how did they come to that conclusion?).

    Also, does this disease lead to a deficiency in the body’s reserves of ceramide. I know we can get glucose from our diet, but how does the lack of this product affect our body’s metabolic homeostasis? Are there other ways your body can make ceramide?

    This is a very interesting disease. You clearly articulate what you are trying to get across, making this an interesting read.

    1. These are very insightful questions that I am happy to answer. I will answer them in turn. 1) Regarding the symptom of low RBC count, the spleen is involved in the process of breaking down red blood cells. When the spleen becomes enlarged (as in Gaucher’s Disease), it becomes overactive. This increases the amount of RBC breakdown, leading to anemia in Gaucher patients. 2) Yes, the lab performing the diagnostic test would see a drop in fluorescence in non-Gaucher patients and a continuous level of fluorescence in Gaucher patients. Physicians offices will usually send the sample from the patient out to another facility to perform the test. 3) Regarding the histology relation to spleen enlargement, the spleen becomes enlarged because of the accumulation of Gaucher cells, which increases the size of the spleen. Spleen samples would normally be collected and analyzed under a microscope to find Gaucher cells. 4) Brady synthesized radioactive (14-C) GlcCer and used spleen samples from patients suspected of having Gaucher’s Disease. The paper states “the hydrolysis of GlcCer-14 C was determined by the formation of water-soluble radioactive products.” GlcCer itself is water-insoluble, but the products of its hydrolysis are water-soluble. 5) Ceramide can be synthesized in the body through different pathways, not just from GlcCer synthase activity. According to a KEGG pathway search, ceramide can be made from palmitoyl-CoA and Serine. I hope I have answered all of your questions and I hope you are doing well!

  2. Hey Zach,

    I was wondering, since you mention in the molecular basis section that there is a common N370S substitution found in type 1 Gaucher’s patients, if sequencing is ever used as a tool of diagnosis (especially since all the references for diagnosis are at least 30 years old). I guess my main question is, is this mutation ever found in patients without the disease, or is having this mutation an absolute indication of the disease.

    Also, is there any biological reason that this disease is found primarily in the Jewish population? Also, 1:450 seems like a relatively high birth incidence and suggests that the carrier rate among the population is even higher, which sometimes points to heterozygotes having increased fitness over wild type homozygotes. Is there anything about heterozygosity of the disease that might point to increased fitness?

    1. Hi Tommy. Yes, genetic testing is often utilized to screen for Gaucher’s Disease, especially among the Jewish population. Due to the fact that the N370S mutation is the most common, I would say that this is an absolute indication of having the disease, with the caveat that individuals may have this mutation and be heterozygous for it without showing symptoms. I think that if this mutation was passed from the parents and resulted in a homozygous recessive offspring with this mutation, then that would definitely result in a GD patient. Your second question is very evolutionarily oriented. It may be possible that this mutation randomly occurred in a geographic location where there was a high concentration of Jewish individuals and that mutation propagated among them. And yes, 1:450 is a high birth incidence, making GD1 the most commonly diagnosed lysosomal storage disorder. I don’t think heterozygotes would have increased fitness. I believe that in the literature, heterozygotes actually have higher susceptibility to Parkinson’s Disease. The activity of GlcCerase is like a gradient – think of individuals without the mutation having 100% GlcCerase activity and homozygote recessive individuals having 0% activity (as an extreme example). But in terms of fitness, I have not read or do not think that having a partially defective GlcCerase would offer a type of advantage. Thanks!

Comments are closed.