Gaucher's disease (pronounced goʃeɪ) is the most common of the lipid storage diseases. It is caused by a deficiency of the enzyme glucocerebrosidase, leading to an accumulation of its substrate, the fatty substance glucocerebroside. Fatty material can collect in the spleen, liver, kidneys, lungs, brain and bone marrow. Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may cause pain, 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 sclera. Persons affected most seriously may also be more susceptible to infection. The disease affects males and females equally. It is the most common lysosomal storage disease. It is named after the French doctor who originally described it in 1882. The International Statistical Classification of Diseases and Related Health Problems (commonly known by the abbreviation ICD) is a detailed description of known diseases and injuries. ... The following codes are used with International Statistical Classification of Diseases and Related Health Problems. ... The International Statistical Classification of Diseases and Related Health Problems (commonly known by the abbreviation ICD) is a detailed description of known diseases and injuries. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... Lipid storage disorders (or lipidoses) are a group of inherited metabolic disorders in which harmful amounts lipids (fats) accumulate in some of the body’s cells and tissues. ... Acid β-glucosidase, drawn from PDB 1OGS. Glucocerebrosidase (also called glucosylceramidase or D-glucosyl-N-acylsphingosine glucohydrolase) is an enzyme (EC 3. ... Cerebrosides are glycosphingolipids which are important components in animal muscle and nerve cell membranes. ... The spleen is a ductless, vertebrate gland that is closely associated with the circulatory system, where it functions in the destruction of old red blood cells in holding a reservoir of blood. ... Human kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... The lungs flank the heart and great vessels in the chest cavity. ... Comparative brain sizes In animals, the brain, or encephalon (Greek for in the head), is the control center of the central nervous system. ... This is a list of skeletal disorders, these affect the development and structure of the skeletal system. ... Neurology is a branch of medicine dealing with disorders of the nervous system. ... Structure of the lymph node. ... This article discusses the medical condition. ... A 250 ml bag of newly collected platelets. ... The lysosomal storage diseases are a group of over thirty disorders that result from defects in lysosomal function. ... An eponym is the name of a person, whether real or fictitious, which has (or is thought to have) given rise to the name of a particular place, tribe, discovery or other item. ... 1882 (MDCCCLXXXII) was a common year starting on Sunday (see link for calendar) of the Gregorian calendar or a common year starting on Tuesday of the 12-day slower Julian calendar. ...

Subtypes

Gaucher disease has three common clinical subtypes. Type 1 (or nonneuropathic type) is the most common form of the disease (more than 99% of cases). 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, which can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia and leukopenia. The brain is not affected, but there may be lung and, rarely, kidney impairment. Patients in this group usually bruise easily and experience fatigue due to low blood platelets. Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild form of the disease or may not show any symptoms. Type 2 (or acute infantile neuropathic Gaucher disease) typically begins within 6 months of birth. 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 2. Type 3 (the chronic neuronopathic form) can begin at any time in childhood or even in adulthood. It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 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 to their early teen years and often into adulthood. Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim (Standard Hebrew: sing. ... This article discusses the medical condition. ... Leukopenia or leukocytopenia refers to a decrease in the number of circulating white blood cells (leukocytes) in the blood. ... A bruise or contusion or ecchymosis is a kind of injury, usually caused by blunt impact, in which the capillaries are damaged, allowing blood to seep into the surrounding tissue. ... Spasticity is a disorder of the bodys motor system in which certain muscles are continuously contracted. ... This article is about the medical term, epileptic seizure, as distinct from psychogenic non-epileptic seizure. ...

Signs and symptoms

• Painless hepatomegaly and splenomegaly; the spleen can be 1500-3000 ml, as opposed to the normal size of 50-200 ml.
• Hypersplenism: increased destruction of red and white blood cells and platelets, leading to anemia, neutropenia and thrombocytopenia (with an increased risk of infection and bleeding)
• Cirrhosis of the liver is rare
• Neurological symptoms occur only in some types of Gaucher's (see below):
  • Type II: serious convulsions, hypertonia, mental retardation, apnea.
  • Type III: myoclonus, convulsions, dementia, ocular muscle apraxia.
• Osteoporosis: 75% develop visible bony abnormalities due to the accumulated glucosylceramide. An Erlenmeyer flask deformity of the distal femur is commonly described.
• Yellowish-brown skin pigmentation
• No cardiac, renal and pulmonary signs

Hepatomegaly is the condition of having an enlarged liver. ... Splenomegaly is an enlargement of the spleen. ... Splenomegaly is an enlargement of the spleen, which usually lies in the left upper quadrant (LUQ) of the human abdomen. ... Human red blood cells Red blood cells are the most common type of blood cell and are the vertebrate bodys principal means of delivering oxygen from the lungs or gills to body tissues via the blood. ... White blood cells (a. ... A 250 ml bag of newly collected platelets. ... This article discusses the medical condition. ... It has been suggested that Agranulocytosis be merged into this article or section. ... Thrombocytopenia (or -paenia, or thrombopenia in short) is the presence of relatively few platelets in blood. ... An infection is the detrimental colonization of a host organism by a foreign species. ... Minor traumatic bleeding from the head Bleeding is the loss of blood from the body. ... Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrotic scar tissue as well as regenerative nodules, leading to progressive loss of liver function. ... Neurology is a branch of medicine dealing with disorders of the nervous system. ... Osteoporosis is a disease of bone in which bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is changed. ... Conical flask An Erlenmeyer flask (also known as a conical flask) is a widely used type of laboratory glassware which features a conical base with a cylindrical neck. ... The femur or thigh bone is the longest, most voluminous, and strongest bone of the human body. ... In biology, pigment is any material resulting in color in plant or animal cells which is the result of selective absorption. ...

Diagnosis

In populations with high rates of carriage (Ashkenazi Jews and Norrbottnian Swedes), some family members of the index patient may already have been diagnosed with Gaucher's. Truly sporadic cases may suffer diagnostic delay due to the protean symptoms. Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim (אַשְׁכֲּנָזִי אַשְׁכֲּנָזִים Standard Hebrew, Aškanazi,Aškanazim, Tiberian Hebrew, ʾAškănāzî, ʾAškănāzîm, pronounced sing. ... Norrbotten is the name of an unofficial Province (landskap) in Sweden, originally a part of Västerbotten, which gradually grow apart from Västerbotten after the creation of Norrbotten County in 1810. ...

Biochemical abnormalities: high alkaline phosphatase, angiotensin-converting enzyme (ACE) and immunoglobulin levels. Alkaline phosphatase, drawn from PDB 1ANI. Alkaline phosphatase (ALP) (EC 3. ... Angiotensin converting enzyme Angiotensin-Converting Enzyme (ACE, EC 3. ... Schematic of antibody binding to an antigen An antibody is a protein complex used by the immune system to identify and neutralize foreign objects like bacteria and viruses. ...

The diagnosis is made with genetic testing of the β-glucosidase gene. As there are numerous different mutations, sequencing of the gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available, and is useful when there is a known genetic risk factor. Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a persons ancestry. ...

Pathophysiology

Acid β-glucosidase

The disease is caused by a defect in the housekeeping gene lysosomal gluco-cerebrosidase (also known as β-glucosidase, EC 3.2.1.45, PDB 1OGS) on the first chromosome (1q21). The enzyme is a 55.6 KD, 497 amino acids long protein that catalyses the breakdown of glucocerebroside, 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 as containing crumpled-up paper. Drawn from 1OGS.PDB by User:Jfdwolff File links The following pages link to this file: Gauchers disease Categories: GFDL images ... A housekeeping gene is a gene that codes for proteins needed all the time. ... The Enzyme Commission number (EC number) is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze. ... The Protein Data Bank (PDB) is a repository for 3-D structural data of proteins and nucleic acids. ... Figure 1: Chromosome. ... I hate FREEHAND?POWERPOINT!!!!year= 2004|title= Simulations of the large kinetic isotope effect and the temperature dependence of the hydrogen atom transfer in lipoxygenase|journal = J. Am. ... The atomic mass unit (amu), unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic masses and molecular masses. ... An amino acid residue is what is left of an amino acid once a molecule of water has been lost (an H+ from the nitrogenous side and an OH- from the carboxylic side) in the formation of a peptide bond. ... Glucocerebroside (also called glucosylceramide) is any of the cerebrosides in which the monosaccharide head group is glucose. ... Drawing of a cell membrane A cell membrane, plasma membrane or plasmalemma is a selectively permeable lipid bilayer coated by proteins which comprises the outer layer of a cell. ... A macrophage of a mouse stretching its arms to engulf two particles, possibly pathogens Macrophages (Greek: big eaters, makros = long, phagein = eat) are white blood cells, more specifically phagocytes, acting in the nonspecific defense as well as the specific defense system of vertebrate animals. ... Microscopy is any technique for producing visible images of structures or details too small to otherwise be seen by the human eye. ...

Different mutations in the β-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype. The phenotype of an individual organism is either its total physical appearance and constitution or a specific manifestation of a trait, such as size, eye color, or behavior that varies between individuals. ...

In the brain (type II and III), glucocerebroside accumulates due to the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves. This article or section does not cite its references or sources. ... In neuroscience, myelin is an electrically insulating fatty layer that surrounds the axons of many neurons, especially those in the peripheral nervous system. ...

Research suggests that heterozygotes for particular acid β-glucosidase mutations are at an increased risk of Parkinson's disease (Aharon-Peretz et al 2004).

Classification and genetics

There are three recognized forms; all have been linked to particular mutations. In all, there are about 80 known mutations.

• Type I (N370S homozygote, the most common, also called the "non-neuropathic" type) occurs mainly (100x the general populace) in Ashkenazi Jews. It is mainly diagnosed in late childhood or early adulthood. Life expectancy is mildly decreased. There are no neurological symptoms. Dor Yeshorim, a non-profit testing organisation, therefore only tests patients on request.
• Type II (1 or 2 alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. Prognosis is dismal: most die before reaching the third birthday.
• Type III (also 1-2 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.

All three types of Gaucher's disease are inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of mutations. A homozygotes cells are diploid or polyploid and have the same alleles at a locus (position) on homologous chromosomes. ... Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim (אַשְׁכֲּנָזִי אַשְׁכֲּנָזִים Standard Hebrew, Aškanazi,Aškanazim, Tiberian Hebrew, ʾAškănāzî, ʾAškănāzîm, pronounced sing. ... Dor Yeshorim (Hebrew: generation [that is] straight/reliable) is an organization that offers genetic screening to members of Orthodox Jewish communities. ... An allele is any one of a number of viable DNA codings occupying a given locus (position) on a chromosome. ... Organelles. ... Norrbotten is the name of an unofficial Province (landskap) in Sweden, originally a part of Västerbotten, which gradually grow apart from Västerbotten after the creation of Norrbotten County in 1810. ... In genetics, the term recessive gene refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele). ... Genetic counseling generally refers to prenatal counseling done when a genetic condition is suspected in a pregnancy. ... Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a persons ancestry. ...

Diaz et al (2000) suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).

Epidemiology

• The National Gaucher Foundation states that around 1 in 100 people in the general U.S. population is a carrier for type 1 Gaucher's disease, giving a prevalence of 1 in 1000: the rate of carriers is considerably higher, at roughly 1 in 14, among Ashkenazi Jews.
• Type 2 Gaucher's disease shows no particular preference for any ethnic group.
• Type 3 Gaucher's disease is especially common in the population of the Northern Swedish region of Norrbotten where the incidence of the disease is 1 in 50,000.

Ashkenazi (אַשְׁכֲּנָזִי, Standard Hebrew Aškanazi, Tiberian Hebrew ʾAškănāzî) Jews or Ashkenazic Jews, also called Ashkenazim (אַשְׁכֲּנָזִי&#1501... Norrbotten is the name of an unofficial Province (landskap) in Sweden, originally a part of Västerbotten, which gradually grow apart from Västerbotten after the creation of Norrbotten County in 1810. ...

Treatment

For type 1 and most type 3 patients, enzyme replacement treatment with mannose-terminated recombinant glucocerebrosidase, 60 Units/kg, given intravenously every two weeks can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. This treatment is becoming the gold standard in treating Gaucher's. Due to the low incidence, this has become an orphan drug in many countries. Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte population with active β-glucosidase. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen (splenectomy) 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 and liver transplants. Substrate reduction therapy may prove to be effective in stopping Type 2, as it can cross through the blood barrier into the brain. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease. Gene therapy may be a future step. Enzyme replacement therapy is a medical treatment replacing an enzyme in patients in whom that particular enzyme is deficient or absent. ... Recombinant proteins are proteins that are produced by different genetically modified organisms following insertion of the relevant DNA into their genome. ... An intravenous drip in a hospital Intravenous therapy or IV therapy is the administration of liquid substances directly into a vein. ... The liver is the largest internal organ of the human body. ... The spleen is a ductless, vertebrate gland that is closely associated with the circulatory system, where it functions in the destruction of old red blood cells in holding a reservoir of blood. ... This article is on the monetary principle. ... In America, an orphan drug is any drug developed under the Orphan Drug Act of 1983, a federal law concerning rare diseases (orphan diseases), defined as diseases affecting fewer than 200,000 people in the United States. ... Bone marrow transplantation is a medical procedure that involves stem cell transplantation. ... Monocyte A monocyte is a leukocyte, part of the human bodys immune system that protect against blood-borne pathogens and move quickly to sites of infection in the tissues. ... A splenectomy is a procedure that involves the removal of the spleen by operative means. ... Blood transfusion is the taking of blood or blood-based products from one individual and inserting them into the circulatory system of another. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... An antibiotic is a drug that kills or slows the growth of bacteria. ... An infection is the detrimental colonization of a host organism by a foreign species. ... The anticonvulsants, sometimes also called antiepileptics, belong to a diverse group of pharmaceuticals used in prevention of the occurrence of epileptic seizures. ... Gene therapy using an Adenovirus vector. ...

Gaucher's disease has recently become a target for more than one effort at pharmacological chaperoning since the crystal structure of glucocerebrosidase is known. A pharmacological chaperone is a relatively new concept in the treatment of certain genetic disease. ... Acid β-glucosidase, drawn from PDB 1OGS. Glucocerebrosidase (also called glucosylceramidase or D-glucosyl-N-acylsphingosine glucohydrolase) is an enzyme (EC 3. ...

Currently existing treatment of Gaucher's disease, cerezyme, costs up to $750,000 annually for a single patient and the treatment should be continued for life. This recombinant β-glucosidase is given intravenously.

Now researchers are developing a novel oral therapy, which not only cuts the price tag of treatment by one in hundred, but also would be very convenient because of the oral formulation.^[1]

History

Philippe Gaucher described the disease in his doctoral thesis in 1882. The biochemical basis for the disease would be elucidated in 1965 by Brady et al. Doctor of Philosophy (Ph. ... 1882 (MDCCCLXXXII) was a common year starting on Sunday (see link for calendar) of the Gregorian calendar or a common year starting on Tuesday of the 12-day slower Julian calendar. ... 1965 (MCMLXV) was a common year starting on Friday (the link is to a full 1965 calendar). ...

References

1. ^ [1]

• Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews. N Engl J Med 2004;351:1972-1977. PMID 15525722.
• Barranger JA, Rice EO. Gaucher disease: diagnosis, monitoring and management. Gaucher Clin Persp 1997;5:1-6.
• Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides. II. Evidence of enzymatic deficiency in Gaucher's disease. Biochem Biophys Res Commun 1965;18:221. PMID 14282020.
• Charrow J et al. Gaucher disease, recommendations on diagnosis, evaluation and monitoring. Arch Intern Med 1998;158:1754-60.
• Diaz GA, Gelb BD, Risch N, Nygaard TG, Frisch A, Cohen IJ, Miranda CS, Amaral O, Maire I, Poenaru L, Caillaud C, Weizberg M, Mistry P, Desnick RJ. Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations. Am J Hum Genet 2000;66:1821-32. PMID 10777718.
• Gaucher PCE. De l'epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie. Academic thesis, Paris, France, 1882.
• Mendelian Inheritance in Man (OMIM) 606463 (acid β-glucosidase), Mendelian Inheritance in Man (OMIM) 230800 (type I), Mendelian Inheritance in Man (OMIM) 230900 (type II), Mendelian Inheritance in Man (OMIM) 231000 (type III)

The New England Journal of Medicine (NEJM) is a peer-reviewed medical journal published by the Massachusetts Medical Society. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ...

External links

• Public domain NINDS Gaucher's Disease Information Page