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| | __NOTOC__ |
| {{Infobox_Disease | | {{Infobox_Disease |
| | Name = {{PAGENAME}} | | | Name = {{PAGENAME}} |
| | Image = Gaucher's disease H shaped vertebral bodies 001.jpg | | | Image = Gaucher's disease H shaped vertebral bodies 001.jpg |
| | Caption = MRI: H-shaped vertebral bodies in a patient with Gaucher's disease. <br> (Image courtesy of RadsWiki) | | | Caption = MRI: H-shaped vertebral bodies in a patient with Gaucher's disease. <br> (Image courtesy of RadsWiki) |
| | DiseasesDB = 5124
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| | ICD10 = {{ICD10|E|75|2|e|70}} ([[ILDS]] E75.220)
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| | ICD9 = {{ICD9|272.7}}
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| | ICDO =
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| | OMIM = 230800
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| | OMIM_mult = {{OMIM2|230900}} {{OMIM2|231000}}
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| | MedlinePlus = 000564
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| | eMedicineSubj = ped
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| | eMedicineTopic = 837
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| | eMedicine_mult = {{eMedicine2|derm|709}}
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| | MeshID = D005776
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| }} | | }} |
| {{SI}} | | {{Gaucher's disease}} |
| {{CMG}}
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| '''Associate Editor-In-Chief:''' {{CZ}} | | '''For patient information [[Gaucher's disease (patient information)|click here]]''' |
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| {{Editor Help}} | | {{CMG}}; {{AE}} {{CZ}} |
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| ==Overview==
| | '''Synonyms and related keywords:''' Cerebroside lipidosis syndrome, Gauchers disease, Gaucher splenomegaly, Gaucher syndrome, GD, Glucocerebrosidase deficiency, Glucocerebrosidosis, Glucosylceramidase deficiency, Glucosylceramide beta-glucosidase deficiency, Glucosylceramide lipidosis, Glucosyl cerebroside lipidosis, Kerasin histiocytosis, Kerasin lipoidosis, Kerasin thesaurismosis, Lipoid histiocytosis (kerasin type) |
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| '''Gaucher's disease''' (pronounced <nowiki>{{goshay}}</nowiki>) is the most common of the [[lysosomal storage disease]]s. It is caused by a deficiency of the enzyme [[glucocerebrosidase]], leading to an accumulation of its substrate, the fatty substance [[cerebroside|glucocerebroside]] (also known as [[glucosylceramide]]). Fatty material can collect in the [[spleen]], liver, [[kidney]]s, [[lung]]s, [[brain]] and bone marrow. Symptoms may include enlarged spleen and liver, liver malfunction, [[List of skeletal disorders|skeletal disorders]] and bone lesions that may cause pain, severe [[Neurology|neurologic]] complications, swelling of [[lymph node]]s and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, [[anemia]], low blood [[platelet]]s and yellow fatty deposits on the [[sclera]]. Persons affected most seriously may also be more susceptible to infection.
| | ==[[Gaucher's disease overview|Overview]]== |
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| Types of Gaucher disease based on their characteristic features.
| | ==[[Gaucher's disease historical perspective|Historical Perspective]]== |
| Type 1 Gaucher disease is the most common form of this condition. Type 1 is also called non-neuronopathic Gaucher disease because the brain and spinal cord (the central nervous system) are usually not affected. The features of this condition range from mild to severe and may appear anytime from childhood to adulthood. Major signs and symptoms include enlargement of the liver and spleen (hepatosplenomegaly), a low number of red blood cells (anemia), easy bruising caused by a decrease in blood platelets (thrombocytopenia), lung disease, and bone abnormalities such as bone pain, fractures, and arthritis.
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| Types 2 and 3 Gaucher disease are known as neuronopathic forms of the disorder because they are characterized by problems that affect the central nervous system. In addition to the signs and symptoms described above, these conditions can cause abnormal eye movements, seizures, and brain damage. Type 2 Gaucher disease usually causes life-threatening medical problems beginning in infancy. Type 3 Gaucher disease also affects the nervous system, but tends to progress more slowly than type 2.
| | ==[[Gaucher's disease classification|Classification]]== |
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| The most severe type of Gaucher disease is called the perinatal lethal form. This condition causes severe or life-threatening complications starting before birth or in infancy. Features of the perinatal lethal form can include extensive swelling caused by fluid accumulation before birth (hydrops fetalis); dry, scaly skin (ichthyosis) or other skin abnormalities; hepatosplenomegaly; distinctive facial features; and serious neurological problems. As its name indicates, most infants with the perinatal lethal form of Gaucher disease survive for only a few days after birth.
| | ==[[Gaucher's disease pathophysiology|Pathophysiology]]== |
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| Another form of Gaucher disease is known as the cardiovascular type because it primarily affects the heart, causing the heart valves to harden (calcify). People with the cardiovascular form of Gaucher disease may also have eye abnormalities, bone disease, and mild enlargement of the spleen (splenomegaly).
| | ==[[Gaucher's disease differential diagnosis|Differentiating Gaucher's disease from other Diseases]]== |
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| ==Genetics== | | ==[[Gaucher's disease epidemiology and demographics|Epidemiology and Demographics]]== |
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| The disease shows [[autosomal recessive]] inheritance, therefore affects males and females equally.
| | ==[[Gaucher's disease risk factors|Risk Factors]]== |
| Mutations in the GBA gene cause Gaucher disease.
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| The GBA gene provides instructions for making an enzyme called beta-glucocerebrosidase. This enzyme breaks down a fatty substance called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide). Mutations in the GBA gene greatly reduce or eliminate the activity of beta-glucocerebrosidase. Without enough of this enzyme, glucocerebroside and related substances can build up to toxic levels within cells. Tissues and organs are damaged by the abnormal accumulation and storage of these substances, causing the characteristic features of Gaucher disease.
| | ==[[Gaucher's disease screening|Screening]]== |
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| ==Etymology== | | ==[[Gaucher's disease natural history|Natural History, Complications and Prognosis]]== |
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| It is [[eponym|named after]] the French doctor [[Philippe Gaucher]] who originally described it in 1882.
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| ==History==
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| [[Philippe Gaucher]] described the disease in his doctoral thesis in 1882.<ref>Gaucher PCE. ''De l'epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie''. Academic thesis, Paris, France, 1882.</ref> The biochemical basis for the disease would be elucidated in 1965 by Brady ''et al''.<ref>{{cite journal |author=Brady RO, Kanfer JN, Shapiro D |title=Metabolism of glucocerebrosides. II. Evidence of an enzymatic deficiency in Gaucher's disease |journal=Biochem. Biophys. Res. Commun. |volume=18 |issue= |pages=221-5 |year=1965 |pmid=14282020 |doi=}}</ref> | |
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| ==Epidemiology==
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| * 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.<ref>{{cite web |url=http://www.gaucherdisease.org/prevalence.php |title=National Gaucher Foundation |accessdate=2007-05-30 |format= |work=}}</ref>
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| * Type 2 Gaucher's disease shows no particular preference for any ethnic group.
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| * 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.
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| ==Pathophysiology==
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| [[Image:Acid beta glucosidase.png|thumb|left|200px|Acid β-glucosidase]]The disease is caused by a defect in the [[housekeeping gene]] ''lysosomal gluco-cerebrosidase'' (also known as β-glucosidase, {{EC number|3.2.1.45}}, {{PDB|1OGS}}) on the first [[chromosome]] (1q21).
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| The [[enzyme]] is a 55.6 [[kilodalton|KD]], 497 [[amino acid]]s long protein that catalyses the breakdown of [[glucocerebroside]], a [[cell membrane]] constituent of red and white blood cells.
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| The [[macrophage]]s 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.
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| Different mutations in the β-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the [[phenotype]].
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| In the brain (type II and III), glucocerebroside accumulates due to the turnover of complex [[lipid]]s during brain development and the formation of the [[myelin sheath]] of nerves.
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| Research suggests that heterozygotes for particular acid β-glucosidase mutations are at an increased risk of [[Parkinson's disease]].<ref>{{cite journal |author=Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R |title=Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews |journal=N. Engl. J. Med. |volume=351 |issue=19 |pages=1972-7 |year=2004 |pmid=15525722 |doi=10.1056/NEJMoa033277}}</ref>
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| 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.<ref>{{cite journal |author=Landgren O, Turesson I, Gridley G, Caporaso NE |title=Risk of Malignant Disease Among 1525 Adult Male US Veterans With Gaucher Disease |journal= |volume=167 |issue=11 |pages=1189-1194 |year=2007 |pmid=17563029 |doi=10.1001/archinte.167.11.1189}}</ref>
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| ==Classification and genetics==
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| 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.
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| Each type has been linked to particular mutations. In all, there are about 80 known mutations, grouped into three main types:<ref>{{OMIM|606463}}</ref>
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| * 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.
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| * Type II (1 or 2 [[allele]]s L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the [[lysosome]]s. Prognosis is dismal: most die before reaching the third birthday.
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| * 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.
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| Diaz ''et al'' suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).<ref>{{cite journal |author=Diaz GA, Gelb BD, Risch N, ''et al'' |title=Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations |journal=Am. J. Hum. Genet. |volume=66 |issue=6 |pages=1821-32 |year=2000 |pmid=10777718 |doi=}}</ref>
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| == Subtypes ==
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| Gaucher's disease has three common clinical subtypes.
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| * 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.
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| * 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]], [[seizure]]s, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2.
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| * 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.
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| These subtypes have come under some criticism for not taking account of the spectrum of [[phenotypes]].[http://www.gaucher.org.uk/consenmarch2002.htm] There are also compound heterozygous variations which considerably increase the complexity of predicting disease course.
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| ==Signs and symptoms==
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| * Painless [[hepatomegaly]] and [[splenomegaly]]; the spleen can be 1500-3000 ml, as opposed to the normal size of 50-200 ml.
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| * [[Hypersplenism]]: increased destruction of [[red blood cell|red]] and [[white blood cell]]s and [[platelet]]s, leading to [[anemia]], [[neutropenia]] and [[thrombocytopenia]] (with an increased risk of [[infection]] and [[bleeding]])
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| * [[Cirrhosis]] of the liver is rare
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| * [[Neurology|Neurological]] symptoms occur only in some types of Gaucher's (see below):
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| ** Type II: serious convulsions, hypertonia, mental retardation, apnea.
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| ** Type III: myoclonus, convulsions, dementia, ocular muscle apraxia.
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| * [[Osteoporosis]]: 75% develop visible bony abnormalities due to the accumulated glucosylceramide. An Erlenmeyer flask deformity of the distal [[femur]] is commonly described
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| * Yellowish-brown skin [[pigmentation]]
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| * No cardiac, renal and pulmonary signs
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| ==Diagnosis== | | ==Diagnosis== |
| In populations with high rates of carriage (Ashkenazi Jews and Norrbottnian Swedes and a few African American 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.
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| Biochemical abnormalities: high [[alkaline phosphatase]], [[angiotensin-converting enzyme]] (ACE) and [[immunoglobulin]] levels.
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| The diagnosis is made with [[genetic test]]ing 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.
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| ===Diagnostic Findings===
| | [[Gaucher's disease history and symptoms|History and Symptoms ]] | [[ Gaucher's disease physical examination|Physical Examination]] | [[Gaucher's disease laboratory findings|Laboratory Findings]] | [[Gaucher's disease chest x ray|Chest X Ray]] | [[Gaucher's disease CT|CT]] | [[Gaucher's disease MRI|MRI]] | [[Gaucher's disease ultrasound|Ultrasound]] | [[Gaucher's disease other imaging findings|Other Imaging Findings]] | [[Gaucher's disease other diagnostic studies|Other Diagnostic Studies]] |
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| MR images demonstrate Erlenmeyer flask deformities and H-shaped vertebral bodies in a patient with Gaucher's disease'''
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| (Images courtesy of RadsWiki)
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| <gallery>
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| Image:Gaucher's disease Erlenmeyer flask deformity 001.jpg|Erlenmeyer flask deformity in a patient with Gaucher's disease'''
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| Image:Gaucher's disease H shaped vertebral bodies 001.jpg|H-shaped vertebral bodies in a patient with Gaucher's disease'''
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| </gallery>
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| ==Treatment== | | ==Treatment== |
| For type 1 and most type 3 patients, [[enzyme replacement treatment]] with mannose-terminated [[Recombinant DNA|recombinant]] glucocerebrosidase, 60 Units/kg, given [[intravenous]]ly 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 [[Replacement joint|joint replacement]] surgery to improve mobility and quality of life. Other treatment options include [[antibiotic]]s for [[infection]]s, [[antiepileptic]]s for seizures, bisphosphonates for bone lesions, and [[liver transplant]]s. 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.
| | [[Gaucher's disease medical therapy|Medical Therapy]] | [[Gaucher's disease surgery |Surgery]] | [[Gaucher's disease primary prevention|Primary Prevention]] | [[Gaucher's disease secondary prevention|Secondary Prevention]] | [[Gaucher's disease cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Gaucher's disease future or investigational therapies|Future or Investigational Therapies]] |
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| Gaucher's disease has recently become a target for more than one effort at [[pharmacological chaperone|pharmacological chaperoning]] since the crystal structure of [[glucocerebrosidase]] is known.
| | ==Case Studies== |
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| 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.
| | [[Gaucher's Disease case study one|Case #1]] |
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| ==Case Examples==
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| ===Case #1===
| | {{Endocrine, nutritional and metabolic pathology}} |
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| ====Clinical Summary====
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| A 23-year-old black female delivered a stillborn infant by Caesarean section, following which she experienced excessive uterine bleeding including the passage of blood clots. Further study revealed an enlarged spleen and thrombocytopenia (platelet count 58,000). A splenectomy was performed with an uneventful postoperative course other than persistent pain in her right leg (the right hip had been fractured 2 years earlier). Subsequently she developed aseptic necrosis of the left femoral head requiring a prosthetic replacement. Microscopic evaluation of the bone removed at the time of surgery revealed Gaucher cells in the marrow space.
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| ====Autopsy Findings====
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| The surgical specimen was a 935-gram spleen. Its surface was pale with an area of bluish discoloration. The cut surface revealed the same pale appearance.
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| ====Histopathological Findings====
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| [http://www.peir.net Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]
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| [[Image:Gaucher disease 001.jpg|left|thumb|400px|This is a gross photograph of spleen from this case. The spleen is enlarged and the surface is finely granular. ]]
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| [[Image:Gaucher disease 002.jpg|left|thumb|400px|This is a cut section of spleen from this case. Again note the fine granular appearance to the tissue. ]]
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| [[Image:Gaucher disease 003.jpg|left|thumb|400px|This is a low-power photomicrograph of normal spleen (left) and the spleen from this case (right). The loose appearance of the tissue in the Gaucher spleen is due to artifactual loss of tissue during histologic processing. ]]
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| [[Image:Gaucher disease 004.jpg|left|thumb|400px|This is a photomicrograph of the spleen from this case. There is very little if any white pulp evident in this section.]]
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| [[Image:Gaucher disease 005.jpg|left|thumb|400px|This is a higher-power photomicrograph of the spleen from this case. Again there is no white pulp and the red pulp is filled with large eosinophilic cells.]]
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| [[Image:Gaucher disease 006.jpg|left|thumb|400px|This is another high-power photomicrograph of the spleen from this case. At this power it is easier to see the large eosinophilic cells. ]]
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| [[Image:Gaucher disease 007.jpg|left|thumb|400px|This is another high-power photomicrograph of the spleen from this case. At this high power individual cells can be better appreciated. ]]
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| [[Image:Gaucher disease 008.jpg|left|thumb|400px|This is a higher-power photomicrograph of the spleen from this case. At this higher power individual cells can be better appreciated and the fibrillar nature of the eosinophilic cytoplasmic material can be seen. ]]
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| ==References==
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| {{Reflist|2}}
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| == External links ==
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| * {{NINDS|gauchers}}
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| *[http://www.gaucher.org.uk/index.htm Gauchers News]
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| *[http://www.gaucher.org.uk/ega/alliance.htm European Gaucher Alliance]
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| *[http://www.gaucherdisease.org National Gaucher Foundation]
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| *[http://www.childrensgaucher.org/ Children's Gaucher Research Fund]
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| *[http://www.hideandseek.org/ Hide & Seek Foundation For Lysosomal Disease Research]
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| {{Endocrine, nutritional and metabolic pathology}}
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| {{SIB}}
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| [[ru:Болезнь Гоше]] | | [[ru:Болезнь Гоше]] |
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