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 {"id": "doc16", "text": "Gaucher disease is rare in the general population. People of Eastern and Central European (Ashkenazi) Jewish heritage are more likely to have this disease. It is an autosomal recessive disease. This means that the mother and father must both pass one abnormal copy of the disease gene to their child in order for the child to develop the disease. A parent who carries an abnormal copy of the gene but doesn't have the disease is called a silent carrier. The lack of the GBA causes harmful substances to build up in the liver, spleen, bones, and bone marrow. These substances prevent cells and organs from working properly. There are three main subtypes of Gaucher disease: Type 1 is most common. It involves bone disease, anemia, an enlarged spleen and low platelets (thrombocytopenia). Type 1 affects both children and adults. It is most common in the Ashkenazi Jewish population. Type 2 usually begins in infancy with severe neurologic involvement. This form can lead to rapid, early death. Type 3 may cause liver, spleen, and brain problems. People with this type may live into adulthood. Symptoms Bleeding because of low platelet count is the most common symptom seen in Gaucher disease. Other symptoms may include: Bone pain and fractures Cognitive impairment (decreased thinking ability) Easy bruising Enlarged spleen Enlarged liver Fatigue Heart valve problems Lung disease (rare) Seizures Severe swelling at birth Skin changes"}
 {"id": "doc17", "text": "Overview Gaucher disease is a rare, inherited disorder that causes fatty substances to build up in the spleen, liver, and other organs. Finding a doctor to diagnose Gaucher disease can sometimes be a frustrating experience for patients. They typically go from one specialist to another and get sicker and sicker as the doctors scratch their heads. At Yale Medicine, we have experts ready to help, and patients come to us from around the country for our expertise in Gaucher disease. It is the most common lyosomal storage disease, a family of inherited metabolic disorders that originate in the lysosomes, or parts of the cell that help with digestion. \u201cWe have an internationally recognized program and a national referral base with incredible models of precision medicine and innovative therapies,\u201d says Yale Medicine\u2019s Pramod K. Mistry, MD, PhD, director of Lyosomal Disease & Inherited Metabolic Liver Disease Program. \u201cPeople come to us because they have very complicated aspects that no one else can figure out.\u201d What is Gaucher disease? Gaucher disease is a rare, inherited disorder where fatty cells build up in areas including the liver, spleen, and bone tissue and marrow. The organs enlarge\u2014sometimes as much as 50 times its normal size for the spleen\u2014and bones are affected, which increases the risk of fracture and severe bone pain (called a \u201cbone crisis\u201d) that requires joint replacement. The disease is caused by the body not having enough of an important enzyme (glucocerebrosidase), which breaks down a fatty chemical (glucocerebroside). Gaucher disease is divided into three main categories: Type 1 is the most common form of the disorder in Western countries, constituting approximately 95 percent of patients. Type 2 is rare and is associated with severe neurological abnormalities and is usually fatal within the first two years of onset. Type 3 is rare in the United States and Europe, but it is the most common form of the disease around the world. It has the same symptoms as type 1, plus some neurological damage. Worldwide, Gaucher disease affects 1 in 40,000 people, but its frequency is as high as 1 in 450 people among Jews of Ashkenazi (Eastern European) descent. Although it is present at birth, symptoms can appear at any age. Research shows that patients with Gaucher disease type 1 may be at increased risk of developing other conditions, usually after age 50. These include: Parkinson disease Some cancer types, including multiple myeloma (a blood cancer) and liver cancer What causes Gaucher disease? To have Gaucher disease, you must have two mutations of a gene called GBA: one from your mother and one from your father. But you can be a carrier and have just one mutation related to the disorder and not have Gaucher disease. If both parents are carriers, each pregnancy has a 1 in 4 chance that the baby will have the disease. Today, prenatal testing can be done early in the pregnancy, which people with a family history of the disease may want to consider. What are the symptoms of Gaucher disease? Symptoms of Gaucher disease type 1 can differ vastly and can range from severe to none at all. Some signs include: Swollen belly (from spleen and liver enlargement) Bone pain and easily fractured bones Anemia (low red blood cell counts) and fatigue Bleeding (frequent nosebleeds, gum bleeding) and bruising problems (caused by decrease in blood platelets) How is Gaucher disease diagnosed? Because the signs and symptoms of Gaucher disease\u2014including bone pain and anemia\u2014can resemble many other diseases and conditions, it can often go diagnosed for many years. Here are some diagnostics that may be used: Physical exam: Your doctor can press on your abdomen to check the size of your spleen and liver. Lab tests: Blood tests can check for levels of the enzyme linked to Gaucher. Imaging tests: Dual energy X-ray absorptiometry (DXA) uses low-level X-rays to measure bone density. Magnetic resonance imaging (MRI) can show if the spleen or liver is enlarged and if bone marrow has been affected. We also do echocardiograms and EKGs to see if the lungs or heart are involved. Genetic tests: These can reveal whether you have the disease. At Yale Medicine, we conduct all of our initial diagnostic and evaluation tests in our medical offices during a single visit. How is Gaucher disease treated? Type 1 Gaucher disease, as well as the non-neurological symptoms of type 3, are treatable. Available therapies include: Enzyme replacement therapy (ERT): This balances the low levels of glucocerebrosidase, which is the underlying cause of Gaucher disease. Patients receive intravenous infusions of the enzyme every two weeks. Substrate reduction therapy (SRT): This is an oral medication that decreases the rate of formation of glucocerebroside in the body so that excess buildup is reduced."}
 {"id": "doc18", "text": "Gaucher (pronounced \"go-SHAY\") disease is an inherited illness caused by a gene mutation. Normally, this gene is responsible for an enzyme called glucocerebrosidase that the body needs to break down a particular kind of fat called glucocerebroside. In people with Gaucher disease, the body is not able to properly produce this enzyme, and the fat can not be broken down. It then accumulates, mostly in the liver, spleen, and bone marrow. Gaucher disease can result in pain, fatigue, jaundice, bone damage, anemia, and even death. Gaucher disease is considerably more common in the descendants of Jewish people from Eastern Europe (Ashkenazi), although individuals from any ethnic group may be affected. Among the Ashkenazi Jewish population, Gaucher disease is the most common genetic disorder, with an incidence of approximately 1 in 450 persons. In the general public, Gaucher disease affects approximately 1 in 100,000 persons. According to the National Gaucher Foundation, 2500 Americans suffer from Gaucher disease. In 1991, enzyme replacement therapy became available as the first effective treatment for Gaucher disease. The treatment consists of a modified form of the glucocerebrosidase enzyme given intravenously. Performed on an outpatient basis, the treatment takes about 1-2 h and is given every 2 weeks. Enzyme replacement therapy can stop and often reverse the symptoms of Gaucher disease, allowing patients to enjoy a better quality of life."}
-{"id": "doc19", "text": "Other names Gaucher's disease Acid beta-glucosidase Specialty Endocrinology, neurology Symptoms Hepatosplenomegaly, hypersplenism, pancytopenia, joint pain, neurological symptoms (usually mild), yellowish skin, and osteoporosis Complications Cirrhosis, splenic rupture, bleeding, and infections Usual onset Young adulthood (Type I), infancy (Type II) Duration Lifelong Types Type I, type II, type III Causes Glucocerebrosidase deficiency Risk factors Having parents with the disease or are carriers of the disease Diagnostic method Genetic testing Differential diagnosis SMPD1-associated Niemann\u2013Pick disease, Fabry disease Prevention Gene editing Treatment Enzyme replacement therapy Medication Alglucerase, imiglucerase, velaglucerase, taliglucerase alfa, miglustat, and eliglustat Prognosis Slightly shortened life expectancy (type I), death in early childhood (type II) Frequency 1 in 100 people are carriers Gaucher's disease or Gaucher disease (/\u0261o\u028a\u02c8\u0283e\u026a/) (GD) is a genetic disorder in which glucocerebroside (a sphingolipid, also known as glucosylceramide) accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as glucosylceramidase), which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages (mononuclear leukocytes, which is often a target for intracellular parasites). Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow. Manifestations may include enlarged spleen and liver, liver malfunction, skeletal disorders or bone lesions that may be painful, severe neurological complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelet count, and yellow fatty deposits on the white of the eye (sclera). Persons seriously affected may also be more susceptible to infection. Some forms of Gaucher's disease may be treated with enzyme replacement therapy. The disease is caused by a recessive mutation in the GBA gene located on chromosome 1 and affects both males and females. About one in 100 people in the United States are carriers of the most common type of Gaucher disease. The carrier rate among Ashkenazi Jews is 8.9% while the birth incidence is 1 in 450.[1] Gaucher's disease is the most common of the lysosomal storage diseases.[2] It is a form of sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism of sphingolipids.[3] The disease is named after the French physician Philippe Gaucher, who originally described it in 1882.[4] Signs and symptoms Painless hepatomegaly and splenomegaly: the size of the spleen can be 1,500\u20133,000 g (3.3\u20136.6 lb), as opposed to the normal size of 50\u2013200 g (0.11\u20130.44 lb). Splenomegaly may decrease the affected individual's capacity for eating by exerting pressure on the stomach. While painless, enlargement of spleen increases the risk of splenic rupture. Hypersplenism and pancytopenia, the rapid and premature destruction of blood cells, leads to anemia, neutropenia, leukopenia, and thrombocytopenia (with an increased risk of infection and bleeding). Cirrhosis of the liver is rare. Severe pain associated with joints and bones occurs, frequently presenting in hips and knees. Neurological symptoms occur only in some types of Gaucher's (see below): Type I: impaired olfaction and cognition Type II: serious convulsions, hypertonia, intellectual disability, and apnea Type III: muscle twitches known as myoclonus, convulsions, dementia, and ocular muscle apraxia Parkinson's disease is recognized as being more common in Gaucher's disease patients and their heterozygous carrier relatives.[5] Osteoporosis: 75% of patients develop visible bony abnormalities due to the accumulated glucosylceramide. A deformity of the distal femur in the shape of an Erlenmeyer flask is commonly described. Yellowish-brown skin pigmentation Genetics The three types of Gaucher's disease are autosomal recessive. Both parents must be carriers for a child to be affected. If both parents are carriers, the chance of the disease is one in four, or 25%, with each pregnancy for an affected child. Each type has been linked to particular mutations. In all, about 80 known GBA gene mutations are grouped into three main types:[6] Type I (N370S homozygote), the most common, also called the \"non-neuropathic\" type occurs mainly in Ashkenazi Jews, at 100 times the occurrence in the general populace. The median age at diagnosis is 28 years of age,[7] and life expectancy is mildly decreased.[8] Type II (one or two alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. Prognosis is poor: most die before the age of three. Type III (also one or two copies of L444P, possibly delayed by protective polymorphisms) occurs in Swedish patients from the Norrbotten region.[9] This group develops the disease somewhat later, but most die before their 30th birthday. The Gaucher-causing mutations may have entered the Ashkenazi Jewish gene pool in the early Middle Ages (48\u201355 generations ago).[10] Pathophysiology Sphingolipidoses The disease is caused by a defect in the housekeeping gene for lysosomal glucocerebrosidase (also known as beta-glucosidase, EC 3.2.1.45, PDB: 1OGS\u200b) on the first chromosome (1q22). The enzyme is a 55.6-kilodalton, 497-amino acid-long protein that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. In Gaucher disease, the enzyme is unable to function correctly and glucocerebroside accumulates. 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 to resemble crumpled-up paper.[3] The exact mechanism of neurotoxicity is not understood, but it is thought to involve a reaction to glucosylsphingosine.[3] Different mutations in the GBA (beta-glucosidase) gene determine the remaining activity of the enzyme. In type I, there is some residual activity of the enzyme, accounting for the lack of neuropathology in this type.[3] Although there is some correlation between genotype and phenotype, neither the amount of stored lipids, nor the residual enzyme activity correlates well with disease symptoms.[11] This circumstance has called for alternative explanations accounting for disease symptoms including jamming of the endo/lysosomal system[12] ER stress[13] altered lipid composition of membranes throughout the cell, including the plasma membrane,[14] and consequent changes in the dynamic and signaling properties of the cell membrane[15] inflammation caused by cytokine secretion as a result of sphingolipid accumulation, and neurodegeneration caused by the accumulation of glucosylsphingosine, a neurotoxin[16] Heterozygotes for particular acid beta-glucosidase mutations carry about a five-fold risk of developing Parkinson's disease, making this the most common known genetic risk factor for Parkinson's.[17][18] Cancer risk may be increased, particularly myeloma.[19][20][21] This is thought to be due to accumulation of glucosylceramide and complex glycosphingolipids.[22] The role of inflammatory processes in Gaucher disease is poorly elucidated. However, sphingolipids are known to participate in inflammation and apoptosis, and markers of macrophage activation are elevated in people with Gaucher disease. These markers include angiotensin-converting enzyme, cathepsin S, chitotriosidase, and CCL18 in the blood plasma; and tumor necrosis factor alpha in splenic Gaucher cells (engorged macrophages).[3] Diagnosis Micrograph showing crinkled paper macrophages in the marrow space in a case of Gaucher disease, H&E stain. Gaucher disease is suggested based on the overall clinical picture. Initial laboratory testing may include enzyme testing. As a result, lower than 15% of mean normal activity is considered to be diagnostic.[23] Decreased enzyme levels will often be confirmed by genetic testing. Numerous different mutations occur; sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available and is useful when a known genetic risk factor is present.[citation needed] A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme, and immunoglobulin levels, or by cell analysis showing \"crinkled paper\" cytoplasm and glycolipid-laden macrophages.[citation needed] Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher's disease activity in response to treatment, and may reflect the severity of the disease[24] Classification Gaucher's disease (GD) has three common clinical subtypes.[25][26] These subtypes have come under some criticism for not taking account of the full spectrum of observable symptoms (the phenotypes[27]). Also, compound heterozygous variations occur which considerably increase the complexity of predicting disease course. GD type I (non-neuropathic) is the most common and least severe form of the disease. Symptoms may begin early in life or in adulthood and mainly affect the liver, spleen, and bone. Enlarged liver and grossly enlarged spleen (together hepatosplenomegaly) are common;[3] the spleen can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive.[3] Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia, and leukopenia. The brain and nervous system are not affected pathologically,[3] but lung and, rarely, kidney impairment may occur. Patients in this group usually bruise easily (due to low levels of platelets) and experience fatigue due to low numbers of red blood cells. Depending on disease onset and severity, type I patients may live well into adulthood. The range and severity of symptoms can vary dramatically between patients.[citation needed] GD type II (acute infantile neuropathic) typically begins within six months of birth and has an incidence rate around 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 two. GD type III (chronic neuropathic) can begin at any time in childhood or even in adulthood, and occurs in about 1 in 100,000 live births. It is characterized by slowly progressive, but milder neurologic symptoms compared to the acute or type II 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.[28] Treatment For those with type-I and most type-III, enzyme replacement treatment with intravenous recombinant glucocerebrosidase can decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations.[16][29] This treatment costs about US$200,000 annually for a single person and should be continued for life. The rarity of the disease means dose-finding studies have been difficult to conduct, so controversy remains over the optimal dose and dosing frequency.[7] Due to the low incidence, this has become an orphan drug in many countries, meaning a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population.[citation needed] The first drug for Gaucher's was alglucerase (Ceredase), which was a version of glucocerebrosidase that was harvested from human placental tissue and then modified with enzymes.[30] It was approved by the FDA in 1991[31] and has been withdrawn from the market[32][33] due to the approval of similar drugs made with recombinant DNA technology instead of being harvested from tissue; drugs made recombinantly are preferable, since there is no concern about diseases being transmitted from the tissue used in harvesting, there are fewer risks of variations in enzyme structure from batch to batch, and they are less expensive to manufacture.[30] Available recombinant glucocerebrosidases are:[16] Imiglucerase (approved in 1995)[30] Velaglucerase (approved in 2010)[34] Taliglucerase alfa (Elelyso) (approved in 2012)[35] Miglustat is a small molecule, orally available drug that was first approved for Gaucher's disease in Europe in 2002.[36] It works by preventing the formation of glucocerebroside, the substance that builds up and causes harm in Gaucher's. This approach is called substrate reduction therapy.[37] Eliglustat (Cerdelga) (approved in 2014)[38] is also a small molecule. The compound is believed to work by inhibition of glucosylceramide synthase."}
+{"id": "doc19", "text": "Gaucher's disease or Gaucher disease (/\u0261o\u028a\u02c8\u0283e\u026a/) (GD) is a genetic disorder in which glucocerebroside (a sphingolipid, also known as glucosylceramide) accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as glucosylceramidase), which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages (mononuclear leukocytes, which is often a target for intracellular parasites). Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow. Manifestations may include enlarged spleen and liver, liver malfunction, skeletal disorders or bone lesions that may be painful, severe neurological complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelet count, and yellow fatty deposits on the white of the eye (sclera). Persons seriously affected may also be more susceptible to infection. Some forms of Gaucher's disease may be treated with enzyme replacement therapy. The disease is caused by a recessive mutation in the GBA gene located on chromosome 1 and affects both males and females. About one in 100 people in the United States are carriers of the most common type of Gaucher disease. The carrier rate among Ashkenazi Jews is 8.9% while the birth incidence is 1 in 450. Gaucher's disease is the most common of the lysosomal storage diseases. It is a form of sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism of sphingolipids. The disease is named after the French physician Philippe Gaucher, who originally described it in 1882. Signs and symptoms Painless hepatomegaly and splenomegaly: the size of the spleen can be 1,500\u20133,000 g (3.3\u20136.6 lb), as opposed to the normal size of 50\u2013200 g (0.11\u20130.44 lb). Splenomegaly may decrease the affected individual's capacity for eating by exerting pressure on the stomach. While painless, enlargement of spleen increases the risk of splenic rupture. Hypersplenism and pancytopenia, the rapid and premature destruction of blood cells, leads to anemia, neutropenia, leukopenia, and thrombocytopenia (with an increased risk of infection and bleeding). Cirrhosis of the liver is rare. Severe pain associated with joints and bones occurs, frequently presenting in hips and knees. Neurological symptoms occur only in some types of Gaucher's (see below): Type I: impaired olfaction and cognition Type II: serious convulsions, hypertonia, intellectual disability, and apnea Type III: muscle twitches known as myoclonus, convulsions, dementia, and ocular muscle apraxia Parkinson's disease is recognized as being more common in Gaucher's disease patients and their heterozygous carrier relatives. Osteoporosis: 75% of patients develop visible bony abnormalities due to the accumulated glucosylceramide. A deformity of the distal femur in the shape of an Erlenmeyer flask is commonly described. Yellowish-brown skin pigmentation Genetics The three types of Gaucher's disease are autosomal recessive. Both parents must be carriers for a child to be affected. If both parents are carriers, the chance of the disease is one in four, or 25%, with each pregnancy for an affected child. Each type has been linked to particular mutations. In all, about 80 known GBA gene mutations are grouped into three main types: Type I (N370S homozygote), the most common, also called the \"non-neuropathic\" type occurs mainly in Ashkenazi Jews, at 100 times the occurrence in the general populace. The median age at diagnosis is 28 years of age, and life expectancy is mildly decreased. Type II (one or two alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. Prognosis is poor: most die before the age of three. Type III (also one or two 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. The Gaucher-causing mutations may have entered the Ashkenazi Jewish gene pool in the early Middle Ages (48\u201355 generations ago). Pathophysiology Sphingolipidoses The disease is caused by a defect in the housekeeping gene for lysosomal glucocerebrosidase (also known as beta-glucosidase, EC 3.2.1.45, PDB: 1OGS\u200b) on the first chromosome (1q22). The enzyme is a 55.6-kilodalton, 497-amino acid-long protein that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. In Gaucher disease, the enzyme is unable to function correctly and glucocerebroside accumulates. 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 to resemble crumpled-up paper. The exact mechanism of neurotoxicity is not understood, but it is thought to involve a reaction to glucosylsphingosine. Different mutations in the GBA (beta-glucosidase) gene determine the remaining activity of the enzyme. In type I, there is some residual activity of the enzyme, accounting for the lack of neuropathology in this type. Although there is some correlation between genotype and phenotype, neither the amount of stored lipids, nor the residual enzyme activity correlates well with disease symptoms. This circumstance has called for alternative explanations accounting for disease symptoms including jamming of the endo/lysosomal system ER stress altered lipid composition of membranes throughout the cell, including the plasma membrane, and consequent changes in the dynamic and signaling properties of the cell membrane inflammation caused by cytokine secretion as a result of sphingolipid accumulation, and neurodegeneration caused by the accumulation of glucosylsphingosine, a neurotoxin Heterozygotes for particular acid beta-glucosidase mutations carry about a five-fold risk of developing Parkinson's disease, making this the most common known genetic risk factor for Parkinson's. Cancer risk may be increased, particularly myeloma. This is thought to be due to accumulation of glucosylceramide and complex glycosphingolipids. The role of inflammatory processes in Gaucher disease is poorly elucidated. However, sphingolipids are known to participate in inflammation and apoptosis, and markers of macrophage activation are elevated in people with Gaucher disease. These markers include angiotensin-converting enzyme, cathepsin S, chitotriosidase, and CCL18 in the blood plasma; and tumor necrosis factor alpha in splenic Gaucher cells (engorged macrophages). Diagnosis Micrograph showing crinkled paper macrophages in the marrow space in a case of Gaucher disease, H&E stain. Gaucher disease is suggested based on the overall clinical picture. Initial laboratory testing may include enzyme testing. As a result, lower than 15% of mean normal activity is considered to be diagnostic. Decreased enzyme levels will often be confirmed by genetic testing. Numerous different mutations occur; sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available and is useful when a known genetic risk factor is present. A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme, and immunoglobulin levels, or by cell analysis showing \"crinkled paper\" cytoplasm and glycolipid-laden macrophages. Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher's disease activity in response to treatment, and may reflect the severity of the disease Classification Gaucher's disease (GD) has three common clinical subtypes. These subtypes have come under some criticism for not taking account of the full spectrum of observable symptoms (the phenotypes). Also, compound heterozygous variations occur which considerably increase the complexity of predicting disease course. GD type I (non-neuropathic) is the most common and least severe form of the disease. Symptoms may begin early in life or in adulthood and mainly affect the liver, spleen, and bone. Enlarged liver and grossly enlarged spleen (together hepatosplenomegaly) are common; the spleen 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 and nervous system are not affected pathologically, but lung and, rarely, kidney impairment may occur. Patients in this group usually bruise easily (due to low levels of platelets) and experience fatigue due to low numbers of red blood cells. Depending on disease onset and severity, type I patients may live well into adulthood. The range and severity of symptoms can vary dramatically between patients. GD type II (acute infantile neuropathic) typically begins within six months of birth and has an incidence rate around 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 two. GD type III (chronic neuropathic) can begin at any time in childhood or even in adulthood, and occurs in about 1 in 100,000 live births. It is characterized by slowly progressive, but milder neurologic symptoms compared to the acute or type II 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. Treatment For those with type-I and most type-III, enzyme replacement treatment with intravenous recombinant glucocerebrosidase can decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. This treatment costs about US$200,000 annually for a single person and should be continued for life. The rarity of the disease means dose-finding studies have been difficult to conduct, so controversy remains over the optimal dose and dosing frequency. Due to the low incidence, this has become an orphan drug in many countries, meaning a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population. The first drug for Gaucher's was alglucerase (Ceredase), which was a version of glucocerebrosidase that was harvested from human placental tissue and then modified with enzymes. It was approved by the FDA in 1991 and has been withdrawn from the market due to the approval of similar drugs made with recombinant DNA technology instead of being harvested from tissue; drugs made recombinantly are preferable, since there is no concern about diseases being transmitted from the tissue used in harvesting, there are fewer risks of variations in enzyme structure from batch to batch, and they are less expensive to manufacture. Available recombinant glucocerebrosidases are: Imiglucerase (approved in 1995) Velaglucerase (approved in 2010) Taliglucerase alfa (Elelyso) (approved in 2012) Miglustat is a small molecule, orally available drug that was first approved for Gaucher's disease in Europe in 2002. It works by preventing the formation of glucocerebroside, the substance that builds up and causes harm in Gaucher's. This approach is called substrate reduction therapy. Eliglustat (Cerdelga) (approved in 2014) is also a small molecule. The compound is believed to work by inhibition of glucosylceramide synthase."}
 {"id": "doc20", "text": "Summary Epidemiology The prevalence is approximately 1/100,000. The annual incidence of GD in the general population is about 1/60,000, but it can reach up to 1/1,000 in Ashkenazi Jewish populations. Clinical description The clinical manifestations of this disease are highly variable. GD type 1 (90% of cases) is the chronic and non-neurological form associated with organomegaly (spleen, liver), bone anomalies (pain, osteonecrosis, pathological fractures) and cytopenia. Type 2, the acute neurological form, is characterized by early onset, rapidly progressing brainstem dysfunction, associated with organomegaly and leading to death before the age of 2. Type 3, the subacute neurological form, affects children or adolescents and is characterized by progressive encephalopathy (oculomotor apraxia, epilepsy and ataxia) with the systemic manifestations seen in type 1. The fetal form manifests with a decrease or absence of fetal movements or anasarca. Gaucher-like disease presents with progressive calcification of the aorta and the aortic and/ or mitral valves as its main feature. Etiology GD is due to mutations in the GBA gene (1q21) that codes for a lysosomal enzyme, glucocerebrosidase, or in very rare cases the PSAP gene that codes for its activator protein (saposin C). The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramide (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, the spleen and the bone marrow (Gaucher cells). Diagnostic methods Formal diagnosis of the disease is determined by the measurement of glucocerebrosidase levels in circulating leukocytes. Genotyping confirms the diagnosis. Differential diagnosis Differential diagnoses include other lysosomal storage disorders. The presence of Gaucher-like cells can be found in certain hematologic diseases (lymphoma, Hodgkin's lymphoma and chronic lymphocytic leukemia; see these terms). Genetic counseling Transmission is autosomal recessive. Management and treatment There are two available treatments for GD type 1 and 3: enzyme substitution therapy (using imiglucerase or velaglucerase) and substrate reduction therapy (miglustat). These treatments are ineffective for GD type 2. Prognosis The prognosis is good in GD type 1. In type 2, death usually occurs before the age of 2. Without specific treatment, GD type 3 progresses to death within a few years."}