Gaucher disease (GD) is a genetic disorder in which glucocerebroside (a sphingolipid, also known as glucosylceramide) accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as glucosylceramidase), which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages (mononuclear leukocytes). Glucocerebroside can be collected in the spleen, liver, kidneys, lungs, brain, and bone marrow.
Manifestations may include enlarged spleen and liver, liver malfunction, skeletal disorders or bone lesions that may be painful, severe neurological complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelet count, and yellow fatty deposits on the white of the eye (sclera). Persons seriously affected may also be more susceptible to infection. Some forms of Gaucher’s disease may be treated with enzyme replacement therapy.
The disease is caused by a recessive mutation in a gene located on chromosome 1 and affects both males and females. Gaucher’s disease is the most common of the lysosomal storage diseases. It is a form of sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism of sphingolipids.
The disease is named after the French physician Philippe Gaucher, who originally described it in 1882.
Signs and symptoms of Gaucher’s disease can vary widely. Siblings, even identical twins, with the disease may have different levels of severity. Some people who have Gaucher’s disease have no symptoms at all.
Most people who have Gaucher’s disease experience varying degrees of the following problems:
- Abdominal complaints. Because the liver and especially the spleen can enlarge dramatically, the abdomen can become painfully distended.
- Skeletal abnormalities. Gaucher’s disease can weaken bone, increasing the risk of painful fractures. It can also interfere with the blood supply to your bones, which can cause portions of the bone to die.
- Blood disorders. A decrease in healthy red blood cells (anemia) can result in severe fatigue. Gaucher’s disease also affects the cells responsible for clotting, which can cause easy bruising and nosebleeds.
More rarely, Gaucher’s disease can affect the brain, which may cause abnormal eye movements, muscle rigidity, swallowing difficulties and seizures.
The three types of Gaucher disease are inherited in an autosomal recessive fashion, this means, both parents must be carriers. If both parents are carriers, the chance of the disease is one in four, or 25%, with each pregnancy for an affected child. Genetic counseling and genetic testing are recommended for families who may be carriers of mutations.
Each type has been linked to particular mutations. In all, about 80 known mutations are grouped into three main types:
- Type I (N370S homozygote), the most common, also called the “non-neuropathic” type occurs mainly in Ashkenazi Jews. The median age at diagnosis is 28 years of age, and life expectancy is mildly decreased. There are no neurological symptoms.
- Type II (one or two alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. Prognosis is poor: most die before the age of three.
- Type III (also one or two copies of L444P, possibly delayed by protective polymorphisms) occurs in Swedish patients from the Norrbotten region. This group develops the disease somewhat later, but most die before their 30th birthday.
Genetic counseling is recommended for prospective parents with a family history of Gaucher disease. Testing can determine if parents carry the gene that could pass on the Gaucher disease. A prenatal test can also tell if the fetus has Gaucher syndrome.
Gaucher disease is suggested based on the overall clinical picture. Initial laboratory testing may include enzyme testing. As a result, lower than 15% of mean normal activity is considered to be diagnostic. Decreased enzyme levels will often be confirmed by genetic testing. Numerous different mutations occur; sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available, and is useful when a known genetic risk factor is present.
A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme, and immunoglobulin levels, or by cell analysis showing “crinkled paper” cytoplasm and glycolipid-laden macrophages.
Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher’s disease activity in response to treatment, and may reflect the severity of the disease.
How well a person does depends on the subtype of the disease. The infantile form of Gaucher disease may lead to early death. Most affected children die before age 5. Adults with the type 1 form of the disease can expect normal life expectancy with enzyme replacement therapy.
Gaucher’s disease may increase the risk of:
- Growth delays in children
- Gynecological and obstetric problems
- Parkinson’s disease
- Cancers such as myeloma, leukemia and lymphoma