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Gaucher Disease

Gaucher Disease

Definition

Gaucher disease is a rare genetic disorder that results in accumulation of fatty molecules called cerebrosides. It can have serious effects on numerous body organs including the liver, spleen, bones and central nervous system. Treatments based on molecular biology are becoming available, but are very expensive.

Description

Gaucher disease was first described by the French physician Philippe Gaucher in 1882. It is the most common of a class of diseases called lysosomal storage diseases, each of which is characterized by the accumulation of a specific chemical substance (a different substance depending on the exact disease). Gaucher disease is characterized by a wide array of different symptoms and the severity of the disease ranges from undetectable to lethal.

Three forms of the disease are recognized: Types I, II and III. Type I is by far the most common and shows the mildest symptoms. It is non-neuronopathic, meaning that the nervous system is not attacked. The onset of Type I can occur at any age in childhood or adult life with the average age of onset at about 21 years. Some affected individuals are have no symptoms throughout adult life. Type II, the infantile form, accounts for less than 1% of patients with Gaucher disease. It is neuronopathic (attacks the nervous system); nervous system effects are severe, and victims often die within the first year of life. Type III most often has its onset during childhood and has some of the features of both the adult and infantile forms. This affects less than 5% of persons with Gaucher disease.

Gaucher disease is caused by the absence, or near absence, of activity of an enzyme called glucocerebrosidase (GC). The normal action of GC is to break down a common molecule called glucocerebroside. If not broken down, glucocerebroside accumulates in certain cells to levels that can cause damage, especially in the spleen, liver, and bone. The common link among these organs is that they house a cell type called a macrophage. A macrophage is a large cell that surrounds and consumes a foreign substance (such as bacteria) in the body. The cellular structures in which glucocerebroside accumulates are called lysosomes.

The three forms of Gaucher disease also differ in their population genetics. Type I is most common in persons of eastern European (Ashkenazi) Jewish descent. Among this population, the disease occurs at a rate of one in 450 live births and about one in 10 to 15 persons are carriers, making it the most common genetic disease affecting Jewish people. The other two types are equally frequent in all ethnic groups. Type II occurs at a rate of one in 100,000 live births, while Type III is estimated to occur in one in 50,000 live births.

Causes and symptoms

Lack of the GC enzyme is caused by a mutation in the glucocerebrosidase gene. The gene is located on chromosome 1. As of 2000, there have been over 100 mutations described in this gene that causes Gaucher disease. Gaucher disease is inherited in an autosomal recessive pattern. This means that two defective gene copies must be inherited, one from each parent, for the disease to manifest itself. Persons with only one gene mutation are carriers for the disorder. A person who is a carrier for Gaucher disease does not have any symptoms and does not know he or she is a carrier unless he or she has had specific testing. When both parents are carriers for Gaucher disease, there is a one in four chance (25%) in each pregnancy for a child to have Gaucher disease. There is a two in three chance that a healthy sibling of an affected child is a carrier.

The results of Gaucher disease are widespread in the body and include excessive growth of the liver and spleen (hepatosplenomegaly), weakening of bones, and, in acute cases, severe nervous system damage. Many patients experience "bone crises," which are episodes of extreme pain in their bones.

There is a wide array of other problems that occur with Gaucher disease, such as anemia (fewer than normal red blood cells). Just how these other symptoms are caused is not known. Nor is it known why some patients have very mild disease and others have much more significant problems. Even identical twins with the disease can have differing symptoms.

Diagnosis

Diagnosis of Gaucher disease, based initially on the symptoms described above, can be confirmed by microscopic, enzymatic, and molecular tests. Biopsy (surgical removal of tissue from a problem area) of tissue is helpful for microscopic diagnosis. When biopsy tissue is examined under the microscope, cells will appear swollen and will show characteristic features of the cytoplasm (part of the cell body along with the nucleus) and nucleus. Enzyme tests will show deficiency (<30% of normal levels) of the enzyme GC. Molecular analysis of DNA samples looking at four of the more common mutations will show defects in the gene for GC in 95% of Ashkenazi Jewish individuals and in 75% of non-Jewish people. Diagnosis can be performed prenatally (before birth) if the parents' mutations are known using amniocentesis or chorionic villus sampling.

Diagnosis as to which of the three types of Gaucher disease an individual has is based on the symptoms, rather than on test results.

Treatment

Until the 1990s, only supportive therapy could be offered. Analgesics are used to control pain. Orthopedic treatment is used for bone fractures. In some cases, surgical removal of the spleen may be necessary. Several treatments for anemia have been used, including vitamin and iron supplements, blood transfusions, and bone marrow transplants.

The newest form of treatment for Gaucher disease is enzyme replacement therapy, in which GC can be administered intravenously. The enzyme can be prepared either by purification from placentas (alglucerase) or by recombinant DNA manufacturing techniques (imiglucerase). Either way, the cost of treatment ranges from $100,000 to $400,000 per year, which can prevent many from obtaining treatment.

Enzyme replacement is effective at reducing most Gaucher symptoms. The notable exception is neurologic damage in Type II disease, which remains unimproved by this treatment. This treatment is not recommended for individuals who are asymptomatic. As of 2000, the efficacy for the treatment of Type III Gaucher disease is not known. Many questions remain about enzyme replacement therapy in regard to dosage, and method and frequency of administration. The treatment program should be individualized for each patient.

Prognosis

A patient's expected lifespan varies greatly with the type of Gaucher disease. Infants with Type II disease have a life span of one to four years. Patients with Types I and III of the disease have highly variable outcomes with some patients dying in childhood and others living full lives. Little is known about the reasons for this variability.

Prevention

Genetic counseling is advised for individuals with Gaucher disease and for their relatives to accurately assess risk and discuss testing options. For couples who previously had a child with Gaucher or in situations where both parents are carriers for known Gaucher mutations, prenatal diagnosis is available to determine whether a pregnancy is affected. Families in which a person has been diagnosed with Gaucher disease can have DNA testing, which enables other relatives to determine their carrier status. Prospective parents can then use that information to conduct family planning or to prepare for a child who may have special circumstances.

Families in which both parents are known to be a carrier of a mutation for Gaucher disease could consider preimplantation genetic diagnosis. This relatively new procedure can select an embryo without both Gaucher disease mutations prior to implantation of the embryo into the uterus. This technique is only available at selected genetics centers.

As of the early 2000s, population screening for Gaucher disease is not standard of care.

KEY TERMS

Cerebrosides Fatty carbohydrates that occur in the brain and nervous system.

Enzymatic replacement therapy A treatment method used to replace missing enzymes. It is possible to synthesize enzymes and then inject them intravenously into patients.

Glucocerebroside A cerebroside that contains glucose in the molecule.

Resources

PERIODICALS

Beutler, E. "Gaucher Disease." Archives of Internal Medicine 159 (1999): 881-2.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. http://www.geneticalliance.org.

Children's Gaucher Research Fund. PO Box 2123, Granite Bay, CA 95746-2123. (916) 797-3700. Fax: (916) 797-3707. http://www.childrensgaucher.org.

National Gaucher Foundation. 11140 Rockville Pike, Suite 350, Rockville, MD 20852-3106. (800) 925-8885. http://www.gaucherdisease.org.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www.rarediseases.org.

OTHER

"Cerezyme." Genzyme Therapeutics. http://www.cerezyme.com.

"Gaucher Disease: Current Issues in Diagnosis and Treatment." http://text.nlm.nih.gov/nih/ta/www/16.html.

"Living with Gaucher Disease: A Guide for Patients, Parents, Relatives, and Friends." http://neurowww3.mgh.harvard.edu/gaucher/living.html.

National Foundation for Jewish Genetic Diseases (NFJGD). http://www.nfjgd.org/.

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Gaucher Disease

Gaucher disease

Definition

Gaucher disease is a rare, inherited disorder in which a deficient or missing enzyme causes an abnormal buildup of a fatty substance called glucosylceramide throughout the body. Abnormal accumulations of this substance are toxic to organs and tissues, resulting in progressive, permanent damage.

Description

Gaucher disease belongs to a group of conditions called lipid storage diseases. Lipids are fatty substances used throughout the body. In lipid storage diseases, enzymes that would ordinarily break down lipids so that they can be appropriately used are absent. This results in the progressive accumulation of large quantities of these lipids.

In Gaucher disease, the specific type of lipid that accumulates is called a glucosylceramide. Deficient activity of an enzyme called beta-glucosidase results in glucosylceramide accumulation throughout the body and damage to normal tissues and organs.

There are three types of Gaucher disease. Type 1 is the most common. Each type has a characteristic age of onset and constellation of symptoms.

Demographics

In the general population, one in 50,000100,000 develop Gaucher disease. However, Gaucher type 1 disease is considerably more common among Jewish people from eastern and central Europe (Ashkenazi Jews), affecting one in 5001,000 individuals.

Causes and symptoms

Gaucher disease is an inherited disease, caused by a defective GBA gene. The disease is recessive, meaning that a child has to inherit a defective gene from both the mother and the father in order to have the actual condition.

Type 1 affects both children and adults. Its major manifestations include easy bruising, anemia, fatigue ,

liver and/or spleen enlargement, bone and joint pain , joint problems, and increased risk of bone fractures.

Type 2 usually begins to show symptoms during infancy. This type causes many of the same symptoms seen in type 1 (easy bruising, anemia, liver and/or spleen enlargement), but it also results in severe and progressive neurological problems. Damage to the central nervous system results in seizures , difficulty walking, paralyzed eye muscles, and progressive dementia . Most patients with type 2 disease die by about age two.

Type 3 causes the same kinds of symptoms seen in type 2, but the neurological involvement is more mild and the progression is more gradual.

Diagnosis

Diagnosis of Gaucher disease can be made by performing a bone marrow examination, and identifying specific "Gaucher cells" within the specimen. Other cells can be examined to demonstrate decreased activity of the enzyme beta-glucosidase. DNA testing can also reveal the specific mutation responsible for the disease, particularly within Ashkenazi Jewish populations.

Treatment team

The treatment team may vary, depending on the patient's specific symptoms. Early in the diagnostic phase, a geneticist may be helpful. If neurological problems predominate, a neurologist will be necessary. A hematologist may be consulted to handle the blood-related complications such as anemia. Other specialists may include an ophthalmologist, orthopedic surgeon, physical and occupational therapists, and speech and language therapist.

Treatment

Symptomatic treatment may include blood transfusions to treat anemia, removal of the enlarged spleen, and joint replacement. Some patients have been cured via bone marrow transplant, but this procedure carries a very high risk of complications and death, and requires a carefully matched donor, which can be difficult to find.

Newer treatments include enzyme replacement therapy. While not curative, intravenous enzyme replacement can decrease the severity of, or reverse, many of the complications of type 1 disease, including liver/spleen enlargement, anemia, neurologic problems, and bone abnormalities. Severe brain damage cannot be reversed, however.

Clinical trials

A variety of clinical trials on Gaucher disease are being conducted, including testing of a medicine called OGT918 that may slow or decrease the accumulation of lipids, hopefully with improved neurological outcomes. Other clinical trials are evaluating the outcome of treatment with enzyme replacement therapy in Gaucher disease types 2 and 3, the effect of alendronate sodium on bone disease in Gaucher disease, and the short- and longer-term outcome of bone marrow or umbilical cord blood transplantation in children with Gaucher disease.

Prognosis

The prognosis of Gaucher disease depends on the specific type. Because type 1 has no neurologic manifestations, it has the best prognosis. Lifespan depends on the severity of the complications, but some patients live into the 70s or 80s. Type 2 is universally fatal, generally by about age two. Patients with type 3 generally survive until about age 20 or 30.

Special concerns

Carriers of the defective gene may be identified during genetic counseling, and prenatal diagnosis is also possible.

Resources

BOOKS

"Nutritional Disorders of the Neuromuscular Transmission and of Motor Neurons." In Nelson Textbook of Pediatrics, edited by Richard E. Behrman, et al. Philadelphia: W. B. Saunders Company, 2004.

Maertens, Paul, and Paul Richard Dyken. "Storage Diseases: Neuronal Ceroid-Lipofuscinoses, Lipidoses, Glycogenoses, and Leukodystrophies." In Textbook of Clinical Neurology, edited by Christopher G. Goetz. Philadelphia: W. B. Saunders Company, 2003.

McGovern, Margaret M., and Robert J. Desnick. "Lysosomal Storage Diseases." In Textbook of Clinical Neurology, edited by Christopher G. Goetz. Philadelphia: W. B. Saunders Company, 2003.

WEBSITES

Genetics Home Reference. National Library of Medicine, National Institutes of Health. (April 27, 2004). http://ghr.nlm.nih.gov/ghr/page/Home;jsessionid=52A6DA98F1237CEFE8E49B215F316502.

National Institute of Neurological Disorders and Stroke (NINDS). (April 27, 2004). Gaucher Disease Fact Sheet. <http://www.ninds.nih.gov>.

ORGANIZATIONS

Center for Jewish Diseases, Department of Human Genetics, Mount Sinai Medical Center. Fifth Avenue at 100th Street, New York, NY 10029. (212) 659-6774 or (212) 241-6947. <http://www.mssm.edu/jewish_genetics/overview.shtml>.

Children's Gaucher Research Fund. PO Box 2123, Granite Bay, CA 95746. (916) 797-3700; Fax: (916) 797-3707. research@childrensgaucher.org. <http://www.childrensgaucher.org>.

National Gaucher Foundation. 5410 Edson Lane, Suite 260, Rockville, MD 20852-3130. (301) 816-1515 or 800-GAUCHER (428-2437); Fax: (301) 816-1516. ngf@gaucherdisease.org. <http://www.gaucherdisease.org>.

Rosalyn Carson-Dewitt, MD

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Gaucher's disease

Gaucher's disease (gōshāz´), rare genetic disease involving a deficiency of an enzyme, glucocerebrosidase, which normally breaks down certain body glycolipids (i.e., lipids (fats) that have a sugar molecule attached). There are three types of the disease. In all three types, the enzyme deficiency results in a buildup of the glycolipid glucocerebroside in the bone marrow, liver, and spleen, resulting in anemia and other blood disorders, bone pain and pathologic fractures, and enlarged liver and spleen. In Type II, the central nervous system is also affected. Patients are severely mentally retarded and have difficulty controlling their muscles. The disease progresses quickly from birth and usually is fatal by the age of two. In Type III disease, the course is chronic and central nervous system involvement begins later on. The symptoms are the same as those of Type II. Type I disease occurs most often in Ashkenazi Jews of Eastern European origin, Type III in people of Swedish origin.

There is no cure for Gaucher's disease, but in 1991 an enzyme replacement drug, Ceridase, was approved and allowed people with Type I disease (the most common) to live nearly normal lives. Ceridase was extracted from human placental tissue in very small amounts and the supply was limited. In 1994, a genetically engineered version of the drug (Cerezyme) was introduced. Both were developed as orphan drugs and were controversial because of their costliness.

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Gaucher's disease

Gaucher's disease (goh-shayz) n. a genetically determined disease, inherited as a recessive condition, resulting from the deposition of fatty compounds in the brain and other tissues (especially bone). It results in mental retardation, abnormal limb posture and spasticity, and difficulty with swallowing. [ P. C. E. Gaucher (1854–1918), French physician]

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