Gaucher's disease is a genetic condition that affects various different tissues and organs in the body. Several forms of this condition have been identified based on the specific features of the disease and the signs and symptoms vary between affected individuals.
Gaucher's disease is caused by a deficiency in the enzyme beta-glucocerebrosidase. This deficiency leads to the build up of a fatty substance called glucocerebroside in important tissues and organs, particularly the liver and spleen. The organs affected become enlarged and their function is impaired. The build up of glucocerebroside can also occur in the bones, which weakens them and increases the likelihood of fracture. If the disease involves the bone marrow, the ability of the blood to clot may also be affected.
Gaucher's disease is an inherited disorder that occurs most commonly in Ashkenazi Jews. In the general population, Gaucher's disease affects around 1 in 50,000 to 1 in 100,000 people. Among people of Ashkenazi Jewish heritage, the most common form of Gaucher's disease (type 1) affects around 1 in 500 to 1 in 1,000 individuals.
Genetics of Gaucher's disease
Gaucher's disease is caused by mutations in the GBA gene, which codes for the beta-glucocerebrosidase enzyme. This enzyme is responsible for breaking down glucocerebroside into glucose (a sugar molecule) and ceramide (a fat molecule). The GBA mutations either significantly reduce the activity of beta-glucocerebrosidase or eliminate its activity altogether. When this enzyme is absent or reduced, glucocerebroside can accumulate to a level that is toxic to cells, which leads to the features of this disease.
Inheritance of Gaucher's disease
Gaucher's disease is inherited in an autosomal recessive manner, which means a couple's child only develops the condition if one mutated allele for the disorder is passed on from each parent. Usually, a person has two normal copies of the GBA gene. However, when one copy of the gene is abnormal, the person is termed a carrier of Gaucher's disease. Carriers still have one normal GBA gene, which makes sufficient amounts of beta-glucocerebrosidase for their bodily functions to be normal. When two carriers each pass on their abnormal copy of the GBA gene to their offspring, the child develops Gaucher's disease.
Each child of two carrier parents has a one-in-four chance of developing the condition, a one-in-two chance of being a carrier and a one-in-four chance of neither developing the condition or being a carrier.
Genetic testing and diagnosis
Genetic testing and counselling are available for people planning a family who think there is a chance their child may be born with this disease.
Gaucher's disease is diagnosed based on symptoms and clinical testing. The disease is suspected when a patient presents with an enlarged liver or spleen, bone problems, an abnormal red blood cell level, a low platelet count, a tendency to bruise or bleed easily and problems related to the nervous system. A blood test is arranged to check the level of beta-glucocerebrosidase in the blood, which is significantly reduced in affected individuals.
Another form of clinical testing involves DNA analysis to check the GBA gene for the most common types of mutations. Once the specific mutation is identified, further genetic testing of family members can be performed to identify carriers.
Researchers have identified numerous mutations that have been associated with Gaucher's disease and nearly 80 known mutations are now linked to this disease. The mutations are grouped into three main types, as follows:
Type I (N370S homozygote)
These mutations leads to the most common form of Gaucher's disease. The condition does not affect the brain and is also referred to as non-neuropathic Gaucher's disease. This illness is common among Ashkenazi Jews and the median age-at-diagnosis is 28 years.
Type II (1 or 2 alleles L444P)
Here, the mutations lead to the most severe form of Gaucher's disease, which affects infants and most of whom do not reach three years of age.
Type III (also 1 or 2 copies of L444P)
This condition occurs in Swedish individuals from the Norrbotten region. Affected individuals usually die before the age of 30.