|Classification and external resources|
|ICD-10||E75.2 (ILDS E75.220)|
|OMIM||230800 230900 231000|
Gaucher's disease or Gaucher disease (//) is a genetic disease in which fatty substances (sphingolipids) accumulate in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen. It is caused by a hereditary deficiency of the enzyme glucocerebrosidase. This enzyme acts on the glycolipid glucocerebroside. When the enzyme is defective, glucosylceramide accumulates, particularly in white blood cells, most often macrophages (mononuclear leukocytes). Glucosylceramide can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.
Manifestations may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may be painful, severe neurologic complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets, and yellow fatty deposits on the white of the eye (sclera). Persons affected most seriously 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. About one in 100 people in the United States are carriers of the most common type of Gaucher disease. The carrier rate among Ashkenazi Jews is 8.9% while the birth incidence is one in 450.
Gaucher's disease is the most common of the lysosomal storage diseases.:536 It is a form of sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism of sphingolipids.
Gaucher's disease has three common clinical subtypes.
- Type I (or non-neuropathic type) is the most common form of the disease, occurring in about one in 50,000 live births. It occurs most often among persons of Ashkenazi Jewish heritage. Symptoms may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen (together hepatosplenomegaly); the spleen can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia, and leukopenia. The brain is not affected pathologically, but lung and, rarely, kidney impairment may occur. Patients in this group usually bruise easily (due to low levels of platelets) and experience fatigue due to low numbers of red blood cells. Depending on disease onset and severity, type I patients may live well into adulthood. The range and severity of symptoms can vary dramatically between patients.
- Type II (or acute infantile neuropathic Gaucher's disease) typically begins within 6 months of birth and has an incidence rate around one 1 in 100,000 live births. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age two.
- Type III (the chronic neuropathic form) can begin at any time in childhood or even in adulthood, and occurs in about one in 100,000 live births. It is characterized by slowly progressive, but milder neurologic symptoms compared to the acute or type II version. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia, and respiratory problems. Patients often live into their early teen years and adulthood.
These subtypes have come under some criticism for not taking account of the full spectrum of observable symptoms (the phenotypes.) Also, compound heterozygous variations occur which considerably increase the complexity of predicting disease course.
Signs and symptoms
- Painless hepatomegaly and splenomegaly: the size of the spleen can be 1500-3000 ml, as opposed to the normal size of 50-200 ml. Splenomegaly may decrease the affected individual's capacity for eating by exerting pressure on the stomach. While painless, enlargement of spleen increases the risk of splenic rupture.
- Hypersplenism and pancytopenia, the rapid and premature destruction of blood cells, leads to anemia, neutropenia, leukopenia, and thrombocytopenia (with an increased risk of infection and bleeding).
- Cirrhosis of the liver is rare.
- Severe pain associated with joints and bones occurs, frequently presenting in hips and knees.
- Neurological symptoms occur only in some types of Gaucher's (see below):
- Type I: impaired olfaction and cognition
- Type II: serious convulsions, hypertonia, mental retardation, and apnea
- Type III: muscle twitches known as myoclonus, convulsions, dementia, and ocular muscle apraxia
- Parkinson's disease is recognised as being more common in Gaucher's disease patients and their heterozygous carrier relatives.
- Osteoporosis: 75% of patients develop visible bony abnormalities due to the accumulated glucosylceramide. A deformity of the distal femur in the shape of an Erlenmeyer flask is commonly described (aseptic necrosis of the femur joint).
- Yellowish-brown skin pigmentation
The disease is caused by a defect in housekeeping gene for lysosomal glucocerebrosidase (also known as beta-glucosidase, EC 184.108.40.206, PDB 1OGS) on the first chromosome (1q22). The enzyme is a 55.6-kilodalton, 497-amino acid-long protein that catalyses the breakdown of glucosylceramide, a cell membrane constituent of red and white blood cells. The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into 'Gaucher cells', which appear on light microscopy to resemble crumpled-up paper.
Different mutations in the beta-glucosidase gene determine the remaining activity of the enzyme, and, to a large extent, the phenotype.
Heterozygotes for particular acid beta-glucosidase mutations carry about a five-fold risk of developing Parkinson's disease, making this the most common known genetic risk factor for Parkinson's. A study of 1525 Gaucher patients in the United States suggested, while cancer risk is not elevated, particular malignancies (non-Hodgkin lymphoma, melanoma, and pancreatic cancer) occurred at a two- to three-fold higher rate.
The three types of Gaucher's disease are inherited in an autosomal recessive fashion. Both parents must be carriers for a child to be affected. 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, at 100 times the occurrence in the general populace. 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.
The Gaucher-causing mutations may have entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).
Gaucher disease is suggested based on the overall clinical picture. Initial laboratory testing may include enzyme testing. 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
For type-I and most type-III patients, enzyme replacement treatment with intravenous recombinant glucocerebrosidase (imiglucerase) can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. This treatment costs about US$200,000 annually for a single patient and should be continued for life. The rarity of the disease means dose-finding studies have been difficult to conduct, so controversy remains over the optimal dose and dosing frequency. Due to the low incidence, this has become an orphan drug in many countries, meaning a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population. Velaglucerase alfa was approved by the US Food and Drug Administration (FDA) as an alternative treatment in February 2010. In May 2012, the FDA approved an additional treatment – taliglucerase alfa, or Elelyso.
Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte population with active beta-glucosidase. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient’s comfort. Blood transfusion may benefit some anemic patients. Other patients may require joint replacement surgery to improve mobility and quality of life. Other treatment options include antibiotics for infections, antiepileptics for seizures, bisphosphonates for bone lesions, and liver transplants. Substrate reduction therapy may prove to be effective in stopping type II, as it can cross through the blood barrier into the brain. No effective treatment is known for the severe brain damage that may occur in patients with types II and III Gaucher disease. Gene therapy may be a future step.
Gaucher's disease has recently become a target for more than one effort at pharmacological chaperoning, which involves the use of orally administered drugs that operate at a molecular level. Miglustat is one of these oral drugs. It was approved for the treatment of this disease in 2003. As of June 2009[update], another oral drug, isofagomine tartrate, is under development.
The National Gaucher Foundation (United States) states the incidence of Gaucher's disease is about one in 20,000 live births. Around one in 100 people in the general US population is a carrier for type I Gaucher's disease, giving a prevalence of one in 40,000. Among Ashkenazi Jews, the rate of carriers is considerably higher, at roughly one in 15.
Type II Gaucher's disease shows no particular preference for any ethnic group.
The disease was first recognized by the French doctor Philippe Gaucher, who originally described it in 1882 and lent his name to the condition. The biochemical basis for the disease was elucidated in 1965. The first effective treatment for the disease, the drug alglucerase (Ceredase), was approved by the FDA in April 1991. An improved drug, imiglucerase (Cerezyme), was approved by the FDA in May 1994 and has replaced the use of Ceredase.
October marks National Gaucher's Disease Awareness Month in the United States.
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