Gaucher Disease

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The genetic disease, Gaucher's disease, causes a disorder of the lipid metabolism. Through this sphingolipidosis (lysosomal storage disease) there can be found an accumulation of sphingolipids in cells, that leads to a morbid impact on the body. The disease was first described in 1882 by a French doctor Philippe Gaucher, after whom it is named.


Some information about the defect protein is presented in the following table.

Structure of lysosomal glucocerebrosidase (source: Wikipedia, Gaucher's disease)
Defect Enzyme in Gaucher's Disease
EC number
  • glucosylceramidase
  • psychosine hydrolase
  • glucosphingosine glucosylhydrolase
  • GlcCer-beta-glucosidase
  • beta-D-glucocerebrosidase
  • glucosylcerebrosidase
  • beta-glucosylceramidase
  • ceramide glucosidase
  • glucocerebrosidase
  • glucosylsphingosine beta-glucosidase
  • glucosylsphingosine beta-D-glucosidase
  • structure: 1OGS
  • molecular weight: 55.6 KD
  • length: 497 amino acids
  • entry: P04062
  • molecular weight: 59.716 KD
  • length: 536 amino acids

Phenotypic description of the disease

There exist three phenotypic expressions of the Gaucher's disease. Dependent on the severe of the disease, the disease shows different symptoms. Moreover, the age at which the first symptoms appear, is in connection with the degree of illness.

Classification of types and symptoms

Phenotypes of Gaucher types (source: Children's Gaucher Research Fund)

Type I: non-neuropathic

The most common type of the Gaucher's disease has also the mildest illnes degree. It mostly occurs the first time in adulthood. Symptoms, that may occur in type I:

  • skeletal abnormalities (osteopenia, bone pain/fractures)
  • hepatomegaly (enlarged liver)
  • splenomegaly (enlarged spleen) that causes anemia (decrease in healthy red blood cells) and can result in thrombocytopenia (greater susceptibility to bruising, which may mean you have a low number of blood platelets) as well as nosebleeds
  • pingueculae (yellow spots in your eyes)
  • delayed puberty

Type II: acute infantile neuropathic

The second disease form starts at the infant stage and has the severest degree of illness. Most children with this type of Gaucher won't reach the age of five. Symptoms, that may occur in type II:

  • type I symptoms
  • rapidly process of brain damage (mental retardation, dementia)
  • Rigidity
  • Seizures

Type III: chronic neuropathic

The Type III of Gaucher’s disease begins in childhood or adolescence. Symptoms, that may occur in type III:

  • type I symptoms especially liver and spleen enlargement are more intense than in the other Gaucher types
  • slow brain damage (mental retardation, dementia)


Biochemical disease mechanism

Sphingolipid Metabolism (source: KEGG)

Old or other disused red/white blood cells are processed in the macrophages. In these immunocells, the lysosomal glucocerebrosidase acts on the fatty acids of the cell membrane. In the lysosome the glucocerebrosidase cleaves the glucosylceramide into ceramide and glucose. After the breakdown of the cell membrane, the macrophage is able to degrade the blood cell. A defect on the glycocerebrosidase enzyme prohibits this fatty acid degradation, so that the fatty acid is stored in the lysosome. Without the enzyme, the glucosylceramide cannot be processed anymore. As macrophages are not able to process the fatty acids of the cell membranes, they cannot eliminate the waste products of the blood cells and the glucosylceramid accumulates. The macrophages that are affected by such a accumulation are called Gaucher cells.

Development of a Gaucher cell (source: Children's Gaucher Research Fund)


Wikipedia, Gaucher's disease

Children's Gaucher Research Fund

Inheritance and Incidence

  • The disease befalls both females and males and is inherited in autosomal recessive manner. That means that if both parents carry the defect gene, their child (in each pregnancy) will be affected (i.e. become the disease) with 1:4 chance.
Autosomal recessive inheritance (source: Children's Gaucher Research Fund)
  • According to National Gaucher Foundation (USA) nearly 1 person in 20,000 has Gaucher's disease.
  • About 1 in 100 humans in general population of USA is a carrier of Gaucher's most common type - type I, which gives a prevalence of 1 in 40,000. The carrier rate is much higher among Ashkenazi Jews: around 1 in 15, with birth incidence 1 in 450.
  • Type II Gaucher's disease does not seem to be preferentially represented by a specific ethnic group.
  • Type III Gaucher's disease occurs most frequently in the northern Swedish region of Norrbotten. The incidence is 1 in 50,000 there.


Children's Gaucher Research Fund

Wikipedia, Gaucher's disease

Gene and mutations associated with the disease

  • The cause of Gaucher disease is a recessive mutation in a houskeeping gene lysosomal glucocerebrosidase (beta-glucosidase, glucosylceramidase) on chromosome 1 (1q21), coding for an enzyme.
  • The phenotype depends on the activity of the beta-glucosidase, which is determined by the different mutations.
  • There are about 80 known mutations causing Gaucher's disease, divided into three main groups, according to the Goucher's types they cause:
    • Type I: N370S homozygote (2 copies)
    • Type II: 1-2 copies of L444P
    • Type III: 1-2 copies of L444P possibly delayed by protective polymorphisms
  • Interesting is that heterozygote individuals for certain acid mutations in the enzyme carry approx. a 5-fold risk to develop Parkinson's disease, which is the highest known risk-factor.
  • Moreover, a study in USA showed that among 1525 Gaucher patients the diseases non-Hodgkin lymphoma, melanoma and pancreatic cancer occurred at a 2-3 times higher rate.


Wikipedia, Gaucher's disease

Wikipedia, Glucocerebrosidase

PDB database, structure ID 1OGS

UniProt, entry P04062

KEGG, Enzyme:


Gaucher cells (source:

A diagnosis of Gaucher’s disease is possible. There exist a number of possibilities.

  • Genetic testing (DNA analysis, genotyping) is done by sequencing the beta-glucocerebrosidase gene and checking for the known mutations. This may be done prenatally, if there is a known genetic risk factor for the disease. It is one of the most reliable ways to confirm the diagnosis of the disease as well as to detect if the person is a carrier.
  • Reliable diagnosis is possible today with a simple blood test where the activity of beta-glucocerebrosidase is determined. A very deficient enzyme activity indicates Gaucher's disease. The test is done in special laboratories.
  • Certain nonspecific abnormalities in patients with type 1 Gaucher's disease can also be identified with blood examinations, for example:
    • high levels of glucosylceramide, angiotensin-converting enzyme (ACE), TRAP, ferritin levels, chitotriosidase, alkaline phosphatase and gamma globulins
    • low levels of LDL and HDL cholesterol, B12 and clotting factors
  • Cell analysis can detect "crinkled paper" macrophages (also called Gaucher cells).

Even though reliable diagnostic methods exist, it is difficult to detect Gaucher's disease. Hematologists may not immediately suspect this rare disease, because the patients have symptoms analogous to other diverse diseases (among them Acute lymphocytic leukemia, Acute myelogenous leukemia, Multiple myeloma, Lymphoma and ITP).


Wikipedia, Gaucher's disease


There does not exist a cure for this disease yet. But several different treatments and therapies were developed to treat patients with Gaucher's disease.

Applied treatments

  • Enzyme replacement treatment: To compensate for the missing amount of glucocerebrosidase a biotechnological produced protein is used. This recombinant glucocerebrosidase (imiglucerase), is intravenous applied to the body. It decreases the size of liver and spleen as well as it reduces skeletal abnormalities. The treatment mechanism is comparable with the procedure of an insulin therapie used of diabetes patient.
  • Substrate reduction therapie: The therapie inhibits the development of the substrate glucosylceramide, t.ex. by using miglustat[1]

, to minimize the accumulation of the waste products. Thereby the small amount of glucocerebrosidase suffices to process the substrate.

  • Symptomatic therapie: This therapy eases the symptoms by using organ transplantation/removal, pain medication, blood transfusion or bone marrow transplantation.

The treatments differ in their acting. While the symptomatic therapie is only treats the phenotypes of the disease, the other treatment act into the metabolic pathways and try to avoid the development of the phenotypes of the Gaucher's disease. Which of these two treatments is applied depends on the Gaucher type. The enzyme replacement treatment is mostly used for patient of Gaucher's disease of all types. In some case of Gaucher's disease type I the ERT is not applicable. The substrate reduction therapie is an option for those patients.

Future Treatments

A Gene therapie is still not developed, but scientists are researching to find a treatment to treat the disease on the gene level. The idea behind this is a once applied therapie to fix the defect by mutating the disease causing SNP back to "normal", so that it does not influence the protein product anymore. This futuristic idea raise questions such as technical as well as a ethic and moral ones.


Children's Gaucher Research Fund