Gaucher Disease 2012
Contents
Summary
Gaucher Disease (GD) is a genetic disease and is known as the most common prevalent Lysosomal Storage disease (LSD). The french doctor Phillipe Gaucher described it originally in 1882 and this disease is named after him. GD is caused by the recessive mutation in gene GBA located in chromosome 1 which leads to the deficiency of the enzyme glucosylceramidase (glucocerebrosidase). This enzyme is needed to catalyze the breakdown of the fatty substance glucosylceramide - a cell membrane component of the red and white blood cells. The lack of the enzyme therefore leads to the accumulation of glucosylceramide in the cells and organs, mostly in the liver, spleen, bone marrow and nervous system and prevent them from working properly.
GD is found as the most common genetic disease affecting Ashkenazi Jewish people who are originally from Eastern, Central and Northern Europe. Compared with that in the general population(approximately 1 in 50,000 to 1 in 100,000 individuals[1]), the frequency of GD in Ashkenazi Jewish population is quite higher (carrier rate approximately 1 in 15 while the birth incidence is 1 in 900[2]).
Phenotype
ongoing!
Symptoms of GD vary from person to person and also depend on both the type of Gaucher disease, and the degree of enzyme deficiency. Generally speaking, Gaucher disease may cause symptoms like:
- Anemia
- Fatigue
- Easy Bruising and Bleeding
- Nosebleeds
- Osteoporosis
- Bone pain and easily broken bones
- Swollen stomach due to enlarged liver and/or spleen
There are three clinical subtypes of Gaucher disease:
Type 1 (non-neuropathic GD)
It is the most common type. Occurring approximately 1 in 50,000 live births in general population but show very high frequency in Ashkenazi Jewish population . In this type there are no signs of nerve system damage. Symptoms can appear at any age. Many individuals may have a mild form of the disorder and not show any symptoms.
Type 2 (acute infantile neuropathic GD)
It has an incidence rate less than 1 in 100,000 live births. It shows severe nerve system damage and progress very fast. Individuals usually die before 2 years of age.
Type 3 (chronic neuropathic GD)
It is also very rare and is characterized by slowly progressive but milder neurological symptoms compared to type 2. Patients often live into their early teen years and adulthood.
Biochemical disease mechanisms
Gaucher disease (GD) is the most prevalent lipid storage disease. It is caused by mutations in the enzyme glucosylceramidase (glucocerebrosidase) which catalysis the hydrolysis of glucosylceramide to glucose and ceramide in the lysosome.
Glucosylceramide is a ceramide (sphingolipid) with a glucose residue which occurs in the lipid bi-layer of red and white blood cells. Worn out blood cells are digested by macrophages which normally break down glucosylceramide in their lysosomes. In GD patients, however, glucosylceramide accumulates due to the deficiency or lower activity of glucosylceramidase. Consequently, Glucosylceramide is "stored" in the lysosomes impairing the function of macrophages which are referred to as Gaucher cells. These Gaucher cells exhibit lysosomes that are filled with glucosylceramide lipids and aggregate in various parts in the body where they are causing the disease symptomes metioned above. For instance, Gaucher cells that accumulate in the liver or spline can cause metabolic disorders, whereas accumulations in the brain often lead to cognitive disabilities (Type 2, Type 3). GD is related to Fabry disease which are both lipid storage diseases induced by enzymatic dysfunctionalities in the sphingolipid metabolism pathway.
Glycosylceramidase
Glucosylceramidase (EC 3.2.1.45) is a hydrolase which breaks down glucosylceramide to glucose and ceramide (see above):
- Alternative names:
- Beta-glucocerebrosidase
- acid β-glucosidase
- D-glucosyl-N-acylsphingosine glucohydrolase
- Enzymatic classification: Hydrolase
- Location: lysosomal lipid bilayer membrane in humans
- Length: 497 bp
- Weight: 55.6 KD
- Domains:
- Chain A: Glycosyl hydrolase domain; TIM beta/alpha-barrel domain
- Chain B: Glycosyl hydrolase domain; TIM beta/alpha-barrel domain
- Crystal structures: 1OGS 2NT0 3GXI 2V3F 2V3D 2V3E 2NSX 2VT0 3GXM
Cross-references
GBA
The glucosylceramidase gene is named GBA (GBA1, GCB, GLUC) and is located on the q arm of chromosome 1 at position 21 (1q21). It is about 7.6 kb long and contains 11 exons as well as 10 introns which are known to be spliced in different ways resulting in various gene transcripts. The tissue level of GBA mRNA vary among different cell lines. High levels were reported in epithelial and fibroblast cell lines. There is a highly homologous pseudogene (GBAP) located 16 kb downstream with a sequence identity of 96%. It has been shown that recombination events between GBA and GBAP can cause mutations involved in GD.
Cross-references
Mutations
GD is an autosomal recessive disease which requires two mutated alleles for being elicited. Both females and males are affected in the same way.
GD is highly polymorphic: about 250 mutations have been reported from which 203 are missense mutations, 18 nonsense mutations, 36 small insertions or deletions, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations. These mutations were associated with the three types of GD. However, there is only a weak genotype-phenotype relationship since the phenotype depends on mutations of both alleles and many other factors including environmental and infectious exposures as well as different genetic modifiers. Hence, estimating the phenotype and the severity of disease symptoms is in most cases not feasible even though the gene sequence is known.[3]
Diagnosis
ongoing!
To dignose GD, there are mainly two methods
- Enzyme analysis is at the moment the most accurate diagnosis. It measures the level of glucosylceramidase enzyme activity. In people with Gaucher disease, the amount of enzyme activity is much lower than normal. But this testing is not reliable for detecting Gaucher carriers, since some carriers have a enzyme level in the normal range.
- Genetic mutation analysis tries to find genetic mutations which are related to cause Gaucher's disease.
Treatments
ongoing!
Till now there is no confirmed cure for GD. The most treatments have focused on controlling specific symptoms and reducing complications.
- Enzyme replacement therapy was commonly used. This approach replaces the deficient enzyme with artificial enzymes in order to improve the enzyme activity level. This treatment is frequently effective in people with type 1 and, in some cases, type 3. But it is not observed effective for the neurological problems.
- Bone marrow transplantation has been used for severe cases of Gaucher's disease. In this technique, blood-forming cells that have been damaged by Gaucher's disease are removed and replaced, which can reverse many of Gaucher's signs and symptoms. Because this is a high-risk approach, it's performed less than enzyme replacement therapy.
- Substrate reduction therapy Instead of increasing the enzyme activity, in this therapy, orally drugs as inhibitor are used, for example Miglustat, to reduce the substrate (glucosylceramide ) level to better balance the activity of the deficient enzyme.
- Gene therapy Some researchers are currently working on gene therapy. The ideas is introducing normal GBA genes into cells of an affected individual. Ideally, these cells would then produce sufficient amounts of enzyme glucosylceramidase. But the research is still ongoing, much work and time is needed before it may become available.
