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NORD is very grateful to Roscoe O. Brady, MD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, for assistance in the preparation of this report.
Gaucher disease is a rare, inherited metabolic disorder in which deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful quantities of certain fats (lipids), specifically the glycolipid glucocerebroside, throughout the body especially within the bone marrow, spleen and liver. The symptoms and physical findings associated with Gaucher disease vary greatly from patient to patient. Some individuals develop few or no symptoms (asymptomatic); others may have serious complications. Common manifestations of Gaucher disease include an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of circulating red blood cells (anemia), low levels of platelets(thrombocytopenia), and skeletal abnormalities. Platelets are blood cells that promote clotting and patients with thrombocytopenia may develop bleeding problems. Three separate forms of Gaucher disease have been identified and are distinguished by the absence of, or the presence and extent of, neurological complications. All three forms of Gaucher disease are inherited as autosomal recessive traits.
Gaucher disease is categorized as a lysosomal storage disorder (LSD). Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or "digest" nutrients, including certain complex carbohydrates and fats. In Gaucher disease certain sugar (glucose) containing fat, known as glycolipids, abnormally accumulate in the body because of the lack of the enzyme, glucocerebrosidase. This accumulation or "storage" of lipids leads to the various symptoms or physical findings associated with a lysosomal storage disease. Gaucher disease is the second most common type of lysosomal storage disorder. (Recent publications indicate that Fabry disease is the most prevalent LSD)
Researchers have identified three distinct forms of Gaucher disease separated by the absence (Type 1) or presence and extent (Type 2 or Type 3) of neurological complications. The majority of affected individuals have Gaucher disease type 1, which lacks overt neurological complications. The specific symptoms present in individuals with Gaucher disease vary greatly from case to case. Some individuals exhibit few or no symptoms (asymptomatic); others experience chronic, and sometimes severe, complications.
Most individuals with Gaucher disease type 1 experience easy bruising due to low levels of blood clotting cells known as platelets (thrombocytopenia), chronic fatigue due to low levels of circulating red blood cells (anemia), and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). Affected individuals may also experience lack of blood supply (infarction) to various bones of the body resulting in dull or intense bone pain (bone crises), degeneration (avascular necrosis) and deformity of affected bones, and thinning and weakening of bones (osteoporosis). Such skeletal abnormalities result in an increased susceptibility to fractures. In rare cases, affected individuals may also experience involvement of the lungs and/or kidneys.
Gaucher disease type 2, also known as acute neuronopathic Gaucher disease, occurs in newborns and infants and is characterized by neurological complications due to the abnormal accumulation of glucocerebroside in the brain. Enlargement of the spleen (splenomegaly) is often the first symptom and may become apparent before six months of age. Enlargement of the liver (hepatomegaly) is not always present. Affected infants may lose previously acquired motor skills and exhibit low muscle tone (hypotonia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the arms and legs, and crossed eyes (strabismus). In addition, affected infants may experience difficulty swallowing (dysphagia), which may result in feeding difficulties; abnormal positioning or bending of the neck (retroflexion); and failure to gain weight and grow at the expected rate (failure to thrive) and high-pitched breathing (stridor) due to contraction of the muscles of the voice box (laryngeal spasm). Anemia and thrombocytopenia may also occur. Gaucher disease type 2 often progresses to life-threatening complications such as respiratory distress or the entrance of food into the respiratory passages (aspiration pneumonia). Severely affected newborns may show skin abnormalities (collodion skin or ichthvosiform changes) and generalized swelling (hydrops), with death in the first few weeks of life. Other children with Gaucher disease type 2 have greatly reduced lifespans, with death usually occurring between 1 and 3 years of life.
Gaucher disease type 3, also known as chronic neuronopathic Gaucher disease, occurs during the first decade of life. In addition to the blood and bone abnormalities discussed above, affected individuals develop neurological complications that develop and progress slower than in Gaucher disease type 2. Associated neurological complications include mental deterioration; an inability to coordinate voluntary movements (ataxia); and brief, shock-like muscle spasms of the arms, legs or entire body (myoclonic seizures). Some individuals with Gaucher disease type 3 may have difficulty moving their eyes side-to-side (horizontal gaze palsy). Patients with Type 3 Gaucher disease can also have a vertical gaze palsy that usually occurs later than the horizontal gaze paresis. A significant proportion of patients also develop pulmonary (lung) disease (interstitial lung disease). There can be wide variability in presentation and clinical course among patients with type 3 Gaucher disease. Some affected patients may live into their teens and early 20's, while others have lived for much longer (30's and 40's). With increasing difficulties, affected individuals may require assistance to fulfill the task of daily living (for example, with eating, bathing, and ambulation).
All three forms of Gaucher disease are inherited as autosomal recessive traits. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In recessive disorders, the condition does not occur unless an individual inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
Investigators have determined that Gaucher disease may be caused by disruption or changes (mutations) of the gene that controls the production of the enzyme glucocerebrosidase. It is thought that different mutations in this gene are associated with the different types of Gaucher disease. The gene is located on the long arm of chromosome 1 (1q21). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. For example, "chromosome 1q21" refers to band 21 on the long arm of chromosome 1.
All forms of Gaucher disease affect males and females in equal numbers. Gaucher disease type 1 is the most common type, accounting for more than 90 percent of cases. Individuals with Gaucher disease type 1 usually exhibit symptoms during adolescence, but the age of onset ranges from childhood to adulthood. The age of onset for Gaucher disease type 2 is during early infancy. The age of onset of Gaucher disease type 3 varies, but the disorder generally begins during childhood or adolescence.
There are approximately 6,000 individuals with Gaucher disease in the United States. Gaucher disease is the most common genetic disorder of persons of Ashkenazic Jewish ancestry, where the incidence may be as high as 1 in 450 births. There is no ethnic prevalence associated with Gaucher disease types 2 or 3. However, there is a subtype of Gaucher disease type 3 that occurs with greater frequency in the Norrbotten region of Sweden (Norrbottnian Gaucher disease). The estimated prevalence in the Swedish Norrbotten population is 1 in 50,000.
Symptoms of the following disorders can be similar to those of Gaucher disease. Comparisons may be useful for a differential diagnosis:
Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found in all tissues, especially in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of an inability to mobilize cholesterol, which results in excessive amounts of cholesterol accumulating in various organs of the body. Symptoms common to all types of Niemann-Pick disease include yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). The different types of Niemann-Pick disease are inherited as autosomal recessive traits. (For more information on this disorder, choose "Niemann Pick" as your search term in the Rare Disease Database.)
Pompe disease is a glycogen storage disease. This inherited metabolic disorder is caused by an inborn lack of the enzyme alpha-1,4 glucosidase (lysosomal glucosidase; acid maltase), which is necessary to break down glycogen, a substance that is a source of energy for the body. This enzyme deficiency causes excess amounts of glycogen to accumulate in the lysosomes, which are structures within cells that break down waste products within the cell. The symptoms and physical findings of Pompe disease result from the abnormal accumulation of glycogen in the cells. Three separate forms of Pompe disease have been identified. The infantile form is characterized by severe muscle weakness and abnormally diminished muscle tone (hypotonia) without muscle wasting, and usually manifests within the first few months of life. Additional abnormalities may include enlargement of the heart (cardiomegaly), the liver (hepatomegaly), and/or the tongue (macroglossia). Progressive cardiac failure usually causes life-threatening complications by the age of 12 to 18 months. The childhood form usually begins during late infancy or early childhood. The extent of organ involvement may vary among affected individuals; however, skeletal muscle weakness is usually present with minimal cardiac involvement. In the adult form of Pompe disease, symptoms include muscle weakness such as that found in other chronic muscle disorders. Onset of symptoms usually occurs in the second to fourth decade. This form of the disorder is slowly progressive without cardiac involvement. (For more information on this disorder, choose "Pompe" as your search term in the Rare Disease Database.)
Hurler syndrome (MPS I) is one of a group of disorders known as the mucopolysaccharidoses (MPS Disorders), which are rare genetic disorders caused by the deficiency of one of ten specific lysosomal enzymes, resulting in an inability to breakdown complex carbohydrates (mucopolysaccharides) into simpler molecules. The accumulation of these large, undegraded mucopolysaccharides (also known as glycosaminoglycans) in the cells of the body causes a number of physical symptoms and abnormalities. There are three forms of Hurler Syndrome with varying severity. Infants with Hurler Syndrome usually appear normal at birth, but may have inguinal and umbilical hernias, clouding of the cornea, enlarged liver and spleen, a large tongue, skeletal abnormalities, poor growth, and joint stiffness. Hurler Syndrome is caused by a deficiency of the enzyme alpha-L-iduronidase. (For more information on this disorder, choose "Hurler" as your search term in the Rare Disease Database.)
Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain. This abnormal accumulation of gangliosides leads to progressive destruction of cells in the central nervous system. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes, gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). The classical form of Tay-Sachs disease occurs during infancy and may resemble some cases of Gaucher disease type II. (For more information on this disorder, choose "Tay-Sachs" as your search term in the Rare Disease Database.)
A diagnosis of Gaucher disease should be considered in individuals with unexplained anemia and easy bruising, particularly if they have enlargement of the spleen and liver and fractures. The diagnosis of Gaucher disease may be confirmed by a thorough clinical evaluation and a variety of specialized tests, particularly tests (i.e., enzyme assay) that measure acid beta-glucosidase activity in white blood cells (leukocytes) or skin cells (fibroblasts) and genetic (DNA) analysis for the causal gene defects (mutations).
Prenatal diagnosis of Gaucher disease is possible through amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the fetus (amniotic fluid) is removed and analyzed, whereas CVS involves the removal of tissue samples from a portion of the placenta. Researchers then study these fetal cells for reduced beta-glucosidase activity that is characteristic of Gaucher disease.
Enzyme replacement therapy (ERT) has proven effective for individuals with Gaucher disease type 1. In studies of ERT, anemia and low platelet counts have improved, enlargement of the liver and spleen have been greatly reduced, and skeletal findings have improved. These systemic manifestations also improve in individuals with Gaucher disease types 2 and 3 who receive ERT. However, ERT has not been effective in reducing or reversing certain neurological symptoms associated with Gaucher disease types 2 and 3.
The orphan drug alglucerase injection (Ceredase), which is a placenta-derived enzyme, was approved by the Food and Drug Administration (FDA) in April 1991 for the treatment of Gaucher disease type 1. It was the first ERT proven effective for the treatment of Gaucher disease type 1.
The synthetic form of this drug, imiglucerase (Cerezyme), was approved in 1994. Recombinant DNA technology, or genetic engineering, is used to produce Cerezyme. This was an important step in overcoming limitations of the availability of Ceredase, which is derived from human placentas. Cerezyme is manufactured by the Genzyme Corporation of Cambridge, Mass. It replaces the human lysosomal enzyme glucocerebrosidase that individuals with Gaucher lack.
For more information on Cerezyme, contact:
500 Kendall Street
Cambridge, MA 02142
Another FDA approved preparation of glucocerebrosidase called Velaglucerase alfa (trade name VPRIV) produced in a continuous human cell line is available from Shire.
300 Shire Way
Kexington MA 02421
Elelyso (also known as Uplyso or taliglucerase alfa) by Pfizer Inc., under license from Protalix BioTherapeutics Inc., was approved by the FDA in 2012 as a treatment for Gaucher disease type 1. Elelyso is an injected long-term enzyme replacement therapy that should be administered by a health care professional every other week. It uses genetically engineered carrot cells to replace glucocerebrosidase,
Patients can call Pfizer at 1-855-ELELYSO (1-855-353-5976) for a free patient information kit about Elelyso or visit http://www.elelyso.com/gps.aspx .
In 2003, the U.S. Food and Drug Administration approved Zavesca, an oral therapy, for the treatment of adult patients with mild to moderate Gaucher disease type 1 for whom enzyme replacement therapy is not a treatment option (as a result of allergy, hypersensitivity, etc.).
For information on Zavesca, contact:
Actelion Pharmaceuticals US, Inc.
5000 Shoreline Court, Suite 200
South San Francisco, CA 94080
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
IInformation on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
In 2006, the FDA granted orphan drug status for the experimental oral therapy AT2101 (isofagomine (IFG) tartrate) manufactured by Amicus Therapeutics. Visit www.amicustherapeutics.com for additional information.
Bone marrow transplantation has been used as a treatment for Gaucher disease type 1. However, bone marrow transplantation is not recommended for individuals with relatively advanced neurological symptoms. Bone marrow transplantation requires a matched donor, and has a high mortality and morbidity rate. With the advent of enzyme replacement therapy, bone marrow transplantation has rarely been performed in the United States.
Contact for additional information about Gaucher disease:
Roscoe O. Brady, M.D.
Building 10 Room 3D03
National Institutes of Health
Bethesda, MD 20892-1260
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Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Gaucher Disease, Type I. Entry No: 230800. Last Updated 03/28/2013. Available at: http://omim.org/entry/230800 Accessed Feb 24, 2014.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Gaucher Disease, Type II. Entry No: 230900. Last updated 02/20/2014.Available at: http://omim.org/entry/230900 Accessed Feb 24, 2014.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Gaucher Disease, Type III. Entry No: 231000. Last Updated 03/23/2012. Available at: http://omim.org/entry/231000 Accessed Feb 24, 2014.
National Institute of Neurological Disorders and Stroke: Gaucher's information page
Last updated July 5, 2013. Available at http://www.ninds.nih.gov/disorders/gauchers/gauchers.htm Accessed Feb 24, 2014.
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Report last updated: 2014/03/04 00:00:00 GMT+0