Gaucher disease (GD) is the most common lysosomal storage disorder. Lysosomes are like the garbage disposal of our cells, and when components of this system are impaired, it leads to the accumulation of waste products in the lysosomes of cells in particular organs. GD can be categorized into 3 main sub-types based on the presence or absence of neurological symptoms: GD1 (non-neuronopathic), GD2 (acute neuronopathic), and GD3 (subacute or chronic neuronopathic). GD1 is the most common sub-type, representing 94% of cases and will be the focus of this page. The prevalence of GD1 is approximately 1-2 per 100,000 in the general population , whereas the prevalence of both GD2 and GD3 is approximately 1 in 100,000-300,000.
What does Gaucher disease look like?
Common symptoms for GD1 include:
- bone disease
- severe bone pain
- weakened bones that are susceptible to fracture
- bone deformities including Erlenmeyer flask deformity
- enlarged liver and spleen (hepatosplenomegaly)
- issues in the blood
- low red blood cells (anemia)
- low platelets (thrombocytopenia)
- low white blood cells (leukopenia)
Importantly, GD1 patients do not typically experience the neurologic symptoms associated with GD2 and GD3, including abnormal eye movements and seizures.
What causes Gaucher disease?
GD is a genetic disease that is caused by mutations in the GBA gene. GBA is an enzyme that is responsible for breaking down a cellular product called glucocerebroside. When the GBA enzyme does not function properly, glucocerebroside accumulates in white blood cells in the bone marrow, liver and spleen, causing the symptoms mentioned above.
GD is inherited in an autosomal recessive fashion. Everyone has two copies of the GBA gene. One copy inherited from their mother, and one copy from their father. When one copy is functional, and the other is not, that person is described as a carrier. They do not show symptoms of GD, but if they have children with another carrier, there is a 25% chance that their child will develop GD. When a child inherits both non-functional copies of the GBA gene from his/her parents, they will have GD.
How is Gaucher disease diagnosed?
When the symptoms above are seen in a person, there may be a suspicion of GD. However, further testing is required to establish a diagnosis. Laboratory testing on a blood sample measures the levels of the GBA enzyme. Patients with GD have 0-15% enzyme levels compared to people without the disease. In addition, the genetic code of the GBA enzyme may be analyzed for any changes that render it non-functional. If a gene change is found in the GBA gene that explains the person’s symptoms, then testing can be done on family members to try to predict whether they may also develop the disease or be unaffected but pass the condition on to their children (carriers).
How is Gaucher disease managed and treated?
Currently there is no cure for GD. Existing treatments aim to reduce the severity of symptoms. However, some experimental treatments including gene therapy for a different lysosomal storage disorder have showed some efficacy in mice and is currently being tested in humans.
Before an individual treatment plan is developed, it is important that an individual is assessed for his/her disease severity, as symptoms vary between individuals and even between family members. Some factors that are important to investigate during the assessment include:
- age of onset of symptoms
- size of liver, spleen
- presence or absence of neurological symptoms
- in children experiencing growth delay, skeletal assessment by x-ray
- Enzyme replacement therapy (ERT) remains the treatment of choice for preventing the development of symptoms of GD. ERT involves the delivery of the GBA enzyme directly into the vein. This is done in the doctor's office. The dose and how often it is administered depends on an individual's symptom severity, weight, and how they respond to the treatment.
- Substrate reduction therapy (SRT) is a second-line treatment option available for GD patients that do not respond to ERT. SRT works by reducing the amount of glucocerebroside in cells (the substrate of the GBA enzyme). With less glucocerebroside present, the remaining GBA enzyme is able to clear it from cells before it accumulates. SRT is taken as an oral medication.
If an individual is experiencing severe symptoms before the initiation of ERT or SRT, it is usually recommended that he/she gets those particular symptoms first. Examples of pre-ERT/SRT treatments include:
- partial or total removal of the spleen if experiencing severe enlargement (splenomegaly)
- blood transfusions for severe anemia
- medications or surgery for bone pain/fractures
A diagnosis of GD has implications for other family members and family planning. Therefore, it is important to speak with a genetic counsellor who can help you make decisions about further testing.
Mentioned above, GD is inherited in an autosomal recessive fashion, meaning that if a couple has a child with GD, it is almost always the case that they are both unaffected carriers. This means that they both have a gene change in one copy the GBA gene, and the other copy is functional. At conception, siblings of a person with GD have a 25% chance of also being affected with GD, 50% chance that they are carriers like their parents, and a 25% chance of being unaffected and non-carriers. After birth, if it is determined that the sibling is unaffected, then there is a 2/3 chance that he/she is a carrier. If a person with GD has children, then all of his/her children will be carriers.
Once the gene changes that cause GD are determined in an affected individual, other family members can undergo molecular genetic testing to see whether they also carry one or both of those changes. Carrier couples may also choose to test a pregnancy (prenatal diagnosis) for these gene changes or test embryos (preimplantation genetic diagnosis) prior to in-vitro fertilization, to prevent having a child with GD.
National Gaucher Foundation of Canada
National Gaucher Foundation (US)
National Society of Genetic Counselors - Find a Genetic Counselor (US)
Canadian Association of Genetic Counselors - Find a Clinic
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