Gaucher's disease (IPA: [goʃez dəsiːz]) is the most common of the lysosomal storage diseases. It is caused by a deficiency of the enzyme glucocerebrosidase, leading to an accumulation of its substrate, the fatty substance glucocerebroside (also known as glucosylceramide). 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 shows autosomal recessive inheritance and therefore affects both males and females. It is named after the French doctor Philippe Gaucher who originally described it in 1882. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) is a coding of diseases and signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or diseases, as classified by the World Health Organization (WHO). ... // E00-E35 - Endocrine diseases (E00-E07) Disorders of thyroid gland (E00) Congenital iodine-deficiency syndrome (E01) Iodine-deficiency-related thyroid disorders and allied conditions (E02) Subclinical iodine-deficiency hypothyroidism (E03) Other hypothyroidism (E030) Congenital hypothyroidism with diffuse goitre (E031) Congenital hypothyroidism without goitre (E032) Hypothyroidism due to medicaments and other... The International League of Dermatological Societies (ILDS) is a non-governmental organization affiliated with the World Health Organization. ... The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... 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 Disease Bold textDatabase is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... MedlinePlus (medlineplus. ... eMedicine is an online clinical medical knowledge base that was founded in 1996. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... The lysosomal storage diseases are a group of which over forty disorders are currently known that result from defects in lysosomal function. ... 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. ... glucose sphingolipid Glucocerebroside (also called glucosylceramide) is any of the cerebrosides in which the monosaccharide head group is glucose. ... The spleen is an organ located in the abdomen, where it functions in the destruction of old red blood cells and holding a reservoir of blood. ... The kidneys are the organs that filter wastes (such as urea) from the blood and excrete them, along with water, as urine. ... Human respiratory system The lungs flank the heart and great vessels in the chest cavity. ... Human brain In animals, the brain (enkephale) (Greek for in the skull), is the control center of the central nervous system, responsible for behavior. ... 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. ... Lymph nodes are components of the lymphatic system. ... This article discusses the medical condition. ... A 250 ml bag of newly collected platelets. ... Schematic diagram of the human eye. ... 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). ... An eponym is the name of a person, whether real or fictitious, who has (or is thought to have) given rise to the name of a particular place, tribe, discovery, or other item. ... Philippe Charles Ernest Gaucher (July 26, 1854 – January 25, 1918) was a French dermatologist who was born in the department of Nièvre. ...

Subtypes

Gaucher's disease has three common clinical subtypes.

• Type I (or nonneuropathic type) is the most common form of the disease, occurring in approximately 1 in 50,000 live births. 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, thrombocytopenia 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 II (or acute infantile neuropathic Gaucher's disease) typically begins within 6 months of birth and has an incidence rate of approximately 1 in 100,000 live births. 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 III (the chronic neuronopathic form) can begin at any time in childhood or even in adulthood, and occurs in approximately 1 in 100,000 live births. 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 into their early teen years and adulthood.

These subtypes have come under some criticism for not taking account of the spectrum of phenotypes.[1] There are also compound heterozygous variations which considerably increase the complexity of predicting disease course. Language(s) Yiddish, Hebrew, Russian, English Religion(s) Judaism Related ethnic groups Sephardi Jews, Mizrahi Jews, and other Jewish ethnic divisions 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, also called a contusion or ecchymosis, is a kind of injury to biological tissue in which the capillaries are damaged, allowing blood to seep into the surrounding tissue. ... Spasticity is a disorder of the bodys motor system,and especially the Central Nervous Systems (CNS), in which certain muscles are continuously contracted. ... This article is about epileptic seizures. ... The phenotype of an individual organism is either its total physical appearance and constitution, or a specific manifestation of a trait, such as size or eye color, that varies between individuals. ...

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, which usually lies in the left upper quadrant (LUQ) of the human abdomen. ... Splenomegaly is an enlargement of the spleen, which usually lies in the left upper quadrant (LUQ) of the human abdomen. ... “Red cell” redirects here. ... White Blood Cells redirects here. ... A 250 ml bag of newly collected platelets. ... This article discusses the medical condition. ... Neutropenia (or neutropaenia, adjective neutrop(a)enic) is a hematological disorder characterized by an abnormally low number of neutrophil granulocytes (a type of white blood cell). ... 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. ... For other uses, see Bleeding (disambiguation). ... 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 - leading to an increased risk of fracture. ... Conical flask For the episode of The X-Files, see The Erlenmeyer Flask. ... The femur or thigh bone is the longest, most voluminous, and strongest bone of the mammalian bodies. ... 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 and a few African tribes), 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. Ball and stick model of alkaline phosphatase 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. ...

Histological findings of cells containing "crinkled paper" cytoplasm and glycolipid-laden macrophages.

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 appearing to contain 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. ... A scheme of a condensed (metaphase) chromosome. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... 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. ... This article is about the class of chemicals. ... Glucocerebroside (also called glucosylceramide) is any of the cerebrosides in which the monosaccharide head group is glucose. ... Look up cell membrane in Wiktionary, the free dictionary. ... A macrophage of a mouse stretching its arms to engulf two particles, possibly pathogens Macrophages (Greek: big eaters, from makros large + phagein eat) are cells within the tissues that originate from specific white blood cells called monocytes. ... 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. Individuals in the mollusk species Donax variabilis show diverse coloration and patterning in their phenotypes. ...

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. Some common lipids. ... 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.^[1] A study of 1525 Gaucher patients in the United States suggested that while cancer risk is not elevated, particular malignancies (non-Hodgkin lymphoma, melanoma and pancreatic cancer) occurred at a 2-3 times higher rate.^[2] Non-Hodgkin lymphoma (NHL) describes a group of cancers arising from lymphocytes, a type of white blood cell. ... Melanoma is a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye (see uveal melanoma). ... Pancreatic cancer is a malignant tumor within the pancreatic gland. ...

Classification and genetics

The 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. 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 is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning in order to prevent, avoid or... Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a persons ancestry. ...

Each type has been linked to particular mutations. In all, there are about 80 known mutations, grouped into three main types:^[3]

• 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.

Diaz et al suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).^[4] This article or section does not cite its references or sources. ... 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 (pronounced , ) (from the Greek αλληλος, meaning each other) is one member of a pair or series of different forms of a gene. ... Various organelles labeled. ... 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. ...

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 40000: the rate of carriers is considerably higher, at roughly 1 in 15, among Ashkenazi Jews.^[5]
• 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 (אַשְׁכֲּנָזִים, Standard Hebrew Aškanazim, Tiberian Hebrew ʾAškănāzîm), are Jews who are descendants of Jews from Germany, Poland, Austria and Eastern Europe. ... 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 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, bisphosphonates for bone lesions, 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 DNA (rDNA) is an artificial DNA sequence resulting from the combination of different DNA sequences. ... 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 in the human body, and is an organ present in vertebrates and some other animals. ... The spleen is an organ located in the abdomen, where it functions in the destruction of old red blood cells and holding a reservoir of blood. ... The granting of the orphan drug status is designed to encourage the development of drugs which are necessary but would be prohibitively expensive/un-profitable to develop under normal circumstances. ... 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 protects against blood-borne pathogens and moves quickly (aprox. ... A splenectomy is a procedure that involves the removal of the spleen by operative means. ... Blood transfusion is the process of transferring blood or blood-based products from one person into the circulatory system of another. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... Staphylococcus aureus - Antibiotics test plate. ... 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. ... Liver transplantation is the replacement of a diseased liver with a healthy liver allograft. ... Gene therapy is the insertion of genes into an individuals cells and tissues to treat a disease, and hereditary diseases in which a defective mutant allele is replaced with a functional one. ...

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. ...

The currently existing treatment of Gaucher's disease, Cerezyme (imiglucerase for injection), costs up to $550,000 annually for a single patient and the treatment should be continued for life. This recombinant β-glucosidase is given intravenously. Miglustat is another drug approved for this disease in 2003. Imiglucerase is a recombinant DNA produced analogue of human β-glucocerebrosidase. ... Miglustat is a drug used to treat Gaucher disease. ...

History

Philippe Gaucher described the disease in his doctoral thesis in 1882.^[6] The biochemical basis for the disease would be elucidated in 1965 by Brady et al.^[7] Philippe Charles Ernest Gaucher (July 26, 1854 – January 25, 1918) was a French dermatologist who was born in the department of Nièvre. ... Doctor of Philosophy (Ph. ... Year 1882 (MDCCCLXXXII) was a common year starting on Sunday (link will display the full calendar) of the Gregorian calendar (or a common year starting on Friday of the 12-day slower Julian calendar). ... Year 1965 (MCMLXV) was a common year starting on Friday (link will display full calendar) of the 1965 Gregorian calendar. ...

References

A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... 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. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era in the 21st century. ... is the 150th day of the year (151st in leap years) in the Gregorian calendar. ...

External links

• gauchers at NINDS
• Gauchers News
• European Gaucher Alliance
• National Gaucher Foundation