Gaucher Disease

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The autosomal recessive disease, Gaucher's disease, caused by a defect protein (glucocerebrosidase) in 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.

Figure 1: Symptoms of type I Gaucher's disease (source


Phenotypic Description of the Disease

There exist three main phenotypic expressions of the Gaucher's disease (in Figure 2). Dependent on the severeness of the disease, different symptoms may occur (Figure 1). Moreover, the age at which the first symptoms appear, is in connection with the degree of illness.

Classification of Types and Symptoms

Figure 2: 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 illness 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 (decreased amount of healthy red blood cells) and can result in thrombocytopenia (faster bruising, because of the low number of blood platelets) as well as nosebleeds
  • pingueculae (yellow spots in the 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 do not 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)


Gene and Protein Causing the Disease

Figure 3: Chromosome 1, band 1q22 (source: Hembase Search)
Figure 4: Structure of lysosomal glucocerebrosidase (source: Wikipedia, Gaucher's disease)
Figure 5: Structure of lysosomal glucocerebrosidase chain A (source: PDB)

The cause of Gaucher's disease is a recessive mutation in a houskeeping gene lysosomal glucocerebrosidase (acid beta-glucosidase, glucosylceramidase) on chromosome 1 (Figure 3), coding for an enzyme.

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

Defect Enzyme in Gaucher's Disease
Gene symbol GBA
Cytogenetic location 1q22
Genomic coordinates 1-155,204,238-155,214,652
Number of exons 11
EC number
  • glucocerebrosidase
  • beta-glucocerebrosidase
  • beta-D-glucocerebrosidase
  • glucosylcerebrosidase
  • acid beta-glucosidase
  • GlcCer-beta-glucosidase
  • ceramide glucosidase
  • glucosylsphingosine beta-glucosidase
  • glucosylsphingosine beta-D-glucosidase
  • glucosylceramidase
  • beta-glucosylceramidase
  • alglucerase
  • imiglucerase
  • psychosine hydrolase
  • glucosphingosine glucosylhydrolase
  • D-glucosyl-N-acylsphingosine glucohydrolase
  • structure: 1OGS
  • molecular weight: 55.6 KD
  • length: 497 amino acids
  • entry: P04062
  • molecular weight: 59.716 KD
  • length: 536 amino acids

Reference Sequence

Sequence of Glucosylceramidase (source: Uniprot):

>sp|P04062|GLCM_HUMAN Glucosylceramidase OS=Homo sapiens GN=GBA PE=1 SV=3


Wikipedia, Gaucher's disease

Wikipedia, Glucocerebrosidase

PDB database, structure ID 1OGS

UniProt, entry P04062

KEGG, Enzyme:

OMIM, entry 606463

Biochemical Disease Mechanism

Figure 6: 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 glucosylceramide accumulates. The macrophages that are affected by such an accumulation are called Gaucher cells (Figure 7).

Figure 7: Development of a Gaucher cell (source: Children's Gaucher Research Fund)


Wikipedia, Gaucher's disease

Children's Gaucher Research Fund

Mutations Associated with the Disease

  • The phenotype may depend on the activity of acid beta-glucosidase, which is determined by the different mutations.
  • According to OMIM, round 200 mutations have been found in patients with all types of the Gaucher's disease. According to Wikipedia, there are about 80 known mutations causing Gaucher's disease. The mutations can be divided into three main groups, according to the prevalence in the Goucher's types.

Gaucher Type I

Gaucher disease type I is caused by homozygous or compound heterozygous mutation in the gene encoding acid beta-glucosidase. Mutations:

  • L444P substitution on a single allele (compound heterozygous with e.g. N370S mutation)
  • N370S substitution, cases among Ashkenazi Jews, homozygous or on a single allele (Zimran et al.(1991) found that among 62 Ashkenazi Jewish patients with type I Gaucher disease, N370S appeared in 73% of the 124 mutant alleles.)

Gaucher Type II


  • L444P substitution, homozygous or on a single allele (Wigderson et al. (1989) reported a case of compound heterozygous with L444P and P415R.)

Gaucher Type III


  • L444P substitution, homozygous (Dahl et al.(1990) showed that the Norrbottnian form of Gaucher's disease is caused by a homozygous L444P mutation and Koprivica et al.(2000) approved that the homozygosity for L444P is associated with type III Gaucher's disease.)
  • Park et al. (2003) studied 16 patients from a rare subgroup (IIIA) of Gaucher's disease type III with progressive myoclonic epilepsy. They detected 14 different genotypes with several shared alleles, including V394L, G377S, and N188S. Some of the shared alleles in these subtype IIIA patients had previously been associated with non-neuronopathic Gaucher disease (type I). According to other studies, these patients lacked the processed 56-kD enzyme isoform which usually indicates neuronopathic disease. The genotypes differed from those found in most type III patients. Nevertheless, Park et al. (2003) concluded that "lack of a specific shared genotype and the variability of clinical presentations indicated a contribution by other genetic and environmental modifiers"[1].
  • Also according to Wikidepia, the L444P mutation, homozygous or on a single allele, is possibly delayed by protective polymorphisms among type III patients.

Cross risk-factors

  • Interesting is that heterozygous 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

OMIM, entry 606463 - GBA

OMIM, entry 230800 - Gaucher type I

OMIM, entry 230900 - Gaucher type II

OMIM, entry 231000 - Gaucher type III

Inheritance and Incidence

Figure 8: Autosomal recessive inheritance (source: Children's Gaucher Research Fund)
  • The disease befalls both females and males. It is inherited in autosomal recessive manner (Figure 8). 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.
  • 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


Figure 9: Gaucher cells (source:

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

  • The first diagnosis of the disease was done by Desnick et al. (1971), who demonstrated that homozygote as well as heterozygote defected alleles could be identified by chemical analysis of the sediment from a 24-hour urine collection. Individual neutral glycosphingolipids were separated by thin-layer chromatography and quantitatively estimated by gas-liquid chromatography, as recorded in OMIM.
  • 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 I 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, Figure 9).

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).


OMIM, entry 230800 - Gaucher type I

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 (ERT): 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 (SRT): The therapie inhibits the development of the substrate glucosylceramide, e.g. by using miglustat[2], 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 or removal, pain medication, blood transfusion or bone marrow transplantation.

The treatments differ in their acting. While the symptomatic therapie only treats the phenotypes of the disease, the other treatments 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 patients of Gaucher's disease of all types. In some cases of Gaucher's disease type I the ERT is not applicable. The substrate reduction therapie is an option for those patients. The ERT and SRT have to be applied regularly for a lifetime.

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


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