Gaucher Disease

Gaucher Disease

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Gaucher Disease is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • cerebroside lipidosis syndrome
  • Gaucher splenomegaly
  • glucocerebrosidase deficiency
  • glucocerebrosidosis
  • glucosylceramidase deficiency
  • glucosyl cerebroside lipidosis
  • kerasin lipoidosis
  • kerasin thesaurismosis
  • lipid histiocytosis (kerasin type)
  • sphingolipidosis 1

Disorder Subdivisions

  • Norrbottnian Gaucher disease
  • type I Gaucher disease
  • type II Gaucher disease
  • type III Gaucher disease

General Discussion

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 case to case. Some individuals will 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. 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 most common type of lysosomal storage disorder.

Symptoms

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 any 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 cause 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 type 2 Gaucher disease 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).

Causes

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.

Affected Populations

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.

Standard Therapies

Diagnosis

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 certain 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.



Treatment

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 tissue sources (specifically, the placenta). 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, please contact:



Genzyme Therapeutics

500 Kendall Street

Cambridge, MA 02142

617-768-9000

800-745-4447

http://www.cerezyme.com/



Elelyso (also known as 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

866-228-3546 http://www.zavesca.com/patient-home.asp



Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information 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

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



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

Telephone: 301-496-3286

References

TEXTBOOKS

Fauci AS, et al., eds. Harrison's Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2174-75.



Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:57-60.



Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:1097-98.



Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:373-74.



Menkes JH, au., Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995:97-100.



JOURNAL ARTICLES

Brady RO. Enzyme replacement therapy for lysosomal diseases. Annual Review of Medicine 2006;57:283-296.



Schiffmann R, Brady RO. New prospects for the treatment of lysosomal storage diseases. Drugs. 2002;62:733-42.



Patlas M, et al. Repeat abdominal ultrasound evaluation of 100 patients with type I Gaucher disease treated with enzyme replacement therapy for up to 7 years. Hematol J. 2002;3:17-20.



Patlas M, et al. Spectrum of abdominal sonographic findings in 103 patients with Gaucher disease. Eur Radiol. 2002;12:397-400.



Stirnemann J, Belmatoug N. Adult Gaucher disease. Rev Med Interne. 2001;22:374s-83s.



Altarescu G, et al. The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher disease. J Pediatr. 2001;138:539-47.



Rosenberg M, et al. Immunosurveillance of alglucerase enzyme therapy for gaucher patients: indication of humoral tolerance in seroconverted patients after repeat administration. Blood. 1999;93(6)). Pp. 2081-88.



Katz K, et al. Involvement of the foot and ankle in patients with Gaucher disease. Foot Ankle Int. 1999;20:104-07.



Ciana G, et al. Short-term effects of pamidronate in patients with Gaucher's disease and severe skeletal involvement. N Eng J Med. 1997;337:712.



Grabowski GA, et al. Enzyme therapy in type Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med. 1995;122:33-39.



Buetler E. Gaucher's disease: new molecular approaches to diagnosis and treatment. Science. 1992;256:794-99.



FROM THE INTERNET

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Gaucher Disease, Type III. Entry No: :231000. Last Updated June 26, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 21, 2011.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Gaucher Disease, Type I. Entry No: 230800. Last Updated April 27, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 21, 2011.



National Institute of Neurological Disorders and Stroke: Gaucher's information page

Last updated October 27, 2010. Available at http://www.ninds.nih.gov/disorders/gauchers/gauchers.htm. Accessed March 21, 2011.



Gaucher's disease-Genetic Home Reference. Reviewed January, 2008. Available at http://ghr.nlm.nih.gov/condition/gaucher-disease. Accessed March 21, 2011.

Resources

Vaincre Les Maladies Lysosomales

2 Ter Avenue

Massy, 91300

France

Tel: 0169754030

Fax: 0160111583

Email: accueil@vml-asso.org

Internet: http://www.vml-asso.org



National Tay-Sachs and Allied Diseases Association, Inc.

2001 Beacon Street

204

Brookline, MA 02146-4227

USA

Tel: (617)277-4463

Fax: (617)277-0134

Tel: (800)906-8723

Email: info@ntsad.org

Internet: http://www.NTSAD.org



March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



National Gaucher Foundation

2227 Idlewood Road, Suite 6

Tucker, GA 30084

USA

Tel: (770)934-2910

Fax: (770)934-2911

Tel: (800)504-3189

Email: ngf@gaucherdisease.org

Internet: http://www.gaucherdisease.org



The Arc

1825 K Street NW, Suite 1200

Washington, DC 20006

Tel: (202)534-3700

Fax: (202)534-3731

Tel: (800)433-5255

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Gauchers Association (UK)

Evesham House Business Centre

48/52 Silver Street

Dursley

Gloucestershire, GL11 4ND

United Kingdom

Tel: 441453549231

Fax: 441453549231

Email: ga@gaucher.org.uk

Internet: http://www.gaucher.org.uk



Cochrane Cystic Fibrosis and Genetic Disorders Group

Institute of Child Health, University of Liverpool

Alder Hey Children's NHS Foundation Trust

Liverpool, L12 2 AP

United Kingdom

Tel: 441512525696

Email: nikkij@liverpool.ac.uk

Internet: http://cfgd.cochrane.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Instituto de Errores Innatos del Metabolismo

Carrera 7 No 40 - 62

Bogota,

Colombia

Tel: 5713208320

Email: abarrera@javeriana.edu.co

Internet: http://www.javeriana.edu.co/ieim/programas_ieim.htm



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Hide & Seek Foundation for Lysosomal Disease Research

6475 East Pacific Coast Highway Suite 466

Long Beach, CA 90803

Tel: (877)621-1122

Fax: (866)215-8850

Email: info@hideandseek.org

Internet: http://www.hideandseek.org



Proyecto Pide un Deseo México, i.a.p.

Altadena #59-501 col. Napoles

delegacion Benito Juarez

03810 Mexico D.F.

Tel: 55 5543-2447

Fax: 55-5543-5450

Email: prayecto.pdeundese.mexico@gmail.com

Internet: http://www.pideundeseo.org



For a Complete Report

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