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 a accumulation of sphingolipids in cells.

Phenotypic description of the disease

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

Classification of types and symptoms

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. Especially the symptom of brain damage shows a rapid progress. Symptoms, that may occur in type II:

  • symptoms of type I
  • brain problems (mental retardation, dementia)
  • Rigidity
  • Seizures

Type III: chronic neuropathic

The Type III of Gaucher’s disease begins in childhood or adolescence. The disease progress is slower than in type II. But liver and spleen symptoms even more intense. Symptoms, that may occur in type III:

  • Symptoms of type I
  • brain problems (mental retardation, dementia)


Biochemical disease mechanism

  • The enzyme lysosomal glucocerebrosidase (beta-glucosidase, glucosylceramidase)catalyzes the breakdown of a cell membrane constituent of red and white blood cells, called glucosylceramide.
  • Macrophages which eliminate these cells cannot process glucosylceramide of the cell membranes. Therefore, the waste product accumulates in fibrils and turns into so called Gaucher cells (that resemble crumpled-up paper on light microscopy).
  • Type II and III: beta-glucosidase accumulates in the brain because of the turnover of complex lipids during brain development and formation of the myelin envelope of nerve cells.


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.

Gaucher inheritance.gif

  • 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.


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).
  • The defect protein is an enzyme with the following properties:
    • EC number
    • PDB structure 1OGS. The molecular weight of the determined structure is 55.6 KD and length 497 amino acids.
    • UniProt entry P04062. The molecolar weight of the native protein is 59.716 KD and length 536 amino acids.

Acid beta glucosidase.png

  • 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.



Diagnosis of Gaucher’s disease is possible. Two possibilities exist:

  • Blood test: tests the activity of beta-glococerebrosidase.
  • DNA analysis (genotyping): examination of the gene for typical mutations (N370S, L444P).



  • Enzyme replacement treatment: the enzyme, recombinant glucocerebrosidase (imiglucerase), is biotechnological produced and intravenous applied to the body. It decreases the size of liver and spleen. (t1+t3) [wie diabetes]
  • Substrate reduction therapie: inhibits the development of the substrate glucosylceramide, so that the small amount of Glucocerebrosidase suffices to process the substrate.
  • Gene therapie: Still not developed, the idea in this is an once applied therapie in which the Mutation is transformed to the "normal".
  • Symptomatic therapie: This therapy doesn't cure the disease but eases the symptoms by using organ transplantation/removal, pain medication, blood transfusion or bone marrow transplantation.