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.
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 Protali. 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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