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Overview of Primary Ciliary Dyskinesia
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Primary ciliary dyskinesia (PCD) is usually an autosomal recessive genetic condition in which the microscopic organelles (cilia) in the respiratory system have defective function. Ciliary dysfunction prevents the clearance of mucous from the lungs, paranasal sinuses and middle ears. Bacteria and other irritants in the mucous lead to frequent respiratory infections. Kartagener syndrome is a type of PCD associated with a mirror-image orientation of the heart and other internal organs (situs inversus). Rare cases of X-linked and autosomal dominant inheritance have been observed.
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Overview of Primary Ciliary Dyskinesia. Primary ciliary dyskinesia (PCD) is usually an autosomal recessive genetic condition in which the microscopic organelles (cilia) in the respiratory system have defective function. Ciliary dysfunction prevents the clearance of mucous from the lungs, paranasal sinuses and middle ears. Bacteria and other irritants in the mucous lead to frequent respiratory infections. Kartagener syndrome is a type of PCD associated with a mirror-image orientation of the heart and other internal organs (situs inversus). Rare cases of X-linked and autosomal dominant inheritance have been observed.
| 1,000 |
Primary Ciliary Dyskinesia
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nord_1000_1
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Symptoms of Primary Ciliary Dyskinesia
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The magnitude symptoms of primary ciliary dyskinesia vary in affected individuals. Symptoms often begin shortly after birth and can include coughing, gagging, choking and lung atelectasis (neonatal respiratory distress). Affected individuals often experience chronic sinus, middle ear and lung infections as well as chronic coughing, excess mucus and hearing loss. The recurring respiratory infections can lead to an irreversible scarring and dilatation in the bronchi (bronchiectasis) and severe lung damage.Cilia are also present in the ventricles of the brain and in the reproductive system so ciliary dysfunction can also affect other body systems. Affected males are typically infertile because movement of sperm (motility) is abnormal. PCD may also be associated with infertility and ectopic pregnancy in females.Movement of cilia may also be important in organ placement in the developing embryo. Approximately 50% of individuals with PCD have Kartagener syndrome in which the internal organs including the heart, liver, spleen and intestine are on the opposite side of the body (situs inversus totalis). Some individuals with PCD have a condition called heterotaxy (situs ambiguus) in which internal organs are abnormally positioned and have abnormal structure. Approximately, 12% of the PCD patients present with heterotaxy and a subset of those have congenital heart defects that can be serious and life threatening.
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Symptoms of Primary Ciliary Dyskinesia. The magnitude symptoms of primary ciliary dyskinesia vary in affected individuals. Symptoms often begin shortly after birth and can include coughing, gagging, choking and lung atelectasis (neonatal respiratory distress). Affected individuals often experience chronic sinus, middle ear and lung infections as well as chronic coughing, excess mucus and hearing loss. The recurring respiratory infections can lead to an irreversible scarring and dilatation in the bronchi (bronchiectasis) and severe lung damage.Cilia are also present in the ventricles of the brain and in the reproductive system so ciliary dysfunction can also affect other body systems. Affected males are typically infertile because movement of sperm (motility) is abnormal. PCD may also be associated with infertility and ectopic pregnancy in females.Movement of cilia may also be important in organ placement in the developing embryo. Approximately 50% of individuals with PCD have Kartagener syndrome in which the internal organs including the heart, liver, spleen and intestine are on the opposite side of the body (situs inversus totalis). Some individuals with PCD have a condition called heterotaxy (situs ambiguus) in which internal organs are abnormally positioned and have abnormal structure. Approximately, 12% of the PCD patients present with heterotaxy and a subset of those have congenital heart defects that can be serious and life threatening.
| 1,000 |
Primary Ciliary Dyskinesia
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nord_1000_2
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Causes of Primary Ciliary Dyskinesia
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Primary ciliary dyskinesia usually follows autosomal recessive genetic inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes for a given trait from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry multiple abnormal genes for various traits. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Primary Ciliary Dyskinesia. Primary ciliary dyskinesia usually follows autosomal recessive genetic inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes for a given trait from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry multiple abnormal genes for various traits. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
| 1,000 |
Primary Ciliary Dyskinesia
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nord_1000_3
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Affects of Primary Ciliary Dyskinesia
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Primary ciliary dyskinesia occurs in approximately 1 in 16,000 to 20,000 births. That translates to the incidence of Kartagener syndrome as 1 in 32,000 to 40,000 births.
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Affects of Primary Ciliary Dyskinesia. Primary ciliary dyskinesia occurs in approximately 1 in 16,000 to 20,000 births. That translates to the incidence of Kartagener syndrome as 1 in 32,000 to 40,000 births.
| 1,000 |
Primary Ciliary Dyskinesia
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nord_1000_4
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Related disorders of Primary Ciliary Dyskinesia
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Symptoms of the following disorders can be similar to those of primary ciliary dyskinesia. Comparisons may be useful for a differential diagnosis:Cystic fibrosis is a genetic disease that affects approximately 30,000 children and adults in the United States. Because of a defective gene (CFTR), mucus within the lining of the lung’s airways (bronchi) is not normally hydrated, which leads to unusually thick, sticky secretions. This clogs the air passages, promotes bacterial growth, and leads to chronic obstruction, inflammation, and infection of the airways. These thick secretions also obstruct the pancreatic ducts, keeping digestive enzymes from reaching the intestines to help break down and absorb food. (For more information on this disorder, choose “cystic fibrosis” as your search term in the Rare Disease Database.)IgG subclass deficiency is characterized by recurrent infections of the ears, sinuses, bronchi and lungs. IgG is a class of antibodies that contains four different types of IgG molecules. Individuals who are missing or have low levels of one or two of these types are at risk for respiratory infections.Granulomatosis with polyangiitis is a rare disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some patients, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of this condition is not known. (For more information on this disorder, choose “granulomatosis with polyangiitis” as your search term in the Rare Disease Database.)Gastroesophageal reflux (GERD) is a digestive disorder characterized by the passage or flowing back (reflux) of the contents of the stomach or small intestines (duodenum) into the esophagus. The esophagus is the tube that carries food from the mouth to the stomach. Symptoms of gastroesophageal reflux may include a sensation of warmth or burning rising up to the neck area (heartburn or pyrosis), swallowing difficulties (dysphagia), and chest pain. This condition is a common problem and may be a symptom of other gastrointestinal disorders.
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Related disorders of Primary Ciliary Dyskinesia. Symptoms of the following disorders can be similar to those of primary ciliary dyskinesia. Comparisons may be useful for a differential diagnosis:Cystic fibrosis is a genetic disease that affects approximately 30,000 children and adults in the United States. Because of a defective gene (CFTR), mucus within the lining of the lung’s airways (bronchi) is not normally hydrated, which leads to unusually thick, sticky secretions. This clogs the air passages, promotes bacterial growth, and leads to chronic obstruction, inflammation, and infection of the airways. These thick secretions also obstruct the pancreatic ducts, keeping digestive enzymes from reaching the intestines to help break down and absorb food. (For more information on this disorder, choose “cystic fibrosis” as your search term in the Rare Disease Database.)IgG subclass deficiency is characterized by recurrent infections of the ears, sinuses, bronchi and lungs. IgG is a class of antibodies that contains four different types of IgG molecules. Individuals who are missing or have low levels of one or two of these types are at risk for respiratory infections.Granulomatosis with polyangiitis is a rare disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some patients, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of this condition is not known. (For more information on this disorder, choose “granulomatosis with polyangiitis” as your search term in the Rare Disease Database.)Gastroesophageal reflux (GERD) is a digestive disorder characterized by the passage or flowing back (reflux) of the contents of the stomach or small intestines (duodenum) into the esophagus. The esophagus is the tube that carries food from the mouth to the stomach. Symptoms of gastroesophageal reflux may include a sensation of warmth or burning rising up to the neck area (heartburn or pyrosis), swallowing difficulties (dysphagia), and chest pain. This condition is a common problem and may be a symptom of other gastrointestinal disorders.
| 1,000 |
Primary Ciliary Dyskinesia
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nord_1000_5
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Diagnosis of Primary Ciliary Dyskinesia
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Primary ciliary dyskinesia is diagnosed definitively through examination of lung or sinus tissue obtained from a biopsy or through genetic testing. Specific structural defects that are present in these tissues can be detected under an electron microscope. Early diagnosis is important in order to provide prophylactic treatment to prevent or decrease damage to the respiratory system from recurrent infections. Screening for levels of nasal nitric oxide (in patients over 5 years of age who can cooperate with palate closure maneuvers) is helpful to identify individuals who may have PCD and should proceed with a biopsy. Currently, mutations in 44 genes are known to be associated with PCD. These do not account for all cases of PCD and hence more PCD genes are yet to be identified. PCD clinical genetic testing is available for some of the 44 genes associated with PCD by the commercial laboratories and new genes are being added to their panels periodically.
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Diagnosis of Primary Ciliary Dyskinesia. Primary ciliary dyskinesia is diagnosed definitively through examination of lung or sinus tissue obtained from a biopsy or through genetic testing. Specific structural defects that are present in these tissues can be detected under an electron microscope. Early diagnosis is important in order to provide prophylactic treatment to prevent or decrease damage to the respiratory system from recurrent infections. Screening for levels of nasal nitric oxide (in patients over 5 years of age who can cooperate with palate closure maneuvers) is helpful to identify individuals who may have PCD and should proceed with a biopsy. Currently, mutations in 44 genes are known to be associated with PCD. These do not account for all cases of PCD and hence more PCD genes are yet to be identified. PCD clinical genetic testing is available for some of the 44 genes associated with PCD by the commercial laboratories and new genes are being added to their panels periodically.
| 1,000 |
Primary Ciliary Dyskinesia
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nord_1000_6
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Therapies of Primary Ciliary Dyskinesia
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TreatmentAirway clearance therapy is used to keep the lung tissue healthy for as long as possible. This therapy may include routine washing and suctioning of the sinus cavities and ear canals. Antibiotics, bronchodilators, steroids and mucus thinners (mucolytics) are also used to treat PCD. Routine hearing evaluation is important for young children and speech therapy and hearing aids may appropriate for children with hearing loss and speech problems. Lung transplantation is an option for severe, advanced lung disease. Surgery may be indicated if heart defects are present.
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Therapies of Primary Ciliary Dyskinesia. TreatmentAirway clearance therapy is used to keep the lung tissue healthy for as long as possible. This therapy may include routine washing and suctioning of the sinus cavities and ear canals. Antibiotics, bronchodilators, steroids and mucus thinners (mucolytics) are also used to treat PCD. Routine hearing evaluation is important for young children and speech therapy and hearing aids may appropriate for children with hearing loss and speech problems. Lung transplantation is an option for severe, advanced lung disease. Surgery may be indicated if heart defects are present.
| 1,000 |
Primary Ciliary Dyskinesia
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nord_1001_0
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Overview of Primary Craniosynostosis
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Primary craniosynostosis is a general term for the improper development of the bones of the skull, which can result in an abnormal head shape in affected individuals. Craniosynostosis refers to the premature fusion of the fibrous joints (sutures) between certain bones of the skull. The severity of primary craniosynostosis can vary from one person to another. While raised intracranial pressure is unlikely with single suture abnormalities with intelligence usually being unaffected, recent data and debate about unrecognized elevated pressure (as well as effects upon cognition) has led to considerable controversy. Until we are able to measure intracranial pressure via non-invasive means, it is likely that the surgical argument between appearance and brain pressure will continue. Primary craniosynostosis may occur as an isolated finding or as part of a syndrome. Patients with syndromic conditions generally have more than one suture involved. Not surprisingly, the therapeutic options and outcomes are dependent upon the degree of suture involvement. The main treatment for primary craniosynostosis is surgery, but not all affected children will require surgery. The exact cause of primary craniosynostosis is unknown, although the skull abnormalities may result from the abnormal hardening (ossification) of the cranial sutures. Primary craniosynostosis is distinguished from secondary craniosynostosis, which occurs because of a primary failure in brain growth which in turn may lead to abnormalities in head shape, occasionally mimicking craniosynostosis.
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Overview of Primary Craniosynostosis. Primary craniosynostosis is a general term for the improper development of the bones of the skull, which can result in an abnormal head shape in affected individuals. Craniosynostosis refers to the premature fusion of the fibrous joints (sutures) between certain bones of the skull. The severity of primary craniosynostosis can vary from one person to another. While raised intracranial pressure is unlikely with single suture abnormalities with intelligence usually being unaffected, recent data and debate about unrecognized elevated pressure (as well as effects upon cognition) has led to considerable controversy. Until we are able to measure intracranial pressure via non-invasive means, it is likely that the surgical argument between appearance and brain pressure will continue. Primary craniosynostosis may occur as an isolated finding or as part of a syndrome. Patients with syndromic conditions generally have more than one suture involved. Not surprisingly, the therapeutic options and outcomes are dependent upon the degree of suture involvement. The main treatment for primary craniosynostosis is surgery, but not all affected children will require surgery. The exact cause of primary craniosynostosis is unknown, although the skull abnormalities may result from the abnormal hardening (ossification) of the cranial sutures. Primary craniosynostosis is distinguished from secondary craniosynostosis, which occurs because of a primary failure in brain growth which in turn may lead to abnormalities in head shape, occasionally mimicking craniosynostosis.
| 1,001 |
Primary Craniosynostosis
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nord_1001_1
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Symptoms of Primary Craniosynostosis
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Primary craniosynostosis is usually apparent at birth or within a few months shortly thereafter (neonatal period). Mild cases may go undiagnosed until early during childhood.An infant’s skull has seven bones and several joints called sutures. Sutures are made of tough, elastic fibrous tissue and separate the bones from one another. Sutures meet up (intersect) at two spots on the skull called fontanelles, which are better known as an infant’s “soft spots”. The seven bones of an infant’s skull normally do not fuse together until around age two or later. The sutures normally remain flexible until this point. In infants with primary craniosynostosis, the sutures abnormally stiffen or harden causing one or more of the bones of the skull to prematurely fuse together. This in turn, may lead to asymmetric skull growth.In primary craniosynostosis, the severity and specific shape of an infant’s skull depends upon how many and which sutures / bones are affected. In most cases, only one suture is affected (simple craniosynostosis). Consequently, growth in that area of the skull is hindered, but growth (in order to accommodate the infant’s expanding brain) in the unaffected areas continues. This results in an abnormal skull shape.In most cases of primary craniosynostosis, affected children usually have normal intelligence and do not have other abnormalities besides the skull malformation. However, when multiple sutures are affected, the skull may be unable to expand enough to accommodate the growing brain. If left untreated, this can cause increased pressure within the skull (intracranial pressure) and can potentially result in cognitive impairment or developmental delays. Increased pressure within the skull can also cause vomiting, headaches, and decreased appetite. In some rare cases, additional symptoms can develop including seizures, misalignment of the spine, or eye abnormalities.Craniosynostosis may be subdivided based upon the exact sutures and bones involved. Most cases of primary craniosynostosis involve only one suture. Each subdivision results in a different characteristic pattern of skull development. The subdivisions of craniosynostosis include sagittal synostosis, coronal synostosis, metopic synostosis, and lambdoid synostosis. (Synostosis is a medical term for the fusion of bones that are normally separate.)The most common form of craniosynostosis is sagittal synostosis (hardening of the sagittal suture). The sagittal suture is the joint that runs from the front to the back of the skull and that separates the two bones that form the sides of the skull (parietal bones). Premature closure of this suture results in an abnormally long, narrow head (scaphocephaly) due to the restricted sideways growth (width) of the skull.Coronal synostosis refers to the premature closure of one of the coronal sutures, which are the joints that separate the two frontal bones from the two parietal bones. The coronal sutures extend across the skull, almost from one ear to the other. The two coronal sutures meet at the “soft spot” (anterior fontanelle) located toward the front and of the skull. The skull may appear twisted or lopsided and the forehead and orbit of the eye may appear flattened on one side whereas the opposite side of the forehead may appear to bulge as part of the brain’s unrestricted growth on this side. This specific skull shape is sometimes referred to as frontal plagiocephaly. When both coronal sutures are involved, it causes the skull to appear abnormally short and disproportionally wide (brachycephaly).Metopic synostosis refers to the premature fusion of the metopic suture, which is the joint that separates the two frontal bones of the skull. It runs from the top of the forehead to the anterior fontanelle (frontal soft spot). This condition causes a keel-shaped forehead and eyes that are set closer together than normal (hypotelorism). When viewed from above the skull may appear to be shaped triangularly, a condition referred to as trigonocephaly. A ridge may be apparent running down the middle of the forehead, which may appear narrow. The soft spot found toward the back of the skull (anterior fontanelle) is usually absent or prematurely closed. The presence of a metopic ridge (a palpable/ visible prominence over the midline of the forehead) is relatively common and not all individuals with this ridge have trigonocephaly.Lambdoid synostosis, also known as posterior plagiocephaly, is the premature fusion of the lambdoid suture, which is the joint that separates the bone that forms the lower back of the skull (occipital bone) from the parietal bones. One side of the rear of the head may appear flatter than the other when viewed from above. The ear on the affected side may be pulled backward and stick out farther than the other ear. A small bump may also be present behind the ear on the affected side. Whereas true lambdoid synostosis is extremely rare (1/200,000), this should not be confused with the nearly ubiquitous lambdoid positional plagiocephaly. Fortunately, there are physical features that help to differentiate these two conditions and children with positional plagiocephaly usually have compensatory overgrowth at the forehead on the same side.In rare cases, individuals with primary craniosynostosis have premature fusion of multiple sutures. A specific form of craniosynostosis involving multiple sutures is known as Kleeblattschadel (which is German for “cloverleaf” ) deformity. Fusion of multiple sutures causes the skull to appear flattened and divided into three lobes, thus resembling a cloverleaf. Kleeblattschadel deformity usually occurs as part of a syndrome.
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Symptoms of Primary Craniosynostosis. Primary craniosynostosis is usually apparent at birth or within a few months shortly thereafter (neonatal period). Mild cases may go undiagnosed until early during childhood.An infant’s skull has seven bones and several joints called sutures. Sutures are made of tough, elastic fibrous tissue and separate the bones from one another. Sutures meet up (intersect) at two spots on the skull called fontanelles, which are better known as an infant’s “soft spots”. The seven bones of an infant’s skull normally do not fuse together until around age two or later. The sutures normally remain flexible until this point. In infants with primary craniosynostosis, the sutures abnormally stiffen or harden causing one or more of the bones of the skull to prematurely fuse together. This in turn, may lead to asymmetric skull growth.In primary craniosynostosis, the severity and specific shape of an infant’s skull depends upon how many and which sutures / bones are affected. In most cases, only one suture is affected (simple craniosynostosis). Consequently, growth in that area of the skull is hindered, but growth (in order to accommodate the infant’s expanding brain) in the unaffected areas continues. This results in an abnormal skull shape.In most cases of primary craniosynostosis, affected children usually have normal intelligence and do not have other abnormalities besides the skull malformation. However, when multiple sutures are affected, the skull may be unable to expand enough to accommodate the growing brain. If left untreated, this can cause increased pressure within the skull (intracranial pressure) and can potentially result in cognitive impairment or developmental delays. Increased pressure within the skull can also cause vomiting, headaches, and decreased appetite. In some rare cases, additional symptoms can develop including seizures, misalignment of the spine, or eye abnormalities.Craniosynostosis may be subdivided based upon the exact sutures and bones involved. Most cases of primary craniosynostosis involve only one suture. Each subdivision results in a different characteristic pattern of skull development. The subdivisions of craniosynostosis include sagittal synostosis, coronal synostosis, metopic synostosis, and lambdoid synostosis. (Synostosis is a medical term for the fusion of bones that are normally separate.)The most common form of craniosynostosis is sagittal synostosis (hardening of the sagittal suture). The sagittal suture is the joint that runs from the front to the back of the skull and that separates the two bones that form the sides of the skull (parietal bones). Premature closure of this suture results in an abnormally long, narrow head (scaphocephaly) due to the restricted sideways growth (width) of the skull.Coronal synostosis refers to the premature closure of one of the coronal sutures, which are the joints that separate the two frontal bones from the two parietal bones. The coronal sutures extend across the skull, almost from one ear to the other. The two coronal sutures meet at the “soft spot” (anterior fontanelle) located toward the front and of the skull. The skull may appear twisted or lopsided and the forehead and orbit of the eye may appear flattened on one side whereas the opposite side of the forehead may appear to bulge as part of the brain’s unrestricted growth on this side. This specific skull shape is sometimes referred to as frontal plagiocephaly. When both coronal sutures are involved, it causes the skull to appear abnormally short and disproportionally wide (brachycephaly).Metopic synostosis refers to the premature fusion of the metopic suture, which is the joint that separates the two frontal bones of the skull. It runs from the top of the forehead to the anterior fontanelle (frontal soft spot). This condition causes a keel-shaped forehead and eyes that are set closer together than normal (hypotelorism). When viewed from above the skull may appear to be shaped triangularly, a condition referred to as trigonocephaly. A ridge may be apparent running down the middle of the forehead, which may appear narrow. The soft spot found toward the back of the skull (anterior fontanelle) is usually absent or prematurely closed. The presence of a metopic ridge (a palpable/ visible prominence over the midline of the forehead) is relatively common and not all individuals with this ridge have trigonocephaly.Lambdoid synostosis, also known as posterior plagiocephaly, is the premature fusion of the lambdoid suture, which is the joint that separates the bone that forms the lower back of the skull (occipital bone) from the parietal bones. One side of the rear of the head may appear flatter than the other when viewed from above. The ear on the affected side may be pulled backward and stick out farther than the other ear. A small bump may also be present behind the ear on the affected side. Whereas true lambdoid synostosis is extremely rare (1/200,000), this should not be confused with the nearly ubiquitous lambdoid positional plagiocephaly. Fortunately, there are physical features that help to differentiate these two conditions and children with positional plagiocephaly usually have compensatory overgrowth at the forehead on the same side.In rare cases, individuals with primary craniosynostosis have premature fusion of multiple sutures. A specific form of craniosynostosis involving multiple sutures is known as Kleeblattschadel (which is German for “cloverleaf” ) deformity. Fusion of multiple sutures causes the skull to appear flattened and divided into three lobes, thus resembling a cloverleaf. Kleeblattschadel deformity usually occurs as part of a syndrome.
| 1,001 |
Primary Craniosynostosis
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nord_1001_2
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Causes of Primary Craniosynostosis
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The exact cause of primary (isolated) craniosynostosis is unknown. Primary isolated craniosynostosis refers to cases that are not associated with a larger syndrome. Most cases occur randomly for no apparent reason (sporadically) although an infant’s position in utero, large size and presence of twins have all been implicated as etiological factors. A variety of different genetic and environmental factors are suspected to play a role in the development of primary isolated craniosynostosis.In extremely rare cases, primary isolated craniosynostosis is genetic and in such cases is usually inherited as an autosomal dominant trait. Most cases of primary craniosynostosis that occur as part of a syndrome are also inherited as autosomal dominant traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.The most widely accepted theory for the development of primary craniosynostosis is a primary defect in the ossification (hardening) of the cranial bones. The underlying cause of this defect is unknown in primary isolated craniosynostosis. In the syndromic forms, the defect is due to a mutation in a specific gene. Syndromic forms of primary craniosynostosis include Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome and Saethre-Chotzen syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Causes of Primary Craniosynostosis. The exact cause of primary (isolated) craniosynostosis is unknown. Primary isolated craniosynostosis refers to cases that are not associated with a larger syndrome. Most cases occur randomly for no apparent reason (sporadically) although an infant’s position in utero, large size and presence of twins have all been implicated as etiological factors. A variety of different genetic and environmental factors are suspected to play a role in the development of primary isolated craniosynostosis.In extremely rare cases, primary isolated craniosynostosis is genetic and in such cases is usually inherited as an autosomal dominant trait. Most cases of primary craniosynostosis that occur as part of a syndrome are also inherited as autosomal dominant traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.The most widely accepted theory for the development of primary craniosynostosis is a primary defect in the ossification (hardening) of the cranial bones. The underlying cause of this defect is unknown in primary isolated craniosynostosis. In the syndromic forms, the defect is due to a mutation in a specific gene. Syndromic forms of primary craniosynostosis include Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome and Saethre-Chotzen syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
| 1,001 |
Primary Craniosynostosis
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nord_1001_3
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Affects of Primary Craniosynostosis
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Primary craniosynostosis affects individuals of all races and ethnicities and is usually present at birth. Most forms of primary craniosynostosis affect men and women in equal numbers (although males outnumber females 2:1 for sagittal synostosis). Primary craniosynostosis affects approximately 0.6 in 100,000 people in the general population. Overall, craniosynostosis affects approximately 1 in 2,000-2,500 people in the general population. Approximately 80-90 percent of individuals with primary craniosynostosis have isolated defects. The remaining cases of primary craniosynostosis occur as part of a larger syndrome. More than 150 different syndromes have been identified that are potentially associated with craniosynostosis.
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Affects of Primary Craniosynostosis. Primary craniosynostosis affects individuals of all races and ethnicities and is usually present at birth. Most forms of primary craniosynostosis affect men and women in equal numbers (although males outnumber females 2:1 for sagittal synostosis). Primary craniosynostosis affects approximately 0.6 in 100,000 people in the general population. Overall, craniosynostosis affects approximately 1 in 2,000-2,500 people in the general population. Approximately 80-90 percent of individuals with primary craniosynostosis have isolated defects. The remaining cases of primary craniosynostosis occur as part of a larger syndrome. More than 150 different syndromes have been identified that are potentially associated with craniosynostosis.
| 1,001 |
Primary Craniosynostosis
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nord_1001_4
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Related disorders of Primary Craniosynostosis
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Symptoms of the following disorders can be similar to those of primary craniosynostosis. Comparisons may be useful for a differential diagnosis.Secondary craniosynostosis refers to the development of an abnormal skull shape due to the premature closure of the cranial sutures that occurs because of a primary failure of brain growth. Proper brain growth pushes the bones of the skull apart, a normal process to allow the skull to accommodate the growing brain. Failure of proper brain growth allows the bones to fuse together prematurely. A variety of different underlying causes can result in the failure of brain growth and subsequent craniosynostosis. These causes include metabolic disorders, certain blood (hematological) disorders, malformation disorders, and the exposure of the fetus to certain drugs including valproic acid or phenytoin. Secondary craniosynostosis is usually associated with additional symptoms including facial abnormalities, developmental delays and microcephaly, a condition in which the head circumference is smaller than would be expected for an infant’s age and sex.Deformational (positional) plagiocephaly, sometimes known as positional plagiocephaly, is a condition in which the skull becomes misshapen due to repeated or constant pressure on a specific area of the skull. Deformational (positional) plagiocephaly is not associated with premature fusion of cranial sutures. It is caused by external forces acting on an infant’s skull. It can develop before birth or after birth. The incidence of deformational (positional) plagiocephaly has increased since the American Academy of Pediatrics recommended that newborns sleep on their backs to prevent sudden infant death syndrome. This repetitive sleeping pattern results in the flattening of the back of the infant’s head or often preceded by the presence of torticollis at birth. Deformational plagiocephaly is not associated with any other abnormalities and does not affect a child’s development.
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Related disorders of Primary Craniosynostosis. Symptoms of the following disorders can be similar to those of primary craniosynostosis. Comparisons may be useful for a differential diagnosis.Secondary craniosynostosis refers to the development of an abnormal skull shape due to the premature closure of the cranial sutures that occurs because of a primary failure of brain growth. Proper brain growth pushes the bones of the skull apart, a normal process to allow the skull to accommodate the growing brain. Failure of proper brain growth allows the bones to fuse together prematurely. A variety of different underlying causes can result in the failure of brain growth and subsequent craniosynostosis. These causes include metabolic disorders, certain blood (hematological) disorders, malformation disorders, and the exposure of the fetus to certain drugs including valproic acid or phenytoin. Secondary craniosynostosis is usually associated with additional symptoms including facial abnormalities, developmental delays and microcephaly, a condition in which the head circumference is smaller than would be expected for an infant’s age and sex.Deformational (positional) plagiocephaly, sometimes known as positional plagiocephaly, is a condition in which the skull becomes misshapen due to repeated or constant pressure on a specific area of the skull. Deformational (positional) plagiocephaly is not associated with premature fusion of cranial sutures. It is caused by external forces acting on an infant’s skull. It can develop before birth or after birth. The incidence of deformational (positional) plagiocephaly has increased since the American Academy of Pediatrics recommended that newborns sleep on their backs to prevent sudden infant death syndrome. This repetitive sleeping pattern results in the flattening of the back of the infant’s head or often preceded by the presence of torticollis at birth. Deformational plagiocephaly is not associated with any other abnormalities and does not affect a child’s development.
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Primary Craniosynostosis
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nord_1001_5
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Diagnosis of Primary Craniosynostosis
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A diagnosis of primary craniosynostosis is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation that includes careful assessment of the shape of the skull. A variety of specialized tests include specialized imaging techniques. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI), although a head CT is best for evaluating suture / bone involvement. Although there has been recent debate about the need for CT’s prior to surgery (and accompanying radiation), there are a number of literature reports documenting their value in ruling out other suture involvement as well as brain abnormalities. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Routine skull x-rays have been discontinued as a routine diagnostic tool in the setting of craniosynostosis due to the lack of sensitivity and frequent inaccuracy.In some cases, a diagnosis of primary craniosynostosis may be made before birth (prenatally) by ultrasound examination. During an ultrasound, reflected sound waves create an image of the developing fetus. An increasing number of children are also being diagnosed via prenatal MRI.
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Diagnosis of Primary Craniosynostosis. A diagnosis of primary craniosynostosis is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation that includes careful assessment of the shape of the skull. A variety of specialized tests include specialized imaging techniques. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI), although a head CT is best for evaluating suture / bone involvement. Although there has been recent debate about the need for CT’s prior to surgery (and accompanying radiation), there are a number of literature reports documenting their value in ruling out other suture involvement as well as brain abnormalities. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Routine skull x-rays have been discontinued as a routine diagnostic tool in the setting of craniosynostosis due to the lack of sensitivity and frequent inaccuracy.In some cases, a diagnosis of primary craniosynostosis may be made before birth (prenatally) by ultrasound examination. During an ultrasound, reflected sound waves create an image of the developing fetus. An increasing number of children are also being diagnosed via prenatal MRI.
| 1,001 |
Primary Craniosynostosis
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nord_1001_6
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Therapies of Primary Craniosynostosis
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Treatment
The treatment of primary craniosynostosis is directed toward the specific symptoms that are apparent in each individual. In general, it is an issue of appearance versus intracranial pressure. Surgery is the main form of therapy for affected children, but not all children will require surgery. Surgery is performed to create and ensure that there is enough room within the skull for the developing brain to grow; to relieve intracranial pressure (if present); and to improve the appearance of an affected child’s head. The various surgical approaches (endoscopic, Pi procedures, total calvarial reconfiguration, springs, distraction, etc) each have their unique advantages / disadvantages and are best discussed in detail with the treating physician at the time of evaluation.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Primary Craniosynostosis. Treatment
The treatment of primary craniosynostosis is directed toward the specific symptoms that are apparent in each individual. In general, it is an issue of appearance versus intracranial pressure. Surgery is the main form of therapy for affected children, but not all children will require surgery. Surgery is performed to create and ensure that there is enough room within the skull for the developing brain to grow; to relieve intracranial pressure (if present); and to improve the appearance of an affected child’s head. The various surgical approaches (endoscopic, Pi procedures, total calvarial reconfiguration, springs, distraction, etc) each have their unique advantages / disadvantages and are best discussed in detail with the treating physician at the time of evaluation.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Primary Craniosynostosis
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nord_1002_0
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Overview of Primary Distal Renal Tubular Acidosis
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Summary Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder that affects the ability of the kidneys to remove acid from the blood. This leads to metabolic acidosis. Metabolic acidosis is a condition in which the circulating chemical acids and bases are out of balance. The blood of affected individuals contains too much acid and the urine contains too little acid. Chronic metabolic acidosis can lead to a variety of symptoms. The specific signs, symptoms, and severity of this disorder can vary from one person to another. There are different forms of primary distal renal tubular acidosis. They are caused by a variation (mutation) in one of at least three different genes; the SLC4A1 gene, the ATP6V0A4 gene, and the ATP6V1B1 gene. A variation in the SLC4A1 gene is usually inherited in an autosomal dominant pattern, and less often in an autosomal recessive pattern. Variations in the ATP6V0A4 and ATP6V1B1 genes are usually inherited in an autosomal recessive pattern. A mixture of sodium and potassium salts in the form of sodium citrate or potassium citrate liquid solutions is usually recommended. Liquid preparations, however, have poor palatability and acceptance among patients. In this case, sodium bicarbonate tablets are used instead or in addition to the drinking solution. Often, potassium supplements may be necessary if not included in the alkali therapy. Introduction Renal tubular acidosis is a general term for when the kidneys cannot properly remove acid from the body. The kidneys contain nephrons, which are hair-sized structures that are the basic filtering units of the kidneys. Each nephron consists of a glomerulus and a renal tubule. The renal tubule reabsorbs electrolytes such as sodium, chloride and potassium back into the blood so that not too much electrolyte is lost through the urine. The kidneys, through the tubules, reclaim bicarbonate, an electrolyte that helps to maintain the acid-base balance in the body, and then excrete acid through the urine. Acid is produced as a byproduct from a normal diet.There are several types of renal tubular acidosis. According to their pathophysiological basis, 4 types of RTA were initially categorized. Distal type I RTA or classic RTA usually referred to as distal renal tubular acidosis (dRTA) is characterized by a buildup of acids in the blood as a consequence of the distal tubules in the kidneys not being able to rid the body of the daily acid load. This results in an inability to lower urine pH regardless of the degree of acidemia (acid level in the blood). pH is the measure of acidity of liquids. The higher the score more alkaline and less acidic a liquid is. Distal refers to being “distant” from the point of origin. In the nephron, it means the defect occurs away from the point where fluid enters the tubule. Distal renal tubular acidosis occurs because the kidneys fail to secrete acids into the urine.
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Overview of Primary Distal Renal Tubular Acidosis. Summary Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder that affects the ability of the kidneys to remove acid from the blood. This leads to metabolic acidosis. Metabolic acidosis is a condition in which the circulating chemical acids and bases are out of balance. The blood of affected individuals contains too much acid and the urine contains too little acid. Chronic metabolic acidosis can lead to a variety of symptoms. The specific signs, symptoms, and severity of this disorder can vary from one person to another. There are different forms of primary distal renal tubular acidosis. They are caused by a variation (mutation) in one of at least three different genes; the SLC4A1 gene, the ATP6V0A4 gene, and the ATP6V1B1 gene. A variation in the SLC4A1 gene is usually inherited in an autosomal dominant pattern, and less often in an autosomal recessive pattern. Variations in the ATP6V0A4 and ATP6V1B1 genes are usually inherited in an autosomal recessive pattern. A mixture of sodium and potassium salts in the form of sodium citrate or potassium citrate liquid solutions is usually recommended. Liquid preparations, however, have poor palatability and acceptance among patients. In this case, sodium bicarbonate tablets are used instead or in addition to the drinking solution. Often, potassium supplements may be necessary if not included in the alkali therapy. Introduction Renal tubular acidosis is a general term for when the kidneys cannot properly remove acid from the body. The kidneys contain nephrons, which are hair-sized structures that are the basic filtering units of the kidneys. Each nephron consists of a glomerulus and a renal tubule. The renal tubule reabsorbs electrolytes such as sodium, chloride and potassium back into the blood so that not too much electrolyte is lost through the urine. The kidneys, through the tubules, reclaim bicarbonate, an electrolyte that helps to maintain the acid-base balance in the body, and then excrete acid through the urine. Acid is produced as a byproduct from a normal diet.There are several types of renal tubular acidosis. According to their pathophysiological basis, 4 types of RTA were initially categorized. Distal type I RTA or classic RTA usually referred to as distal renal tubular acidosis (dRTA) is characterized by a buildup of acids in the blood as a consequence of the distal tubules in the kidneys not being able to rid the body of the daily acid load. This results in an inability to lower urine pH regardless of the degree of acidemia (acid level in the blood). pH is the measure of acidity of liquids. The higher the score more alkaline and less acidic a liquid is. Distal refers to being “distant” from the point of origin. In the nephron, it means the defect occurs away from the point where fluid enters the tubule. Distal renal tubular acidosis occurs because the kidneys fail to secrete acids into the urine.
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Primary Distal Renal Tubular Acidosis
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nord_1002_1
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Symptoms of Primary Distal Renal Tubular Acidosis
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Primary distal renal tubular acidosis is a highly variable disorder; this means that the disorder affects people differently. Some individuals may only have slightly elevated acid levels and no accompanying symptoms (asymptomatic). Some individuals living with primary dRTA may experience kidney stones and others may not. Generally, people with an autosomal dominant pattern of inheritance have milder symptoms and a later age of onset of symptoms than people with an autosomal recessive pattern of inheritance. However, this is not always true and sometimes more severe complications such as growth failure or rickets (bowing of the bones) can affect individuals with dominantly-inherited primary distal renal tubular acidosis. Primary dRTA can cause severe complications in infants, especially if unrecognized and untreated. Affected infants can experience vomiting, dehydration, and poor growth that can result in being short for their age and gender (short stature). Additional symptoms can include excessive thirst (polydipsia), urinating frequently (polyuria), constipation, muscle weakness, and fatigue. Sometimes, affected individuals may have diminished reflexes. Many of these symptoms are related to metabolic acidosis, a serious and often life-threatening condition. Parents should seek prompt medical attention if a baby shows signs of metabolic acidosis. Some children develop rickets, which is a condition characterized by improper hardening (calcification) of the bones leading to softening and distortion/bowing of the bones and bone pain. If unrecognized and untreated, primary distal renal tubular acidosis usually causes too much calcium to build up in the kidneys (nephrocalcinosis), and the formation of kidney stones (nephrolithiasis). If untreated, nephrocalcinosis can progress to cause damage to the kidneys resulting in chronic kidney disease (CKD) and reduced kidney function. In severe instances, if untreated, extreme muscle weakness (muscle paralysis), abnormal heartbeats (cardiac arrhythmia), and episodes of having difficulty breathing or stopping breathing (respiratory arrest) can develop. These symptoms are related to low levels of potassium in the blood (hypokalemia). Potassium is an important electrolyte for the health of nerve and muscles. The kidneys excrete excess potassium through the urine. However, in primary distal renal tubular acidosis the kidneys sometimes excrete too much potassium. Hypokalemia may also contribute to excessive urination (polyuria). A subset of individuals with the autosomal recessive forms develop sensorineural hearing loss. Sensorineural hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain, and is not caused by problems with the ear itself. The degree and progression of sensorineural hearing loss can vary from one child to another, but often affects both ears (bilateral) and is usually severe. Affected individuals with an autosomal dominant dRTA usually experience a milder form of the disorder with onset of symptoms in adolescence or adulthood. Affected adults may develop reduced bone mass (osteopenia) and abnormal softening of the bones (osteomalacia) and bone pain. Weakened bones may be prone to fracture. Some individuals may develop an abnormal increase in red blood cell mass (erythrocytosis). They may develop kidney stones or kidney issues as adolescents or adults if the disorder is unrecognized and untreated. Occasionally, individuals with an inherited variation in the SLC4A1 gene have experienced the premature breakdown of red blood cells, which leads to low levels of circulating red blood cells (hemolytic anemia). The main function of red blood cells is to deliver oxygen throughout the body. People with hemolytic anemia can experience shortness of breath (dyspnea), lightheadedness, fatigue, weakness, pale skin color, and headaches.
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Symptoms of Primary Distal Renal Tubular Acidosis. Primary distal renal tubular acidosis is a highly variable disorder; this means that the disorder affects people differently. Some individuals may only have slightly elevated acid levels and no accompanying symptoms (asymptomatic). Some individuals living with primary dRTA may experience kidney stones and others may not. Generally, people with an autosomal dominant pattern of inheritance have milder symptoms and a later age of onset of symptoms than people with an autosomal recessive pattern of inheritance. However, this is not always true and sometimes more severe complications such as growth failure or rickets (bowing of the bones) can affect individuals with dominantly-inherited primary distal renal tubular acidosis. Primary dRTA can cause severe complications in infants, especially if unrecognized and untreated. Affected infants can experience vomiting, dehydration, and poor growth that can result in being short for their age and gender (short stature). Additional symptoms can include excessive thirst (polydipsia), urinating frequently (polyuria), constipation, muscle weakness, and fatigue. Sometimes, affected individuals may have diminished reflexes. Many of these symptoms are related to metabolic acidosis, a serious and often life-threatening condition. Parents should seek prompt medical attention if a baby shows signs of metabolic acidosis. Some children develop rickets, which is a condition characterized by improper hardening (calcification) of the bones leading to softening and distortion/bowing of the bones and bone pain. If unrecognized and untreated, primary distal renal tubular acidosis usually causes too much calcium to build up in the kidneys (nephrocalcinosis), and the formation of kidney stones (nephrolithiasis). If untreated, nephrocalcinosis can progress to cause damage to the kidneys resulting in chronic kidney disease (CKD) and reduced kidney function. In severe instances, if untreated, extreme muscle weakness (muscle paralysis), abnormal heartbeats (cardiac arrhythmia), and episodes of having difficulty breathing or stopping breathing (respiratory arrest) can develop. These symptoms are related to low levels of potassium in the blood (hypokalemia). Potassium is an important electrolyte for the health of nerve and muscles. The kidneys excrete excess potassium through the urine. However, in primary distal renal tubular acidosis the kidneys sometimes excrete too much potassium. Hypokalemia may also contribute to excessive urination (polyuria). A subset of individuals with the autosomal recessive forms develop sensorineural hearing loss. Sensorineural hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain, and is not caused by problems with the ear itself. The degree and progression of sensorineural hearing loss can vary from one child to another, but often affects both ears (bilateral) and is usually severe. Affected individuals with an autosomal dominant dRTA usually experience a milder form of the disorder with onset of symptoms in adolescence or adulthood. Affected adults may develop reduced bone mass (osteopenia) and abnormal softening of the bones (osteomalacia) and bone pain. Weakened bones may be prone to fracture. Some individuals may develop an abnormal increase in red blood cell mass (erythrocytosis). They may develop kidney stones or kidney issues as adolescents or adults if the disorder is unrecognized and untreated. Occasionally, individuals with an inherited variation in the SLC4A1 gene have experienced the premature breakdown of red blood cells, which leads to low levels of circulating red blood cells (hemolytic anemia). The main function of red blood cells is to deliver oxygen throughout the body. People with hemolytic anemia can experience shortness of breath (dyspnea), lightheadedness, fatigue, weakness, pale skin color, and headaches.
| 1,002 |
Primary Distal Renal Tubular Acidosis
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nord_1002_2
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Causes of Primary Distal Renal Tubular Acidosis
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Primary distal renal tubular acidosis is caused by a variation (mutation) in one of at least three different genes, the SLC4A1 gene, the ATP6V0A4 gene, and the ATP6V1B1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In some affected individuals, no variation in these three genes can be identified suggesting that other, as-yet-unidentified genes can play a role in primary dRTA. The SLC4A1 gene contains instructions for producing (encoding) a protein called anion exchanger 1 or AE1. This protein helps negatively-charged atoms cross cell membranes; specifically, it helps exchange chlorine ions for bicarbonate ions. Bicarbonate is an electrolyte that helps maintain the acid-base balance in the body and is filtered by the kidneys; but, most of the bicarbonate is still retained in the blood and the urine contains very small amounts. The AE1 protein is found in the membranes of kidney cells and red blood cells. The kidneys reclaim filtered bicarbonate and then release acid into the urine to be excreted from the body. Researchers have speculated that a variation in the SLC4A1 gene prevents enough functional AE1 protein from reaching the cell membranes of kidney and red blood cells. Ultimately, this prevents the kidneys from releasing acid into the urine. Acid then builds up in the blood and tissues of the body (metabolic acidosis). The reason why some people develop metabolic acidosis and others do not is not fully understood. In red blood cells, AEI protein cannot reach the red cell membrane resulting in red blood cells that break down prematurely. Some altered AE1 protein can still reach the membranes of red blood cells because it is helped by another protein called glycophorin A. This is most likely why many people with a disease-causing variation in the SLC4A1 gene do not develop hemolytic anemia. The ATP6V0A4 and the ATP6V1B1 genes encode specific proteins that are part of a protein complex called vacuolar H+-ATPase (V-ATPase). This protein complex acts as a proton pump that helps to move positively-charged atoms (protons) across cell membranes, and helps to regulate acid levels of cells and their surrounding areas. These proteins are commonly found in cells of the inner ear and within the nephron, which is the basic filtering unit of the kidneys. These proteins have a role in regulating the amount of acid removed from the blood to the urine, and in maintaining the proper acid balance within the ear. Variations in the SLCA41 gene are usually inherited in an autosomal dominant pattern, and, less often, in an autosomal recessive pattern. Variations in the ATP6V0A4 and the ATP6V1B1 genes are inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Disease-causing variations in the SLC4A1 gene can be inherited from a parent or it can occur as a new (sporadic or de novo) mutation, which means that the gene variation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Affected individuals can then pass on the altered gene in an autosomal dominant pattern. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
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Causes of Primary Distal Renal Tubular Acidosis. Primary distal renal tubular acidosis is caused by a variation (mutation) in one of at least three different genes, the SLC4A1 gene, the ATP6V0A4 gene, and the ATP6V1B1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In some affected individuals, no variation in these three genes can be identified suggesting that other, as-yet-unidentified genes can play a role in primary dRTA. The SLC4A1 gene contains instructions for producing (encoding) a protein called anion exchanger 1 or AE1. This protein helps negatively-charged atoms cross cell membranes; specifically, it helps exchange chlorine ions for bicarbonate ions. Bicarbonate is an electrolyte that helps maintain the acid-base balance in the body and is filtered by the kidneys; but, most of the bicarbonate is still retained in the blood and the urine contains very small amounts. The AE1 protein is found in the membranes of kidney cells and red blood cells. The kidneys reclaim filtered bicarbonate and then release acid into the urine to be excreted from the body. Researchers have speculated that a variation in the SLC4A1 gene prevents enough functional AE1 protein from reaching the cell membranes of kidney and red blood cells. Ultimately, this prevents the kidneys from releasing acid into the urine. Acid then builds up in the blood and tissues of the body (metabolic acidosis). The reason why some people develop metabolic acidosis and others do not is not fully understood. In red blood cells, AEI protein cannot reach the red cell membrane resulting in red blood cells that break down prematurely. Some altered AE1 protein can still reach the membranes of red blood cells because it is helped by another protein called glycophorin A. This is most likely why many people with a disease-causing variation in the SLC4A1 gene do not develop hemolytic anemia. The ATP6V0A4 and the ATP6V1B1 genes encode specific proteins that are part of a protein complex called vacuolar H+-ATPase (V-ATPase). This protein complex acts as a proton pump that helps to move positively-charged atoms (protons) across cell membranes, and helps to regulate acid levels of cells and their surrounding areas. These proteins are commonly found in cells of the inner ear and within the nephron, which is the basic filtering unit of the kidneys. These proteins have a role in regulating the amount of acid removed from the blood to the urine, and in maintaining the proper acid balance within the ear. Variations in the SLCA41 gene are usually inherited in an autosomal dominant pattern, and, less often, in an autosomal recessive pattern. Variations in the ATP6V0A4 and the ATP6V1B1 genes are inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Disease-causing variations in the SLC4A1 gene can be inherited from a parent or it can occur as a new (sporadic or de novo) mutation, which means that the gene variation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Affected individuals can then pass on the altered gene in an autosomal dominant pattern. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
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Primary Distal Renal Tubular Acidosis
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nord_1002_3
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Affects of Primary Distal Renal Tubular Acidosis
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Primary distal renal tubular acidosis affects females and males in equal numbers. The exact number of people who have this disorder is unknown. Rare disorders like primary distal renal tubular acidosis often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.
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Affects of Primary Distal Renal Tubular Acidosis. Primary distal renal tubular acidosis affects females and males in equal numbers. The exact number of people who have this disorder is unknown. Rare disorders like primary distal renal tubular acidosis often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.
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Primary Distal Renal Tubular Acidosis
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nord_1002_4
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Related disorders of Primary Distal Renal Tubular Acidosis
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Symptoms of the following disorders can be similar to those of primary distal renal tubular acidosis. Comparisons may be useful for a differential diagnosis.Acquired forms or distal renal tubular acidosis are caused by autoimmune disorders including Sjogren syndrome and systemic lupus erythematosus. Autoimmune disorders are ones in which the body’s immune system mistakenly attacks healthy tissue. Sometimes, in certain autoimmune disorders the immune system attacks the distal portion of the renal tubules. Distal renal tubular acidosis can also occur in people with sickle cell disease, chronic obstructive uropathy, hypogammaglobulinemia, chronic liver disease, and following a kidney transplant. Distal renal tubular acidosis can also be caused by drug-induced kidney damage.
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Related disorders of Primary Distal Renal Tubular Acidosis. Symptoms of the following disorders can be similar to those of primary distal renal tubular acidosis. Comparisons may be useful for a differential diagnosis.Acquired forms or distal renal tubular acidosis are caused by autoimmune disorders including Sjogren syndrome and systemic lupus erythematosus. Autoimmune disorders are ones in which the body’s immune system mistakenly attacks healthy tissue. Sometimes, in certain autoimmune disorders the immune system attacks the distal portion of the renal tubules. Distal renal tubular acidosis can also occur in people with sickle cell disease, chronic obstructive uropathy, hypogammaglobulinemia, chronic liver disease, and following a kidney transplant. Distal renal tubular acidosis can also be caused by drug-induced kidney damage.
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Primary Distal Renal Tubular Acidosis
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nord_1002_5
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Diagnosis of Primary Distal Renal Tubular Acidosis
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A diagnosis of primary distal renal tubular acidosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with unexplained metabolic acidosis and an elevated plasma chloride (so called normal anion gap metabolic acidosis). Clinical Testing and Workup
Doctors may order blood and urine tests to show that the blood is more acidic than it should be and that the urine is less acidic than it should be. The pH levels in the urine of affected individuals is variable, but usually does not fall below 5.5. pH is the measure of acidity of these liquids. The higher the score, the more alkaline and less acidic a liquid is. This indicates that the kidneys are not filtering acid out from the blood. Consequently, blood tests will show excessive levels of acid, and may also be low in bicarbonate and potassium. These tests may be followed by an estimation of the amount of ammonia excreted through the urine. Most laboratories usually do not perform a direct measurement of ammonia excretion. Urine ammonium is often roughly estimated indirectly by calculating the urine anion gap which is always positive (range 0-80 mEq/L) when the patient has distal renal tubular acidosis but negative (0 to -80 mEq/L) with other types of acidosis such as that caused by diarrhea.A 24-urine test may be conducted to check for the levels of calcium, citrate, potassium, and oxalate. Individuals with primary distal renal tubular acidosis may have high levels of calcium (hypercalcinemia), significantly low levels of citrate (hypocitraturia), and potassium wasting, which is the excessive excretion of potassium in the urine. Citrate is an acid and low levels of this acid increases the risk of nephrocalcinosis and kidney stone formation. Oxalate is a natural chemical in the body that comes from various sources of food. Too much oxalate in the urine (hyperoxaluria) can have many causes including several genetic disorders affecting the kidneys. Primary distal renal tubular acidosis needs to be distinguished from proximal distal renal tubular acidosis. This can be accomplished by examining the pattern of urinary bicarbonate excretion in the urine in conjunction with the urine pH. Patients with proximal renal tubular acidosis normally have a high urine pH but are able to lower it when the plasma bicarbonate is very low.Plain x-rays (radiographs) or specialized imaging techniques such as computerized tomography (CT) scanning or ultrasonography can help to further confirm a diagnosis, or help determine the extent of disease. These tests can show the accumulation or deposition of calcium in the kidneys and help to rule out other conditions. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. During ultrasonography, reflected sound waves are used to create an image of structures within the body including the kidneys.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect disease-causing variants in the specific genes known to cause primary distal renal tubular acidosis, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Primary Distal Renal Tubular Acidosis. A diagnosis of primary distal renal tubular acidosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with unexplained metabolic acidosis and an elevated plasma chloride (so called normal anion gap metabolic acidosis). Clinical Testing and Workup
Doctors may order blood and urine tests to show that the blood is more acidic than it should be and that the urine is less acidic than it should be. The pH levels in the urine of affected individuals is variable, but usually does not fall below 5.5. pH is the measure of acidity of these liquids. The higher the score, the more alkaline and less acidic a liquid is. This indicates that the kidneys are not filtering acid out from the blood. Consequently, blood tests will show excessive levels of acid, and may also be low in bicarbonate and potassium. These tests may be followed by an estimation of the amount of ammonia excreted through the urine. Most laboratories usually do not perform a direct measurement of ammonia excretion. Urine ammonium is often roughly estimated indirectly by calculating the urine anion gap which is always positive (range 0-80 mEq/L) when the patient has distal renal tubular acidosis but negative (0 to -80 mEq/L) with other types of acidosis such as that caused by diarrhea.A 24-urine test may be conducted to check for the levels of calcium, citrate, potassium, and oxalate. Individuals with primary distal renal tubular acidosis may have high levels of calcium (hypercalcinemia), significantly low levels of citrate (hypocitraturia), and potassium wasting, which is the excessive excretion of potassium in the urine. Citrate is an acid and low levels of this acid increases the risk of nephrocalcinosis and kidney stone formation. Oxalate is a natural chemical in the body that comes from various sources of food. Too much oxalate in the urine (hyperoxaluria) can have many causes including several genetic disorders affecting the kidneys. Primary distal renal tubular acidosis needs to be distinguished from proximal distal renal tubular acidosis. This can be accomplished by examining the pattern of urinary bicarbonate excretion in the urine in conjunction with the urine pH. Patients with proximal renal tubular acidosis normally have a high urine pH but are able to lower it when the plasma bicarbonate is very low.Plain x-rays (radiographs) or specialized imaging techniques such as computerized tomography (CT) scanning or ultrasonography can help to further confirm a diagnosis, or help determine the extent of disease. These tests can show the accumulation or deposition of calcium in the kidneys and help to rule out other conditions. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. During ultrasonography, reflected sound waves are used to create an image of structures within the body including the kidneys.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect disease-causing variants in the specific genes known to cause primary distal renal tubular acidosis, but is available only as a diagnostic service at specialized laboratories.
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Therapies of Primary Distal Renal Tubular Acidosis
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Treatment
The treatment of primary distal renal tubular acidosis may require the coordinated efforts of a team of specialists. A kidney doctor (nephrologist) who specialize in diagnosing and treating kidney disorders may be a critical member of the care team. A pediatric nephrologist specializes in kidney disorders in children. Physicians who specialize in diagnosing and treating skeletal disorders (orthopedists), an audiologist to monitor hearing and other healthcare professionals may need to systematically and comprehensively help guide treatment.Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family can be essential as well. The organizations listed in the Resources section of this report provide support and information for individuals with kidney disease. Individuals with primary distal renal tubular acidosis are treated with alkali therapy. Alkali are chemical compounds that neutralize acids. Alkali therapy usually leads to normal growth in children, and can improve other symptoms including lowering the tendency to develop calcium build up in the kidneys and calcium stones and reverse bone disease. Alkali therapy usually consists of drinking a solution of sodium bicarbonate (baking soda) or sodium citrate every day to counteract the acids produced from eating each day. The dose and specific type of alkali therapy depends upon the bicarbonate and potassium concentrations in the blood serum. Children generally require larger doses; these doses are adjusted as a child ages. Most individuals do not experience symptoms (asymptomatic) when properly treated, except for irreversible kidney or skeletal damage that has occurred before treatment was begun.If low potassium levels persist (hypokalemia), then affected individuals may require treatment with alkylating potassium salt like potassium citrate. Potassium citrate (versus sodium citrate) may also be recommended when calcium stones are present because sodium can increase calcium stone formation. Citrate salts like potassium citrate correct low levels of citrate (hypocitraturia) and prevent calcium stone formation. The focus of treatment in individuals with severe hypokalemia that causes paralysis or breathing problems (respiratory compromise) should be to correct the low potassium levels with an intravenous potassium chloride. Children with autosomal recessive primary distal renal tubular acidosis should receive routine hearing assessments through childhood to detect hearing loss. Hearing loss does not usually respond to alkali therapy. Other treatments can include supplementation with vitamin D or oral calcium supplements to help reduce skeletal abnormalities such as rickets or osteomalacia.
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Therapies of Primary Distal Renal Tubular Acidosis. Treatment
The treatment of primary distal renal tubular acidosis may require the coordinated efforts of a team of specialists. A kidney doctor (nephrologist) who specialize in diagnosing and treating kidney disorders may be a critical member of the care team. A pediatric nephrologist specializes in kidney disorders in children. Physicians who specialize in diagnosing and treating skeletal disorders (orthopedists), an audiologist to monitor hearing and other healthcare professionals may need to systematically and comprehensively help guide treatment.Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family can be essential as well. The organizations listed in the Resources section of this report provide support and information for individuals with kidney disease. Individuals with primary distal renal tubular acidosis are treated with alkali therapy. Alkali are chemical compounds that neutralize acids. Alkali therapy usually leads to normal growth in children, and can improve other symptoms including lowering the tendency to develop calcium build up in the kidneys and calcium stones and reverse bone disease. Alkali therapy usually consists of drinking a solution of sodium bicarbonate (baking soda) or sodium citrate every day to counteract the acids produced from eating each day. The dose and specific type of alkali therapy depends upon the bicarbonate and potassium concentrations in the blood serum. Children generally require larger doses; these doses are adjusted as a child ages. Most individuals do not experience symptoms (asymptomatic) when properly treated, except for irreversible kidney or skeletal damage that has occurred before treatment was begun.If low potassium levels persist (hypokalemia), then affected individuals may require treatment with alkylating potassium salt like potassium citrate. Potassium citrate (versus sodium citrate) may also be recommended when calcium stones are present because sodium can increase calcium stone formation. Citrate salts like potassium citrate correct low levels of citrate (hypocitraturia) and prevent calcium stone formation. The focus of treatment in individuals with severe hypokalemia that causes paralysis or breathing problems (respiratory compromise) should be to correct the low potassium levels with an intravenous potassium chloride. Children with autosomal recessive primary distal renal tubular acidosis should receive routine hearing assessments through childhood to detect hearing loss. Hearing loss does not usually respond to alkali therapy. Other treatments can include supplementation with vitamin D or oral calcium supplements to help reduce skeletal abnormalities such as rickets or osteomalacia.
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Overview of Primary Familial Brain Calcification
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Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by the presence of abnormal calcium/hydroxyapatite deposits (calcifications) in the brain. The clinical presentations generally attributed to these brain calcifications are highly heterogeneous, ranging from asymptomatic patients to severe cases with progressive neuropsychiatric features. To date, disease-causing changes (pathogenic variants or mutations) in six genes have been associated with PFBC: SLC20A2, PDGFB, PDGFRB, XPR1, MYORG and JAM-2. PFBC has recently become the preferred name for this condition because variants in specific genes are now known to be the cause of the condition. Previously, familial idiopathic basal ganglia calcification was the preferred name, and Fahr's disease is often used for either familial or sporadic brain calcification, and it is unknown if these are the same or different diseases.
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Overview of Primary Familial Brain Calcification. Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by the presence of abnormal calcium/hydroxyapatite deposits (calcifications) in the brain. The clinical presentations generally attributed to these brain calcifications are highly heterogeneous, ranging from asymptomatic patients to severe cases with progressive neuropsychiatric features. To date, disease-causing changes (pathogenic variants or mutations) in six genes have been associated with PFBC: SLC20A2, PDGFB, PDGFRB, XPR1, MYORG and JAM-2. PFBC has recently become the preferred name for this condition because variants in specific genes are now known to be the cause of the condition. Previously, familial idiopathic basal ganglia calcification was the preferred name, and Fahr's disease is often used for either familial or sporadic brain calcification, and it is unknown if these are the same or different diseases.
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Symptoms of Primary Familial Brain Calcification
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PFBC is characterized by symmetric and bilateral brain calcifications mainly in the basal ganglia, but also seen in the cerebellum, thalami, cerebral white matter and/or pons. These calcium phosphate deposits are commonly found in the fourth to fifth decade of life, while symptoms usually begin in the third to fifth decade of life, even though some individuals with PFBC may be clinically asymptomatic for several decades. PFBC is rare among children but, when present, most of these children present with seizures. Neuropsychiatric and movement disorders are the main PFBC clinical presentations in adults.Early symptoms may include clumsiness, fatigue, slow or slurred speech and difficulty swallowing (dysphagia). Progressive deterioration of mental/cognitive abilities (dementia) and loss of previous motor development are accompanied by spastic paralysis and in some patients, twisting movements of the hands and feet (athetosis). Features of Parkinson disease found in this disorder may include tremors and rigidity (Parkinsonism), a masklike facial expression, shuffling walk and a pill rolling motion of the fingers. Muscle cramping (dystonia), uncontrollable spasmodic irregular movements characterized by irregular, rapid, jerky moves (chorea) and seizures can also occur. Occasional symptoms include sensory changes, headaches and urinary incontinence. Other associated symptoms include loss of contact with reality (psychosis), mood swings, depression and loss of acquired motor skills. As the condition progresses, paralysis may develop associated with increased muscle stiffness (rigidity) and restricted movements (spastic paralysis). Recently, stroke in young people with no risk factors has been related to MYORG gene variants (Yang et al, 2022).A recent study indicated that Parkinsonism was the most frequent symptom in a group of 44 PFBC patients, followed by cognitive impairment, psychiatric symptoms and cerebellar signs (Ramos et al., 2018). Other analyses have also suggested that males are more severely affected than females, especially those who have SLC20A2 gene variants, followed by those with PDGFB and PDGFRB gene variants (Nicolas et al., 2015).
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Symptoms of Primary Familial Brain Calcification. PFBC is characterized by symmetric and bilateral brain calcifications mainly in the basal ganglia, but also seen in the cerebellum, thalami, cerebral white matter and/or pons. These calcium phosphate deposits are commonly found in the fourth to fifth decade of life, while symptoms usually begin in the third to fifth decade of life, even though some individuals with PFBC may be clinically asymptomatic for several decades. PFBC is rare among children but, when present, most of these children present with seizures. Neuropsychiatric and movement disorders are the main PFBC clinical presentations in adults.Early symptoms may include clumsiness, fatigue, slow or slurred speech and difficulty swallowing (dysphagia). Progressive deterioration of mental/cognitive abilities (dementia) and loss of previous motor development are accompanied by spastic paralysis and in some patients, twisting movements of the hands and feet (athetosis). Features of Parkinson disease found in this disorder may include tremors and rigidity (Parkinsonism), a masklike facial expression, shuffling walk and a pill rolling motion of the fingers. Muscle cramping (dystonia), uncontrollable spasmodic irregular movements characterized by irregular, rapid, jerky moves (chorea) and seizures can also occur. Occasional symptoms include sensory changes, headaches and urinary incontinence. Other associated symptoms include loss of contact with reality (psychosis), mood swings, depression and loss of acquired motor skills. As the condition progresses, paralysis may develop associated with increased muscle stiffness (rigidity) and restricted movements (spastic paralysis). Recently, stroke in young people with no risk factors has been related to MYORG gene variants (Yang et al, 2022).A recent study indicated that Parkinsonism was the most frequent symptom in a group of 44 PFBC patients, followed by cognitive impairment, psychiatric symptoms and cerebellar signs (Ramos et al., 2018). Other analyses have also suggested that males are more severely affected than females, especially those who have SLC20A2 gene variants, followed by those with PDGFB and PDGFRB gene variants (Nicolas et al., 2015).
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Causes of Primary Familial Brain Calcification
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PFBC is caused by variants in several different genes, and it can either be inherited or develop spontaneously. In inherited cases, the vast majority follow autosomal dominant inheritance, but autosomal recessive inheritance have also been reported.As previously mentioned, autosomal dominant genetic disorders occur when a single copy of an abnormal gene is necessary to cause a disease. The abnormal gene can be inherited from either parent, and the risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy, being the same for males and females. Variants in four different genes have been described to cause PFBC in an autosomal dominant fashion: SLC20A2, PDGFB, PDGFRB and XPR1.Wang and colleagues (2012) reported 7 families with PFBC from China, Spain and Brazil, with different variants in the SLC20A2 gene on chromosome 8, encoding for a phosphate inorganic transporter (PiT-2). In the following years, more than 50 variants in this gene have been identified, and variants in this gene are the most common cause of PFBC (Lemos et al., 2015).Since then, three other genes have been linked to autosomal dominant forms of PFBC: the beta subunit of platelet-derived growth factor (PDGFB) and its receptor (PDGFRB), which are involved in the blood brain barrier integrity (Nicolas et al., 2013; Keller et al., 2013); and more recently, the xenotropic and polytropic retrovirus receptor 1 (XPR1) gene, which is involved in intracellular phosphate homeostasis (Legati et al., 2015).Autosomal recessive genetic disorders occur when two copies of an abnormal gene are necessary to cause a disease. The abnormal gene then must be inherited from both parents in order to cause the disease in children. So far, two genes have been linked to a recessive pattern: MYORG and JAM-2 (Yao et al., 2018; Schottlaender et al, 2020). Patients with variants in these genes are generally more severely affected. Patients with MYORG gene variants often have calcification present in the pons as a very predictable finding.Lastly, in some individuals the disorder is due to spontaneous (de novo) genetic variants that may occur in the egg or sperm cell. It is not known how many people have PFBC as a result of a new gene variant, but there is a case linked to SLC20A2 and twins linked to PDGFB pathogenic variants. In such situations, the disorder is not inherited from the parents, but can still be passed on to children (with a 50% chance for each child) (Keller et al, 2013; Ferreira et al, 2014).
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Causes of Primary Familial Brain Calcification. PFBC is caused by variants in several different genes, and it can either be inherited or develop spontaneously. In inherited cases, the vast majority follow autosomal dominant inheritance, but autosomal recessive inheritance have also been reported.As previously mentioned, autosomal dominant genetic disorders occur when a single copy of an abnormal gene is necessary to cause a disease. The abnormal gene can be inherited from either parent, and the risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy, being the same for males and females. Variants in four different genes have been described to cause PFBC in an autosomal dominant fashion: SLC20A2, PDGFB, PDGFRB and XPR1.Wang and colleagues (2012) reported 7 families with PFBC from China, Spain and Brazil, with different variants in the SLC20A2 gene on chromosome 8, encoding for a phosphate inorganic transporter (PiT-2). In the following years, more than 50 variants in this gene have been identified, and variants in this gene are the most common cause of PFBC (Lemos et al., 2015).Since then, three other genes have been linked to autosomal dominant forms of PFBC: the beta subunit of platelet-derived growth factor (PDGFB) and its receptor (PDGFRB), which are involved in the blood brain barrier integrity (Nicolas et al., 2013; Keller et al., 2013); and more recently, the xenotropic and polytropic retrovirus receptor 1 (XPR1) gene, which is involved in intracellular phosphate homeostasis (Legati et al., 2015).Autosomal recessive genetic disorders occur when two copies of an abnormal gene are necessary to cause a disease. The abnormal gene then must be inherited from both parents in order to cause the disease in children. So far, two genes have been linked to a recessive pattern: MYORG and JAM-2 (Yao et al., 2018; Schottlaender et al, 2020). Patients with variants in these genes are generally more severely affected. Patients with MYORG gene variants often have calcification present in the pons as a very predictable finding.Lastly, in some individuals the disorder is due to spontaneous (de novo) genetic variants that may occur in the egg or sperm cell. It is not known how many people have PFBC as a result of a new gene variant, but there is a case linked to SLC20A2 and twins linked to PDGFB pathogenic variants. In such situations, the disorder is not inherited from the parents, but can still be passed on to children (with a 50% chance for each child) (Keller et al, 2013; Ferreira et al, 2014).
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Affects of Primary Familial Brain Calcification
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The prevalence of PFBC is unknown, but more people are being diagnosed, probably due to the growing availability of neuroimaging screening and genetic testing.A recent study by Nicolas and collaborators indicates that the prevalence of PFBC may be higher than what was initially thought. Through a population-based genomic analysis, the authors estimated that the prevalence of the condition ranges from 4.5/10,000 to 2.1/1,000, which means the disease is much more common than previously considered (Nicolas et al., 2018).
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Affects of Primary Familial Brain Calcification. The prevalence of PFBC is unknown, but more people are being diagnosed, probably due to the growing availability of neuroimaging screening and genetic testing.A recent study by Nicolas and collaborators indicates that the prevalence of PFBC may be higher than what was initially thought. Through a population-based genomic analysis, the authors estimated that the prevalence of the condition ranges from 4.5/10,000 to 2.1/1,000, which means the disease is much more common than previously considered (Nicolas et al., 2018).
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Related disorders of Primary Familial Brain Calcification
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Calcification of the basal nuclei in the brain is found in many medical conditions and can be caused by infections as well as metabolic and other genetic syndromes. It is also not uncommon to observe calcium deposits of the basal ganglia in individuals over 60 years of age and this finding is not usually associated with diseases. Symptoms of the following disorders may be similar to those of PFBC. Comparisons may be useful for a differential diagnosis:Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (tremor), muscular stiffness or inflexibility (rigidity), slowness of movement and difficulty carrying out voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal in the brain. Hypoparathyroidism is a condition characterized by insufficient production of parathyroid hormones by the parathyroid glands, the small, oval glands located near the thyroid gland in the neck. Parathyroid hormones (along with vitamin D and the hormone calcitonin, which is produced by the thyroid gland) play a role in regulating levels of calcium in the blood. Due to deficiency of parathyroid hormones, affected individuals exhibit abnormally low levels of calcium in the blood (hypocalcemia). Symptoms and findings associated with hypoparathyroidism may include weakness, muscle cramps, excessive nervousness, headaches and/or increased excitability (hyperexcitability) of nerves resulting in uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, arms and/or face (tetany). Hypoparathyroidism may result from absence of the parathyroid glands, removal or damage to the parathyroid glands or from several different underlying disorders. In rare cases, hypoparathyroidism may be inherited in an autosomal recessive pattern. (For more information on this disorder, choose “hypoparathyroidism” as your search term in the Rare Disease Database.)Pseudohypoparathyroidism is a hereditary disorder characterized by an inadequate response to the parathyroid hormone, although the hormone is present in normal amounts. This inadequate response affects bone growth and affected individuals may also experience headaches, unusual sensations, weakness, easy fatigue, reduced energy, blurred vision and/or hypersensitivity to light. Additional symptoms and findings may include stiffness or cramps in the arms and/or legs, palpitations and/or abdominal pain. In addition, individuals with pseudohypoparathyroidism may have an abnormally round face, thick short stature, unusually short fourth fingers and intellectual disability. Hormonal and calcium replacement therapy is often helpful, but the lack of growth may persist. (For more information on this disorder, choose “pseudohypoparathyroidism” as your search term in the Rare Disease Database.)
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Related disorders of Primary Familial Brain Calcification. Calcification of the basal nuclei in the brain is found in many medical conditions and can be caused by infections as well as metabolic and other genetic syndromes. It is also not uncommon to observe calcium deposits of the basal ganglia in individuals over 60 years of age and this finding is not usually associated with diseases. Symptoms of the following disorders may be similar to those of PFBC. Comparisons may be useful for a differential diagnosis:Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (tremor), muscular stiffness or inflexibility (rigidity), slowness of movement and difficulty carrying out voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal in the brain. Hypoparathyroidism is a condition characterized by insufficient production of parathyroid hormones by the parathyroid glands, the small, oval glands located near the thyroid gland in the neck. Parathyroid hormones (along with vitamin D and the hormone calcitonin, which is produced by the thyroid gland) play a role in regulating levels of calcium in the blood. Due to deficiency of parathyroid hormones, affected individuals exhibit abnormally low levels of calcium in the blood (hypocalcemia). Symptoms and findings associated with hypoparathyroidism may include weakness, muscle cramps, excessive nervousness, headaches and/or increased excitability (hyperexcitability) of nerves resulting in uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, arms and/or face (tetany). Hypoparathyroidism may result from absence of the parathyroid glands, removal or damage to the parathyroid glands or from several different underlying disorders. In rare cases, hypoparathyroidism may be inherited in an autosomal recessive pattern. (For more information on this disorder, choose “hypoparathyroidism” as your search term in the Rare Disease Database.)Pseudohypoparathyroidism is a hereditary disorder characterized by an inadequate response to the parathyroid hormone, although the hormone is present in normal amounts. This inadequate response affects bone growth and affected individuals may also experience headaches, unusual sensations, weakness, easy fatigue, reduced energy, blurred vision and/or hypersensitivity to light. Additional symptoms and findings may include stiffness or cramps in the arms and/or legs, palpitations and/or abdominal pain. In addition, individuals with pseudohypoparathyroidism may have an abnormally round face, thick short stature, unusually short fourth fingers and intellectual disability. Hormonal and calcium replacement therapy is often helpful, but the lack of growth may persist. (For more information on this disorder, choose “pseudohypoparathyroidism” as your search term in the Rare Disease Database.)
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Diagnosis of Primary Familial Brain Calcification
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Neuroimaging techniques such as computed tomography (CT) of the brain (the most sensitive technique) and magnetic resonance imaging (MRI) are used to diagnose the calcium deposits in the brain. Although not necessary, the combination of these findings with a progressive movement disorder, neuropsychiatric problems beginning in the 40’s or 50’s, and a lack of biochemical abnormalities or other known causes (infection, toxic exposure, trauma) makes the diagnosis very likely.Genetic testing for variants in genes that cause PFBC (SLC20A2, PDGFB, PDGFRB, XPR1, MYORG and JAM-2), should be performed, as this is currently the best way to determine with certainty if an individual has PFBC. The molecular genetic testing may be DNA sequencing, whole exome sequencing (WES) or whole genome sequencing (WGS).
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Diagnosis of Primary Familial Brain Calcification. Neuroimaging techniques such as computed tomography (CT) of the brain (the most sensitive technique) and magnetic resonance imaging (MRI) are used to diagnose the calcium deposits in the brain. Although not necessary, the combination of these findings with a progressive movement disorder, neuropsychiatric problems beginning in the 40’s or 50’s, and a lack of biochemical abnormalities or other known causes (infection, toxic exposure, trauma) makes the diagnosis very likely.Genetic testing for variants in genes that cause PFBC (SLC20A2, PDGFB, PDGFRB, XPR1, MYORG and JAM-2), should be performed, as this is currently the best way to determine with certainty if an individual has PFBC. The molecular genetic testing may be DNA sequencing, whole exome sequencing (WES) or whole genome sequencing (WGS).
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Therapies of Primary Familial Brain Calcification
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To date, no specific treatment for PFBC is known. Medications can be used to treat symptoms associated with this condition, such as movement disorders, seizures, anxiety, headaches, depression, psychosis and urinary incontinence (Oliveira JRM, 2011). Medications established in psychiatric clinical practice are generally prescribed to control other disorders, such as mood stabilizers (mainly anticonvulsants) that may be useful in managing depressive symptoms, irritability, euphoria or agitation. Antipsychotics are also used to treat symptoms such as delusions and hallucinations, but they are also useful for managing psychomotor agitation. Genetic counseling is recommended for affected individuals and their relatives, especially for those with mutations in PFBC-associated genes.
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Therapies of Primary Familial Brain Calcification. To date, no specific treatment for PFBC is known. Medications can be used to treat symptoms associated with this condition, such as movement disorders, seizures, anxiety, headaches, depression, psychosis and urinary incontinence (Oliveira JRM, 2011). Medications established in psychiatric clinical practice are generally prescribed to control other disorders, such as mood stabilizers (mainly anticonvulsants) that may be useful in managing depressive symptoms, irritability, euphoria or agitation. Antipsychotics are also used to treat symptoms such as delusions and hallucinations, but they are also useful for managing psychomotor agitation. Genetic counseling is recommended for affected individuals and their relatives, especially for those with mutations in PFBC-associated genes.
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Overview of Primary Gastric Lymphoma
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SummaryPrimary gastric lymphoma is a general term for a type of cancer that originates within the stomach. Approximately 90 percent of patients of primary gastric lymphoma are either mucosa-associated lymphoid tissue (MALT) gastric lymphoma or diffuse large B-cell lymphoma (DLBCL) of the stomach. MALT gastric lymphoma is often associated with infection with the Helicobacter pylori bacterium. Within the medical literature, controversy exists regarding the exact definition, classification and staging of primary gastric lymphoma.The term lymphoma refers to cancer that arises in the lymphatic system. As part of the immune system, the lymphatic system helps protect the body against infection and disease, and has a network of tubes known as lymph vessels that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph collects in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other waste (dead cells and their fragments) from the bloodstream.Most types of lymphoma result from errors in the production of a type of white blood cell (lymphocyte) or transformation of a single lymphocyte into a malignant (cancerous) cell. Abnormal, uncontrolled growth of malignant lymphocytes leads to enlargement of a specific lymph node region or regions. Involvement of other lymphatic tissues, such as the spleen and bone marrow and spread to other body tissues and organs can lead to life-threatening complications. The specific symptoms (fever, night sweats, itchiness, etc.) and physical findings (weight loss, enlarged spleen, lumps over the neck or axilla, etc.) may vary from person to person depending upon the extent and region(s) of involvement.Most cases of lymphoma arise in the lymph nodes. When lymphoma arises outside the lymph nodes, it is referred to as extranodal lymphoma. Primary gastric lymphoma is the most common form of extranodal lymphoma.Most cases of primary gastric lymphoma are B-cell subtypes of non-Hodgkin lymphoma (NHL). NHL may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphoma) and those derived from abnormal T-lymphocytes (T-cell lymphoma).The types of NHL may also be based upon certain characteristics of the cancer cells as seen under a microscope and how quickly they may tend to grow and spread. For example, NHL may be characterized as “low-grade” (or indolent), meaning it tends to grow slowly and result in few associated symptoms, or “intermediate-” to “high-grade” (aggressive) lymphomas, which typically grow rapidly, requiring prompt treatment. MALT gastric lymphoma is generally an indolent (slow growing) lymphoma; DLBCL of the stomach is generally a more aggressive lymphoma. Rarely, individuals may have both low and high grade lymphomas at the same time.
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Overview of Primary Gastric Lymphoma. SummaryPrimary gastric lymphoma is a general term for a type of cancer that originates within the stomach. Approximately 90 percent of patients of primary gastric lymphoma are either mucosa-associated lymphoid tissue (MALT) gastric lymphoma or diffuse large B-cell lymphoma (DLBCL) of the stomach. MALT gastric lymphoma is often associated with infection with the Helicobacter pylori bacterium. Within the medical literature, controversy exists regarding the exact definition, classification and staging of primary gastric lymphoma.The term lymphoma refers to cancer that arises in the lymphatic system. As part of the immune system, the lymphatic system helps protect the body against infection and disease, and has a network of tubes known as lymph vessels that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph collects in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other waste (dead cells and their fragments) from the bloodstream.Most types of lymphoma result from errors in the production of a type of white blood cell (lymphocyte) or transformation of a single lymphocyte into a malignant (cancerous) cell. Abnormal, uncontrolled growth of malignant lymphocytes leads to enlargement of a specific lymph node region or regions. Involvement of other lymphatic tissues, such as the spleen and bone marrow and spread to other body tissues and organs can lead to life-threatening complications. The specific symptoms (fever, night sweats, itchiness, etc.) and physical findings (weight loss, enlarged spleen, lumps over the neck or axilla, etc.) may vary from person to person depending upon the extent and region(s) of involvement.Most cases of lymphoma arise in the lymph nodes. When lymphoma arises outside the lymph nodes, it is referred to as extranodal lymphoma. Primary gastric lymphoma is the most common form of extranodal lymphoma.Most cases of primary gastric lymphoma are B-cell subtypes of non-Hodgkin lymphoma (NHL). NHL may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphoma) and those derived from abnormal T-lymphocytes (T-cell lymphoma).The types of NHL may also be based upon certain characteristics of the cancer cells as seen under a microscope and how quickly they may tend to grow and spread. For example, NHL may be characterized as “low-grade” (or indolent), meaning it tends to grow slowly and result in few associated symptoms, or “intermediate-” to “high-grade” (aggressive) lymphomas, which typically grow rapidly, requiring prompt treatment. MALT gastric lymphoma is generally an indolent (slow growing) lymphoma; DLBCL of the stomach is generally a more aggressive lymphoma. Rarely, individuals may have both low and high grade lymphomas at the same time.
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Symptoms of Primary Gastric Lymphoma
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The symptoms of primary gastric lymphoma are usually vague and nonspecific, seen in other conditions beside cancer. In many cases, there may be no noticeable physical findings upon diagnosis. Specific symptoms can be very different from one person to another. Abdominal pain or cramping is probably the most common, and may be one of the first symptoms noted. Additional symptoms that may occur in individuals with primary gastric lymphoma include a feeling of stomach fullness after only eating a little food (early satiety), abdominal tenderness, nausea, vomiting, unintended weight loss, a general feeling of poor health (malaise), and indigestion. Bleeding from the stomach may occur in some individuals and can also be the first noticeable sign of primary gastric lymphoma. A mass large enough to be able to be felt when applying pressure to the stomach may also be present in some advanced cases. Less frequently, weakness, fatigue, night sweats, jaundice (yellowing of the skin and the whites of the eyes), fever, and dysphagia (difficulty swallowing) may occur. Additional less common findings associated with primary gastric lymphoma include abnormal enlargement of the liver or spleen, obstruction of the gastrointestinal tract, and development of a hole or tear in the wall of the stomach (perforation).
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Symptoms of Primary Gastric Lymphoma. The symptoms of primary gastric lymphoma are usually vague and nonspecific, seen in other conditions beside cancer. In many cases, there may be no noticeable physical findings upon diagnosis. Specific symptoms can be very different from one person to another. Abdominal pain or cramping is probably the most common, and may be one of the first symptoms noted. Additional symptoms that may occur in individuals with primary gastric lymphoma include a feeling of stomach fullness after only eating a little food (early satiety), abdominal tenderness, nausea, vomiting, unintended weight loss, a general feeling of poor health (malaise), and indigestion. Bleeding from the stomach may occur in some individuals and can also be the first noticeable sign of primary gastric lymphoma. A mass large enough to be able to be felt when applying pressure to the stomach may also be present in some advanced cases. Less frequently, weakness, fatigue, night sweats, jaundice (yellowing of the skin and the whites of the eyes), fever, and dysphagia (difficulty swallowing) may occur. Additional less common findings associated with primary gastric lymphoma include abnormal enlargement of the liver or spleen, obstruction of the gastrointestinal tract, and development of a hole or tear in the wall of the stomach (perforation).
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Causes of Primary Gastric Lymphoma
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The exact cause of primary gastric lymphoma is unknown. However, a strong association between infection with Helicobacter pylori (H. pylori) and the development of MALT gastric lymphoma has been established. H. pylori is a bacterium that is found in the stomach and the upper portion of the intestines and is well known for causing ulcers. In approximately 90 percent of cases, MALT gastric lymphoma is strongly associated with chronic H. pylori infection. MALT gastric lymphoma originally arises from certain white blood cells (lymphocytes) found within the lymphoid tissue of the stomach’s inner lining (mucous membranes or mucosa). This lymphoid tissue is not normally found in the stomach but develops as a result of chronic inflammation as occurs with chronic H. pylori infection. Although H. pylori infection plays a role in the development of MALT gastric lymphoma, the infection is quite common in the general population. Yet only a very small number of individuals with this bacterium develop MALT gastric lymphoma. This indicates that other factors, such as a weak response to the infection by the body’s immune system, also play a role in the development of MALT gastric lymphoma. Some individuals with MALT gastric lymphoma have chromosomal abnormalities within the tumor(s), specifically a translocation. A translocation means that a piece of one chromosome breaks off and attaches to another. These chromosomal abnormalities may be significant in terms of treatment or prognosis. For example, some affected individuals have a translocation involving chromosomes 11 and 18 (translocation t [11; 18]), which seems to be associated with poorer response to antibiotic therapy and the eradication of H. pylori infection. Diffuse large B-cell lymphoma (DLBCL) of the stomach may arise spontaneously in individuals without a previous history of cancer, or it may occur from the transformation of an indolent MALT gastric lymphoma into the more aggressive DLBCL form. Some researchers have suggested that DLBCL of the stomach may also be associated with H. pylori infection. Some individuals with DLBCL of the stomach have been infected with the H. pylori bacterium, but some researchers believe that these cases are examples of long-standing MALT gastric lymphoma that has transformed into the more aggressive DLBCL of the stomach.
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Causes of Primary Gastric Lymphoma. The exact cause of primary gastric lymphoma is unknown. However, a strong association between infection with Helicobacter pylori (H. pylori) and the development of MALT gastric lymphoma has been established. H. pylori is a bacterium that is found in the stomach and the upper portion of the intestines and is well known for causing ulcers. In approximately 90 percent of cases, MALT gastric lymphoma is strongly associated with chronic H. pylori infection. MALT gastric lymphoma originally arises from certain white blood cells (lymphocytes) found within the lymphoid tissue of the stomach’s inner lining (mucous membranes or mucosa). This lymphoid tissue is not normally found in the stomach but develops as a result of chronic inflammation as occurs with chronic H. pylori infection. Although H. pylori infection plays a role in the development of MALT gastric lymphoma, the infection is quite common in the general population. Yet only a very small number of individuals with this bacterium develop MALT gastric lymphoma. This indicates that other factors, such as a weak response to the infection by the body’s immune system, also play a role in the development of MALT gastric lymphoma. Some individuals with MALT gastric lymphoma have chromosomal abnormalities within the tumor(s), specifically a translocation. A translocation means that a piece of one chromosome breaks off and attaches to another. These chromosomal abnormalities may be significant in terms of treatment or prognosis. For example, some affected individuals have a translocation involving chromosomes 11 and 18 (translocation t [11; 18]), which seems to be associated with poorer response to antibiotic therapy and the eradication of H. pylori infection. Diffuse large B-cell lymphoma (DLBCL) of the stomach may arise spontaneously in individuals without a previous history of cancer, or it may occur from the transformation of an indolent MALT gastric lymphoma into the more aggressive DLBCL form. Some researchers have suggested that DLBCL of the stomach may also be associated with H. pylori infection. Some individuals with DLBCL of the stomach have been infected with the H. pylori bacterium, but some researchers believe that these cases are examples of long-standing MALT gastric lymphoma that has transformed into the more aggressive DLBCL of the stomach.
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Affects of Primary Gastric Lymphoma
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Primary gastric lymphoma is estimated to affect approximately 1 in 100,000 people in the general population in Western countries. Several reports have noted that the incidence is increasing. Most cases of primary gastric lymphoma occur in individuals 50 years or older, with a peak incidence in the 60s and 70s. However, cases have been reported in children, adolescents, and young adults as well. Some reports suggest that men are affected more often than women. Primary gastric lymphoma has also been reported to occur more frequently in Caucasians than African-Americans. As mentioned earlier, primary gastric lymphoma is the most common form of extranodal non-Hodgkin lymphoma (NHL), accounting for 30-40 percent of all extranodal sites. Primary gastric lymphoma accounts for 10-15 percent of all NHL cases. Although it is the most common extranodal site for NHL, primary gastric lymphoma is extremely rare, accounting for only 2-8 percent of all cases of stomach cancers. Diffuse large B-cell lymphoma (DLBCL) and MALT lymphoma are the second and third most common subtypes of NHL (this is for all cases of these subtypes, not just those confined to the gastrointestinal tract).
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Affects of Primary Gastric Lymphoma. Primary gastric lymphoma is estimated to affect approximately 1 in 100,000 people in the general population in Western countries. Several reports have noted that the incidence is increasing. Most cases of primary gastric lymphoma occur in individuals 50 years or older, with a peak incidence in the 60s and 70s. However, cases have been reported in children, adolescents, and young adults as well. Some reports suggest that men are affected more often than women. Primary gastric lymphoma has also been reported to occur more frequently in Caucasians than African-Americans. As mentioned earlier, primary gastric lymphoma is the most common form of extranodal non-Hodgkin lymphoma (NHL), accounting for 30-40 percent of all extranodal sites. Primary gastric lymphoma accounts for 10-15 percent of all NHL cases. Although it is the most common extranodal site for NHL, primary gastric lymphoma is extremely rare, accounting for only 2-8 percent of all cases of stomach cancers. Diffuse large B-cell lymphoma (DLBCL) and MALT lymphoma are the second and third most common subtypes of NHL (this is for all cases of these subtypes, not just those confined to the gastrointestinal tract).
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Related disorders of Primary Gastric Lymphoma
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The following disorders can have symptoms similar to those of primary gastric lymphoma. Gastric adenocarcinoma is the most common form of stomach cancer. It is important not to confuse gastric cancer (a.k.a. gastric adenocarcinoma and stomach cancer) with gastric lymphoma, as these conditions are treated very differently. Some reports state that gastric adenocarcinomas account for more than 90 percent of all cancers of the stomach. Adenocarcinoma of the stomach is rare in the United States but is more common in Asia. Symptoms may include unintended weight loss, fatigue, low levels of circulating red blood cells (anemia), abdominal and/or back pain, loss of appetite (anorexia), nausea, vomiting, and/or constipation. In some cases, it may be possible to feel a mass in the abdomen. The vomiting up of blood (hematemesis) or blood in the stools (melena) may also occur. The disease occurs predominantly in males over fifty years of age. People with a high consumption of foods high in nitrates and salt (common in cured meats) seem to develop this type of cancer more readily than persons with diets consisting of more fresh fruits and vegetables. Treatment of gastric adenocarcinoma involves surgery, chemotherapy, and radiation. Typically, the surgery performed is complete removal of the stomach (gastrectomy). Zollinger-Ellison syndrome (ZES) is characterized by the development of a tumor (gastrinoma) or tumors that secrete excessive levels of gastrin, a hormone that stimulates production of acid by the stomach. Many affected individuals develop multiple gastrinomas, approximately half to two-thirds of which may be cancerous (malignant). In most cases, the tumors arise within the pancreas and/or the upper region of the small intestine (duodenum). Due to excessive acid production (gastric acid hypersecretion), individuals with ZES may develop ulcers of the stomach, the duodenum, and/or other regions of the digestive tract. Peptic ulcers are sores or raw areas within the digestive tract where the lining has been eroded by stomach acid and digestive juices. Symptoms and findings associated with ZES may include mild to severe abdominal pain; diarrhea; increased amounts of fat in the stools (steatorrhea); and/or other abnormalities. In most affected individuals, ZES appears to develop randomly (sporadically) for unknown reasons. In approximately 25 percent of cases, ZES occurs in association with a genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). (For more information on this disorder, choose “Zollinger Ellison” as your search term in the Rare Disease Database.)
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Related disorders of Primary Gastric Lymphoma. The following disorders can have symptoms similar to those of primary gastric lymphoma. Gastric adenocarcinoma is the most common form of stomach cancer. It is important not to confuse gastric cancer (a.k.a. gastric adenocarcinoma and stomach cancer) with gastric lymphoma, as these conditions are treated very differently. Some reports state that gastric adenocarcinomas account for more than 90 percent of all cancers of the stomach. Adenocarcinoma of the stomach is rare in the United States but is more common in Asia. Symptoms may include unintended weight loss, fatigue, low levels of circulating red blood cells (anemia), abdominal and/or back pain, loss of appetite (anorexia), nausea, vomiting, and/or constipation. In some cases, it may be possible to feel a mass in the abdomen. The vomiting up of blood (hematemesis) or blood in the stools (melena) may also occur. The disease occurs predominantly in males over fifty years of age. People with a high consumption of foods high in nitrates and salt (common in cured meats) seem to develop this type of cancer more readily than persons with diets consisting of more fresh fruits and vegetables. Treatment of gastric adenocarcinoma involves surgery, chemotherapy, and radiation. Typically, the surgery performed is complete removal of the stomach (gastrectomy). Zollinger-Ellison syndrome (ZES) is characterized by the development of a tumor (gastrinoma) or tumors that secrete excessive levels of gastrin, a hormone that stimulates production of acid by the stomach. Many affected individuals develop multiple gastrinomas, approximately half to two-thirds of which may be cancerous (malignant). In most cases, the tumors arise within the pancreas and/or the upper region of the small intestine (duodenum). Due to excessive acid production (gastric acid hypersecretion), individuals with ZES may develop ulcers of the stomach, the duodenum, and/or other regions of the digestive tract. Peptic ulcers are sores or raw areas within the digestive tract where the lining has been eroded by stomach acid and digestive juices. Symptoms and findings associated with ZES may include mild to severe abdominal pain; diarrhea; increased amounts of fat in the stools (steatorrhea); and/or other abnormalities. In most affected individuals, ZES appears to develop randomly (sporadically) for unknown reasons. In approximately 25 percent of cases, ZES occurs in association with a genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). (For more information on this disorder, choose “Zollinger Ellison” as your search term in the Rare Disease Database.)
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Diagnosis of Primary Gastric Lymphoma
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Primary gastric lymphoma is diagnosed based upon a thorough clinical evaluation, detection of certain symptoms and physical findings, a detailed patient history and a variety of specialized tests. Such testing is necessary to confirm the specific type (and subtype) of NHL present, to assess the nature and extent of the disease and to determine the most appropriate treatments. For individuals with suspected gastric lymphoma as suggested by patient history and physical examination, various diagnostic tests may be recommended. These include blood tests, biopsies, bone marrow aspirates, and specialized imaging tests. For example, blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies.) For individuals suspected of primary gastric lymphoma, a surgeon or gastroenterologist (a physician specializing in diseases of the digestive organs) will perform a procedure called an esophagogastroduodenoscopy (EGD), also called an upper GI (gastrointestinal) endoscopy. During an EGD, a light, flexible tube with a camera (endoscope) is inserted into the stomach or gastrointestinal tract to allow a physician to view the areas of abnormal tissue. An endoscope also allows a physician to perform a biopsy or biopsies (removal of a small sample of tissue or multiple samples for study under a microscope by a pathologist–a physician who specializes in diagnosing disease through the study of tissue, fluids and blood). The EGD and biopsy procedure may be conducted under local or whole body (general) anesthesia. Microscopic analysis of affected tissue lets pathologists determine additional microscopic features that may be important in the malignancy’s classification, such as the size of malignant lymphocytes, appearance of the nucleus within a lymphoma cell, distribution or pattern of the abnormal cells, etc. In addition, specialized studies are conducted to help determine the malignancy’s specific cell type of origin. For example, gastric lymphoma cells–and the normal cells from which the malignancy develops–produce distinctive proteins (antigens) that may promote an antibody (immune) response (e.g., antigens such as CD20). They also may express certain antibodies on their outer surfaces (e.g., immunoglobulin M [IgM]). Thus, testing to identify such markers assists in determining the normal cells from which the malignancy derived, helping to distinguish primary gastric lymphoma from other types of lymphoma and aiding in diagnosis and treatment decisions. Various specialized imaging procedures may also be recommended, such as standard x-ray imaging or computed tomography (CT) scanning. Specialized imaging procedures are generally used to help establish a diagnosis and to determine the extent of the disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. For those with suspected or diagnosed NHL, CT scans may be taken of the neck, chest, abdominal, and/or pelvic regions to help detect enlargement of certain lymph nodes or spread of the malignancy to certain organs. Although abnormalities of the stomach mucosa are difficult to see on CT scans, such scans are useful in showing any extension or spread of the lymphoma to other parts of the body where they can be more easily seen on CT. PET scans (positron emission tomography) are an important diagnostic exam for lymphoma. Cancer cells, like lymphoma, metabolize sugar more rapidly than normal cells. PET scans are a nuclear medicine imaging technology where radioactive glucose is injected into the patient and cancer cells take up this glucose more rapidly and in much higher quantities than normal cells, causing the cancer cells to “light-up” on the scan. PET scans are useful in showing to what extent the lymphoma has spread. They can also be used to measure a patient’s response to treatment. PET scans are often performed in conjunction with a CT scan, and when this is done, a separate CT scan can often be omitted. Unfortunately, PET scans can light up in parts of the body where there is infection or inflammation in the absence of cancer, resulting in a false positive scan. Although PET scans are commonly used to stage and follow patients with nodal NHL, they are only used in selected cases of gastric lymphomas getting radiation therapy, as PET images can help define the target for treatment. MRI (magnetic resonance imaging) can be considered when CT scans and/or PET scans do not provide the needed information. Nevertheless, MRI is not considered a standard imaging study used in the staging, workup, and follow-up of gastric lymphomas. Staging
When an individual is diagnosed with primary gastric lymphoma, the “stage” needs to be determined. Staging helps describe how far the disease has spread, characterize the potential disease course, and determine the right treatment. Some of the same diagnostic tests described above may be used in staging a primary gastric lymphoma (e.g., blood tests, CT scanning, PET scan, bone marrow aspiration and biopsy). Different staging systems have been proposed for primary gastric lymphoma. One of the more widely used staging systems used for primary gastric lymphoma was proposed during an international conference in Lugano, Switzerland, known as the Lugano Modification of Ann Arbor Staging System for Primary Nodal Lymphomas. Because this staging system applies to all lymphomas, there is a more specific Lugano Staging System for primary gastrointestinal lymphoma. The “E” subscript stands for extranodal, since gastric lymphomas tend to originate from the lining of the stomach instead of lymph nodes. It includes the following stages: Stage IE – Lymphoma is confined to the gastrointestinal tract (single lesion or multiple non-contiguous lesions).
IE1 = mucosa, submucosa
IE2 = muscularis propria, serosa
Stage II – Lymphoma extends into the abdomen from the primary site within the gastrointestinal tract.
II1 = local nodal involvement
II2 = distant nodal involvement
Stage IIE – Penetration of serosa to involve adjacent organs or tissues.
Stage IV – Disseminated extranodal involvement or concomitant supra-diaphragmatic nodal involvement. Note: Stage III involves lymphoma above and below the diaphragm and gastric lymphoma is always below the diaphragm, so Stage III does not exist for gastric lymphomas. If there is any involvement of lymph nodes above the diaphragm, the patient would be a Stage IV.
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Diagnosis of Primary Gastric Lymphoma. Primary gastric lymphoma is diagnosed based upon a thorough clinical evaluation, detection of certain symptoms and physical findings, a detailed patient history and a variety of specialized tests. Such testing is necessary to confirm the specific type (and subtype) of NHL present, to assess the nature and extent of the disease and to determine the most appropriate treatments. For individuals with suspected gastric lymphoma as suggested by patient history and physical examination, various diagnostic tests may be recommended. These include blood tests, biopsies, bone marrow aspirates, and specialized imaging tests. For example, blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies.) For individuals suspected of primary gastric lymphoma, a surgeon or gastroenterologist (a physician specializing in diseases of the digestive organs) will perform a procedure called an esophagogastroduodenoscopy (EGD), also called an upper GI (gastrointestinal) endoscopy. During an EGD, a light, flexible tube with a camera (endoscope) is inserted into the stomach or gastrointestinal tract to allow a physician to view the areas of abnormal tissue. An endoscope also allows a physician to perform a biopsy or biopsies (removal of a small sample of tissue or multiple samples for study under a microscope by a pathologist–a physician who specializes in diagnosing disease through the study of tissue, fluids and blood). The EGD and biopsy procedure may be conducted under local or whole body (general) anesthesia. Microscopic analysis of affected tissue lets pathologists determine additional microscopic features that may be important in the malignancy’s classification, such as the size of malignant lymphocytes, appearance of the nucleus within a lymphoma cell, distribution or pattern of the abnormal cells, etc. In addition, specialized studies are conducted to help determine the malignancy’s specific cell type of origin. For example, gastric lymphoma cells–and the normal cells from which the malignancy develops–produce distinctive proteins (antigens) that may promote an antibody (immune) response (e.g., antigens such as CD20). They also may express certain antibodies on their outer surfaces (e.g., immunoglobulin M [IgM]). Thus, testing to identify such markers assists in determining the normal cells from which the malignancy derived, helping to distinguish primary gastric lymphoma from other types of lymphoma and aiding in diagnosis and treatment decisions. Various specialized imaging procedures may also be recommended, such as standard x-ray imaging or computed tomography (CT) scanning. Specialized imaging procedures are generally used to help establish a diagnosis and to determine the extent of the disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. For those with suspected or diagnosed NHL, CT scans may be taken of the neck, chest, abdominal, and/or pelvic regions to help detect enlargement of certain lymph nodes or spread of the malignancy to certain organs. Although abnormalities of the stomach mucosa are difficult to see on CT scans, such scans are useful in showing any extension or spread of the lymphoma to other parts of the body where they can be more easily seen on CT. PET scans (positron emission tomography) are an important diagnostic exam for lymphoma. Cancer cells, like lymphoma, metabolize sugar more rapidly than normal cells. PET scans are a nuclear medicine imaging technology where radioactive glucose is injected into the patient and cancer cells take up this glucose more rapidly and in much higher quantities than normal cells, causing the cancer cells to “light-up” on the scan. PET scans are useful in showing to what extent the lymphoma has spread. They can also be used to measure a patient’s response to treatment. PET scans are often performed in conjunction with a CT scan, and when this is done, a separate CT scan can often be omitted. Unfortunately, PET scans can light up in parts of the body where there is infection or inflammation in the absence of cancer, resulting in a false positive scan. Although PET scans are commonly used to stage and follow patients with nodal NHL, they are only used in selected cases of gastric lymphomas getting radiation therapy, as PET images can help define the target for treatment. MRI (magnetic resonance imaging) can be considered when CT scans and/or PET scans do not provide the needed information. Nevertheless, MRI is not considered a standard imaging study used in the staging, workup, and follow-up of gastric lymphomas. Staging
When an individual is diagnosed with primary gastric lymphoma, the “stage” needs to be determined. Staging helps describe how far the disease has spread, characterize the potential disease course, and determine the right treatment. Some of the same diagnostic tests described above may be used in staging a primary gastric lymphoma (e.g., blood tests, CT scanning, PET scan, bone marrow aspiration and biopsy). Different staging systems have been proposed for primary gastric lymphoma. One of the more widely used staging systems used for primary gastric lymphoma was proposed during an international conference in Lugano, Switzerland, known as the Lugano Modification of Ann Arbor Staging System for Primary Nodal Lymphomas. Because this staging system applies to all lymphomas, there is a more specific Lugano Staging System for primary gastrointestinal lymphoma. The “E” subscript stands for extranodal, since gastric lymphomas tend to originate from the lining of the stomach instead of lymph nodes. It includes the following stages: Stage IE – Lymphoma is confined to the gastrointestinal tract (single lesion or multiple non-contiguous lesions).
IE1 = mucosa, submucosa
IE2 = muscularis propria, serosa
Stage II – Lymphoma extends into the abdomen from the primary site within the gastrointestinal tract.
II1 = local nodal involvement
II2 = distant nodal involvement
Stage IIE – Penetration of serosa to involve adjacent organs or tissues.
Stage IV – Disseminated extranodal involvement or concomitant supra-diaphragmatic nodal involvement. Note: Stage III involves lymphoma above and below the diaphragm and gastric lymphoma is always below the diaphragm, so Stage III does not exist for gastric lymphomas. If there is any involvement of lymph nodes above the diaphragm, the patient would be a Stage IV.
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Therapies of Primary Gastric Lymphoma
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TreatmentThe diagnosis and therapeutic management of primary gastric lymphoma requires the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer with chemotherapy and other drugs (medical oncologists), disorders of the gastrointestinal tract (gastroenterologists), disorders of the blood and blood-forming tissues (hematologists), or the diagnosis and treatment of cancer with radiation (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other professionals. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific lymphoma subtype; the presence or absence of certain symptoms; individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. A wide variety of treatment options exist for individuals with primary gastric lymphoma including observation, antibiotic therapy, surgery, chemotherapy, and radiation therapy. These treatments may be used alone or in varied combinations. Because MALT gastric lymphoma is slow-growing (indolent) form of lymphoma and because some individuals remain free of symptoms or disease progression for many years, physicians may recommend a watch and wait strategy. Watch and wait refers to when physicians follow a patient with a slow-growing cancer without giving treatment until progression of the disease occurs. This allows some people to avoid undergoing such therapies for many years and even decades in some cases, thus delaying the need to experience the side effects associated with treatment. For individuals with early stage MALT gastric lymphoma confined to the stomach, antibiotics alone may be prescribed. Many studies have shown that curing MALT gastric lymphoma is possible with just antibiotics in many patients. The eradication of H. pylori with antibiotics is considered by many physicians to be a reasonable initial therapy for individuals with early stage MALT gastric lymphoma. Thorough follow up studies (e.g., blood tests and endoscopic biopsies) are required to confirm the eradication of the bacteria and to assess the response of lymphoma therapy. Continued follow up is also necessary because MALT gastric lymphoma can return if a person becomes re-infected with H. pylori. On the other hand, anecdotal reports in the medical literature have described some cases of the more aggressive DLBCL of the stomach that have responded to antibiotic therapy including individuals who have gone into complete remission (all bloodwork, scans, and physical examination indicate the cancer is no longer present). Some researchers advocate that all individuals with DLBCL of the stomach and H. pylori infection should receive antibiotic therapy. Other researchers believe more research is necessary to determine whether antibiotic therapy is appropriate for treating this form of gastric lymphoma. RADIATION THERAPY
Some individuals with MALT gastric lymphoma may not respond to therapy with antibiotics. In these cases, radiation therapy to the stomach is often used. Radiation therapy is a treatment method that uses radiation to destroy cancer cells using beams generated from a linear accelerator (a large advanced X-ray machine) aimed at the tumor. A dose of 30 Gy or 3000 cGy is typically given, although a lower dose of 2400 cGy is also acceptable. In cases of advanced MALT lymphoma, and in cases of the more aggressive DLBCL of the stomach, chemotherapy is often used with or without radiation therapy. Higher doses of radiation (36 Gy or 3600 cGy) are used for cases of DLBCL of the stomach. Most people treated with radiation for MALT lymphoma are cured, with 87% of patients being alive after 10 years.
SURGERY
Despite the success of surgery in the past, surgery’s role in the treatment of primary gastric lymphoma is now only reserved for highly selected cases that do not respond to chemotherapy or radiation. The current standard of care for MALT gastric lymphoma is nonsurgical and includes antibiotics (if H. pylori positive) or locoregional radiation therapy to the stomach if there is persistent disease after antibiotics or if the patient does not have H. pylori infection. The current standard of care for gastric DLBCL is also nonsurgical and includes chemotherapy with or without subsequent locoregional radiation therapy depending on response to chemotherapy, or size of the initial tumor. CHEMOTHERAPY
Chemotherapy is the use of several different drugs (given intravenously) alone or in combination to kill cancer cells. Chemotherapy is usually not needed for MALT gastric lymphoma, but biologic therapy with rituximab (discussed below) is used in patients who for one reason or another, cannot receive radiation therapy. Chemotherapy is used frequently in DLBCL of the stomach. The most common chemotherapeutic regimen used to treat individuals with DLBCL of the stomach is R-CHOP. The “R” stands for rituximab (Rituxan), a biological therapy (or immunotherapy), which has been highly successful in treating many types of lymphoma including DLBCL (although its role in treating of DLBCL of the stomach is less studied). Rituximab is a monoclonal antibody that is specifically directed against the CD20 antigen, which is a protein that may be found on the surface of certain lymphoma B-cells. Monoclonal antibodies are produced by mature B-cells known as plasma cells; each plasma cell secretes a specific type of monoclonal antibody, which in turn acts against a specific antigen as part of an antibody-mediated immune response. Laboratories can now make large amounts of a specific monoclonal antibody that can be directed against a particular target, such as the CD20 antigen on lymphoma cells, often destroying the cell. Rituximab is an antibody that targets the CD20 antigen, and is often given with a standard chemotherapy regimen called “CHOP”. CHOP stands for: cyclophosphamide, hydroxydaunorubicin (doxorubicin or Adriamycin), Oncovin (vincristine) and prednisone. The response to such treatments may vary widely. Nevertheless, Stage I-II DLBCL of the stomach are typically treated with 3 to 6 cycles of R-CHOP, followed by radiation therapy to the stomach to a dose of 3000 to 3600 cGy if there was a complete response to chemotherapy. If there was only a partial response, higher doses of radiation are often used. Stage III-IV DLBCL of the stomach is often treated with chemotherapy alone. Some individuals may have insufficient response to standard chemotherapeutic regimens or may experience relapses, or the disease may become resistant (refractory) to treatment, potentially leading to life-threatening complications. Therefore, researchers are exploring the potential effectiveness of differing combinations of various chemotherapeutic drugs, high-dose chemotherapy regimens followed by stem cell/bone marrow transplantation, and/or other investigational therapies that may be warranted for selected individuals, possibly at the time of diagnosis, following certain standard therapies, and/or for those with refractory disease or relapse. They are also investigating appropriate ways in which to combine various therapies and to reduce potential side effects. Other therapies for individuals with primary gastric lymphoma include symptomatic and supportive measures. These include but are not limited to medications to counteract nausea and vomiting, intravenous fluids to treat dehydration, pain medications, antacids to lower the risk of ulcers, stenting to open up any obstruction, and bone marrow stimulating drugs to reverse the low white blood cell counts (leukopenia) and red blood cell counts (anemia) caused by chemotherapy. After completing treatment for primary gastric lymphoma, it is recommended that the patient get an EGD with biopsy in 3 to 6 months. If the biopsies show no evidence of lymphoma or H. pylori infection, then patients should follow up with their oncologist every 3 to 6 months for 5 years, then once a year. There is no set recommendation for how often a patient should get an EGD after the first post treatment EGD; however, if a patient begins experiencing unexplained nausea, abdominal pain, or fullness after eating small meals, then an EGD should be done.
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Therapies of Primary Gastric Lymphoma. TreatmentThe diagnosis and therapeutic management of primary gastric lymphoma requires the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer with chemotherapy and other drugs (medical oncologists), disorders of the gastrointestinal tract (gastroenterologists), disorders of the blood and blood-forming tissues (hematologists), or the diagnosis and treatment of cancer with radiation (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other professionals. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific lymphoma subtype; the presence or absence of certain symptoms; individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. A wide variety of treatment options exist for individuals with primary gastric lymphoma including observation, antibiotic therapy, surgery, chemotherapy, and radiation therapy. These treatments may be used alone or in varied combinations. Because MALT gastric lymphoma is slow-growing (indolent) form of lymphoma and because some individuals remain free of symptoms or disease progression for many years, physicians may recommend a watch and wait strategy. Watch and wait refers to when physicians follow a patient with a slow-growing cancer without giving treatment until progression of the disease occurs. This allows some people to avoid undergoing such therapies for many years and even decades in some cases, thus delaying the need to experience the side effects associated with treatment. For individuals with early stage MALT gastric lymphoma confined to the stomach, antibiotics alone may be prescribed. Many studies have shown that curing MALT gastric lymphoma is possible with just antibiotics in many patients. The eradication of H. pylori with antibiotics is considered by many physicians to be a reasonable initial therapy for individuals with early stage MALT gastric lymphoma. Thorough follow up studies (e.g., blood tests and endoscopic biopsies) are required to confirm the eradication of the bacteria and to assess the response of lymphoma therapy. Continued follow up is also necessary because MALT gastric lymphoma can return if a person becomes re-infected with H. pylori. On the other hand, anecdotal reports in the medical literature have described some cases of the more aggressive DLBCL of the stomach that have responded to antibiotic therapy including individuals who have gone into complete remission (all bloodwork, scans, and physical examination indicate the cancer is no longer present). Some researchers advocate that all individuals with DLBCL of the stomach and H. pylori infection should receive antibiotic therapy. Other researchers believe more research is necessary to determine whether antibiotic therapy is appropriate for treating this form of gastric lymphoma. RADIATION THERAPY
Some individuals with MALT gastric lymphoma may not respond to therapy with antibiotics. In these cases, radiation therapy to the stomach is often used. Radiation therapy is a treatment method that uses radiation to destroy cancer cells using beams generated from a linear accelerator (a large advanced X-ray machine) aimed at the tumor. A dose of 30 Gy or 3000 cGy is typically given, although a lower dose of 2400 cGy is also acceptable. In cases of advanced MALT lymphoma, and in cases of the more aggressive DLBCL of the stomach, chemotherapy is often used with or without radiation therapy. Higher doses of radiation (36 Gy or 3600 cGy) are used for cases of DLBCL of the stomach. Most people treated with radiation for MALT lymphoma are cured, with 87% of patients being alive after 10 years.
SURGERY
Despite the success of surgery in the past, surgery’s role in the treatment of primary gastric lymphoma is now only reserved for highly selected cases that do not respond to chemotherapy or radiation. The current standard of care for MALT gastric lymphoma is nonsurgical and includes antibiotics (if H. pylori positive) or locoregional radiation therapy to the stomach if there is persistent disease after antibiotics or if the patient does not have H. pylori infection. The current standard of care for gastric DLBCL is also nonsurgical and includes chemotherapy with or without subsequent locoregional radiation therapy depending on response to chemotherapy, or size of the initial tumor. CHEMOTHERAPY
Chemotherapy is the use of several different drugs (given intravenously) alone or in combination to kill cancer cells. Chemotherapy is usually not needed for MALT gastric lymphoma, but biologic therapy with rituximab (discussed below) is used in patients who for one reason or another, cannot receive radiation therapy. Chemotherapy is used frequently in DLBCL of the stomach. The most common chemotherapeutic regimen used to treat individuals with DLBCL of the stomach is R-CHOP. The “R” stands for rituximab (Rituxan), a biological therapy (or immunotherapy), which has been highly successful in treating many types of lymphoma including DLBCL (although its role in treating of DLBCL of the stomach is less studied). Rituximab is a monoclonal antibody that is specifically directed against the CD20 antigen, which is a protein that may be found on the surface of certain lymphoma B-cells. Monoclonal antibodies are produced by mature B-cells known as plasma cells; each plasma cell secretes a specific type of monoclonal antibody, which in turn acts against a specific antigen as part of an antibody-mediated immune response. Laboratories can now make large amounts of a specific monoclonal antibody that can be directed against a particular target, such as the CD20 antigen on lymphoma cells, often destroying the cell. Rituximab is an antibody that targets the CD20 antigen, and is often given with a standard chemotherapy regimen called “CHOP”. CHOP stands for: cyclophosphamide, hydroxydaunorubicin (doxorubicin or Adriamycin), Oncovin (vincristine) and prednisone. The response to such treatments may vary widely. Nevertheless, Stage I-II DLBCL of the stomach are typically treated with 3 to 6 cycles of R-CHOP, followed by radiation therapy to the stomach to a dose of 3000 to 3600 cGy if there was a complete response to chemotherapy. If there was only a partial response, higher doses of radiation are often used. Stage III-IV DLBCL of the stomach is often treated with chemotherapy alone. Some individuals may have insufficient response to standard chemotherapeutic regimens or may experience relapses, or the disease may become resistant (refractory) to treatment, potentially leading to life-threatening complications. Therefore, researchers are exploring the potential effectiveness of differing combinations of various chemotherapeutic drugs, high-dose chemotherapy regimens followed by stem cell/bone marrow transplantation, and/or other investigational therapies that may be warranted for selected individuals, possibly at the time of diagnosis, following certain standard therapies, and/or for those with refractory disease or relapse. They are also investigating appropriate ways in which to combine various therapies and to reduce potential side effects. Other therapies for individuals with primary gastric lymphoma include symptomatic and supportive measures. These include but are not limited to medications to counteract nausea and vomiting, intravenous fluids to treat dehydration, pain medications, antacids to lower the risk of ulcers, stenting to open up any obstruction, and bone marrow stimulating drugs to reverse the low white blood cell counts (leukopenia) and red blood cell counts (anemia) caused by chemotherapy. After completing treatment for primary gastric lymphoma, it is recommended that the patient get an EGD with biopsy in 3 to 6 months. If the biopsies show no evidence of lymphoma or H. pylori infection, then patients should follow up with their oncologist every 3 to 6 months for 5 years, then once a year. There is no set recommendation for how often a patient should get an EGD after the first post treatment EGD; however, if a patient begins experiencing unexplained nausea, abdominal pain, or fullness after eating small meals, then an EGD should be done.
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Primary Gastric Lymphoma
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Overview of Primary Hyperoxaluria
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SummaryPrimary hyperoxaluria (PH) is a group of rare genetic metabolic disorders that are characterized by the accumulation of a substance known as oxalate in the kidneys and other organ systems of the body. Affected individuals lack functional levels of a specific enzyme that normally prevents the accumulation of oxalate. There are three main types of PH – PH types I, II, and III – differentiated by the specific enzyme that is deficient. In the kidneys, excess oxalate binds with calcium to form a hard compound (calcium oxalate) that is the main component of kidney and urinary stones. Common symptoms include the formation of stones throughout the urinary tract (urolithiasis) and kidneys (nephrolithiasis) and progressively increased levels of calcium in the kidneys (nephrocalcinosis). Chronic, recurrent stone formation and the accumulation of calcium oxalate in kidney tissue can cause chronic kidney disease, which can ultimately progress to kidney failure. Eventually, kidney function can deteriorate to the point where oxalate begins to accumulate in other organ systems. Overall, the symptoms and severity of PH may vary greatly from one person to another. Chronic kidney disease and kidney failure may already be present when a diagnosis is first made. PH is a treatable disorder and complications may be minimized with early recognition and prompt treatment.PH is inherited in an autosomal recessive pattern. The genetic mutations that cause PH control the production of different enzymes found primarily in the liver in PH type I and PH type II, and in the kidney and liver in PH type III. The significance of the enzyme found in the kidney remains to be determined.
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Overview of Primary Hyperoxaluria. SummaryPrimary hyperoxaluria (PH) is a group of rare genetic metabolic disorders that are characterized by the accumulation of a substance known as oxalate in the kidneys and other organ systems of the body. Affected individuals lack functional levels of a specific enzyme that normally prevents the accumulation of oxalate. There are three main types of PH – PH types I, II, and III – differentiated by the specific enzyme that is deficient. In the kidneys, excess oxalate binds with calcium to form a hard compound (calcium oxalate) that is the main component of kidney and urinary stones. Common symptoms include the formation of stones throughout the urinary tract (urolithiasis) and kidneys (nephrolithiasis) and progressively increased levels of calcium in the kidneys (nephrocalcinosis). Chronic, recurrent stone formation and the accumulation of calcium oxalate in kidney tissue can cause chronic kidney disease, which can ultimately progress to kidney failure. Eventually, kidney function can deteriorate to the point where oxalate begins to accumulate in other organ systems. Overall, the symptoms and severity of PH may vary greatly from one person to another. Chronic kidney disease and kidney failure may already be present when a diagnosis is first made. PH is a treatable disorder and complications may be minimized with early recognition and prompt treatment.PH is inherited in an autosomal recessive pattern. The genetic mutations that cause PH control the production of different enzymes found primarily in the liver in PH type I and PH type II, and in the kidney and liver in PH type III. The significance of the enzyme found in the kidney remains to be determined.
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Symptoms of Primary Hyperoxaluria
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PH has characteristic or “core” symptoms, but some aspects of these disorders are still not fully understood. Several factors including the small number of identified cases (especially with PH types II and III), the lack of large clinical studies, and multiple genes influencing the disorders prevent physicians from developing a complete picture of associated symptoms and prognosis. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.The age of onset, progression, severity and specific symptoms that develop can vary greatly from one person to another, even in individuals with the same subtype and even among members of the same family. Some individuals may have mild cases that go undiagnosed well into adulthood; others may develop severe complications during infancy. In some individuals kidney involvement may progress slowly, while in others it may progress rapidly.PRIMARY HYPEROXALURIA TYPE I
PH type I is the most severe and most common of the three types. It is estimated to account for 70 to 80% of all diagnosed PH patients. The severe infantile form is associated with the failure to gain weight and grow at the expected rate for age and gender (failure to thrive), widespread calcium oxalate crystal deposits in the kidneys, and/or kidney stones or stones elsewhere in the urinary tract such as the bladder or urethra. Kidney and urinary stones can cause a variety of symptoms including blood in the urine (hematuria), painful urination (dysuria), the urge to urinate often, abdominal pain (renal colic), blockage of the urinary tract, and repeated urinary tract infections. PH type I often causes progressive kidney damage and kidney failure.When PH type I develops during childhood or adolescence, the disorder is usually characterized by recurrent stones in the kidney or elsewhere in the urinary tract such as the bladder or urethra. Younger children may experience difficulty controlling their urine and/or bedwetting (enuresis). Progressive kidney damage leading to kidney failure may develop.Some individuals are not diagnosed with PH type I until adulthood and only experience occasional or recurrent episodes of kidney stones. In some cases, these individuals may develop kidney failure due to the obstruction of the kidneys by stones. Although usually described as a mild form of the disorder, approximately 20-50% of individuals diagnosed with PH type I in adulthood have advanced kidney disease or even kidney failure. In rare cases, a diagnosis may not be made until a kidney transplant rapidly fails due to recurrent disease. If kidney function declines in a person with PH, oxalate begins to accumulate in other organ systems of the body particularly bone, skin, retinas in the eyes, the middle layer of the wall of the heart (myocardium), various blood vessels, and the central nervous system. This is known as systemic oxalosis and occurs in patients with PH once oxalate levels in the blood become very high and kidney disease is advanced. Depending upon the organ system involved, affected individuals can develop additional symptoms including bone pain; multiple fractures; abnormal hardening and density of bone (osteosclerosis); anemia that is difficult to treat (erythropoietin-resistant anemia); degeneration of the cranial nerve that transmits light signals to the brain (optic atrophy) and disease of the retina (retinopathy); root resorption, pulp exposure, tooth mobility, and dental pain; damage to the nerves outside of the central nervous system (peripheral neuropathy); heart block, irregular heartbeats (arrhythmias), inflammation of the myocardium (myocarditis), and cardioembolic stroke; narrowing of a blood vessel due to spasms of the vessel (vasospasm); joint disease (arthropathy); enlargement of the liver and/or spleen (hepatosplenomegaly); and purplish mottling of the skin (livedo reticularis); tissue death (necrosis) on the hands and feet (peripheral gangrene); and a skin rash caused by calcium deposits in the skin (calcinosis cutis metastatica).PRIMARY HYPEROXALURIA TYPE II
PH type II usually presents during childhood and the disorder is more likely to have a milder presentation than PH type I. It is thought to account for approximately 10% of PH cases. Affected individuals can develop similar symptoms and have similar oxalate levels to those seen in individuals with PH type I but usually develop kidney and urinary stones less often. PH type II can eventually progress to cause kidney failure, although this often happens later than it does in PH type I. When kidney function declines, the accumulation of oxalate in other organ systems of the body as described above may also occur.PRIMARY HYPEROXALURIA TYPE III
Because so few cases of PH type III have been identified, it is difficult to make definite statements about disease severity and progression, but it is estimated to be at least as common as PH type II, accounting for approximately 10% of cases. The disorder is considered milder than PH types I or II. Affected individuals may have no symptoms, or may only experience kidney stone formation. Symptoms due to frequent kidney stones can begin at an early age, but overall decline in kidney function is slowest with type III, and oxalate levels are lowest. Typical signs and symptoms include stone formation in the urinary tract in the first decade of life that can persist throughout adulthood. Nephrocalcinosis and chronic kidney disease are uncommon. Advanced kidney disease has rarely been reported.UNCLASSIFIED PRIMARY HYPEROXALURIA
In some cases, patients present with signs and symptoms typical of PH but lack any identifiable mutation in the known associated genes AGXT, GRHPR, or HOGA1. They are currently diagnosed with unclassified PH, leading researchers to suspect there are other yet to be identified genetic mutations that can cause PH.
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Symptoms of Primary Hyperoxaluria. PH has characteristic or “core” symptoms, but some aspects of these disorders are still not fully understood. Several factors including the small number of identified cases (especially with PH types II and III), the lack of large clinical studies, and multiple genes influencing the disorders prevent physicians from developing a complete picture of associated symptoms and prognosis. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.The age of onset, progression, severity and specific symptoms that develop can vary greatly from one person to another, even in individuals with the same subtype and even among members of the same family. Some individuals may have mild cases that go undiagnosed well into adulthood; others may develop severe complications during infancy. In some individuals kidney involvement may progress slowly, while in others it may progress rapidly.PRIMARY HYPEROXALURIA TYPE I
PH type I is the most severe and most common of the three types. It is estimated to account for 70 to 80% of all diagnosed PH patients. The severe infantile form is associated with the failure to gain weight and grow at the expected rate for age and gender (failure to thrive), widespread calcium oxalate crystal deposits in the kidneys, and/or kidney stones or stones elsewhere in the urinary tract such as the bladder or urethra. Kidney and urinary stones can cause a variety of symptoms including blood in the urine (hematuria), painful urination (dysuria), the urge to urinate often, abdominal pain (renal colic), blockage of the urinary tract, and repeated urinary tract infections. PH type I often causes progressive kidney damage and kidney failure.When PH type I develops during childhood or adolescence, the disorder is usually characterized by recurrent stones in the kidney or elsewhere in the urinary tract such as the bladder or urethra. Younger children may experience difficulty controlling their urine and/or bedwetting (enuresis). Progressive kidney damage leading to kidney failure may develop.Some individuals are not diagnosed with PH type I until adulthood and only experience occasional or recurrent episodes of kidney stones. In some cases, these individuals may develop kidney failure due to the obstruction of the kidneys by stones. Although usually described as a mild form of the disorder, approximately 20-50% of individuals diagnosed with PH type I in adulthood have advanced kidney disease or even kidney failure. In rare cases, a diagnosis may not be made until a kidney transplant rapidly fails due to recurrent disease. If kidney function declines in a person with PH, oxalate begins to accumulate in other organ systems of the body particularly bone, skin, retinas in the eyes, the middle layer of the wall of the heart (myocardium), various blood vessels, and the central nervous system. This is known as systemic oxalosis and occurs in patients with PH once oxalate levels in the blood become very high and kidney disease is advanced. Depending upon the organ system involved, affected individuals can develop additional symptoms including bone pain; multiple fractures; abnormal hardening and density of bone (osteosclerosis); anemia that is difficult to treat (erythropoietin-resistant anemia); degeneration of the cranial nerve that transmits light signals to the brain (optic atrophy) and disease of the retina (retinopathy); root resorption, pulp exposure, tooth mobility, and dental pain; damage to the nerves outside of the central nervous system (peripheral neuropathy); heart block, irregular heartbeats (arrhythmias), inflammation of the myocardium (myocarditis), and cardioembolic stroke; narrowing of a blood vessel due to spasms of the vessel (vasospasm); joint disease (arthropathy); enlargement of the liver and/or spleen (hepatosplenomegaly); and purplish mottling of the skin (livedo reticularis); tissue death (necrosis) on the hands and feet (peripheral gangrene); and a skin rash caused by calcium deposits in the skin (calcinosis cutis metastatica).PRIMARY HYPEROXALURIA TYPE II
PH type II usually presents during childhood and the disorder is more likely to have a milder presentation than PH type I. It is thought to account for approximately 10% of PH cases. Affected individuals can develop similar symptoms and have similar oxalate levels to those seen in individuals with PH type I but usually develop kidney and urinary stones less often. PH type II can eventually progress to cause kidney failure, although this often happens later than it does in PH type I. When kidney function declines, the accumulation of oxalate in other organ systems of the body as described above may also occur.PRIMARY HYPEROXALURIA TYPE III
Because so few cases of PH type III have been identified, it is difficult to make definite statements about disease severity and progression, but it is estimated to be at least as common as PH type II, accounting for approximately 10% of cases. The disorder is considered milder than PH types I or II. Affected individuals may have no symptoms, or may only experience kidney stone formation. Symptoms due to frequent kidney stones can begin at an early age, but overall decline in kidney function is slowest with type III, and oxalate levels are lowest. Typical signs and symptoms include stone formation in the urinary tract in the first decade of life that can persist throughout adulthood. Nephrocalcinosis and chronic kidney disease are uncommon. Advanced kidney disease has rarely been reported.UNCLASSIFIED PRIMARY HYPEROXALURIA
In some cases, patients present with signs and symptoms typical of PH but lack any identifiable mutation in the known associated genes AGXT, GRHPR, or HOGA1. They are currently diagnosed with unclassified PH, leading researchers to suspect there are other yet to be identified genetic mutations that can cause PH.
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Causes of Primary Hyperoxaluria
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PH type I is caused by changes (mutations) in the AGXT gene. PH type II is caused by mutations in the GRHPR gene. PH type III is caused by mutations in the HOGA1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The AGXT gene creates (encodes) the liver-specific peroxisomal enzyme alanine-glyoxylate aminotransferase. The GRHPR gene encodes the enzyme glyoxylate reductase-hydroxypyruvate reductase. Mutations in either of these genes lead to deficient levels of the corresponding enzyme. These enzymes play a role in regulating the production of oxalate. Deficient levels of these enzymes ultimately lead to the overproduction of oxalate in the body. The HOGA1 gene encodes liver-specific mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase. The exact role this enzyme plays in the production of oxalate is not fully understood. Thus researchers are not sure why a mutation in this gene leads to the overproduction of oxalate.Oxalate is a chemical found in the body. It is a dicarboxylic acid that is a normal end product of metabolism. It cannot be further metabolized. Metabolism refers to the various normal chemical processes that occur within a living organism. Most oxalate in the body is produced in the liver, although some may come from certain foods. Oxalate has no known role in the body and is considered a waste product of metabolism. Normally, most oxalate in the body (in the form of calcium salt) is removed from the body (excreted) through the kidneys. In individuals with PH, deficiency of the abovementioned enzymes results in overproduction of oxalate by the liver, which causes increased oxalate excretion by the kidneys. Some of the excess oxalate begins to accumulate in kidney tissue in the form of calcium oxalate crystals. This abnormal accumulation causes progressive damage to the kidneys and, if untreated, may ultimately cause kidney failure.A second phase of PH occurs when the glomerular filtration rate (GFR) of the kidneys drops far enough. The GFR is the flow rate of filtered fluid through the kidneys. When the GFR of a PH patient drops low enough, the kidneys are no longer able to handle the excess amounts of oxalate and the chemical begins to accumulate in other tissues of the body causing a wide variety of symptoms. The progression and severity of PH is highly variable. This may be due, in part, to specific mutations in genes corresponding with specific symptoms or disease progression. The association of a specific mutation in a gene to specific symptoms is known as genotype-phenotype correlation. Some individuals with specific AGXT mutations that cause PH type I (for example the mutations called p.G170R and p.F152I) respond to treatment with vitamin B6 (pyridoxine) while patients with other AGXT mutations do not. To date more than 170 different mutations in the AGXT gene have been identified that cause PH type I. Certain genetic mutations within each of the three types of PH are also predictive of which patients are less likely to develop kidney failure. Some research suggests that specific mutations of the AGXT gene, such as p.G170R, are associated with milder disease or later onset kidney failure. No specific genotype-phenotype correlation has been established yet in PH type II and III. There is more variation between genetic mutations for PH type I and II compared with PH type III.Because of variability in symptoms and disease progression, recent research has focused on identifying factors that help predict which patients will progress to kidney failure before it occurs. Factors associated with an increased likelihood of eventual progression to kidney failure include diagnosis of PH type I, older age when diagnosed with PH, higher urine oxalate levels, and low GFR at diagnosis. Urine oxalate levels are considered the greatest predictor among these. Higher urinary oxalate is associated with the development of nephrocalcinosis, which lead to chronic kidney damage through repetitive inflammation and permanent tissue changes that alter the function of the kidneys.It is likely that other factors contribute to disease variability in PH. These may include environmental factors and additional genetic factors (i.e., other genes that modify the disease course). However, no specific environmental or additional genetic factors have yet been identified.PH is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two parents that are each carriers to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier is 50% with each pregnancy. The chance for a child to receive working genes from both parents and thus be unaffected is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. PH appears to be more common in countries in which consanguineous marriage is common.
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Causes of Primary Hyperoxaluria. PH type I is caused by changes (mutations) in the AGXT gene. PH type II is caused by mutations in the GRHPR gene. PH type III is caused by mutations in the HOGA1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The AGXT gene creates (encodes) the liver-specific peroxisomal enzyme alanine-glyoxylate aminotransferase. The GRHPR gene encodes the enzyme glyoxylate reductase-hydroxypyruvate reductase. Mutations in either of these genes lead to deficient levels of the corresponding enzyme. These enzymes play a role in regulating the production of oxalate. Deficient levels of these enzymes ultimately lead to the overproduction of oxalate in the body. The HOGA1 gene encodes liver-specific mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase. The exact role this enzyme plays in the production of oxalate is not fully understood. Thus researchers are not sure why a mutation in this gene leads to the overproduction of oxalate.Oxalate is a chemical found in the body. It is a dicarboxylic acid that is a normal end product of metabolism. It cannot be further metabolized. Metabolism refers to the various normal chemical processes that occur within a living organism. Most oxalate in the body is produced in the liver, although some may come from certain foods. Oxalate has no known role in the body and is considered a waste product of metabolism. Normally, most oxalate in the body (in the form of calcium salt) is removed from the body (excreted) through the kidneys. In individuals with PH, deficiency of the abovementioned enzymes results in overproduction of oxalate by the liver, which causes increased oxalate excretion by the kidneys. Some of the excess oxalate begins to accumulate in kidney tissue in the form of calcium oxalate crystals. This abnormal accumulation causes progressive damage to the kidneys and, if untreated, may ultimately cause kidney failure.A second phase of PH occurs when the glomerular filtration rate (GFR) of the kidneys drops far enough. The GFR is the flow rate of filtered fluid through the kidneys. When the GFR of a PH patient drops low enough, the kidneys are no longer able to handle the excess amounts of oxalate and the chemical begins to accumulate in other tissues of the body causing a wide variety of symptoms. The progression and severity of PH is highly variable. This may be due, in part, to specific mutations in genes corresponding with specific symptoms or disease progression. The association of a specific mutation in a gene to specific symptoms is known as genotype-phenotype correlation. Some individuals with specific AGXT mutations that cause PH type I (for example the mutations called p.G170R and p.F152I) respond to treatment with vitamin B6 (pyridoxine) while patients with other AGXT mutations do not. To date more than 170 different mutations in the AGXT gene have been identified that cause PH type I. Certain genetic mutations within each of the three types of PH are also predictive of which patients are less likely to develop kidney failure. Some research suggests that specific mutations of the AGXT gene, such as p.G170R, are associated with milder disease or later onset kidney failure. No specific genotype-phenotype correlation has been established yet in PH type II and III. There is more variation between genetic mutations for PH type I and II compared with PH type III.Because of variability in symptoms and disease progression, recent research has focused on identifying factors that help predict which patients will progress to kidney failure before it occurs. Factors associated with an increased likelihood of eventual progression to kidney failure include diagnosis of PH type I, older age when diagnosed with PH, higher urine oxalate levels, and low GFR at diagnosis. Urine oxalate levels are considered the greatest predictor among these. Higher urinary oxalate is associated with the development of nephrocalcinosis, which lead to chronic kidney damage through repetitive inflammation and permanent tissue changes that alter the function of the kidneys.It is likely that other factors contribute to disease variability in PH. These may include environmental factors and additional genetic factors (i.e., other genes that modify the disease course). However, no specific environmental or additional genetic factors have yet been identified.PH is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two parents that are each carriers to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier is 50% with each pregnancy. The chance for a child to receive working genes from both parents and thus be unaffected is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. PH appears to be more common in countries in which consanguineous marriage is common.
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Primary Hyperoxaluria
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Affects of Primary Hyperoxaluria
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PH affects males and females in equal numbers. The exact incidence and prevalence of these disorders is unknown. Because some cases go undiagnosed or misdiagnosed, determining the true frequency of these conditions in the general population is difficult. Molecular genetic testing of young patients with recurring kidney stone formation can aid in diagnosis. However, some patients with common symptoms of PH are not found to have the known genetic mutations linked to PH, which likely underestimates the true number of people with PH. PH type I is the most common form. One estimate places the prevalence of PH type I at 1-3 cases per 1,000,000 people in the general population with fewer than 1,000 individuals with PH in the United States and the incidence at 1 case per 120,000 live births per year in Europe. PH is thought to be approximately 2.5 times more common in European Americans than African Americans.
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Affects of Primary Hyperoxaluria. PH affects males and females in equal numbers. The exact incidence and prevalence of these disorders is unknown. Because some cases go undiagnosed or misdiagnosed, determining the true frequency of these conditions in the general population is difficult. Molecular genetic testing of young patients with recurring kidney stone formation can aid in diagnosis. However, some patients with common symptoms of PH are not found to have the known genetic mutations linked to PH, which likely underestimates the true number of people with PH. PH type I is the most common form. One estimate places the prevalence of PH type I at 1-3 cases per 1,000,000 people in the general population with fewer than 1,000 individuals with PH in the United States and the incidence at 1 case per 120,000 live births per year in Europe. PH is thought to be approximately 2.5 times more common in European Americans than African Americans.
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Related disorders of Primary Hyperoxaluria
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Symptoms of the following disorders can be similar to those of PH. Comparisons may be useful for a differential diagnosis.Secondary hyperoxaluria is a general term for disorders in which elevated levels of oxalate occur due to a specific known cause. This is generally broken down into enteric and dietary hyperoxaluria. Enteric hyperoxaluria refers to the development of hyperoxaluria because of a disease of the small bowel such as Crohn’s disease, inflammation of the pancreas (pancreatitis), or short bowel syndrome. Certain forms of bariatric surgery are currently a common cause of enteric hyperoxaluria. All of these disorders lead to excess oxalate absorption and, consequently, elevated levels of oxalate in the urine. Dietary hyperoxaluria results from the excess intake of foods high in oxalate leading to elevated levels of oxalate in the plasma and urine, even in the absence of an underlying cause of enteric hyperoxaluria.Idiopathic calcium oxalate urolithiasis is a condition in which calcium oxalate stones develop for unknown reasons (idiopathic). Generally, this condition is less severe, has lower urinary excretion of oxalate and progresses to end stage renal disease less often than PH type I.There are several rare disorders characterized by symptoms similar to those seen in PH including the formation of stones in the kidney or urinary tract. Such disorders include Dent disease, familial hypercalciuria-hypomagnesaemia-nephrocalcinosis (Michelis-Castrillo syndrome), adenine phosphoribosyltransferase (APRT) deficiency, and cystinuria. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Primary Hyperoxaluria. Symptoms of the following disorders can be similar to those of PH. Comparisons may be useful for a differential diagnosis.Secondary hyperoxaluria is a general term for disorders in which elevated levels of oxalate occur due to a specific known cause. This is generally broken down into enteric and dietary hyperoxaluria. Enteric hyperoxaluria refers to the development of hyperoxaluria because of a disease of the small bowel such as Crohn’s disease, inflammation of the pancreas (pancreatitis), or short bowel syndrome. Certain forms of bariatric surgery are currently a common cause of enteric hyperoxaluria. All of these disorders lead to excess oxalate absorption and, consequently, elevated levels of oxalate in the urine. Dietary hyperoxaluria results from the excess intake of foods high in oxalate leading to elevated levels of oxalate in the plasma and urine, even in the absence of an underlying cause of enteric hyperoxaluria.Idiopathic calcium oxalate urolithiasis is a condition in which calcium oxalate stones develop for unknown reasons (idiopathic). Generally, this condition is less severe, has lower urinary excretion of oxalate and progresses to end stage renal disease less often than PH type I.There are several rare disorders characterized by symptoms similar to those seen in PH including the formation of stones in the kidney or urinary tract. Such disorders include Dent disease, familial hypercalciuria-hypomagnesaemia-nephrocalcinosis (Michelis-Castrillo syndrome), adenine phosphoribosyltransferase (APRT) deficiency, and cystinuria. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Primary Hyperoxaluria
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Diagnosis of Primary Hyperoxaluria
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A diagnosis of PH is based upon identification of characteristic symptoms (e.g. chronic stone formation), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Children with nephrocalcinosis or kidney stones should be screened for PH. PH may be suspected in individuals with a history of recurrent kidney stones and/or nephrocalcinosis. Because these conditions are rare, there may a delay from symptom onset to diagnosis.Investigation for PH includes measuring urine and plasma oxalate levels, ruling out other causes of high oxalate levels (dietary or enteric hyperoxaluria), molecular genetic testing for mutations known to be associated with PH and detecting the presence of kidney stones and examining their composition. Clinical Testing and Workup
Chemical analysis of urine samples may reveal elevated levels of oxalate, although this is a fluctuating and variable finding. Glycolate (glycolic acid) in PH type I and L-glycerate in PH type II may also be elevated in urine samples, but are nonspecific (i.e., they may be elevated for reasons other than PH). In some cases of PH type III, urinary calcium levels are abnormally high. Most individuals with PH type III have elevated levels of 4-hydroxyglutamate in the urine and blood, which could potentially be incorporated into multiple-analyte panels for newborn screening for inborn errors of metabolism. Blood tests can reveal high plasma oxalate concentration in individuals with PH who have chronic kidney disease. Otherwise, plasma oxalate levels are often normal or only mildly increased because the kidneys are able to excrete enough oxalate to keep plasma levels in the normal range.X-ray examinations can reveal the presence of kidney stones or calcium oxalate deposits in tissue. Computed tomography (CT) scanning, a specialized imaging technique, uses a computer and x-rays to create a film showing cross-sectional images of certain tissue structures such as kidney tissue. CT or MRI can detect the severity of systemic oxalosis by imaging the retina, heart, and bone in greater detail.A biopsy of affected kidney tissue can also reveal the abnormal accumulation of oxalate. A biopsy involves the surgical removal and microscopic examination of a piece of affected tissue. Previously, a liver biopsy was used to obtain a tissue sample to conduct an enzyme assay as a way to diagnose primary hyperoxaluria. An enzyme assay is a test that measures the activity of a specific enzyme. Such an assay can demonstrate low levels of the specific enzymes that are associated with the specific forms of PH. Today the need for liver biopsy has been greatly decreased due to the increasingly lower cost and improved sensitivity of modern molecular genetic testing.Examination of kidney stones can provide evidence to support the possibility of PH in comparison to other causes of kidney stone disease. The stones associated with PH tend to consist of more than 95% calcium oxalate monohydrate (whewellite), are usually pale-colored and may come in varying sizes, shapes and appearances (non-homogeneous). Although idiopathic stone formers can also produce calcium oxalate monohydrate stones, they also often contain some amount of calcium oxalate dihydrate and or calcium phosphate.Molecular genetic testing for mutations in the 3 specific genes known to cause PH confirms the diagnosis of PH.
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Diagnosis of Primary Hyperoxaluria. A diagnosis of PH is based upon identification of characteristic symptoms (e.g. chronic stone formation), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Children with nephrocalcinosis or kidney stones should be screened for PH. PH may be suspected in individuals with a history of recurrent kidney stones and/or nephrocalcinosis. Because these conditions are rare, there may a delay from symptom onset to diagnosis.Investigation for PH includes measuring urine and plasma oxalate levels, ruling out other causes of high oxalate levels (dietary or enteric hyperoxaluria), molecular genetic testing for mutations known to be associated with PH and detecting the presence of kidney stones and examining their composition. Clinical Testing and Workup
Chemical analysis of urine samples may reveal elevated levels of oxalate, although this is a fluctuating and variable finding. Glycolate (glycolic acid) in PH type I and L-glycerate in PH type II may also be elevated in urine samples, but are nonspecific (i.e., they may be elevated for reasons other than PH). In some cases of PH type III, urinary calcium levels are abnormally high. Most individuals with PH type III have elevated levels of 4-hydroxyglutamate in the urine and blood, which could potentially be incorporated into multiple-analyte panels for newborn screening for inborn errors of metabolism. Blood tests can reveal high plasma oxalate concentration in individuals with PH who have chronic kidney disease. Otherwise, plasma oxalate levels are often normal or only mildly increased because the kidneys are able to excrete enough oxalate to keep plasma levels in the normal range.X-ray examinations can reveal the presence of kidney stones or calcium oxalate deposits in tissue. Computed tomography (CT) scanning, a specialized imaging technique, uses a computer and x-rays to create a film showing cross-sectional images of certain tissue structures such as kidney tissue. CT or MRI can detect the severity of systemic oxalosis by imaging the retina, heart, and bone in greater detail.A biopsy of affected kidney tissue can also reveal the abnormal accumulation of oxalate. A biopsy involves the surgical removal and microscopic examination of a piece of affected tissue. Previously, a liver biopsy was used to obtain a tissue sample to conduct an enzyme assay as a way to diagnose primary hyperoxaluria. An enzyme assay is a test that measures the activity of a specific enzyme. Such an assay can demonstrate low levels of the specific enzymes that are associated with the specific forms of PH. Today the need for liver biopsy has been greatly decreased due to the increasingly lower cost and improved sensitivity of modern molecular genetic testing.Examination of kidney stones can provide evidence to support the possibility of PH in comparison to other causes of kidney stone disease. The stones associated with PH tend to consist of more than 95% calcium oxalate monohydrate (whewellite), are usually pale-colored and may come in varying sizes, shapes and appearances (non-homogeneous). Although idiopathic stone formers can also produce calcium oxalate monohydrate stones, they also often contain some amount of calcium oxalate dihydrate and or calcium phosphate.Molecular genetic testing for mutations in the 3 specific genes known to cause PH confirms the diagnosis of PH.
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Primary Hyperoxaluria
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nord_1005_6
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Therapies of Primary Hyperoxaluria
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Treatment
The treatment of PH is directed toward the specific symptoms that are present in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who assess and treat problems of the kidneys (nephrologists), specialists who assess and treat problems of the liver (hepatologists), specialists who assess and treat problems of the urinary tract (urologists), dieticians, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended to help families understand the genetics and natural history of PH and to provide psychosocial support.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; specific subtype; responsiveness to pyridoxine; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Prompt diagnosis and early therapy are essential to slowing progression of the disorder and preserving kidney function as long as possible. Early conservative methods can reduce or prevent kidney stone formation. Adequate fluid intake can help to prevent the formation of kidney stones. Drinking large amounts of water dilutes the oxalate that ends up in the urine and reduces the risk of its crystallization with calcium. Some infants and small children may require a procedure known as gastrostomy to ensure proper fluid intake and dilution of the urine. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the direct intake of food, fluids, and/or medicine.Certain medications may be used to treat individuals with PH including potassium citrate, thiazides, magnesium, or orthophosphates. These medications in combination with water intake can further reduce the risk of calcium and oxalate crystallization but often do not entirely prevent stone formation or kidney failure. Some individuals with PH type I (but not with other forms of PH) respond to dietary supplementation with pyridoxine, also known as vitamin B6. In such cases, pyridoxine supplementation leads to a reduction in oxalate levels. Not all individuals with PH type I respond to pyridoxine therapy. Pyridoxine is a metabolic precursor to a co-factor necessary for function of AGT, the protein affected in PH type I. Certain PH type I mutations are known to predict a good response to pyridoxine. Patients with one copy of these mutations are typically partially responsive, while those with two copies are completely responsive. For individuals who experience repeated stone formation, sometimes referred to as a high stone burden, a procedure that uses shock waves (lithotripsy) to break up stones in the urinary tract and kidneys may be recommended. The most common type, extracorporeal shock wave lithotripsy, is usually not recommended for individuals with PH because the stones are hard and don’t easily break up by this method. Instead, minimally invasive methods such as ureteroscopic laser lithotripsy may be recommended. During this procedure, a small tube or scope is inserted into the bladder and the ureter (the tube through which urine passes from the kidneys to the bladder). If a stone is small, the scope can be used to remove the stone whole. If the stone is too large, the stone will be broken apart with a laser. The stone fragments are then removed.Some physicians recommend dietary restriction of foods high in oxalate as a precautionary measure. Although the amount of oxalate in the diet is usually small in comparison to that produced by the liver, however avoiding a high oxalate intake makes good common sense. Foods high in oxalate include chocolate, rhubarb, and starfruit. Vitamin D and vitamin C should be avoided in large doses. Affected individuals should also avoid becoming dehydrated as maintaining dilute urine is extremely important in preventing stone formation.If kidney function declines over time, or in cases where an individual is first diagnosed with PH after the development of advanced kidney disease or kidney failure, additional specific treatments will be required. It is critically important that PH patients that developed kidney failure promptly diagnosed because the treatment of kidney failure differs compared to other causes of kidney failure. Specific treatments may include intensive dialysis, a liver transplant, a combined liver-kidney transplant or a kidney transplant. The specific therapy used will depend upon an individual’s specific case and requirements.Dialysis may be used to treat individuals with PH but is not considered an effective long-term solution. Dialysis is a procedure in which a machine is used to perform the kidney’s basic functions of fluid and waste removal. Dialysis can help clear oxalate and other toxins from the body. However, dialysis (both conventional hemodialysis and peritoneal dialysis) fails to adequately remove enough oxalate to prevent oxalate accumulation. Thus, patients often require more frequent dialysis session than typical kidney failure patients (often 5 or 6 times per week as opposed to the usual 3 times per week). In addition, peritoneal dialysis is not very effective for removing oxalate and many home hemodialysis systems are also not particularly effective for oxalate removal. However, dialysis less often be used in specific situations or until a kidney and/or liver transplant can be performed. Unfortunately, kidney transplant alone is usually not an effective means of treatment either, since the high oxalate levels excreted into the urine can damage the new transplanted kidney.For some individuals, a liver transplantation may be recommended. Since the liver is the only organ that produces the enzyme that is deficient in PH type I, a new liver will restore production of the missing enzyme. A liver transplantation may be considered in individuals without advanced kidney disease (preemptive liver transplantation), but its use as an isolated procedure early in the course of the renal decline is controversial because the benefits must be weighed against a relatively high immediate post-operative mortality. Life-long immunosuppression is also required after transplantation.In some cases of PH type I, affected individuals may be recommended for a combined liver-kidney transplant if the kidneys are already too damaged (i.e. stage 4 chronic kidney disease). In other cases (stage 5 chronic kidney disease), sequential transplantation, the liver followed by the kidney, may be recommended.An isolated kidney transplant may also be performed in individuals with PH type I, but has generally been replaced by preemptive liver transplantation or combined liver-kidney transplantation. Since the underlying defect in PH type I is in the liver, an isolated kidney transplant has a high level of recurrence of kidney disease.PH type II may be treated by isolated kidney transplantation, which has been varyingly successful. Although the enzyme that is deficient in PH type II is widespread throughout tissues of the body, it appears that the majority of oxalate is produced in the liver much like PH type I. Consequently, a combined liver-kidney transplant has been reported in a few cases to date suggesting this strategy may also be effective in PH type II.At this time, only one case of renal failure has been reported in PH type III, so transplants are not typically needed for this type.Oxlumo (lumasiran) is the first viable drug alternative to transplantation for PH type I to be approved by the U.S. Food and Drug Administration (FDA). Oxlumo successfully lowers urinary oxalate levels. It is a type of gene therapy known as RNA interference that silences defective genes by disrupting protein formation necessary for gene expression. Oxlumo does not target the defective AGT enzyme itself but instead targets glycolate oxidase (GO), a normally-functioning enzyme that contributes to oxalate production. By reducing the amount of GO, Oxlumo compensates for the overproduction of oxalate that results from the defective genes in PH type I.
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Therapies of Primary Hyperoxaluria. Treatment
The treatment of PH is directed toward the specific symptoms that are present in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who assess and treat problems of the kidneys (nephrologists), specialists who assess and treat problems of the liver (hepatologists), specialists who assess and treat problems of the urinary tract (urologists), dieticians, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended to help families understand the genetics and natural history of PH and to provide psychosocial support.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; specific subtype; responsiveness to pyridoxine; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Prompt diagnosis and early therapy are essential to slowing progression of the disorder and preserving kidney function as long as possible. Early conservative methods can reduce or prevent kidney stone formation. Adequate fluid intake can help to prevent the formation of kidney stones. Drinking large amounts of water dilutes the oxalate that ends up in the urine and reduces the risk of its crystallization with calcium. Some infants and small children may require a procedure known as gastrostomy to ensure proper fluid intake and dilution of the urine. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the direct intake of food, fluids, and/or medicine.Certain medications may be used to treat individuals with PH including potassium citrate, thiazides, magnesium, or orthophosphates. These medications in combination with water intake can further reduce the risk of calcium and oxalate crystallization but often do not entirely prevent stone formation or kidney failure. Some individuals with PH type I (but not with other forms of PH) respond to dietary supplementation with pyridoxine, also known as vitamin B6. In such cases, pyridoxine supplementation leads to a reduction in oxalate levels. Not all individuals with PH type I respond to pyridoxine therapy. Pyridoxine is a metabolic precursor to a co-factor necessary for function of AGT, the protein affected in PH type I. Certain PH type I mutations are known to predict a good response to pyridoxine. Patients with one copy of these mutations are typically partially responsive, while those with two copies are completely responsive. For individuals who experience repeated stone formation, sometimes referred to as a high stone burden, a procedure that uses shock waves (lithotripsy) to break up stones in the urinary tract and kidneys may be recommended. The most common type, extracorporeal shock wave lithotripsy, is usually not recommended for individuals with PH because the stones are hard and don’t easily break up by this method. Instead, minimally invasive methods such as ureteroscopic laser lithotripsy may be recommended. During this procedure, a small tube or scope is inserted into the bladder and the ureter (the tube through which urine passes from the kidneys to the bladder). If a stone is small, the scope can be used to remove the stone whole. If the stone is too large, the stone will be broken apart with a laser. The stone fragments are then removed.Some physicians recommend dietary restriction of foods high in oxalate as a precautionary measure. Although the amount of oxalate in the diet is usually small in comparison to that produced by the liver, however avoiding a high oxalate intake makes good common sense. Foods high in oxalate include chocolate, rhubarb, and starfruit. Vitamin D and vitamin C should be avoided in large doses. Affected individuals should also avoid becoming dehydrated as maintaining dilute urine is extremely important in preventing stone formation.If kidney function declines over time, or in cases where an individual is first diagnosed with PH after the development of advanced kidney disease or kidney failure, additional specific treatments will be required. It is critically important that PH patients that developed kidney failure promptly diagnosed because the treatment of kidney failure differs compared to other causes of kidney failure. Specific treatments may include intensive dialysis, a liver transplant, a combined liver-kidney transplant or a kidney transplant. The specific therapy used will depend upon an individual’s specific case and requirements.Dialysis may be used to treat individuals with PH but is not considered an effective long-term solution. Dialysis is a procedure in which a machine is used to perform the kidney’s basic functions of fluid and waste removal. Dialysis can help clear oxalate and other toxins from the body. However, dialysis (both conventional hemodialysis and peritoneal dialysis) fails to adequately remove enough oxalate to prevent oxalate accumulation. Thus, patients often require more frequent dialysis session than typical kidney failure patients (often 5 or 6 times per week as opposed to the usual 3 times per week). In addition, peritoneal dialysis is not very effective for removing oxalate and many home hemodialysis systems are also not particularly effective for oxalate removal. However, dialysis less often be used in specific situations or until a kidney and/or liver transplant can be performed. Unfortunately, kidney transplant alone is usually not an effective means of treatment either, since the high oxalate levels excreted into the urine can damage the new transplanted kidney.For some individuals, a liver transplantation may be recommended. Since the liver is the only organ that produces the enzyme that is deficient in PH type I, a new liver will restore production of the missing enzyme. A liver transplantation may be considered in individuals without advanced kidney disease (preemptive liver transplantation), but its use as an isolated procedure early in the course of the renal decline is controversial because the benefits must be weighed against a relatively high immediate post-operative mortality. Life-long immunosuppression is also required after transplantation.In some cases of PH type I, affected individuals may be recommended for a combined liver-kidney transplant if the kidneys are already too damaged (i.e. stage 4 chronic kidney disease). In other cases (stage 5 chronic kidney disease), sequential transplantation, the liver followed by the kidney, may be recommended.An isolated kidney transplant may also be performed in individuals with PH type I, but has generally been replaced by preemptive liver transplantation or combined liver-kidney transplantation. Since the underlying defect in PH type I is in the liver, an isolated kidney transplant has a high level of recurrence of kidney disease.PH type II may be treated by isolated kidney transplantation, which has been varyingly successful. Although the enzyme that is deficient in PH type II is widespread throughout tissues of the body, it appears that the majority of oxalate is produced in the liver much like PH type I. Consequently, a combined liver-kidney transplant has been reported in a few cases to date suggesting this strategy may also be effective in PH type II.At this time, only one case of renal failure has been reported in PH type III, so transplants are not typically needed for this type.Oxlumo (lumasiran) is the first viable drug alternative to transplantation for PH type I to be approved by the U.S. Food and Drug Administration (FDA). Oxlumo successfully lowers urinary oxalate levels. It is a type of gene therapy known as RNA interference that silences defective genes by disrupting protein formation necessary for gene expression. Oxlumo does not target the defective AGT enzyme itself but instead targets glycolate oxidase (GO), a normally-functioning enzyme that contributes to oxalate production. By reducing the amount of GO, Oxlumo compensates for the overproduction of oxalate that results from the defective genes in PH type I.
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Primary Hyperoxaluria
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nord_1006_0
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Overview of Primary Hyperparathyroidism
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Primary hyperparathyroidism is a condition in which the parathyroid glands produce too much parathyroid hormone and the calcium level in the blood becomes elevated. The parathyroid glands are part of the endocrine system, the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. Endocrine glands release hormones that regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure, as well as cell differentiation and growth, and in modulation of several metabolic processes. There are four tiny parathyroid glands found in the neck. They are about the size of a pea. Parathyroid hormone (along with vitamin D) is the main regulator of the level of calcium in the blood. It also affects the blood phosphorus level, bone growth and bone cell activity. Most individuals with primary hyperparathyroidism do not develop symptoms (asymptomatic) or have only extremely mild symptoms. Primary hyperparathyroidism mainly affects the skeleton and the kidneys, but the heart, gastrointestinal, and nervous system can sometimes be involved. About 80-85% of the time, the disorder is caused by a benign tumor called an adenoma that is usually found in one of the four parathyroid glands.
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Overview of Primary Hyperparathyroidism. Primary hyperparathyroidism is a condition in which the parathyroid glands produce too much parathyroid hormone and the calcium level in the blood becomes elevated. The parathyroid glands are part of the endocrine system, the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. Endocrine glands release hormones that regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure, as well as cell differentiation and growth, and in modulation of several metabolic processes. There are four tiny parathyroid glands found in the neck. They are about the size of a pea. Parathyroid hormone (along with vitamin D) is the main regulator of the level of calcium in the blood. It also affects the blood phosphorus level, bone growth and bone cell activity. Most individuals with primary hyperparathyroidism do not develop symptoms (asymptomatic) or have only extremely mild symptoms. Primary hyperparathyroidism mainly affects the skeleton and the kidneys, but the heart, gastrointestinal, and nervous system can sometimes be involved. About 80-85% of the time, the disorder is caused by a benign tumor called an adenoma that is usually found in one of the four parathyroid glands.
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Primary Hyperparathyroidism
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nord_1006_1
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Symptoms of Primary Hyperparathyroidism
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Asymptomatic Primary Hyperparathyroidism
The most common presentation of primary hyperparathyroidism is when doctors find high levels of calcium in the blood, but no associated symptoms. This is also called asymptomatic hypercalcemia. Some individuals with asymptomatic primary hyperparathyroidism report fatigue, weakness, mild depression, or mild cognitive dysfunction such as mild issues with concentration or memory. Whether these are caused by the condition or reversible with surgery is not clear. A recent randomized controlled trial of parathyroidectomy versus observation showed no clear benefit of surgery on depression or quality of life 10 years after treatment. Patients with asymptomatic disease may also have bone loss (low bone mineral density) and silent kidney stones and spine fractures detected by imaging. Eventually, asymptomatic primary hyperparathyroidism can progress, and individuals may develop symptoms seen in the classic form. Classic Primary Hyperparathyroidism
A characteristic finding of primary hyperparathyroidism is the development of calcium stones in the kidneys (nephrolithiasis). This has occurred with less and less frequency in the United States in recent years. Nephrolithiasis can cause low back pain in the area of the kidneys (renal colic) and pain in the lower back and lower abdomen. Sometimes, kidney damage can develop, and the kidneys may function less efficiently than they should (chronic renal insufficiency). Affected individuals may lose bone mineral density, which can contribute to thinning and weakening of bones (osteoporosis). Affected individuals can be prone to fractures of bones and can experience bone pain. Primary hyperparathyroidism can cause a form of bone disease called osteitis fibrosa cystica. However, this is rarely seen in the United States (less than 2% of individuals) and other developed countries. Affected individuals are prone to fractures and there may be other skeletal abnormalities and bone pain or tenderness in the affected areas. Osteitis fibrosa cystica occurs in advanced disease. A variety of nonspecific symptoms have been associated with classical primary hyperparathyroidism. Nonspecific means that the symptoms are common to many different disorders. These symptoms include unintended weight loss, vomiting, nausea, constipation, drinking lots of water (polydipsia), and urinating frequently (polyuria). Some affected individuals experience weakness and fatigue. Many individuals with primary hyperparathyroidism have reported neuropsychiatric symptoms including depression, irritability, psychosis, and decreased social interaction. There may be cognitive dysfunction, which means there may be problems with concentration or memory, or individuals may experience a lack of mental clarity (“brain fog”). Sometimes, primary hyperparathyroidism may be associated with cardiovascular disease including high blood pressure (hypertension), irregular heart rhythms (arrhythmias), enlargement and thickening of the left lower chamber of the heart (ventricular hypertrophy) and hardening due to calcium buildup (calcification) of blood vessels and valves of the circulatory system. Generally, cardiovascular disease has been reported in people with severe primary hyperparathyroidism. Much about the relationship between primary hyperparathyroidism and cardiovascular disease is not fully understood (e.g., the underlying cause of cardiovascular problems, their response to treatment, etc.). Research is ongoing to better understand these two conditions and how they interact or influence each other. A large observational study showed an increased risk of death and cardiovascular events in patients with primary hyperparathyroidism and improvement after parathyroidectomy. On the other hand, a recent smaller randomized controlled trial evaluated the effect of randomization to surgery on cardiovascular outcomes and death and found no benefit. Normocalcemic Hyperparathyroidism
This condition is characterized by high parathyroid hormone but normal blood calcium levels. Symptoms associated with this form of primary hyperparathyroidism include kidney stones, bone loss, and fragile bones that may be prone to fracture (osteoporosis). Much about the disorder remains unknown or not completely understood. Some researchers believe the normocalcemic form may be an early or mild form of classic primary hyperparathyroidism. Parathyroid (Hypercalcemic) Crisis
Parathyroid crisis is a rare complication of primary hyperparathyroidism. Affected individuals develop severe hypercalcemia that is life-threatening. Symptoms can include changes in mental status, bone disease, dehydration, and kidney stones. Sometimes, nausea, vomiting, and severe abdominal pain may occur. Some individuals with hypercalcemia or mild hyperparathyroidism develop parathyroid crisis later. It may be triggered by an intercurrent illness or dehydration, though sometimes there is not an identifiable precipitant. In other individuals, a parathyroid crisis can be the first sign of the disorder.
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Symptoms of Primary Hyperparathyroidism. Asymptomatic Primary Hyperparathyroidism
The most common presentation of primary hyperparathyroidism is when doctors find high levels of calcium in the blood, but no associated symptoms. This is also called asymptomatic hypercalcemia. Some individuals with asymptomatic primary hyperparathyroidism report fatigue, weakness, mild depression, or mild cognitive dysfunction such as mild issues with concentration or memory. Whether these are caused by the condition or reversible with surgery is not clear. A recent randomized controlled trial of parathyroidectomy versus observation showed no clear benefit of surgery on depression or quality of life 10 years after treatment. Patients with asymptomatic disease may also have bone loss (low bone mineral density) and silent kidney stones and spine fractures detected by imaging. Eventually, asymptomatic primary hyperparathyroidism can progress, and individuals may develop symptoms seen in the classic form. Classic Primary Hyperparathyroidism
A characteristic finding of primary hyperparathyroidism is the development of calcium stones in the kidneys (nephrolithiasis). This has occurred with less and less frequency in the United States in recent years. Nephrolithiasis can cause low back pain in the area of the kidneys (renal colic) and pain in the lower back and lower abdomen. Sometimes, kidney damage can develop, and the kidneys may function less efficiently than they should (chronic renal insufficiency). Affected individuals may lose bone mineral density, which can contribute to thinning and weakening of bones (osteoporosis). Affected individuals can be prone to fractures of bones and can experience bone pain. Primary hyperparathyroidism can cause a form of bone disease called osteitis fibrosa cystica. However, this is rarely seen in the United States (less than 2% of individuals) and other developed countries. Affected individuals are prone to fractures and there may be other skeletal abnormalities and bone pain or tenderness in the affected areas. Osteitis fibrosa cystica occurs in advanced disease. A variety of nonspecific symptoms have been associated with classical primary hyperparathyroidism. Nonspecific means that the symptoms are common to many different disorders. These symptoms include unintended weight loss, vomiting, nausea, constipation, drinking lots of water (polydipsia), and urinating frequently (polyuria). Some affected individuals experience weakness and fatigue. Many individuals with primary hyperparathyroidism have reported neuropsychiatric symptoms including depression, irritability, psychosis, and decreased social interaction. There may be cognitive dysfunction, which means there may be problems with concentration or memory, or individuals may experience a lack of mental clarity (“brain fog”). Sometimes, primary hyperparathyroidism may be associated with cardiovascular disease including high blood pressure (hypertension), irregular heart rhythms (arrhythmias), enlargement and thickening of the left lower chamber of the heart (ventricular hypertrophy) and hardening due to calcium buildup (calcification) of blood vessels and valves of the circulatory system. Generally, cardiovascular disease has been reported in people with severe primary hyperparathyroidism. Much about the relationship between primary hyperparathyroidism and cardiovascular disease is not fully understood (e.g., the underlying cause of cardiovascular problems, their response to treatment, etc.). Research is ongoing to better understand these two conditions and how they interact or influence each other. A large observational study showed an increased risk of death and cardiovascular events in patients with primary hyperparathyroidism and improvement after parathyroidectomy. On the other hand, a recent smaller randomized controlled trial evaluated the effect of randomization to surgery on cardiovascular outcomes and death and found no benefit. Normocalcemic Hyperparathyroidism
This condition is characterized by high parathyroid hormone but normal blood calcium levels. Symptoms associated with this form of primary hyperparathyroidism include kidney stones, bone loss, and fragile bones that may be prone to fracture (osteoporosis). Much about the disorder remains unknown or not completely understood. Some researchers believe the normocalcemic form may be an early or mild form of classic primary hyperparathyroidism. Parathyroid (Hypercalcemic) Crisis
Parathyroid crisis is a rare complication of primary hyperparathyroidism. Affected individuals develop severe hypercalcemia that is life-threatening. Symptoms can include changes in mental status, bone disease, dehydration, and kidney stones. Sometimes, nausea, vomiting, and severe abdominal pain may occur. Some individuals with hypercalcemia or mild hyperparathyroidism develop parathyroid crisis later. It may be triggered by an intercurrent illness or dehydration, though sometimes there is not an identifiable precipitant. In other individuals, a parathyroid crisis can be the first sign of the disorder.
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Primary Hyperparathyroidism
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nord_1006_2
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Causes of Primary Hyperparathyroidism
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The most common cause of primary hyperparathyroidism is a tiny, benign tumor called an adenoma. Usually, one adenoma forms in one of the four parathyroid glands, but it is possible for more adenomas to form in multiple parathyroid glands. An adenoma causes the affected gland to become overactive. Multiple gland hyperplasia accounts for about 6-12%. This condition is characterized by enlargement of multiple parathyroid glands because of an increased reproduction rate of their cells. Multiple gland hyperplasia occurs randomly (sporadically) or as part of a larger genetic syndrome. Double adenomas account for about 2-5%. Researchers do not know why adenomas form in the parathyroid glands. In most instances they appear to occur sporadically and there is usually no family history of the disorder. Sometimes, genetic factors can play a role in the development of primary hyperparathyroidism. In sporadic forms, these genetic variations occur after the fertilization of the embryo and are acquired not inherited (somatic mutation). Various genetic changes (e.g., rearrangements, mutations, etc.) have been described in parathyroid adenomas. In inherited forms of primary hyperparathyroidism, variations in oncogenes and tumor suppressor genes have both been identified with greater frequency than in the general population. Oncogenes cause out-of-control growth when either one of the paired copies (alleles) is defective. Tumor suppressor genes normally limit or stop the growth of cells. These variations are passed on from the parents or occur randomly with no previous family history (de novo mutation). Primary hyperparathyroidism can be seen as part of a larger genetic disorder including multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2A, hyperparathyroidism jaw tumor syndrome, or familial isolated primary hypercalcinemia. These are extremely rare disorders. (For more information, choose the specific disorder name as your search term in the NORD Rare Disease Database.) Individuals who have received irradiation to the head and neck region appear to be at a greater risk of developing primary hyperparathyroidism, often 20 to 40 years after exposure. The parathyroid glands release hormones in response to low calcium levels. In primary hyperparathyroidism, they release the hormones when the body doesn’t need calcium (overactivity). The increased levels of parathyroid hormone cause the bones to release more calcium into the blood, leading to elevated calcium levels (hypercalcemia). The signs and symptoms of primary hyperparathyroidism develop because of elevated parathyroid hormone levels and hypercalcemia. Calcium is a mineral that is stored in bones. It is important for the health of bones and teeth. Calcium also plays a role in the cardiovascular system, muscle contractions, blood clotting, and transmitting nerve signals. Vitamin D also helps to regulate calcium and is sometimes deficient in individuals with primary hyperparathyroidism.
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Causes of Primary Hyperparathyroidism. The most common cause of primary hyperparathyroidism is a tiny, benign tumor called an adenoma. Usually, one adenoma forms in one of the four parathyroid glands, but it is possible for more adenomas to form in multiple parathyroid glands. An adenoma causes the affected gland to become overactive. Multiple gland hyperplasia accounts for about 6-12%. This condition is characterized by enlargement of multiple parathyroid glands because of an increased reproduction rate of their cells. Multiple gland hyperplasia occurs randomly (sporadically) or as part of a larger genetic syndrome. Double adenomas account for about 2-5%. Researchers do not know why adenomas form in the parathyroid glands. In most instances they appear to occur sporadically and there is usually no family history of the disorder. Sometimes, genetic factors can play a role in the development of primary hyperparathyroidism. In sporadic forms, these genetic variations occur after the fertilization of the embryo and are acquired not inherited (somatic mutation). Various genetic changes (e.g., rearrangements, mutations, etc.) have been described in parathyroid adenomas. In inherited forms of primary hyperparathyroidism, variations in oncogenes and tumor suppressor genes have both been identified with greater frequency than in the general population. Oncogenes cause out-of-control growth when either one of the paired copies (alleles) is defective. Tumor suppressor genes normally limit or stop the growth of cells. These variations are passed on from the parents or occur randomly with no previous family history (de novo mutation). Primary hyperparathyroidism can be seen as part of a larger genetic disorder including multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2A, hyperparathyroidism jaw tumor syndrome, or familial isolated primary hypercalcinemia. These are extremely rare disorders. (For more information, choose the specific disorder name as your search term in the NORD Rare Disease Database.) Individuals who have received irradiation to the head and neck region appear to be at a greater risk of developing primary hyperparathyroidism, often 20 to 40 years after exposure. The parathyroid glands release hormones in response to low calcium levels. In primary hyperparathyroidism, they release the hormones when the body doesn’t need calcium (overactivity). The increased levels of parathyroid hormone cause the bones to release more calcium into the blood, leading to elevated calcium levels (hypercalcemia). The signs and symptoms of primary hyperparathyroidism develop because of elevated parathyroid hormone levels and hypercalcemia. Calcium is a mineral that is stored in bones. It is important for the health of bones and teeth. Calcium also plays a role in the cardiovascular system, muscle contractions, blood clotting, and transmitting nerve signals. Vitamin D also helps to regulate calcium and is sometimes deficient in individuals with primary hyperparathyroidism.
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Primary Hyperparathyroidism
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nord_1006_3
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Affects of Primary Hyperparathyroidism
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Estimates of the incidence and prevalence of primary hyperparathyroidism in the Western world vary. Most people with the disorder, more than 80% in the Western world, do not have any symptoms (asymptomatic). Individuals with symptoms, particularly severe symptoms, are a rarer occurrence in developed countries where routine screening of calcium is common. Primary hyperparathyroidism can occur at any age but is most likely to affect individuals over 50. The incidence is highest among individuals of African American heritage, followed by Caucasians. Women are affected about three times more often than men. According to one estimate, about 100,000 people in the United States develop primary hyperparathyroidism each year.
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Affects of Primary Hyperparathyroidism. Estimates of the incidence and prevalence of primary hyperparathyroidism in the Western world vary. Most people with the disorder, more than 80% in the Western world, do not have any symptoms (asymptomatic). Individuals with symptoms, particularly severe symptoms, are a rarer occurrence in developed countries where routine screening of calcium is common. Primary hyperparathyroidism can occur at any age but is most likely to affect individuals over 50. The incidence is highest among individuals of African American heritage, followed by Caucasians. Women are affected about three times more often than men. According to one estimate, about 100,000 people in the United States develop primary hyperparathyroidism each year.
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Primary Hyperparathyroidism
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Related disorders of Primary Hyperparathyroidism
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Some characteristics or symptoms of the following disorders can be similar to those of primary hyperparathyroidism. Comparisons may be useful for a differential diagnosis. Familial hypocalciuric hypercalcemia (FHH) is a genetic condition in which there is a variation in the gene that encodes a protein that senses the level of calcium in the blood (the calcium sensing receptor). Sometimes the variation is in a different gene. As in primary hyperparathyroidism, the blood calcium is elevated. Parathyroid hormone is usually in the upper normal range. Individuals with this condition have a higher blood calcium level set point than is usual for the general population and that is ‘normal’ for their body. FHH is distinguished from primary hyperparathyroidism by low urine calcium, family history and genetic testing in some cases. Surgery is not curative and virtually never indicated in FHH. Familial isolated hyperparathyroidism is a rare genetic disorder characterized by overactivity of the parathyroid gland(s). Affected individuals have elevated levels of calcium in the blood, which can cause weakness, fatigue, high blood pressure, kidney stones, and weakened bones that are prone to fractures (osteoporosis). Familial isolated hyperparathyroidism is caused by a variation in a gene, including the MEN1, CDC73, and CASR genes, and is diagnosed when there are no other associated endocrine gland disorders besides primary hyperparathyroidism. These variations are inherited in an autosomal dominant pattern. Sometimes the underlying cause is unknown, and no variation can be found in these genes, suggesting variations in other genes may cause familial isolated hyperparathyroidism. Parathyroid carcinoma is a rare form of cancer affecting the parathyroid glands. It accounts for about 1% or less of people with primary hyperparathyroidism. Affected individuals usually have extremely high levels of calcium in the blood (hypercalcemia) and can experience fatigue, weakness, constipation, depression and confusion. They may also experience bone pain, are prone to fractures, and develop kidney stones. Most individuals with this form of cancer have a variation in the CDC73 gene. Parathyroid carcinoma can occur by itself or as part of a larger, genetic disorder. Surgery to remove the affected parathyroid tissue is the main treatment option. Medical therapies to lower blood calcium are also sometimes used in conjunction with surgery. Secondary hyperparathyroidism refers to a condition in which the parathyroid hormone level is high, but blood calcium is normal. This is not caused by an abnormality of the parathyroid glands but is due to another underlying condition. This can include chronic kidney disease, a lack of calcium in the diet, malabsorption, and severe vitamin D deficiency. In some cases, secondary hyperparathyroidism is reversible with treatment of the underlying cause.
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Related disorders of Primary Hyperparathyroidism. Some characteristics or symptoms of the following disorders can be similar to those of primary hyperparathyroidism. Comparisons may be useful for a differential diagnosis. Familial hypocalciuric hypercalcemia (FHH) is a genetic condition in which there is a variation in the gene that encodes a protein that senses the level of calcium in the blood (the calcium sensing receptor). Sometimes the variation is in a different gene. As in primary hyperparathyroidism, the blood calcium is elevated. Parathyroid hormone is usually in the upper normal range. Individuals with this condition have a higher blood calcium level set point than is usual for the general population and that is ‘normal’ for their body. FHH is distinguished from primary hyperparathyroidism by low urine calcium, family history and genetic testing in some cases. Surgery is not curative and virtually never indicated in FHH. Familial isolated hyperparathyroidism is a rare genetic disorder characterized by overactivity of the parathyroid gland(s). Affected individuals have elevated levels of calcium in the blood, which can cause weakness, fatigue, high blood pressure, kidney stones, and weakened bones that are prone to fractures (osteoporosis). Familial isolated hyperparathyroidism is caused by a variation in a gene, including the MEN1, CDC73, and CASR genes, and is diagnosed when there are no other associated endocrine gland disorders besides primary hyperparathyroidism. These variations are inherited in an autosomal dominant pattern. Sometimes the underlying cause is unknown, and no variation can be found in these genes, suggesting variations in other genes may cause familial isolated hyperparathyroidism. Parathyroid carcinoma is a rare form of cancer affecting the parathyroid glands. It accounts for about 1% or less of people with primary hyperparathyroidism. Affected individuals usually have extremely high levels of calcium in the blood (hypercalcemia) and can experience fatigue, weakness, constipation, depression and confusion. They may also experience bone pain, are prone to fractures, and develop kidney stones. Most individuals with this form of cancer have a variation in the CDC73 gene. Parathyroid carcinoma can occur by itself or as part of a larger, genetic disorder. Surgery to remove the affected parathyroid tissue is the main treatment option. Medical therapies to lower blood calcium are also sometimes used in conjunction with surgery. Secondary hyperparathyroidism refers to a condition in which the parathyroid hormone level is high, but blood calcium is normal. This is not caused by an abnormality of the parathyroid glands but is due to another underlying condition. This can include chronic kidney disease, a lack of calcium in the diet, malabsorption, and severe vitamin D deficiency. In some cases, secondary hyperparathyroidism is reversible with treatment of the underlying cause.
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Primary Hyperparathyroidism
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Diagnosis of Primary Hyperparathyroidism
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A diagnosis of primary hyperparathyroidism is based primarily upon blood and urine tests. A thorough clinical evaluation that assesses symptoms and family history as well as a variety of specialized tests is also performed to determine the cause, effects on the skeleton and kidney and the need for surgery. Individuals with kidney stones may be suspected of having primary hyperparathyroidism. Clinical Testing and Workup
Routine blood tests that assess for lots of conditions (biochemical screening) can reveal elevated levels of calcium. Excessive levels of calcium are characteristic of the disorder but can be due to other causes. Assays, which are tests that can measure the amount of a substance, can be conducted to determine the levels of parathyroid hormone in the blood. Elevated levels of calcium and parathyroid hormone indicate a diagnosis of primary hyperparathyroidism. Parathyroid hormone levels that are in the middle to upper end of normal in the setting of a high blood calcium level are also consistent with primary hyperparathyroidism. Normocalcemic hyperparathyroidism is usually diagnosed in people with low bone density when circulating parathyroid hormone levels are tested and found to be high and there are normal levels of calcium. Causes of secondary hyperparathyroidism such as vitamin D deficiency or renal disease among others must be ruled out in these situations. A test known as dual energy x-ray absorptiometry (DXA) is recommended to measure bone mineral density. During this exam, a person lies on a table and a robotic arm is passed over the area to be examined. A narrow beam of low dose x-rays is used to measure bone density. Spine x-rays are also recommended in some individuals to detect silent spine fractures. Sometimes, CT scans or an ultrasound can be used to detect silent kidney stones. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Ultrasound uses reflected sound waves to create pictures of internal organs and other structures. An ultrasound is a test that uses high frequency sound waves to create pieces of organs and tissues of the body. This device produces sound waves which bounce back (or echo) and are recorded and then converted into images by a computer. A blood test may be given specifically to look for vitamin D deficiency. A 24-hour urine collection is recommended to assess the levels of calcium and certain other chemicals. This can help doctors determine the health of the kidneys and the risk of kidney stone formation as well as help distinguish primary hyperparathyroidism from FHH.
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Diagnosis of Primary Hyperparathyroidism. A diagnosis of primary hyperparathyroidism is based primarily upon blood and urine tests. A thorough clinical evaluation that assesses symptoms and family history as well as a variety of specialized tests is also performed to determine the cause, effects on the skeleton and kidney and the need for surgery. Individuals with kidney stones may be suspected of having primary hyperparathyroidism. Clinical Testing and Workup
Routine blood tests that assess for lots of conditions (biochemical screening) can reveal elevated levels of calcium. Excessive levels of calcium are characteristic of the disorder but can be due to other causes. Assays, which are tests that can measure the amount of a substance, can be conducted to determine the levels of parathyroid hormone in the blood. Elevated levels of calcium and parathyroid hormone indicate a diagnosis of primary hyperparathyroidism. Parathyroid hormone levels that are in the middle to upper end of normal in the setting of a high blood calcium level are also consistent with primary hyperparathyroidism. Normocalcemic hyperparathyroidism is usually diagnosed in people with low bone density when circulating parathyroid hormone levels are tested and found to be high and there are normal levels of calcium. Causes of secondary hyperparathyroidism such as vitamin D deficiency or renal disease among others must be ruled out in these situations. A test known as dual energy x-ray absorptiometry (DXA) is recommended to measure bone mineral density. During this exam, a person lies on a table and a robotic arm is passed over the area to be examined. A narrow beam of low dose x-rays is used to measure bone density. Spine x-rays are also recommended in some individuals to detect silent spine fractures. Sometimes, CT scans or an ultrasound can be used to detect silent kidney stones. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Ultrasound uses reflected sound waves to create pictures of internal organs and other structures. An ultrasound is a test that uses high frequency sound waves to create pieces of organs and tissues of the body. This device produces sound waves which bounce back (or echo) and are recorded and then converted into images by a computer. A blood test may be given specifically to look for vitamin D deficiency. A 24-hour urine collection is recommended to assess the levels of calcium and certain other chemicals. This can help doctors determine the health of the kidneys and the risk of kidney stone formation as well as help distinguish primary hyperparathyroidism from FHH.
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Primary Hyperparathyroidism
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Therapies of Primary Hyperparathyroidism
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Treatment
Surgery is the main treatment option for primary hyperparathyroidism. Watchful waiting and medications may also have a role in treatment in some patients. Surgical removal of the parathyroid glands (parathyroidectomy) is the only potential cure for primary hyperparathyroidism. Surgery, when performed by an experienced parathyroid surgeon, can successfully cure this disorder in 95% of individuals. The preferred surgical technique for one affected parathyroid gland is either bilateral neck exploration or minimally invasive parathyroidectomy, both of which are out-patient procedures. When minimally invasive surgery is planned, the procedure is proceeded by imaging techniques to identify and locate the affected parathyroid gland first. If the imaging localizes the abnormal gland, the surgeon will make a small incision in the neck and focus on removing the affected gland Another option is called bilateral neck exploration. During this procedure, a surgeon identifies all four parathyroid glands to determine which one(s) are affected at the time of surgery. This procedure involves making an incision, usually in the middle to lower portion of the neck. The skin is folded back, and the muscles are separated so that the surgeon can see each parathyroid gland. Sometimes, a biopsy, which involves cutting out a small sample of tissue and viewing the sample under a microscope, is performed on any parathyroid glands that appear affected. This surgery is highly successful but is slightly more invasive. Bilateral neck exploration is used when the affected parathyroid gland cannot be identified by imaging before surgery or when multiple glands are affected or may be used depending on surgeon preference or expertise. This procedure is also known as open parathyroidectomy, standard parathyroidectomy, and conventional parathyroidectomy. Imaging techniques including ultrasound, sestamibi scan and others such as high-resolution CT are used to determine which parathyroid glands are affected and to aid the surgeon during surgery. A sestamibi parathyroid scan uses sestamibi, which is a radioactive compound. This compound is injected into the affected individual and is eventually absorbed by overactive parathyroid glands. The compound is visible using a special camera and the overactive parathyroid glands can be identified. Surgery is recommended for all individuals with symptomatic primary hyperparathyroidism (those have constitutional symptoms related to high calcium such as nausea and vomiting etc., those who develop kidney stones, those who have fractures related to the condition and those with osteitis fibrosa cystica). Surgery may also be beneficial for patients with asymptomatic disease without any contraindications. There are published guidelines developed by the Fifth International Workshop on the Evaluation and Management of Primary Hyperparathyroidism that many doctors use to determine whether individuals with asymptomatic primary hyperparathyroidism should be treated by watchful waiting or surgery. The criteria for recommending surgery take into account age, blood calcium level, kidney function, bone density, urine calcium and the presence of silent kidney stones and fractures, as well as other factors. These guidelines do not recommend parathyroidectomy to improve neurocognitive function, quality of life, and/or cardiovascular indices because the evidence for improvement after surgery is inconclusive. Guidelines from some other societies do include cardiovascular and neuropsychological indications but acknowledge that evidence is weak to support their inclusion. Watchful waiting means that an asymptomatic person will be periodically monitored by physicians to detect if primary hyperthyroidism becomes symptomatic or is causing silent damage to the kidneys or skeleton. Surgery may be considered in individuals with normocalcemic hyperparathyroidism if patients become hypercalcemic and have other indications for surgery; surgery may also be considered when there is disease progression regardless of hypercalcemia. Everyone, including asymptomatic individuals should have a consultation with an endocrinologist (hormone specialist) to learn about the condition’s risks and treatment options. Affected individuals with mild hyperparathyroidism who do not have surgery should be regularly monitored to determine whether the disease has progressed. Dehydration should be avoided by drinking plenty of fluids and avoiding diuretics, which are drugs that increase the rate of urination. These individuals should receive monitoring on kidney function and assessments of bone mineral density to detect any decline or changes. Medications can be used to treat some individuals with primary hyperparathyroidism who are not having surgery. Bisphosphonates, a class of drugs that can prevent bone loss and/or increase bone density, can be used to treat osteoporosis. Denosumab and estrogen have also been used in some patients with primary hyperparathyroidism to treat bone loss. Calcimimetics are medications that mimic the action of calcium on tissues and can ‘trick’ the parathyroid glands to produce less parathyroid hormone. The U.S. Food and Drug Administration has approved cinacalcet (Sensipar) for the treatment of individuals with primary hyperparathyroidism who have severe hypercalcemia and are unable to undergo surgery, and in individuals whose hyperparathyroidism occurs because of parathyroid carcinoma. The drug is also approved for hyperparathyroidism secondary to chronic kidney disease and parathyroid cancer. Cinacalcet is a type of calcimimetic. Vitamin D deficiency should be treated cautiously by vitamin D supplementation. The optimal dose or regimen of vitamin D supplementation for individuals with primary hyperparathyroidism is not known. Affected individuals should avoid becoming dehydrated as this can lead to an increase in calcium. This can occur when a person becomes dehydrated because of nausea and vomiting when sick. Affected individuals who become dehydrated should seek medical attention. Generally, individuals with primary hyperparathyroidism do not need to avoid dairy products or calcium-rich foods.
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Therapies of Primary Hyperparathyroidism. Treatment
Surgery is the main treatment option for primary hyperparathyroidism. Watchful waiting and medications may also have a role in treatment in some patients. Surgical removal of the parathyroid glands (parathyroidectomy) is the only potential cure for primary hyperparathyroidism. Surgery, when performed by an experienced parathyroid surgeon, can successfully cure this disorder in 95% of individuals. The preferred surgical technique for one affected parathyroid gland is either bilateral neck exploration or minimally invasive parathyroidectomy, both of which are out-patient procedures. When minimally invasive surgery is planned, the procedure is proceeded by imaging techniques to identify and locate the affected parathyroid gland first. If the imaging localizes the abnormal gland, the surgeon will make a small incision in the neck and focus on removing the affected gland Another option is called bilateral neck exploration. During this procedure, a surgeon identifies all four parathyroid glands to determine which one(s) are affected at the time of surgery. This procedure involves making an incision, usually in the middle to lower portion of the neck. The skin is folded back, and the muscles are separated so that the surgeon can see each parathyroid gland. Sometimes, a biopsy, which involves cutting out a small sample of tissue and viewing the sample under a microscope, is performed on any parathyroid glands that appear affected. This surgery is highly successful but is slightly more invasive. Bilateral neck exploration is used when the affected parathyroid gland cannot be identified by imaging before surgery or when multiple glands are affected or may be used depending on surgeon preference or expertise. This procedure is also known as open parathyroidectomy, standard parathyroidectomy, and conventional parathyroidectomy. Imaging techniques including ultrasound, sestamibi scan and others such as high-resolution CT are used to determine which parathyroid glands are affected and to aid the surgeon during surgery. A sestamibi parathyroid scan uses sestamibi, which is a radioactive compound. This compound is injected into the affected individual and is eventually absorbed by overactive parathyroid glands. The compound is visible using a special camera and the overactive parathyroid glands can be identified. Surgery is recommended for all individuals with symptomatic primary hyperparathyroidism (those have constitutional symptoms related to high calcium such as nausea and vomiting etc., those who develop kidney stones, those who have fractures related to the condition and those with osteitis fibrosa cystica). Surgery may also be beneficial for patients with asymptomatic disease without any contraindications. There are published guidelines developed by the Fifth International Workshop on the Evaluation and Management of Primary Hyperparathyroidism that many doctors use to determine whether individuals with asymptomatic primary hyperparathyroidism should be treated by watchful waiting or surgery. The criteria for recommending surgery take into account age, blood calcium level, kidney function, bone density, urine calcium and the presence of silent kidney stones and fractures, as well as other factors. These guidelines do not recommend parathyroidectomy to improve neurocognitive function, quality of life, and/or cardiovascular indices because the evidence for improvement after surgery is inconclusive. Guidelines from some other societies do include cardiovascular and neuropsychological indications but acknowledge that evidence is weak to support their inclusion. Watchful waiting means that an asymptomatic person will be periodically monitored by physicians to detect if primary hyperthyroidism becomes symptomatic or is causing silent damage to the kidneys or skeleton. Surgery may be considered in individuals with normocalcemic hyperparathyroidism if patients become hypercalcemic and have other indications for surgery; surgery may also be considered when there is disease progression regardless of hypercalcemia. Everyone, including asymptomatic individuals should have a consultation with an endocrinologist (hormone specialist) to learn about the condition’s risks and treatment options. Affected individuals with mild hyperparathyroidism who do not have surgery should be regularly monitored to determine whether the disease has progressed. Dehydration should be avoided by drinking plenty of fluids and avoiding diuretics, which are drugs that increase the rate of urination. These individuals should receive monitoring on kidney function and assessments of bone mineral density to detect any decline or changes. Medications can be used to treat some individuals with primary hyperparathyroidism who are not having surgery. Bisphosphonates, a class of drugs that can prevent bone loss and/or increase bone density, can be used to treat osteoporosis. Denosumab and estrogen have also been used in some patients with primary hyperparathyroidism to treat bone loss. Calcimimetics are medications that mimic the action of calcium on tissues and can ‘trick’ the parathyroid glands to produce less parathyroid hormone. The U.S. Food and Drug Administration has approved cinacalcet (Sensipar) for the treatment of individuals with primary hyperparathyroidism who have severe hypercalcemia and are unable to undergo surgery, and in individuals whose hyperparathyroidism occurs because of parathyroid carcinoma. The drug is also approved for hyperparathyroidism secondary to chronic kidney disease and parathyroid cancer. Cinacalcet is a type of calcimimetic. Vitamin D deficiency should be treated cautiously by vitamin D supplementation. The optimal dose or regimen of vitamin D supplementation for individuals with primary hyperparathyroidism is not known. Affected individuals should avoid becoming dehydrated as this can lead to an increase in calcium. This can occur when a person becomes dehydrated because of nausea and vomiting when sick. Affected individuals who become dehydrated should seek medical attention. Generally, individuals with primary hyperparathyroidism do not need to avoid dairy products or calcium-rich foods.
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Primary Hyperparathyroidism
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nord_1007_0
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Overview of Primary Intestinal Lymphangiectasia
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Primary intestinal lymphangiectasia (PIL) is a rare digestive disorder characterized by abnormally enlarged (dilatated) lymph vessels supplying the lining of the small intestine. The main symptoms are swelling (edema) of the limbs and abdominal discomfort. The disorder is usually diagnosed before three years of age but is sometimes diagnosed later in life.
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Overview of Primary Intestinal Lymphangiectasia. Primary intestinal lymphangiectasia (PIL) is a rare digestive disorder characterized by abnormally enlarged (dilatated) lymph vessels supplying the lining of the small intestine. The main symptoms are swelling (edema) of the limbs and abdominal discomfort. The disorder is usually diagnosed before three years of age but is sometimes diagnosed later in life.
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Primary Intestinal Lymphangiectasia
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nord_1007_1
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Symptoms of Primary Intestinal Lymphangiectasia
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The most obvious sign of the disorder is moderate to severe swelling in the lower limbs, eventually face, abdomen and external genitalia due to fluid retention (edema). Fluid is retained because the blood protein (albumin) levels are low. Lymphedema may also be associated and not easy to differentiate from edema.Abdominal pain and/or nausea, vomiting and diarrhea may also be present. Affected individuals may experience fatigue, weight loss, and an inability to gain weight in childhood. The blood lymphocyte count is usually low as are blood protein (albumin, globulins because protein in the lymph leaks into the intestine and the feces called exudative enteropathy) and blood cholesterol levels (because cholesterol from food is not properly absorbed).Swelling of the membrane surrounding the heart (pericarditis) and fluid in the chest (pleural effusion) or ascites (abdominal effusion) can occur. Extreme generalized swelling of the body (anasarca) can be a rare life threatening complication in children
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Symptoms of Primary Intestinal Lymphangiectasia. The most obvious sign of the disorder is moderate to severe swelling in the lower limbs, eventually face, abdomen and external genitalia due to fluid retention (edema). Fluid is retained because the blood protein (albumin) levels are low. Lymphedema may also be associated and not easy to differentiate from edema.Abdominal pain and/or nausea, vomiting and diarrhea may also be present. Affected individuals may experience fatigue, weight loss, and an inability to gain weight in childhood. The blood lymphocyte count is usually low as are blood protein (albumin, globulins because protein in the lymph leaks into the intestine and the feces called exudative enteropathy) and blood cholesterol levels (because cholesterol from food is not properly absorbed).Swelling of the membrane surrounding the heart (pericarditis) and fluid in the chest (pleural effusion) or ascites (abdominal effusion) can occur. Extreme generalized swelling of the body (anasarca) can be a rare life threatening complication in children
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Primary Intestinal Lymphangiectasia
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nord_1007_2
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Causes of Primary Intestinal Lymphangiectasia
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The cause of PIL is unknown. Multiple affected family members have been reported rarely.
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Causes of Primary Intestinal Lymphangiectasia. The cause of PIL is unknown. Multiple affected family members have been reported rarely.
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Primary Intestinal Lymphangiectasia
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nord_1007_3
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Affects of Primary Intestinal Lymphangiectasia
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PIL is a rare disease that affects males and females in equal numbers. The prevalence is unknown.
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Affects of Primary Intestinal Lymphangiectasia. PIL is a rare disease that affects males and females in equal numbers. The prevalence is unknown.
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Primary Intestinal Lymphangiectasia
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Related disorders of Primary Intestinal Lymphangiectasia
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Related disorders of Primary Intestinal Lymphangiectasia.
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Primary Intestinal Lymphangiectasia
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nord_1007_5
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Diagnosis of Primary Intestinal Lymphangiectasia
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The diagnosis of PIL is made by viewing the intestine with a flexible scope (endoscope), removing tissue samples from several areas (biopsy) and examining these tissues for signs of abnormal dilation. This exam is rarely normal and videocapsule endoscopy may be useful when endoscopic findings are not contributive. Intestinal lymph oozing may be confirmed by the increased clearance of alpha-1 antitrypsin in the stools.PIL may be suspected on a prenatal ultrasound if edema of lower limbs or generalized edema is noted.
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Diagnosis of Primary Intestinal Lymphangiectasia. The diagnosis of PIL is made by viewing the intestine with a flexible scope (endoscope), removing tissue samples from several areas (biopsy) and examining these tissues for signs of abnormal dilation. This exam is rarely normal and videocapsule endoscopy may be useful when endoscopic findings are not contributive. Intestinal lymph oozing may be confirmed by the increased clearance of alpha-1 antitrypsin in the stools.PIL may be suspected on a prenatal ultrasound if edema of lower limbs or generalized edema is noted.
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Primary Intestinal Lymphangiectasia
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nord_1007_6
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Therapies of Primary Intestinal Lymphangiectasia
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TreatmentTreatment of PIL may include a strictly low-fat long-term diet supplemented by medium-chain triglycerides to supply essential fatty acids and nutrients associated with fat-soluble vitamin such as vitamin D. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet interruption. The administration of water pills (diuretics) may sometimes be helpful. Albumin infusion is sometimes proposed in patients with important serous effusion or uncomfortable lower limb edema. Very occasionally surgical removal of the diseased portion of the intestine may be beneficial if the damage is limited to a local area. In some patients, octreotide is prescribed in addition to dietary modifications. Compression stocking can be used to stabilize in associated lower limb lymphedema.
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Therapies of Primary Intestinal Lymphangiectasia. TreatmentTreatment of PIL may include a strictly low-fat long-term diet supplemented by medium-chain triglycerides to supply essential fatty acids and nutrients associated with fat-soluble vitamin such as vitamin D. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet interruption. The administration of water pills (diuretics) may sometimes be helpful. Albumin infusion is sometimes proposed in patients with important serous effusion or uncomfortable lower limb edema. Very occasionally surgical removal of the diseased portion of the intestine may be beneficial if the damage is limited to a local area. In some patients, octreotide is prescribed in addition to dietary modifications. Compression stocking can be used to stabilize in associated lower limb lymphedema.
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Primary Intestinal Lymphangiectasia
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nord_1008_0
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Overview of Primary Lateral Sclerosis
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Primary lateral sclerosis (PLS) is a rare, neuromuscular disorder that affects the central motor neurons and is characterized by progressive weakness and stiffness of the muscles of the legs. Such weakness may progress to affect the arms and the muscles at the base of the brain (bulbar muscles). Less frequently, the muscles of the face are affected. In most cases, the disorder affects adults during midlife. The exact cause of primary lateral sclerosis is unknown.
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Overview of Primary Lateral Sclerosis. Primary lateral sclerosis (PLS) is a rare, neuromuscular disorder that affects the central motor neurons and is characterized by progressive weakness and stiffness of the muscles of the legs. Such weakness may progress to affect the arms and the muscles at the base of the brain (bulbar muscles). Less frequently, the muscles of the face are affected. In most cases, the disorder affects adults during midlife. The exact cause of primary lateral sclerosis is unknown.
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Primary Lateral Sclerosis
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nord_1008_1
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Symptoms of Primary Lateral Sclerosis
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Primary lateral sclerosis is a rare disorder affecting the nerve cells that control voluntary muscles. In most cases, the muscles of the legs are involved first. However, in some cases, the disorder may begin in the muscles of the hands or tongue. In many cases, the initial symptom of primary lateral sclerosis is progressive muscle weakness and stiffness of the voluntary muscles of legs. The disorder usually affects one leg and then progresses to the other. Affected individuals experience involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs. As a result, affected individuals may have difficulty walking and maintaining balance, may experience cramping of affected muscles, and may appear clumsy. As the disorder progresses, affected individuals may have increasing difficulties walking and may eventually require a cane or similar device to assist in walking. Although primary lateral sclerosis begins in the legs, it progresses to affect the muscles of the hands and at the base of the brain. As a result, affected individuals may also exhibit difficulty forming words (dysarthria) and difficulty swallowing (dysphagia). In some cases, these symptoms may precede the development of muscle weakness in the legs. Some affected individuals may experience loss of bladder control late in the course of primary lateral sclerosis. The specific course of primary lateral sclerosis varies from case to case. The disorder may progress rapidly within a few years or slowly over a few decades.
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Symptoms of Primary Lateral Sclerosis. Primary lateral sclerosis is a rare disorder affecting the nerve cells that control voluntary muscles. In most cases, the muscles of the legs are involved first. However, in some cases, the disorder may begin in the muscles of the hands or tongue. In many cases, the initial symptom of primary lateral sclerosis is progressive muscle weakness and stiffness of the voluntary muscles of legs. The disorder usually affects one leg and then progresses to the other. Affected individuals experience involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs. As a result, affected individuals may have difficulty walking and maintaining balance, may experience cramping of affected muscles, and may appear clumsy. As the disorder progresses, affected individuals may have increasing difficulties walking and may eventually require a cane or similar device to assist in walking. Although primary lateral sclerosis begins in the legs, it progresses to affect the muscles of the hands and at the base of the brain. As a result, affected individuals may also exhibit difficulty forming words (dysarthria) and difficulty swallowing (dysphagia). In some cases, these symptoms may precede the development of muscle weakness in the legs. Some affected individuals may experience loss of bladder control late in the course of primary lateral sclerosis. The specific course of primary lateral sclerosis varies from case to case. The disorder may progress rapidly within a few years or slowly over a few decades.
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Causes of Primary Lateral Sclerosis
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The exact cause of primary lateral sclerosis is not known. Most cases seem to occur randomly, for no apparent reason (sporadically). Primary lateral sclerosis is one of a group of disorders known as motor neuron diseases. Motor neuron diseases are characterized by malfunction of the nerve cells (motor neurons) within the brain and spinal cord that carry instructions from the brain to the muscles.
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Causes of Primary Lateral Sclerosis. The exact cause of primary lateral sclerosis is not known. Most cases seem to occur randomly, for no apparent reason (sporadically). Primary lateral sclerosis is one of a group of disorders known as motor neuron diseases. Motor neuron diseases are characterized by malfunction of the nerve cells (motor neurons) within the brain and spinal cord that carry instructions from the brain to the muscles.
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Affects of Primary Lateral Sclerosis
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Primary lateral sclerosis is a rare disorder that affects males and females in equal numbers. In most cases, the disorder occurs during the fifth decade. However, according to the medical literature a familial form may exist that affects children. The exact prevalence of primary lateral sclerosis and motor neuron diseases is unknown.
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Affects of Primary Lateral Sclerosis. Primary lateral sclerosis is a rare disorder that affects males and females in equal numbers. In most cases, the disorder occurs during the fifth decade. However, according to the medical literature a familial form may exist that affects children. The exact prevalence of primary lateral sclerosis and motor neuron diseases is unknown.
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Related disorders of Primary Lateral Sclerosis
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Symptoms of the following disorders can be similar to those of primary lateral sclerosis. Comparisons may be useful for a differential diagnosis:Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is a disorder that affects the motor neuron cells. It generally affects both the upper and lower motor neurons and results in the progressive wasting and weakening of those muscles that have lost their nerve supply. A number of different forms of ALS exist, all exhibiting some of the classic symptoms. The early symptoms of ALS include slight muscle weakness, clumsy hand movements, and/or difficulty performing tasks that require delicate movements of the fingers and/or hands. Muscular weakness in the legs may cause tripping and falling. People with ALS may have difficulty swallowing (dysphagia), and speech may be slowed. The exact cause of amyotrophic lateral sclerosis is unknown. (For more information on this disorder, choose “ALS” as your search term in the Rare Disease Database.)Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders characterized by progressive weakness (paraplegia) and increased muscle tone and stiffness (spasticity) of leg muscles. HSP is also sometimes referred to as familial spastic paraplegia (FSP) or Strumpell-Lorraine syndrome. The age at symptom onset and the degree of muscle weakness and spasticity may be extremely variable from case to case, including among individuals within the same family (kindred). According to reports in the medical literature, symptom onset may occur as early as infancy or as late as the eighth or ninth decade of life; however, symptoms most often develop during early to mid-adulthood. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, unexplained tripping and falls, and an unusually “clumsy” manner of walking (gait). As the disorder progresses, walking may become increasingly difficult; however, complete loss of the ability to walk is relatively rare. (For more information on this disorder, choose “hereditary spastic paraplegia” as your search term in the Rare Disease Database.)Multiple sclerosis is a chronic disorder of the central nervous system (CNS) that causes the destruction of the covering (myelin sheath) over the nerves. The course of this disease is variable; it may advance, relapse, remit, or stabilize. The demyelinating plaques or patches scattered throughout the central nervous system interfere with the ability of the nerves to communicate (neurotransmission) and can cause a wide range of neurological symptoms including impairment of speech, numbness or tingling sensation in the limbs and difficulty walking. Dysfunction of the bladder and bowel may also be present. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)
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Related disorders of Primary Lateral Sclerosis. Symptoms of the following disorders can be similar to those of primary lateral sclerosis. Comparisons may be useful for a differential diagnosis:Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is a disorder that affects the motor neuron cells. It generally affects both the upper and lower motor neurons and results in the progressive wasting and weakening of those muscles that have lost their nerve supply. A number of different forms of ALS exist, all exhibiting some of the classic symptoms. The early symptoms of ALS include slight muscle weakness, clumsy hand movements, and/or difficulty performing tasks that require delicate movements of the fingers and/or hands. Muscular weakness in the legs may cause tripping and falling. People with ALS may have difficulty swallowing (dysphagia), and speech may be slowed. The exact cause of amyotrophic lateral sclerosis is unknown. (For more information on this disorder, choose “ALS” as your search term in the Rare Disease Database.)Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders characterized by progressive weakness (paraplegia) and increased muscle tone and stiffness (spasticity) of leg muscles. HSP is also sometimes referred to as familial spastic paraplegia (FSP) or Strumpell-Lorraine syndrome. The age at symptom onset and the degree of muscle weakness and spasticity may be extremely variable from case to case, including among individuals within the same family (kindred). According to reports in the medical literature, symptom onset may occur as early as infancy or as late as the eighth or ninth decade of life; however, symptoms most often develop during early to mid-adulthood. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, unexplained tripping and falls, and an unusually “clumsy” manner of walking (gait). As the disorder progresses, walking may become increasingly difficult; however, complete loss of the ability to walk is relatively rare. (For more information on this disorder, choose “hereditary spastic paraplegia” as your search term in the Rare Disease Database.)Multiple sclerosis is a chronic disorder of the central nervous system (CNS) that causes the destruction of the covering (myelin sheath) over the nerves. The course of this disease is variable; it may advance, relapse, remit, or stabilize. The demyelinating plaques or patches scattered throughout the central nervous system interfere with the ability of the nerves to communicate (neurotransmission) and can cause a wide range of neurological symptoms including impairment of speech, numbness or tingling sensation in the limbs and difficulty walking. Dysfunction of the bladder and bowel may also be present. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)
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Diagnosis of Primary Lateral Sclerosis
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Diagnosis of Primary Lateral Sclerosis.
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Therapies of Primary Lateral Sclerosis
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Treatment of primary lateral sclerosis involves the use of drugs to help control specific symptoms. Baclofen and tizanidine may be prescribed for spasticity, quinine for cramps, and diazepam, a drug that relaxes muscles, for muscular contractions. Additional treatments may include physical therapy to prevent stiffness of joints, and speech therapy may be needed to aid affected individuals whose ability to speak has been impaired by muscle weakness. Other treatment is symptomatic and supportive.
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Therapies of Primary Lateral Sclerosis. Treatment of primary lateral sclerosis involves the use of drugs to help control specific symptoms. Baclofen and tizanidine may be prescribed for spasticity, quinine for cramps, and diazepam, a drug that relaxes muscles, for muscular contractions. Additional treatments may include physical therapy to prevent stiffness of joints, and speech therapy may be needed to aid affected individuals whose ability to speak has been impaired by muscle weakness. Other treatment is symptomatic and supportive.
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Overview of Primary Mitochondrial Myopathies
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Summary
Primary mitochondrial myopathies (PMM) are a group of disorders that are associated with changes in genetic material (e.g., depletions, deletions, or mutations) found within the DNA of mitochondria (mtDNA) or with genes outside the mitochondria (nuclear DNA), affecting predominantly the skeletal muscle. Mitochondria, found by the hundreds within every cell of the body, regulate the production of cellular energy and carry the genetic blueprints for this process within their own unique DNA (mtDNA). These disorders often hamper the ability of affected cells to break down food and oxygen and produce energy. Mitochondria provide more than 90% of the energy used by the body’s tissues; mitochondrial disorders are characterized by a lack of sufficient energy for cells of the body to function properly. High-energy tissues like muscle, brain, or heart tissue are most likely to be affected by mitochondrial disorders. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. Most mitochondrial diseases affect the muscles (myopathy). Sometimes, muscle disease is the only or predominant sign of a mitochondrial disorder, thus defined as PMM. There are no disease-modifying treatments for PMM; treatment is aimed at improving or resolving specific symptoms.IntroductionPrimary mitochondrial myopathies (PMM) are genetically defined disorders leading to defects of oxidative phosphorylation (see Causes section below) affecting predominantly, but not exclusively, skeletal muscle. Thus, secondary involvement of mitochondria, frequently observed in other neuromuscular diseases (e.g., Duchenne muscular dystrophy) is not considered PMM. Moreover, individuals with muscle disease symptoms but with other systems are affected (i.e., brain, liver, kidney, etc.) are not considered affected by PMM, and they may fit into a more straightforward clinical syndrome like Kearns-Sayre syndrome, MELAS syndrome, etc. NORD has individual reports on many different forms of mitochondrial disease. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Overview of Primary Mitochondrial Myopathies. Summary
Primary mitochondrial myopathies (PMM) are a group of disorders that are associated with changes in genetic material (e.g., depletions, deletions, or mutations) found within the DNA of mitochondria (mtDNA) or with genes outside the mitochondria (nuclear DNA), affecting predominantly the skeletal muscle. Mitochondria, found by the hundreds within every cell of the body, regulate the production of cellular energy and carry the genetic blueprints for this process within their own unique DNA (mtDNA). These disorders often hamper the ability of affected cells to break down food and oxygen and produce energy. Mitochondria provide more than 90% of the energy used by the body’s tissues; mitochondrial disorders are characterized by a lack of sufficient energy for cells of the body to function properly. High-energy tissues like muscle, brain, or heart tissue are most likely to be affected by mitochondrial disorders. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. Most mitochondrial diseases affect the muscles (myopathy). Sometimes, muscle disease is the only or predominant sign of a mitochondrial disorder, thus defined as PMM. There are no disease-modifying treatments for PMM; treatment is aimed at improving or resolving specific symptoms.IntroductionPrimary mitochondrial myopathies (PMM) are genetically defined disorders leading to defects of oxidative phosphorylation (see Causes section below) affecting predominantly, but not exclusively, skeletal muscle. Thus, secondary involvement of mitochondria, frequently observed in other neuromuscular diseases (e.g., Duchenne muscular dystrophy) is not considered PMM. Moreover, individuals with muscle disease symptoms but with other systems are affected (i.e., brain, liver, kidney, etc.) are not considered affected by PMM, and they may fit into a more straightforward clinical syndrome like Kearns-Sayre syndrome, MELAS syndrome, etc. NORD has individual reports on many different forms of mitochondrial disease. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Symptoms of Primary Mitochondrial Myopathies
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The signs and symptoms of PMM are varied and how one of these disorders affects one person can be vastly different from how it affects another person. This is true for people with the same disorder, or even people within the same family and with the same genetic variation (mutation). PMM may present at any age, patients with severe generalized muscle involvement typically present early in life, although individuals with milder forms of the disease, or symptoms confined to specific muscles tend to have later presentations. Generally, the earlier the onset (e.g., infancy or early childhood), the more severe a mitochondrial disorder will be.Myopathy is defined as muscle disease. Mitochondrial myopathy is when muscle fibers cannot function properly because of an underlying defect in mitochondria. The most common presentation, which is estimated to affect about two-thirds of all people classified within this group, is progressive paralysis of certain eye muscles (progressive external ophthalmoplegia). This occurs slowly over time and limits the movements of the eyes so that affected individuals must turn their heads to see things in their peripheral vision. Sometimes, double vision (diplopia) may occur. Affected individuals often experience drooping of both their upper eyelids (bilateral ptosis). Ptosis is caused by paralysis of one of the muscles of the eyelid. Sometimes, this drooping can partially block vision. Other muscles involved in coordinating eye movements may be affected next, growing progressively weaker and eventually resulting in paralysis of certain eye movements. In severe instances, affected individuals may tilt their head.Progressive external ophthalmoplegia can be a syndrome on its own unassociated with other signs or symptoms, or it can occur as part of a larger syndrome. In some people primary mitochondrial myopathy can cause weakness and paralysis of other facial muscles. This can lead to additional symptoms including difficulty swallowing or slurred speech. Some people can develop problems breathing (respiratory problems).Some people may have involvement of the muscles of the arms and legs. The hips, shoulder girdle, or neck muscles can also be involved. Sometimes, only muscles in one area of the body are affected: sometimes in multiple areas of the body. Cramping, stiffness, weakness, and paralysis of the affected muscles can potentially develop. Muscle fatigue, muscle pain (myalgia) and muscle wasting can also develop. Exercise intolerance, which is a decreased ability to perform physical tasks, is a common symptom, and is sometimes the first noticeable symptoms in adults. Sometimes, symptoms of primary mitochondrial myopathy may only be present following exercise or physical activity. In severe instances, progressive muscle weakness in the legs can lead to the need for devices to help with walking (e.g., cane) or, eventually, a wheelchair.Encephalomyopathy
Encephalomyopathy (and not PMM as defined above) of infancy or childhood is when there are neurological problems along with problems affecting the muscles. The specific signs and symptoms of encephalomyopathy can vary greatly from person to person. Vision loss can occur because of involvement of the eye or the part of the brain that controls sight. Sensorineural hearing loss can also occur. This type of hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain and is not caused by problems with the ear itself. The degree and production of hearing loss can vary. Additional symptoms of encephalopathy in infancy or childhood can include migraines, seizures, or poor coordination (ataxia). Some children may experience delays in reaching develomental milestones (developmental delays). Some children may fail to gain weight and grow as would be otherwise expected (failure to thrive) leading to poor growth. Some children may be shorter than would be expected for age and gender (short stature). Neurological involvement can lead to various problems including difficulty swallowing (dysphagia), difficulty speaking (dysarthria) and muscle weakness and muscle tightness (spasticity). Some individuals experience peripheral neuropathy, which is a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness and stabbing pain in the affected extremities. Mitochondrial diseases that cause neurological problems may be referred to as mitochondrial encephalomyopathies, and not primary mitochondrial myopathies.Multisystem Mitochondrial Diseases
There are many genetic disorders that are classified as mitochondrial disease that can have mitochondrial myopathy as a feature. These disorders affect multiple organ systems of the body and include Barth syndrome; growth delay, amino aciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome); Kearns-Sayre syndrome; Leigh syndrome; maternally inherited deafness and diabetes (MIDD); mitochondrial DNA depletion syndrome; mitochondrial encephalomyopathy, lactic acidosis, and stroke-like (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); mitochondrial recessive ataxia syndrome (MIRAS); myoclonus epilepsy with ragged red fibers (MERFF); neuropathy, ataxia, and retinitis pigmentosa (NARP); and Pearson syndrome. NORD has individual reports on many of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Symptoms of Primary Mitochondrial Myopathies. The signs and symptoms of PMM are varied and how one of these disorders affects one person can be vastly different from how it affects another person. This is true for people with the same disorder, or even people within the same family and with the same genetic variation (mutation). PMM may present at any age, patients with severe generalized muscle involvement typically present early in life, although individuals with milder forms of the disease, or symptoms confined to specific muscles tend to have later presentations. Generally, the earlier the onset (e.g., infancy or early childhood), the more severe a mitochondrial disorder will be.Myopathy is defined as muscle disease. Mitochondrial myopathy is when muscle fibers cannot function properly because of an underlying defect in mitochondria. The most common presentation, which is estimated to affect about two-thirds of all people classified within this group, is progressive paralysis of certain eye muscles (progressive external ophthalmoplegia). This occurs slowly over time and limits the movements of the eyes so that affected individuals must turn their heads to see things in their peripheral vision. Sometimes, double vision (diplopia) may occur. Affected individuals often experience drooping of both their upper eyelids (bilateral ptosis). Ptosis is caused by paralysis of one of the muscles of the eyelid. Sometimes, this drooping can partially block vision. Other muscles involved in coordinating eye movements may be affected next, growing progressively weaker and eventually resulting in paralysis of certain eye movements. In severe instances, affected individuals may tilt their head.Progressive external ophthalmoplegia can be a syndrome on its own unassociated with other signs or symptoms, or it can occur as part of a larger syndrome. In some people primary mitochondrial myopathy can cause weakness and paralysis of other facial muscles. This can lead to additional symptoms including difficulty swallowing or slurred speech. Some people can develop problems breathing (respiratory problems).Some people may have involvement of the muscles of the arms and legs. The hips, shoulder girdle, or neck muscles can also be involved. Sometimes, only muscles in one area of the body are affected: sometimes in multiple areas of the body. Cramping, stiffness, weakness, and paralysis of the affected muscles can potentially develop. Muscle fatigue, muscle pain (myalgia) and muscle wasting can also develop. Exercise intolerance, which is a decreased ability to perform physical tasks, is a common symptom, and is sometimes the first noticeable symptoms in adults. Sometimes, symptoms of primary mitochondrial myopathy may only be present following exercise or physical activity. In severe instances, progressive muscle weakness in the legs can lead to the need for devices to help with walking (e.g., cane) or, eventually, a wheelchair.Encephalomyopathy
Encephalomyopathy (and not PMM as defined above) of infancy or childhood is when there are neurological problems along with problems affecting the muscles. The specific signs and symptoms of encephalomyopathy can vary greatly from person to person. Vision loss can occur because of involvement of the eye or the part of the brain that controls sight. Sensorineural hearing loss can also occur. This type of hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain and is not caused by problems with the ear itself. The degree and production of hearing loss can vary. Additional symptoms of encephalopathy in infancy or childhood can include migraines, seizures, or poor coordination (ataxia). Some children may experience delays in reaching develomental milestones (developmental delays). Some children may fail to gain weight and grow as would be otherwise expected (failure to thrive) leading to poor growth. Some children may be shorter than would be expected for age and gender (short stature). Neurological involvement can lead to various problems including difficulty swallowing (dysphagia), difficulty speaking (dysarthria) and muscle weakness and muscle tightness (spasticity). Some individuals experience peripheral neuropathy, which is a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness and stabbing pain in the affected extremities. Mitochondrial diseases that cause neurological problems may be referred to as mitochondrial encephalomyopathies, and not primary mitochondrial myopathies.Multisystem Mitochondrial Diseases
There are many genetic disorders that are classified as mitochondrial disease that can have mitochondrial myopathy as a feature. These disorders affect multiple organ systems of the body and include Barth syndrome; growth delay, amino aciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome); Kearns-Sayre syndrome; Leigh syndrome; maternally inherited deafness and diabetes (MIDD); mitochondrial DNA depletion syndrome; mitochondrial encephalomyopathy, lactic acidosis, and stroke-like (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); mitochondrial recessive ataxia syndrome (MIRAS); myoclonus epilepsy with ragged red fibers (MERFF); neuropathy, ataxia, and retinitis pigmentosa (NARP); and Pearson syndrome. NORD has individual reports on many of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Causes of Primary Mitochondrial Myopathies
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Primary mitochondrial myopathies are caused by a variation (mutation) in a gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain. Most of the genes involved with primary mitochondrial myopathy involve proteins that are essential for the proper function, development and health of mitochondria.These genes contain instructions for creating (encoding) proteins that are part of the mitochondrial respiratory chain. This is a group of proteins involved in a process called oxidative phosphorylation. This cellular process uses oxygen combined with simple sugars and fats (obtained from food) to manufacture adenosine triphosphate (ATP), the main source of energy for a cell. A cell with too little ATP can build up unused sugars and fats and can generate potentially harmful substances such as lactate. The lack of energy supplied to tissue and the buildup of harmful substances causes the signs and symptoms of the disorder.Genetic information is contained in two types of DNA: nuclear or autosomal DNA (nDNA), which is contained in the nucleus of a cell and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is contained outside of the nucleus in the mitochondria of cells and is inherited exclusively from a child’s mother. Both changes in nDNA or mtDNA can cause PMM. Most mitochondrial proteins are encoded by genes that are part of the nuclear genome.All human mtDNA comes from the mother. This is because mtDNA that is found in sperm cells typically break off during fertilization. An affected mother will pass the mutation(s) on to all her children, but only her daughters will pass thegene variants on to their children. Sometimes, a variant in mtDNA occurs spontaneously during the development of an embryo and there is no previous family history of the disorder. Each individual mitochondrion contains about 10 copies of mtDNA. This means that within the same cell, there may be mutated mtDNA and unaffected mtDNA. This is called heteroplasmy. Generally, symptoms do not occur until gene variants are present in a significant percentage of the mitochondria. The uneven distribution of unaffected and mutated mtDNA in different tissues can affect different organ systems in members of the same family. Thus, affected family members may exhibit a variety of different symptoms and varying degrees of severity.Genetic diseases due to nDNA mutations (also called autosomal inheritance) are determined by two genes, one received from the father and one from the mother. PMM can be inherited in an autosomal recessive pattern, an autosomal dominant pattern, or it can occur spontaneously during the development of the embryo without any family history of the disorder.Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Less often, PMM can be inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new gene change in the affected individual. A new variant occurs spontaneously and there is no previous family history of the disorder. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Primary Mitochondrial Myopathies. Primary mitochondrial myopathies are caused by a variation (mutation) in a gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain. Most of the genes involved with primary mitochondrial myopathy involve proteins that are essential for the proper function, development and health of mitochondria.These genes contain instructions for creating (encoding) proteins that are part of the mitochondrial respiratory chain. This is a group of proteins involved in a process called oxidative phosphorylation. This cellular process uses oxygen combined with simple sugars and fats (obtained from food) to manufacture adenosine triphosphate (ATP), the main source of energy for a cell. A cell with too little ATP can build up unused sugars and fats and can generate potentially harmful substances such as lactate. The lack of energy supplied to tissue and the buildup of harmful substances causes the signs and symptoms of the disorder.Genetic information is contained in two types of DNA: nuclear or autosomal DNA (nDNA), which is contained in the nucleus of a cell and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is contained outside of the nucleus in the mitochondria of cells and is inherited exclusively from a child’s mother. Both changes in nDNA or mtDNA can cause PMM. Most mitochondrial proteins are encoded by genes that are part of the nuclear genome.All human mtDNA comes from the mother. This is because mtDNA that is found in sperm cells typically break off during fertilization. An affected mother will pass the mutation(s) on to all her children, but only her daughters will pass thegene variants on to their children. Sometimes, a variant in mtDNA occurs spontaneously during the development of an embryo and there is no previous family history of the disorder. Each individual mitochondrion contains about 10 copies of mtDNA. This means that within the same cell, there may be mutated mtDNA and unaffected mtDNA. This is called heteroplasmy. Generally, symptoms do not occur until gene variants are present in a significant percentage of the mitochondria. The uneven distribution of unaffected and mutated mtDNA in different tissues can affect different organ systems in members of the same family. Thus, affected family members may exhibit a variety of different symptoms and varying degrees of severity.Genetic diseases due to nDNA mutations (also called autosomal inheritance) are determined by two genes, one received from the father and one from the mother. PMM can be inherited in an autosomal recessive pattern, an autosomal dominant pattern, or it can occur spontaneously during the development of the embryo without any family history of the disorder.Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Less often, PMM can be inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new gene change in the affected individual. A new variant occurs spontaneously and there is no previous family history of the disorder. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Affects of Primary Mitochondrial Myopathies
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Mitochondrial diseases are one of the most common forms of metabolic disease. They are estimated to affect about 1 in 5,000 people in the general population of the United States. Within the group of mitochondrial diseases, PMM are very common but epidemiological studies are not available yet. This is also because PMM often go misdiagnosed or undiagnosed so determining their true frequency in the general population is difficult. These disorders affect both men and women, children and adults, and individuals of all ethnic and racial groups.
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Affects of Primary Mitochondrial Myopathies. Mitochondrial diseases are one of the most common forms of metabolic disease. They are estimated to affect about 1 in 5,000 people in the general population of the United States. Within the group of mitochondrial diseases, PMM are very common but epidemiological studies are not available yet. This is also because PMM often go misdiagnosed or undiagnosed so determining their true frequency in the general population is difficult. These disorders affect both men and women, children and adults, and individuals of all ethnic and racial groups.
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Related disorders of Primary Mitochondrial Myopathies
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Symptoms of the following disorders can be similar to those of PMM. Comparisons may be useful for a differential diagnosis.The list of disorders that can have signs and symptoms similar to mitochondrial disease is long. Any disorder that can cause progressive, multisystem disease may need to be differentiated from mitochondrial diseases.Some disorders cause damage to or hamper the ability of mitochondria. This is referred to as secondary mitochondrial disease. The list of disorders that cause secondary mitochondrial dysfunction is constantly increasing and includes spinal muscular atrophy, Friedreich ataxia, Charcot-Tooth-Marie disease type 2K, hereditary spastic paraplegia 7, inclusion body myositis, Wilson disease, and some forms of muscular dystrophy including Duchenne muscular dystrophy and limb-girdle muscular dystrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Primary Mitochondrial Myopathies. Symptoms of the following disorders can be similar to those of PMM. Comparisons may be useful for a differential diagnosis.The list of disorders that can have signs and symptoms similar to mitochondrial disease is long. Any disorder that can cause progressive, multisystem disease may need to be differentiated from mitochondrial diseases.Some disorders cause damage to or hamper the ability of mitochondria. This is referred to as secondary mitochondrial disease. The list of disorders that cause secondary mitochondrial dysfunction is constantly increasing and includes spinal muscular atrophy, Friedreich ataxia, Charcot-Tooth-Marie disease type 2K, hereditary spastic paraplegia 7, inclusion body myositis, Wilson disease, and some forms of muscular dystrophy including Duchenne muscular dystrophy and limb-girdle muscular dystrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Primary Mitochondrial Myopathies
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A diagnosis of PMM is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough physical and clinical evaluation and a variety of specialized tests. The characteristic signs and symptoms of primary mitochondrial myopathy are common to many different types of disorders. The diagnostic workup requires a complex approach that includes routine and special laboratory tests.Clinical Testing and Workup
Initial tests may be conducted to assess the extent of disease in various organ systems and detect evidence of a potential mitochondrial disease. These tests do not confirm a diagnosis of PMM.A physical exam can include tests that measure strength and endurance. A neurological exam can include tests that assess reflexes, vision, speech and intellectual abilities. These tests can support a diagnosis of PMM or a mitochondrial disease or rule out other conditions.Laboratory tests can include metabolic screening tests including a complete blood count, urine analysis and, if a brain involvement is suspected, cerebrospinal fluid (CSF) analysis. These tests measure for certain substances including lactate and pyruvate levels in the blood or CSF, creatinine kinase (an enzyme that is found in elevated levels when muscle is damaged), ammonia, plasma amino acids, plasma carnitine, urinary organic acids and plasma acetyl-carnitine profile. Lactate is often elevated in mitochondrial disorders and is known as lactic acidosis. A fasting blood glucose test can be ordered to confirm diabetes.A test that assesses the health of muscles and the nerves that control muscles (electromyography) may be recommended. During this exam, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscles themselves or nerves that control the muscles. A nerve conduction study, in which motor and sensory nerves are electrically stimulated to assess a nerve’s ability and speed in conducting nerve impulses, may also be performed. Electromyography and nerve conduction studies can rule out other conditions. Electromyography can support a diagnosis of PMM, but not everyone with a mitochondrial disorder will have changes detectable by this test.A test called electroencephalography (EEG) may be recommended for individuals with seizures or signs of encephalopathy. An EEG records the brain’s electrical impulses.Specialized imaging techniques like computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be recommended, especially for individuals with central nervous system involvement. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. These tests can show characteristic findings in the brain that can support a diagnosis of specific mitochondrial disorders or indicate another type of neurological disorder.A test called magnetic resonance spectroscopy can be used to detect lactate, which is elevated in the brain or muscles at rest in some affected individuals. This noninvasive test is a specialized imaging technique that allows physicians to assess changes in brain or muscle tissue biochemistry.If initial tests suggest PMM, then a muscle biopsy and molecular genetic testing are recommended. A muscle biopsy involves taking a small sample of affected muscle tissue that is studied under a microscope. The visual appearance of muscle tissue under a microscope can be indicative of mitochondrial disease or another disorder that affects the disorder. Chemical tests conducted on the muscle tissue sample can also indicate a diagnosis.Molecular genetic testing is necessary to confirm a diagnosis of PMM. Molecular genetic testing can detect variations in the genes known to cause these disorders but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Primary Mitochondrial Myopathies. A diagnosis of PMM is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough physical and clinical evaluation and a variety of specialized tests. The characteristic signs and symptoms of primary mitochondrial myopathy are common to many different types of disorders. The diagnostic workup requires a complex approach that includes routine and special laboratory tests.Clinical Testing and Workup
Initial tests may be conducted to assess the extent of disease in various organ systems and detect evidence of a potential mitochondrial disease. These tests do not confirm a diagnosis of PMM.A physical exam can include tests that measure strength and endurance. A neurological exam can include tests that assess reflexes, vision, speech and intellectual abilities. These tests can support a diagnosis of PMM or a mitochondrial disease or rule out other conditions.Laboratory tests can include metabolic screening tests including a complete blood count, urine analysis and, if a brain involvement is suspected, cerebrospinal fluid (CSF) analysis. These tests measure for certain substances including lactate and pyruvate levels in the blood or CSF, creatinine kinase (an enzyme that is found in elevated levels when muscle is damaged), ammonia, plasma amino acids, plasma carnitine, urinary organic acids and plasma acetyl-carnitine profile. Lactate is often elevated in mitochondrial disorders and is known as lactic acidosis. A fasting blood glucose test can be ordered to confirm diabetes.A test that assesses the health of muscles and the nerves that control muscles (electromyography) may be recommended. During this exam, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscles themselves or nerves that control the muscles. A nerve conduction study, in which motor and sensory nerves are electrically stimulated to assess a nerve’s ability and speed in conducting nerve impulses, may also be performed. Electromyography and nerve conduction studies can rule out other conditions. Electromyography can support a diagnosis of PMM, but not everyone with a mitochondrial disorder will have changes detectable by this test.A test called electroencephalography (EEG) may be recommended for individuals with seizures or signs of encephalopathy. An EEG records the brain’s electrical impulses.Specialized imaging techniques like computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be recommended, especially for individuals with central nervous system involvement. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. These tests can show characteristic findings in the brain that can support a diagnosis of specific mitochondrial disorders or indicate another type of neurological disorder.A test called magnetic resonance spectroscopy can be used to detect lactate, which is elevated in the brain or muscles at rest in some affected individuals. This noninvasive test is a specialized imaging technique that allows physicians to assess changes in brain or muscle tissue biochemistry.If initial tests suggest PMM, then a muscle biopsy and molecular genetic testing are recommended. A muscle biopsy involves taking a small sample of affected muscle tissue that is studied under a microscope. The visual appearance of muscle tissue under a microscope can be indicative of mitochondrial disease or another disorder that affects the disorder. Chemical tests conducted on the muscle tissue sample can also indicate a diagnosis.Molecular genetic testing is necessary to confirm a diagnosis of PMM. Molecular genetic testing can detect variations in the genes known to cause these disorders but is available only as a diagnostic service at specialized laboratories.
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Primary Mitochondrial Myopathies
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Therapies of Primary Mitochondrial Myopathies
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Treatment
Treatment of mitochondrial diseases may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who specialize in diagnosing and treating disorders of the central nervous system and brain (neurologists), physicians who specialize in diagnosing and treating disorders of the bones, muscles, tendons, and ligaments (orthopedists), physicians who specialize in diagnosing and treating disorders of the heart (cardiologists), physicians who specialize in diagnosing and treating disorders of the eye (ophthalmologists), physical therapists, social workers and other healthcare professionals may need to systematically and comprehensively plan treatment.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. The organizations listed in the Resources section of this report provide support and information for individuals with mitochondrial disorders.There is no cure or disease-modifying treatment for PMM. Treatment is supportive and based on the specific type of PMM that is present and is directed toward the specific symptoms that are apparent in each individual.Some individuals with mitochondrial disease have responded to a combination of vitamins and supplements – this is sometimes referred to as “mito-cocktails.” Common ingredients include riboflavin (vitamin B2), thiamine (vitamin B1), L-carnitine, creatine, coenzyme Q10 and antioxidants. These treatments are developed in close consultation with the entire medical team and preferably medical professionals with experience in treating mitochondrial disorders. In some individuals, these vitamins and supplements do not bring about any improvement in mitochondrial function.Exercise has shown some benefit for people with primary mitochondrial myopathy. Researchers have studied aerobic, endurance, and resistance training programs. Aerobic exercise has shown benefit in improving strength and lessening fatigue. Exercise programs have been shown to improve quality of life in many affected individuals.In rare instances, affected individuals have coenzyme Q10 deficiency and some of these individuals may respond to therapy with high doses of coenzyme Q10 supplementation.Additional therapies are supportive and generally follow standard guidelines. For example, seizures may be treated with anti-seizure medications called anti-epileptics or anti-convulsants. Eyelid drooping can be treated with eye crutches or surgery. Hearing loss can be treated with hearing aids called cochlear implants.Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical and speech therapies be instituted. Periodic reassessments and adjustment of services should be provided for all individuals. Additional medical, social, and/or vocational services including specialized learning programs for affected children may be necessary.
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Therapies of Primary Mitochondrial Myopathies. Treatment
Treatment of mitochondrial diseases may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who specialize in diagnosing and treating disorders of the central nervous system and brain (neurologists), physicians who specialize in diagnosing and treating disorders of the bones, muscles, tendons, and ligaments (orthopedists), physicians who specialize in diagnosing and treating disorders of the heart (cardiologists), physicians who specialize in diagnosing and treating disorders of the eye (ophthalmologists), physical therapists, social workers and other healthcare professionals may need to systematically and comprehensively plan treatment.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. The organizations listed in the Resources section of this report provide support and information for individuals with mitochondrial disorders.There is no cure or disease-modifying treatment for PMM. Treatment is supportive and based on the specific type of PMM that is present and is directed toward the specific symptoms that are apparent in each individual.Some individuals with mitochondrial disease have responded to a combination of vitamins and supplements – this is sometimes referred to as “mito-cocktails.” Common ingredients include riboflavin (vitamin B2), thiamine (vitamin B1), L-carnitine, creatine, coenzyme Q10 and antioxidants. These treatments are developed in close consultation with the entire medical team and preferably medical professionals with experience in treating mitochondrial disorders. In some individuals, these vitamins and supplements do not bring about any improvement in mitochondrial function.Exercise has shown some benefit for people with primary mitochondrial myopathy. Researchers have studied aerobic, endurance, and resistance training programs. Aerobic exercise has shown benefit in improving strength and lessening fatigue. Exercise programs have been shown to improve quality of life in many affected individuals.In rare instances, affected individuals have coenzyme Q10 deficiency and some of these individuals may respond to therapy with high doses of coenzyme Q10 supplementation.Additional therapies are supportive and generally follow standard guidelines. For example, seizures may be treated with anti-seizure medications called anti-epileptics or anti-convulsants. Eyelid drooping can be treated with eye crutches or surgery. Hearing loss can be treated with hearing aids called cochlear implants.Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical and speech therapies be instituted. Periodic reassessments and adjustment of services should be provided for all individuals. Additional medical, social, and/or vocational services including specialized learning programs for affected children may be necessary.
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Primary Mitochondrial Myopathies
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Overview of Primary Myelofibrosis
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SummaryPrimary myelofibrosis (PMF) is a rare bone marrow disorder that is characterized by abnormalities in blood cell production (hematopoiesis) and scarring (formation of fibrous tissue) within the bone marrow. Bone marrow is the soft, spongy tissue that fills the center of most bones. Bone marrow contains specialized cells called hematopoietic stem cells that grow and eventually develop into one of the three main types of blood cells: red blood cells, white blood cells or platelets. In primary myelofibrosis, a change in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself. Eventually, these abnormal cells crowd out normal, healthy cells in the marrow and, along with scarring within the marrow, disrupt the production of red and white blood cells and platelets.The symptoms associated with primary myelofibrosis vary and are related to the abnormalities affecting blood cell production. Affected individuals may not have symptoms at the time of diagnosis (asymptomatic) may remain symptom-free for many years. Eventually, affected individuals may develop fatigue, fever, frequent infections, pale skin, night sweats and unexplained weight loss. An enlarged (spleen) is a common finding. An enlarged liver (hepatomegaly) may also occur.In approximately 50 percent of patients, a mutation of the JAK2 gene has been detected. The exact role this abnormal gene plays in the development of the disorder is unknown.IntroductionPrimary myelofibrosis belongs to a group of diseases known as the myeloproliferative neoplasms (MPNs). This group of disorders is characterized by the overproduction (proliferation) of one or more of the three main blood cell lines – red or white blood cells or platelets. Three other disorders are commonly classified as MPNs: chronic myeloid leukemia, essential thrombocythemia and polycythemia vera. Myelofibrosis may occur as a secondary characteristic of polycythemia vera or essential thrombocytyemia. Because the MPNs are characterized by uncontrolled cell growth, they may also be classified as blood cancers.
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Overview of Primary Myelofibrosis. SummaryPrimary myelofibrosis (PMF) is a rare bone marrow disorder that is characterized by abnormalities in blood cell production (hematopoiesis) and scarring (formation of fibrous tissue) within the bone marrow. Bone marrow is the soft, spongy tissue that fills the center of most bones. Bone marrow contains specialized cells called hematopoietic stem cells that grow and eventually develop into one of the three main types of blood cells: red blood cells, white blood cells or platelets. In primary myelofibrosis, a change in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself. Eventually, these abnormal cells crowd out normal, healthy cells in the marrow and, along with scarring within the marrow, disrupt the production of red and white blood cells and platelets.The symptoms associated with primary myelofibrosis vary and are related to the abnormalities affecting blood cell production. Affected individuals may not have symptoms at the time of diagnosis (asymptomatic) may remain symptom-free for many years. Eventually, affected individuals may develop fatigue, fever, frequent infections, pale skin, night sweats and unexplained weight loss. An enlarged (spleen) is a common finding. An enlarged liver (hepatomegaly) may also occur.In approximately 50 percent of patients, a mutation of the JAK2 gene has been detected. The exact role this abnormal gene plays in the development of the disorder is unknown.IntroductionPrimary myelofibrosis belongs to a group of diseases known as the myeloproliferative neoplasms (MPNs). This group of disorders is characterized by the overproduction (proliferation) of one or more of the three main blood cell lines – red or white blood cells or platelets. Three other disorders are commonly classified as MPNs: chronic myeloid leukemia, essential thrombocythemia and polycythemia vera. Myelofibrosis may occur as a secondary characteristic of polycythemia vera or essential thrombocytyemia. Because the MPNs are characterized by uncontrolled cell growth, they may also be classified as blood cancers.
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Primary Myelofibrosis
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Symptoms of Primary Myelofibrosis
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Most of the symptoms of primary myelofibrosis are related to abnormalities affecting the production of the three main types of blood cells: red and white cells and platelets. Most blood cells are produced in the bone marrow and released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding.In primary myelofibrosis there are often low levels of circulating red blood cells, a condition known as anemia. Red blood cells may also be misshapen (i.e., shaped like teardrops) and underdeveloped (immature). White blood cells and platelets are also misshapen and immature. However, there are often too many white blood cells produced. There may be abnormally low or high levels of platelets.The specific symptoms and progression of primary myelofibrosis vary from person to person. Some individuals may not exhibit symptoms for many years (asymptomatic). Eventually, individuals with anemia may experience tiredness, shortness of breath, weakness, lightheadedness, irritability, headaches, and pale skin color. Fever and excessive sweating at night (night sweats) may also occur. Although there may be too many white blood cells, these abnormal cells do not function properly and fail to properly fight off infection. Therefore, affected individuals may have an increased risk of contracting bacterial and fungal infections. Abnormalities in platelet production may make individuals more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose.An abnormally enlarged spleen is a common finding in individuals with primary myelofibrosis. Splenomegaly may cause pain or a feeling of fullness in the upper left portion of the stomach. Splenomegaly can also cause severe pain in the upper left shoulder (referred pain). Abnormal enlargement of the liver (hepatomegaly) occurs in approximately two-thirds of patients. Abnormal enlargement of the spleen or liver may occur, in part, due to extramedullary hematopoiesis, an abnormal process where blood cells develop outside of the bone marrow.Extramedullary hematopoiesis may also cause masses (fibrohematopoietic tumors) to form in the gastrointestinal tract, lungs, skin, liver, spleen and other areas of the body. Symptoms associated with these tumors occur due to compression of nearby structures or impaired function of an affected organ. Fibrohematopoietic tumors in the gastrointestinal tract may lead to excessive bleeding, tumors in the brain can cause neurological complications, and tumors near the spine can compress the spinal cord.Bone or joint pain may develop later in the course of the disease. Additional complications may occur in some cases of primary myelofibrosis including increased blood pressure of the main artery delivering blood to the liver (portal hypertension) due to excess blood flow from the spleen. The liver cannot absorb the excess blood flow, which may be forced into small veins within the stomach or esophagus. These veins may expand and eventually rupture causing bleeding (esophageal or gastric varices). Increased blood pressure of the main artery of lungs (pulmonary hypertension) may also occur.In approximately 20 percent of individuals, primary myelofibrosis will progress to acute myelogenous leukemia, a specific type of blood cancer.
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Symptoms of Primary Myelofibrosis. Most of the symptoms of primary myelofibrosis are related to abnormalities affecting the production of the three main types of blood cells: red and white cells and platelets. Most blood cells are produced in the bone marrow and released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding.In primary myelofibrosis there are often low levels of circulating red blood cells, a condition known as anemia. Red blood cells may also be misshapen (i.e., shaped like teardrops) and underdeveloped (immature). White blood cells and platelets are also misshapen and immature. However, there are often too many white blood cells produced. There may be abnormally low or high levels of platelets.The specific symptoms and progression of primary myelofibrosis vary from person to person. Some individuals may not exhibit symptoms for many years (asymptomatic). Eventually, individuals with anemia may experience tiredness, shortness of breath, weakness, lightheadedness, irritability, headaches, and pale skin color. Fever and excessive sweating at night (night sweats) may also occur. Although there may be too many white blood cells, these abnormal cells do not function properly and fail to properly fight off infection. Therefore, affected individuals may have an increased risk of contracting bacterial and fungal infections. Abnormalities in platelet production may make individuals more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose.An abnormally enlarged spleen is a common finding in individuals with primary myelofibrosis. Splenomegaly may cause pain or a feeling of fullness in the upper left portion of the stomach. Splenomegaly can also cause severe pain in the upper left shoulder (referred pain). Abnormal enlargement of the liver (hepatomegaly) occurs in approximately two-thirds of patients. Abnormal enlargement of the spleen or liver may occur, in part, due to extramedullary hematopoiesis, an abnormal process where blood cells develop outside of the bone marrow.Extramedullary hematopoiesis may also cause masses (fibrohematopoietic tumors) to form in the gastrointestinal tract, lungs, skin, liver, spleen and other areas of the body. Symptoms associated with these tumors occur due to compression of nearby structures or impaired function of an affected organ. Fibrohematopoietic tumors in the gastrointestinal tract may lead to excessive bleeding, tumors in the brain can cause neurological complications, and tumors near the spine can compress the spinal cord.Bone or joint pain may develop later in the course of the disease. Additional complications may occur in some cases of primary myelofibrosis including increased blood pressure of the main artery delivering blood to the liver (portal hypertension) due to excess blood flow from the spleen. The liver cannot absorb the excess blood flow, which may be forced into small veins within the stomach or esophagus. These veins may expand and eventually rupture causing bleeding (esophageal or gastric varices). Increased blood pressure of the main artery of lungs (pulmonary hypertension) may also occur.In approximately 20 percent of individuals, primary myelofibrosis will progress to acute myelogenous leukemia, a specific type of blood cancer.
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Causes of Primary Myelofibrosis
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The underlying cause of primary myelofibrosis is unknown (idiopathic). Approximately, 50 percent of people with PMF have a mutation of the JAK2 gene. This gene is also mutated in essential thrombocythemia and polycythemia vera. Mutations in the CALR gene occur in approximately 20% of the patients. Approximately 10 percent of those affected have mutations of the MPL gene. The exact role that JAK2, CALR or MPL gene mutations play in the development of primary myelofibrosis is not fully understood.Many of the symptoms of primary myelofibrosis occur because abnormalities affecting the formation of blood cells. The disorder begins with an acquired, change in the DNA of one hematopoietic stem cell. This defective cell produces copies of itself that also carry the same mutated DNA. These abnormal cells eventually outnumber healthy cells in the marrow. In response to this process, scar (fibrous) tissue forms within the bone marrow (fibrosis) further affecting blood cell production. In primary myelofibrosis, there is overproduction of megakaryocytes, which are cells that eventually become platelets.These megakaryocytes release certain substances called cytokine, which some researchers believe may stimulate the formation of fibrous tissue within the marrow. Additional changes may affect the marrow including abnormal density or hardening of bone or marrow (osteosclerosis) and the development of too many small blood vessels (angiogenesis) within the marrow.Some people with myelofibrosis may have been exposed to tuberculosis or exposed to toxic substances, such as benzene, fluoride or phosphorus. Myelofibrosis may occur as a result of the spread of cancer (metastasis) to bone marrow from primary tumors. These tumors most often originate in the breast, prostate, kidney, lung, or adrenal or thyroid gland. Myelofibrosis may occur as a secondary characteristic of another bone marrow disorder such as polycythemia vera, multiple myeloma, certain metabolic disorders, and/or chronic myeloid leukemia. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Causes of Primary Myelofibrosis. The underlying cause of primary myelofibrosis is unknown (idiopathic). Approximately, 50 percent of people with PMF have a mutation of the JAK2 gene. This gene is also mutated in essential thrombocythemia and polycythemia vera. Mutations in the CALR gene occur in approximately 20% of the patients. Approximately 10 percent of those affected have mutations of the MPL gene. The exact role that JAK2, CALR or MPL gene mutations play in the development of primary myelofibrosis is not fully understood.Many of the symptoms of primary myelofibrosis occur because abnormalities affecting the formation of blood cells. The disorder begins with an acquired, change in the DNA of one hematopoietic stem cell. This defective cell produces copies of itself that also carry the same mutated DNA. These abnormal cells eventually outnumber healthy cells in the marrow. In response to this process, scar (fibrous) tissue forms within the bone marrow (fibrosis) further affecting blood cell production. In primary myelofibrosis, there is overproduction of megakaryocytes, which are cells that eventually become platelets.These megakaryocytes release certain substances called cytokine, which some researchers believe may stimulate the formation of fibrous tissue within the marrow. Additional changes may affect the marrow including abnormal density or hardening of bone or marrow (osteosclerosis) and the development of too many small blood vessels (angiogenesis) within the marrow.Some people with myelofibrosis may have been exposed to tuberculosis or exposed to toxic substances, such as benzene, fluoride or phosphorus. Myelofibrosis may occur as a result of the spread of cancer (metastasis) to bone marrow from primary tumors. These tumors most often originate in the breast, prostate, kidney, lung, or adrenal or thyroid gland. Myelofibrosis may occur as a secondary characteristic of another bone marrow disorder such as polycythemia vera, multiple myeloma, certain metabolic disorders, and/or chronic myeloid leukemia. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Affects of Primary Myelofibrosis
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Primary myelofibrosis is a chronic blood disorder that affects males and females in equal numbers. It can occur at any age although it usually affects individuals more than 50 years of age. The median age at diagnosis is approximately 65. The incidence is estimated to be 1.5 cases per 100,000 people in the United States. In studies of Northern European countries, the incidence was estimated to be .5 cases per 100,000 people. The worldwide incidence is unknown. When primary myelofibrosis affects children, it is usually before three years of age. In younger children, girls are affected twice as often as boys.
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Affects of Primary Myelofibrosis. Primary myelofibrosis is a chronic blood disorder that affects males and females in equal numbers. It can occur at any age although it usually affects individuals more than 50 years of age. The median age at diagnosis is approximately 65. The incidence is estimated to be 1.5 cases per 100,000 people in the United States. In studies of Northern European countries, the incidence was estimated to be .5 cases per 100,000 people. The worldwide incidence is unknown. When primary myelofibrosis affects children, it is usually before three years of age. In younger children, girls are affected twice as often as boys.
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Related disorders of Primary Myelofibrosis
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Symptoms of the following disorders can be similar to those of primary myelofibrosis. Comparisons may be useful for a differential diagnosis.Polycythemia vera is a rare, chronic disorder involving the overproduction of blood cells in the bone marrow (myeloproliferation). The overproduction of red blood cells is most dramatic, but the production of white blood cells and platelets are also elevated in most people. Since red blood cells are overproduced in the marrow, this leads to abnormally high numbers of circulating red blood cells (red blood mass) within the blood. Consequently, the blood thickens and increases in volume, a condition called hyperviscosity. Thickened blood may not flow through smaller blood vessels properly. A variety of symptoms can occur in individuals with polycythemia vera including nonspecific symptoms such as headaches, fatigue, weakness, dizziness or itchy skin; an enlarged spleen (splenomegaly); a variety of gastrointestinal issues; and the risk of blood clot formation, which may prevent blood flow to vital organs. More than 90 percent of individuals with polycythemia vera have a mutation of the JAK2 gene. The exact role that this mutation plays in the development of polycythemia vera is not yet known. (For more information on this disorder, choose “polycythemia vera” as your search term in the Rare Disease Database.)Essential thrombocythemia (ET) is one of the myeloproliferative neoplasms (MPNs). Myeloproliferative means uncontrolled production of cells by the bone marrow. Each of the myeloproliferative neoplasms is characterized by over-production of a different, but essential, type of blood cell resulting in a high concentration of these cells in the blood. Essential thrombocythemia is characterized by overproduction of the precursor cells to blood platelets (megakaryocytes) which, in turn, leads to a vastly increased number of platelets in the blood. Platelets are specialized cells in blood essential for the normal process of clotting. In addition to over-production of platelets, other symptoms and signs of ET may include an enlarged spleen (splenomegaly); bleeding from the gut, gums and/or nose (hemorrhaging); and constricted or blocked arteries (thrombosis). As many as two-thirds of patients are without symptoms (asymptomatic) upon initial examination. Most patients present with symptoms related to small or large vessel thrombosis or minor bleeding. Presentation with a major bleeding episode is very unusual. Clots may occur in the small arteries of the toes and fingers, leading to pain, warmth, tissue death (gangrene) and/or classic erythromelalgia. Erythromelalgia refers to a syndrome of redness and burning pain in the extremities. The incidence of the thrombotic and bleeding episodes is minimized, but not eliminated, with reduction of the platelet count to normal. In some instances, this chronic disorder may be progressive, evolving relatively rarely into acute leukemia or myelofibrosis. (For more information on this disorder, choose “essential thrombocythemia” as your search term in the Rare Disease Database.)Myelodysplastic syndromes (MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some cases, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. The exact cause of MDS is unknown. There are no certain environmental risk factors. (For more information on this disorder, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.)
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Related disorders of Primary Myelofibrosis. Symptoms of the following disorders can be similar to those of primary myelofibrosis. Comparisons may be useful for a differential diagnosis.Polycythemia vera is a rare, chronic disorder involving the overproduction of blood cells in the bone marrow (myeloproliferation). The overproduction of red blood cells is most dramatic, but the production of white blood cells and platelets are also elevated in most people. Since red blood cells are overproduced in the marrow, this leads to abnormally high numbers of circulating red blood cells (red blood mass) within the blood. Consequently, the blood thickens and increases in volume, a condition called hyperviscosity. Thickened blood may not flow through smaller blood vessels properly. A variety of symptoms can occur in individuals with polycythemia vera including nonspecific symptoms such as headaches, fatigue, weakness, dizziness or itchy skin; an enlarged spleen (splenomegaly); a variety of gastrointestinal issues; and the risk of blood clot formation, which may prevent blood flow to vital organs. More than 90 percent of individuals with polycythemia vera have a mutation of the JAK2 gene. The exact role that this mutation plays in the development of polycythemia vera is not yet known. (For more information on this disorder, choose “polycythemia vera” as your search term in the Rare Disease Database.)Essential thrombocythemia (ET) is one of the myeloproliferative neoplasms (MPNs). Myeloproliferative means uncontrolled production of cells by the bone marrow. Each of the myeloproliferative neoplasms is characterized by over-production of a different, but essential, type of blood cell resulting in a high concentration of these cells in the blood. Essential thrombocythemia is characterized by overproduction of the precursor cells to blood platelets (megakaryocytes) which, in turn, leads to a vastly increased number of platelets in the blood. Platelets are specialized cells in blood essential for the normal process of clotting. In addition to over-production of platelets, other symptoms and signs of ET may include an enlarged spleen (splenomegaly); bleeding from the gut, gums and/or nose (hemorrhaging); and constricted or blocked arteries (thrombosis). As many as two-thirds of patients are without symptoms (asymptomatic) upon initial examination. Most patients present with symptoms related to small or large vessel thrombosis or minor bleeding. Presentation with a major bleeding episode is very unusual. Clots may occur in the small arteries of the toes and fingers, leading to pain, warmth, tissue death (gangrene) and/or classic erythromelalgia. Erythromelalgia refers to a syndrome of redness and burning pain in the extremities. The incidence of the thrombotic and bleeding episodes is minimized, but not eliminated, with reduction of the platelet count to normal. In some instances, this chronic disorder may be progressive, evolving relatively rarely into acute leukemia or myelofibrosis. (For more information on this disorder, choose “essential thrombocythemia” as your search term in the Rare Disease Database.)Myelodysplastic syndromes (MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some cases, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. The exact cause of MDS is unknown. There are no certain environmental risk factors. (For more information on this disorder, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.)
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Diagnosis of Primary Myelofibrosis
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Diagnosis of primary myelofibrosis may be made based upon a thorough clinical evaluation, detailed patient history, and various specialized tests. In many people, the presenting sign of the disorder is an abnormally enlarged spleen (splenomegaly) that may be detected upon routine examination or low levels of circulating red blood cells. A complete blood count (CBC) may demonstrate low levels of red blood cells or elevated levels of platelets or white blood cells. Since blood cell counts vary at different times in affected individuals, blood counts are not definitive in diagnosing primary myelofibrosis. Surgical removal and microscopic examination of bone marrow tissue (biopsy) is often used to confirm a suspected diagnosis of primary myelofibrosis.
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Diagnosis of Primary Myelofibrosis. Diagnosis of primary myelofibrosis may be made based upon a thorough clinical evaluation, detailed patient history, and various specialized tests. In many people, the presenting sign of the disorder is an abnormally enlarged spleen (splenomegaly) that may be detected upon routine examination or low levels of circulating red blood cells. A complete blood count (CBC) may demonstrate low levels of red blood cells or elevated levels of platelets or white blood cells. Since blood cell counts vary at different times in affected individuals, blood counts are not definitive in diagnosing primary myelofibrosis. Surgical removal and microscopic examination of bone marrow tissue (biopsy) is often used to confirm a suspected diagnosis of primary myelofibrosis.
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Primary Myelofibrosis
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Therapies of Primary Myelofibrosis
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Treatment
Since the cause of primary myelofibrosis is unknown, treatment is directed toward the specific symptoms present in each patient. In asymptomatic individuals, physicians may recommend that no therapy be given until symptoms appear (watch and wait). Affected individuals receive regular checkups to detect progression of the disease. Individuals may remain symptom-free for many years.Blood transfusions may be prescribed if for individuals with severe anemia. However, several medications may be able to improve red blood cells so that blood transfusions are not necessary. In some people, moderate success has been obtained using male hormones (androgens) and/or corticosteroids in an attempt to increase red blood cell production or decrease their destruction.Drugs that hinder the ability of the bone marrow to develop blood cells (myelosuppressive agents) such as hydroxyurea have been used to treat primary myelofibrosis. Busulfan may be used in individuals who do not respond to therapy with hydroxyurea. These drugs may improve some symptoms associated with primary myelofibrosis, such as abnormally high levels of white blood cells in the blood (leukocytosis), abnormally high levels of platelets in the blood (thrombocytosis), and abnormally enlarged organs (organomegaly).In some people, an abnormally enlarged spleen (splenomegaly) may cause severe pain, anemia, a low platelet count or portal hypertension. If such cases fail to respond to other forms of therapy, surgery to remove the spleen (splenomegaly) or treatment with radiation (splenic irradiation) may be recommended. In some cases, these treatments have led to temporary improvement in some of the associated symptoms of primary myelofibrosis. Both of these procedures carry risks, which are weighed against benefits in each individual.Bisphosphates such as zoledronic acid have been used to relieve bone pain and may improve blood cell production.Jakafi (ruxolitinib) was approved by the U.S. Food and Drug Administration (FDA) in 2011 for treatment of individuals with intermediate or high risk myelofibrosis, including primary myelofibrosis. This medication inhibits the JAK 1 and 2 enzymes that are involved in regulating blood and immunological functioning. In 2019, the FDA approved Inrebic (fedratinib) to treat patients with intermediate-2 or high-risk primary or secondary myelofibrosis.
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Therapies of Primary Myelofibrosis. Treatment
Since the cause of primary myelofibrosis is unknown, treatment is directed toward the specific symptoms present in each patient. In asymptomatic individuals, physicians may recommend that no therapy be given until symptoms appear (watch and wait). Affected individuals receive regular checkups to detect progression of the disease. Individuals may remain symptom-free for many years.Blood transfusions may be prescribed if for individuals with severe anemia. However, several medications may be able to improve red blood cells so that blood transfusions are not necessary. In some people, moderate success has been obtained using male hormones (androgens) and/or corticosteroids in an attempt to increase red blood cell production or decrease their destruction.Drugs that hinder the ability of the bone marrow to develop blood cells (myelosuppressive agents) such as hydroxyurea have been used to treat primary myelofibrosis. Busulfan may be used in individuals who do not respond to therapy with hydroxyurea. These drugs may improve some symptoms associated with primary myelofibrosis, such as abnormally high levels of white blood cells in the blood (leukocytosis), abnormally high levels of platelets in the blood (thrombocytosis), and abnormally enlarged organs (organomegaly).In some people, an abnormally enlarged spleen (splenomegaly) may cause severe pain, anemia, a low platelet count or portal hypertension. If such cases fail to respond to other forms of therapy, surgery to remove the spleen (splenomegaly) or treatment with radiation (splenic irradiation) may be recommended. In some cases, these treatments have led to temporary improvement in some of the associated symptoms of primary myelofibrosis. Both of these procedures carry risks, which are weighed against benefits in each individual.Bisphosphates such as zoledronic acid have been used to relieve bone pain and may improve blood cell production.Jakafi (ruxolitinib) was approved by the U.S. Food and Drug Administration (FDA) in 2011 for treatment of individuals with intermediate or high risk myelofibrosis, including primary myelofibrosis. This medication inhibits the JAK 1 and 2 enzymes that are involved in regulating blood and immunological functioning. In 2019, the FDA approved Inrebic (fedratinib) to treat patients with intermediate-2 or high-risk primary or secondary myelofibrosis.
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Primary Myelofibrosis
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Overview of Primary Orthostatic Tremor
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SummaryPrimary orthostatic tremor is a rare movement disorder characterized by a rapid tremor in the legs that occurs when standing. The tremor disappears partially or completely when an affected person is walking or sitting. Individuals with primary orthostatic tremor experience feelings of unsteadiness or imbalance. The tremor is sometimes described as causing “shaky legs” and can cause affected individuals to immediately attempt to sit or walk because of a fear of falling. In many patients, the tremors become more severe over time. Primary orthostatic tremor is a constant problem that can affect the quality of life of affected individuals. The exact cause of primary orthostatic tremor is unknown.IntroductionPrimary orthostatic tremor was first described in 1984 by Heilman. There is controversy within the medical literature regarding whether primary orthostatic tremor is a variant of essential tremor, an exaggerated physiological response to standing still or a distinct clinical entity.
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Overview of Primary Orthostatic Tremor. SummaryPrimary orthostatic tremor is a rare movement disorder characterized by a rapid tremor in the legs that occurs when standing. The tremor disappears partially or completely when an affected person is walking or sitting. Individuals with primary orthostatic tremor experience feelings of unsteadiness or imbalance. The tremor is sometimes described as causing “shaky legs” and can cause affected individuals to immediately attempt to sit or walk because of a fear of falling. In many patients, the tremors become more severe over time. Primary orthostatic tremor is a constant problem that can affect the quality of life of affected individuals. The exact cause of primary orthostatic tremor is unknown.IntroductionPrimary orthostatic tremor was first described in 1984 by Heilman. There is controversy within the medical literature regarding whether primary orthostatic tremor is a variant of essential tremor, an exaggerated physiological response to standing still or a distinct clinical entity.
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Primary Orthostatic Tremor
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Symptoms of Primary Orthostatic Tremor
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The main symptom of primary orthostatic tremor is the occurrence of a rapid tremor affecting both legs while standing. A tremor is involuntary, rhythmic contractions of various muscles. Orthostatic tremor causes feelings of “vibration”, unsteadiness or imbalance in the legs. The tremor associated with primary orthostatic tremor has such high frequency that it may not visible to the naked eye but can be palpated by touching the thighs or calves, by listening to these muscles with a stethoscope, or by electromyography. The tremor is position-specific (standing) and disappears partially or completely when an affected individual walks, sits or lies down. In many cases, the tremor becomes progressively more severe and feelings of unsteadiness become more intense. Some affected individuals can stand for several minutes before the tremor begins; others can only stand momentarily. Eventually, affected individuals may experience stiffness, weakness and, in rare cases, pain in the legs. Orthostatic tremor, despite usually becoming progressively more pronounced, does not develop into other conditions or affect other systems of the body.Some affected individuals may also have a tremor affecting the arms. In one case reported in the medical literature, overgrowth of the affected muscles (muscular hypertrophy) occurred in association with primary orthostatic tremor.
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Symptoms of Primary Orthostatic Tremor. The main symptom of primary orthostatic tremor is the occurrence of a rapid tremor affecting both legs while standing. A tremor is involuntary, rhythmic contractions of various muscles. Orthostatic tremor causes feelings of “vibration”, unsteadiness or imbalance in the legs. The tremor associated with primary orthostatic tremor has such high frequency that it may not visible to the naked eye but can be palpated by touching the thighs or calves, by listening to these muscles with a stethoscope, or by electromyography. The tremor is position-specific (standing) and disappears partially or completely when an affected individual walks, sits or lies down. In many cases, the tremor becomes progressively more severe and feelings of unsteadiness become more intense. Some affected individuals can stand for several minutes before the tremor begins; others can only stand momentarily. Eventually, affected individuals may experience stiffness, weakness and, in rare cases, pain in the legs. Orthostatic tremor, despite usually becoming progressively more pronounced, does not develop into other conditions or affect other systems of the body.Some affected individuals may also have a tremor affecting the arms. In one case reported in the medical literature, overgrowth of the affected muscles (muscular hypertrophy) occurred in association with primary orthostatic tremor.
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Causes of Primary Orthostatic Tremor
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The exact cause of primary orthostatic tremor is unknown (idiopathic). Some researchers believe that the disorder is a variant or subtype of essential tremor. Other researchers believe the disorder is a separate entity. Some individuals with primary orthostatic tremor have had a family history of tremor suggesting that in these cases genetic factors may play a role in the development of the disorder. However, more research is necessary to determine the exact, underlying cause(s) of primary orthostatic tremor.
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Causes of Primary Orthostatic Tremor. The exact cause of primary orthostatic tremor is unknown (idiopathic). Some researchers believe that the disorder is a variant or subtype of essential tremor. Other researchers believe the disorder is a separate entity. Some individuals with primary orthostatic tremor have had a family history of tremor suggesting that in these cases genetic factors may play a role in the development of the disorder. However, more research is necessary to determine the exact, underlying cause(s) of primary orthostatic tremor.
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Primary Orthostatic Tremor
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Affects of Primary Orthostatic Tremor
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Primary orthostatic tremor affects females slightly more frequently than males. Because many affected individuals of primary orthostatic tremor often go unrecognized or misdiagnosed, the disorder is believed by some to be under-diagnosed, making it difficult to determine the true frequency of this disorder in the general population.
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Affects of Primary Orthostatic Tremor. Primary orthostatic tremor affects females slightly more frequently than males. Because many affected individuals of primary orthostatic tremor often go unrecognized or misdiagnosed, the disorder is believed by some to be under-diagnosed, making it difficult to determine the true frequency of this disorder in the general population.
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Related disorders of Primary Orthostatic Tremor
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Tremors, involuntary quivering, or trembling movements can occur in association with many disorders. They may occur at any age and may be rhythmic or intermittent. Tremors mainly occur in disorders of the central nervous system, and especially in disorders of the cerebellum or basal ganglia. Examples of cerebellar diseases might be tumors of the cerebellum, multiple sclerosis involving the cerebellum, or a degenerative disease such as spinocerebellar degeneration. Examples of disorders of the basal ganglia include Parkinson’s disease (discussed in more detail below), Wilson’s disease, and many other rare and common disorders. Tremor may also occur as a result of anxiety, medication, or be of unknown cause (idiopathic).Orthostatic myoclonus is a rare condition that is similar to primary orthostatic tremor, but myoclonus refers to sudden, involuntary jerking of a muscle or group of muscles caused by muscle contraction or relaxation. Orthostatic myoclonus is characterized by slowly progressive unsteadiness when standing that is relieved by walking or sitting. Some affected individuals experienced bouncing stance and recurrent falls. More research is necessary to determine when orthostatic myoclonus and primary orthostatic tremor are the same disorder or similar, yet distinct, disorders. In rare cases, orthostatic myoclonus may be associated with underlying neoplasm.Essential tremor is a common movement disorder characterized by an involuntary rhythmic tremor of a body part or parts, primarily the hands, arms, and neck.. In many affected individuals, upper limb tremor may occur as an isolated finding. However, in others, tremor may gradually involve other anatomic regions, such as the head, voice, and tongue, leading to a quiver in the voice or difficulties articulating speech. Less commonly, tremor may affect muscles of the trunk or legs. Patients with essential tremor involving the legs are often misdiagnosed as having orthostatic tremor, but in the latter condition the tremor is much more frequent (14-6Hz) than in essential tremor (4-12Hz). In individuals with the condition, tremor tends to occur while voluntarily maintaining a fixed posture against gravity (“postural tremor”) or while performing certain goal-directed movements (“kinetic intention tremor”). Although tremor is typically absent with rest–i.e., when the affected muscle is not voluntary activated–some individuals with advanced disease may develop resting tremors and some may even evolve into Parkinson’s disease. Essential tremor may appear to occur randomly for unknown reasons (sporadically) or be transmitted as an autosomal dominant trait. Researchers suggest that changes (mutations) of different genes may be responsible for the disorder (genetic heterogeneity). (For more information on this disorder, choose “essential tremor” as your search term in the Rare Disease Database.)Parkinson’s disease is a common slowly progressive neurologic condition characterized by involuntary trembling (tremor), muscular stiffness or inflexibility (rigidity), slowness of movement and difficulty carrying out voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal in the brain. Parkinsonian symptoms can also develop secondary to degenerative diseases such as multiple system atrophy, hydrocephalus (a condition in which areas of the brain accumulate excessive fluids, resulting in an increase in pressure on the brain), head trauma, inflammation of the brain (encephalitis), circulatory disturbances (infarcts) or tumors deep within the cerebral hemispheres involving the area just above the brain stem (basal ganglia), or exposure to certain drugs and toxins. Parkinson’s disease is slowly progressive and may not become incapacitating for many years.
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Related disorders of Primary Orthostatic Tremor. Tremors, involuntary quivering, or trembling movements can occur in association with many disorders. They may occur at any age and may be rhythmic or intermittent. Tremors mainly occur in disorders of the central nervous system, and especially in disorders of the cerebellum or basal ganglia. Examples of cerebellar diseases might be tumors of the cerebellum, multiple sclerosis involving the cerebellum, or a degenerative disease such as spinocerebellar degeneration. Examples of disorders of the basal ganglia include Parkinson’s disease (discussed in more detail below), Wilson’s disease, and many other rare and common disorders. Tremor may also occur as a result of anxiety, medication, or be of unknown cause (idiopathic).Orthostatic myoclonus is a rare condition that is similar to primary orthostatic tremor, but myoclonus refers to sudden, involuntary jerking of a muscle or group of muscles caused by muscle contraction or relaxation. Orthostatic myoclonus is characterized by slowly progressive unsteadiness when standing that is relieved by walking or sitting. Some affected individuals experienced bouncing stance and recurrent falls. More research is necessary to determine when orthostatic myoclonus and primary orthostatic tremor are the same disorder or similar, yet distinct, disorders. In rare cases, orthostatic myoclonus may be associated with underlying neoplasm.Essential tremor is a common movement disorder characterized by an involuntary rhythmic tremor of a body part or parts, primarily the hands, arms, and neck.. In many affected individuals, upper limb tremor may occur as an isolated finding. However, in others, tremor may gradually involve other anatomic regions, such as the head, voice, and tongue, leading to a quiver in the voice or difficulties articulating speech. Less commonly, tremor may affect muscles of the trunk or legs. Patients with essential tremor involving the legs are often misdiagnosed as having orthostatic tremor, but in the latter condition the tremor is much more frequent (14-6Hz) than in essential tremor (4-12Hz). In individuals with the condition, tremor tends to occur while voluntarily maintaining a fixed posture against gravity (“postural tremor”) or while performing certain goal-directed movements (“kinetic intention tremor”). Although tremor is typically absent with rest–i.e., when the affected muscle is not voluntary activated–some individuals with advanced disease may develop resting tremors and some may even evolve into Parkinson’s disease. Essential tremor may appear to occur randomly for unknown reasons (sporadically) or be transmitted as an autosomal dominant trait. Researchers suggest that changes (mutations) of different genes may be responsible for the disorder (genetic heterogeneity). (For more information on this disorder, choose “essential tremor” as your search term in the Rare Disease Database.)Parkinson’s disease is a common slowly progressive neurologic condition characterized by involuntary trembling (tremor), muscular stiffness or inflexibility (rigidity), slowness of movement and difficulty carrying out voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal in the brain. Parkinsonian symptoms can also develop secondary to degenerative diseases such as multiple system atrophy, hydrocephalus (a condition in which areas of the brain accumulate excessive fluids, resulting in an increase in pressure on the brain), head trauma, inflammation of the brain (encephalitis), circulatory disturbances (infarcts) or tumors deep within the cerebral hemispheres involving the area just above the brain stem (basal ganglia), or exposure to certain drugs and toxins. Parkinson’s disease is slowly progressive and may not become incapacitating for many years.
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Primary Orthostatic Tremor
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Diagnosis of Primary Orthostatic Tremor
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A diagnosis of primary orthostatic tremor is based upon a thorough clinical evaluation, a detailed patient history, and supported by specialized tests such as a surface electromyogram (EMG). Misdiagnosis is common. Many individuals may be initially suspected of having a psychogenic disorder (a disorder caused by a psychological cause rather than a physical one).Clinical Testing and Work-UpA surface EMG measures the electrical impulses of muscles at rest and during contraction. A surface electromyogram can often rapidly establish a diagnosis of primary orthostatic tremor by reproducing the characteristic tremor in the legs. With a surface electromyogram electrodes are placed on the skin overlying the muscles that are to be tested.
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Diagnosis of Primary Orthostatic Tremor. A diagnosis of primary orthostatic tremor is based upon a thorough clinical evaluation, a detailed patient history, and supported by specialized tests such as a surface electromyogram (EMG). Misdiagnosis is common. Many individuals may be initially suspected of having a psychogenic disorder (a disorder caused by a psychological cause rather than a physical one).Clinical Testing and Work-UpA surface EMG measures the electrical impulses of muscles at rest and during contraction. A surface electromyogram can often rapidly establish a diagnosis of primary orthostatic tremor by reproducing the characteristic tremor in the legs. With a surface electromyogram electrodes are placed on the skin overlying the muscles that are to be tested.
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Primary Orthostatic Tremor
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Therapies of Primary Orthostatic Tremor
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TreatmentVarious medications may help relieve symptoms associated with primary orthostatic tremor. Most affected individuals are treated with a drug called clonazepam (Klonopin). However, some affected individuals do not respond to this first-line drug treatment.Some affected individuals responded favorably after being treated with an anti-seizure (anticonvulsant) drug called gabapentin (Neurontin). A very small double-blind, placebo controlled study demonstrated that affected individuals experienced a sustained improvement when treated with the drug. Authors of the study suggested that gabapentin be considered a first-line therapy for individuals with primary orthostatic tremor.Additional drug therapies that have been used to treat individuals with primary orthostatic tremor include primidone (Mysoline), chlordiazepoxide (Librium), pregabalin (Lyrica), pramipexole (Mirapex), phenobarbital and valproic acid (Depakote). Drugs commonly used to treat people with Parkinson’s disease (levodopa or pramipexole) may also be prescribed for individuals with primary orthostatic tremor. Botulinum toxin injections into the leg muscles may be helpful. Surgical treatments such as spinal cord stimulation or deep brain stimulation should be reserved only for the most disabling cases that do not respond adequately to medical therapy. Additional treatment is symptomatic and supportive.
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Therapies of Primary Orthostatic Tremor. TreatmentVarious medications may help relieve symptoms associated with primary orthostatic tremor. Most affected individuals are treated with a drug called clonazepam (Klonopin). However, some affected individuals do not respond to this first-line drug treatment.Some affected individuals responded favorably after being treated with an anti-seizure (anticonvulsant) drug called gabapentin (Neurontin). A very small double-blind, placebo controlled study demonstrated that affected individuals experienced a sustained improvement when treated with the drug. Authors of the study suggested that gabapentin be considered a first-line therapy for individuals with primary orthostatic tremor.Additional drug therapies that have been used to treat individuals with primary orthostatic tremor include primidone (Mysoline), chlordiazepoxide (Librium), pregabalin (Lyrica), pramipexole (Mirapex), phenobarbital and valproic acid (Depakote). Drugs commonly used to treat people with Parkinson’s disease (levodopa or pramipexole) may also be prescribed for individuals with primary orthostatic tremor. Botulinum toxin injections into the leg muscles may be helpful. Surgical treatments such as spinal cord stimulation or deep brain stimulation should be reserved only for the most disabling cases that do not respond adequately to medical therapy. Additional treatment is symptomatic and supportive.
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Primary Orthostatic Tremor
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Overview of Primary Sclerosing Cholangitis
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SummaryPrimary sclerosing cholangitis (PSC) is a rare progressive disorder characterized by inflammation, thickening, and abnormal formation of fibrous tissue (fibrosis) within the passages that carry bile from the liver (bile ducts). Both the bile ducts within the liver (intrahepatic) and outside the liver (extrahepatic) are affected. This often results in the obstruction or interruption of bile flow from the liver (cholestasis). Symptoms associated with PSC include fatigue and itching (pruritus), followed by yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Affected individuals may also have dark urine, light-colored stools, abdominal pain, and/or nausea. In some cases, the liver may also become abnormally enlarged (hepatomegaly). Scarring of the liver (cirrhosis) eventually develops and many individuals will ultimately require a liver transplant. According to the medical literature, approximately 60 to 80 percent of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis. The relationship between these disorders and the exact cause of PSC are not fully understood.IntroductionPSC is a complex disorder and the cause (etiology) and underlying manner the disease develops (pathogenesis) are not fully understood. PSC was first described in the medical literature in 1867. Some researchers believe that PSC represents a group of disorders or a disorder with several distinct subtypes (e.g. PSC with IBD or without IBD). It is likely that PSC may have different underlying causes in different individuals. PSC is a rapidly evolving disease concept and information about PSC is constantly changing and emerging as researchers work to better understand this disorder.
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Overview of Primary Sclerosing Cholangitis. SummaryPrimary sclerosing cholangitis (PSC) is a rare progressive disorder characterized by inflammation, thickening, and abnormal formation of fibrous tissue (fibrosis) within the passages that carry bile from the liver (bile ducts). Both the bile ducts within the liver (intrahepatic) and outside the liver (extrahepatic) are affected. This often results in the obstruction or interruption of bile flow from the liver (cholestasis). Symptoms associated with PSC include fatigue and itching (pruritus), followed by yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Affected individuals may also have dark urine, light-colored stools, abdominal pain, and/or nausea. In some cases, the liver may also become abnormally enlarged (hepatomegaly). Scarring of the liver (cirrhosis) eventually develops and many individuals will ultimately require a liver transplant. According to the medical literature, approximately 60 to 80 percent of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis. The relationship between these disorders and the exact cause of PSC are not fully understood.IntroductionPSC is a complex disorder and the cause (etiology) and underlying manner the disease develops (pathogenesis) are not fully understood. PSC was first described in the medical literature in 1867. Some researchers believe that PSC represents a group of disorders or a disorder with several distinct subtypes (e.g. PSC with IBD or without IBD). It is likely that PSC may have different underlying causes in different individuals. PSC is a rapidly evolving disease concept and information about PSC is constantly changing and emerging as researchers work to better understand this disorder.
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Primary Sclerosing Cholangitis
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Symptoms of Primary Sclerosing Cholangitis
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Primary sclerosing cholangitis primarily involves the bile ducts. The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body, it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and helps eliminate excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.PSC is characterized by episodes of interrupted or obstructed bile flow from the liver (cholestasis), resulting from inflammation, thickening, and/or abnormal formation of fibrous tissue (fibrosis) within the bile ducts. The specific symptoms, progression and severity of PSC can vary greatly from one individual to another. Initially, many affected individuals may not have any noticeable symptoms (asymptomatic) or only mild symptoms. Some individuals will only display mild symptoms for many years.Common initial symptoms of PSC are fatigue, abdominal discomfort, and itching (pruritus). Itching can potentially be severe and even disabling. When the flow of bile from the liver is blocked, the bile may be absorbed into the bloodstream, resulting in yellowing of the skin, mucous membranes, and whites of the eyes (obstructive jaundice). Additional symptoms include a general feeling of ill health (malaise); abdominal pain, especially the upper right portion of the abdomen; nausea; dark urine; light-colored stools; unintended weight loss, and/or abnormal enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly).Some individuals may develop deficiency of certain vitamins, including vitamins A, D, E and K. These are fat-soluble vitamins. Bile normally helps fat to be broken down and these vitamins to be absorbed by the body.Some individuals with chronic liver disease develop metabolic bone disease, which may be referred to as hepatic osteodystrophy. Affected individuals can eventually develop osteoporosis, a condition in which the bones become brittle and fragile. Individuals with osteoporosis are prone to repeated fractures. In severe cases, fractures may occur from even mild stresses such as coughing. Bones in the wrist, hips and spine are often affected.In some cases, affected individuals may experience episodes of fever, chills, and night sweats resulting from infection of the bile ducts (bacterial cholangitis). In addition, PSC may progress to cause scarring and damage to the liver (cirrhosis) and increased blood pressure in the veins carrying blood from the gastrointestinal (GI) tract back to the heart through the liver (portal hypertension). Portal hypertension can result in serious complications including fluid accumulation in the stomach (ascites), bleeding from blood vessels within the esophagus, stomach and rectum, and hepatic encephalopathy, a brain disorder that ranges from a subtle condition with no outward signs or symptoms to a severe condition that can cause severe complications, such as confusion and coma.As individuals with PSC age, they often eventually develop life-threatening complications such as liver (hepatic) failure. Individuals with PSC are at a greater risk than the general population of developing a form of cancer that affects the bile ducts (cholangiocarcinoma). Approximately 8-15% of affected individuals eventually develop cholangiocarcinoma. Affected individuals are also at risk of developing gallbladder cancer.In approximately 60 to 80 percent of cases, individuals with PSC also have ulcerative colitis, an inflammatory bowel disease (IBD) of unknown cause that is characterized by chronic inflammation and ulceration of the lining of the major portion of the large intestine (colon). PSC is also associated with Crohn’s disease, another form of IBD. These conditions can be mild or even “silent” causing no apparent symptoms (asymptomatic). Individuals with PSC and IBD (and particularly ulcerative colitis) or Crohn’s disease are at a greater risk of developing colon cancer compared to individuals with only one of these conditions or to the general population.In addition to IBD, numerous autoimmune or immune-mediated disorders have been reported to occur in association with PSC. Such disorders include sarcoidosis, thyroid disease, Peyronie’s disease, retroperitoneal fibrosis, psoriasis, rheumatoid arthritis, Celiac disease, Sjogren’s syndrome, chronic pancreatitis, lupus, diabetes mellitus, Wegener’s granulomatosis, pyoderma gangrenosum, Grave’s disease, Langerhans cell histiocytosis and certain immunodeficiency disorders. The exact relationship between these disorders and PSC is unknown. It is possible that PSC develops as a secondary condition to some of these disorders. (For more information on these disorders, choose exact disorder name as your search term in the Rare Disease Database.)
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Symptoms of Primary Sclerosing Cholangitis. Primary sclerosing cholangitis primarily involves the bile ducts. The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body, it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and helps eliminate excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.PSC is characterized by episodes of interrupted or obstructed bile flow from the liver (cholestasis), resulting from inflammation, thickening, and/or abnormal formation of fibrous tissue (fibrosis) within the bile ducts. The specific symptoms, progression and severity of PSC can vary greatly from one individual to another. Initially, many affected individuals may not have any noticeable symptoms (asymptomatic) or only mild symptoms. Some individuals will only display mild symptoms for many years.Common initial symptoms of PSC are fatigue, abdominal discomfort, and itching (pruritus). Itching can potentially be severe and even disabling. When the flow of bile from the liver is blocked, the bile may be absorbed into the bloodstream, resulting in yellowing of the skin, mucous membranes, and whites of the eyes (obstructive jaundice). Additional symptoms include a general feeling of ill health (malaise); abdominal pain, especially the upper right portion of the abdomen; nausea; dark urine; light-colored stools; unintended weight loss, and/or abnormal enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly).Some individuals may develop deficiency of certain vitamins, including vitamins A, D, E and K. These are fat-soluble vitamins. Bile normally helps fat to be broken down and these vitamins to be absorbed by the body.Some individuals with chronic liver disease develop metabolic bone disease, which may be referred to as hepatic osteodystrophy. Affected individuals can eventually develop osteoporosis, a condition in which the bones become brittle and fragile. Individuals with osteoporosis are prone to repeated fractures. In severe cases, fractures may occur from even mild stresses such as coughing. Bones in the wrist, hips and spine are often affected.In some cases, affected individuals may experience episodes of fever, chills, and night sweats resulting from infection of the bile ducts (bacterial cholangitis). In addition, PSC may progress to cause scarring and damage to the liver (cirrhosis) and increased blood pressure in the veins carrying blood from the gastrointestinal (GI) tract back to the heart through the liver (portal hypertension). Portal hypertension can result in serious complications including fluid accumulation in the stomach (ascites), bleeding from blood vessels within the esophagus, stomach and rectum, and hepatic encephalopathy, a brain disorder that ranges from a subtle condition with no outward signs or symptoms to a severe condition that can cause severe complications, such as confusion and coma.As individuals with PSC age, they often eventually develop life-threatening complications such as liver (hepatic) failure. Individuals with PSC are at a greater risk than the general population of developing a form of cancer that affects the bile ducts (cholangiocarcinoma). Approximately 8-15% of affected individuals eventually develop cholangiocarcinoma. Affected individuals are also at risk of developing gallbladder cancer.In approximately 60 to 80 percent of cases, individuals with PSC also have ulcerative colitis, an inflammatory bowel disease (IBD) of unknown cause that is characterized by chronic inflammation and ulceration of the lining of the major portion of the large intestine (colon). PSC is also associated with Crohn’s disease, another form of IBD. These conditions can be mild or even “silent” causing no apparent symptoms (asymptomatic). Individuals with PSC and IBD (and particularly ulcerative colitis) or Crohn’s disease are at a greater risk of developing colon cancer compared to individuals with only one of these conditions or to the general population.In addition to IBD, numerous autoimmune or immune-mediated disorders have been reported to occur in association with PSC. Such disorders include sarcoidosis, thyroid disease, Peyronie’s disease, retroperitoneal fibrosis, psoriasis, rheumatoid arthritis, Celiac disease, Sjogren’s syndrome, chronic pancreatitis, lupus, diabetes mellitus, Wegener’s granulomatosis, pyoderma gangrenosum, Grave’s disease, Langerhans cell histiocytosis and certain immunodeficiency disorders. The exact relationship between these disorders and PSC is unknown. It is possible that PSC develops as a secondary condition to some of these disorders. (For more information on these disorders, choose exact disorder name as your search term in the Rare Disease Database.)
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Primary Sclerosing Cholangitis
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Causes of Primary Sclerosing Cholangitis
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Primary sclerosing cholangitis is a multifactorial disorder, which means that several different factors such as genetic, environmental and immunologic ones occurring in combination are necessary for the development of the disorder. The specific factors involved in the development of PSC have not been conclusively identified.Researchers believe that the disorder results due to a nonspecific triggering event that causes an abnormal immune system response, specifically an abnormal allergic or inflammatory reaction (immune-mediated disorder) or because of the immune system mistakenly attacking healthy tissue (autoimmunity) in people who are genetically susceptible to such a reaction. This abnormal response ultimately causes progressive damage to the bile ducts. The triggering event is most likely an infectious or toxic agent.Genetics plays an important role in the development of PSC and the incidence of the disorder among first-degree relatives, especially siblings, is higher than otherwise would be expected. Researchers have discovered sixteen different genetic regions that are associated with the disorder. Certain genes in these genetic areas may predispose affected individuals to developing PSC. A genetic predisposition means that a person carries a gene or gene(s) for a disease, but it may not be expressed unless something in the environment triggers the disease. Some, but not all, of these gene regions involve a genetically determined human leukocyte antigen or HLA. HLAs are proteins that play an important role in the body’s immune system. Several of the genetic areas associated with PSC are also associated with inflammatory bowel disease (IBD).There are several theories as to the underlying cause and pathogenesis of PSC including the leaky gut syndrome for individuals with PSC and IBD or the toxic bile theory, which has been established in mouse models of the disease, but has not been established in studies on people with PSC. No theory explains all cases of PSC, which further suggests that PSC has distinct subtypes or represents a group of similar disorders. More research is necessary to understand the underlying cause and various mechanisms that ultimately result in the development of PSC, and to create a classification system defining specific subtypes of the disorder.
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Causes of Primary Sclerosing Cholangitis. Primary sclerosing cholangitis is a multifactorial disorder, which means that several different factors such as genetic, environmental and immunologic ones occurring in combination are necessary for the development of the disorder. The specific factors involved in the development of PSC have not been conclusively identified.Researchers believe that the disorder results due to a nonspecific triggering event that causes an abnormal immune system response, specifically an abnormal allergic or inflammatory reaction (immune-mediated disorder) or because of the immune system mistakenly attacking healthy tissue (autoimmunity) in people who are genetically susceptible to such a reaction. This abnormal response ultimately causes progressive damage to the bile ducts. The triggering event is most likely an infectious or toxic agent.Genetics plays an important role in the development of PSC and the incidence of the disorder among first-degree relatives, especially siblings, is higher than otherwise would be expected. Researchers have discovered sixteen different genetic regions that are associated with the disorder. Certain genes in these genetic areas may predispose affected individuals to developing PSC. A genetic predisposition means that a person carries a gene or gene(s) for a disease, but it may not be expressed unless something in the environment triggers the disease. Some, but not all, of these gene regions involve a genetically determined human leukocyte antigen or HLA. HLAs are proteins that play an important role in the body’s immune system. Several of the genetic areas associated with PSC are also associated with inflammatory bowel disease (IBD).There are several theories as to the underlying cause and pathogenesis of PSC including the leaky gut syndrome for individuals with PSC and IBD or the toxic bile theory, which has been established in mouse models of the disease, but has not been established in studies on people with PSC. No theory explains all cases of PSC, which further suggests that PSC has distinct subtypes or represents a group of similar disorders. More research is necessary to understand the underlying cause and various mechanisms that ultimately result in the development of PSC, and to create a classification system defining specific subtypes of the disorder.
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Primary Sclerosing Cholangitis
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Affects of Primary Sclerosing Cholangitis
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Primary sclerosing cholangitis is a rare disorder that affects males twice as often as females. Although it may affect individuals of any age, the disorder most often occurs in middle-aged adults. The exact incidence and prevalence of the disorder is unknown. One estimate places the incidence at approximately 1 person per each 100,000 in the general population in the United States or Europe. Some studies suggest that the incidence of PSC is increasing. PSC is one of the leading reasons people require a liver transplant in the United States. In Nordic countries, PSC is the number one cause for a liver transplant.
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Affects of Primary Sclerosing Cholangitis. Primary sclerosing cholangitis is a rare disorder that affects males twice as often as females. Although it may affect individuals of any age, the disorder most often occurs in middle-aged adults. The exact incidence and prevalence of the disorder is unknown. One estimate places the incidence at approximately 1 person per each 100,000 in the general population in the United States or Europe. Some studies suggest that the incidence of PSC is increasing. PSC is one of the leading reasons people require a liver transplant in the United States. In Nordic countries, PSC is the number one cause for a liver transplant.
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Primary Sclerosing Cholangitis
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Related disorders of Primary Sclerosing Cholangitis
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Symptoms of the following disorders can be similar to primary sclerosing cholangitis. Comparisons may be useful for a differential diagnosis:Primary biliary cholangitis (PBC) is a rare liver disorder that primarily affects females and typically becomes apparent during middle age. It is characterized by yellow discoloration of the skin (jaundice) associated with obstruction and inflammation of the bile ducts (cholestasis). Additional symptoms include fatigue, pain in the upper right portion of the abdomen, diarrhea, itching (pruritus), dry eyes, dry mouth, swelling of the feet and ankles, and the formation of small fatty deposits (xanthomas) on the skin around the eyes or in the skin creases of the palms, soles, elbows or knees. In some cases, serious complications can develop including cirrhosis, portal hypertension, osteoporosis, and vitamin deficiencies. Affected individuals are at risk of developing liver cancer. Although the exact cause of PBC is unknown, various factors including immunologic, genetic, and environmental ones are believed to play a role in the development of the disorder. (For more information on this disorder, choose “primary biliary cholangitis” as your search term in the Rare Disease Database.)Autoimmune hepatitis is a liver disease that occurs when the body’s immune system mistakenly attacks liver tissue. The reason why the body attacks healthy tissue is unknown. Symptoms can include those commonly associated with liver disease including fatigue, nausea, vomiting, itching, abdominal pain, jaundice, loss of appetite, dark urine, skin rashes, and an abnormally enlarged liver. Autoimmune hepatitis may be mild or severe and can develop slowly over time or rapidly. Untreated, the disorder can eventually progress to cirrhosis and liver failure. In many cases, if treated early enough, immunosuppressive drugs can manage the disorder. Although the exact cause of autoimmune hepatitis is unknown, multiple factors including environmental, immunologic and genetic ones are suspected to play a role.When features of autoimmune hepatitis occur with either PSC or PBC, this is defined as overlap. Some researchers believe that, despite overlapping symptoms, a primary diagnosis of one of the disorders should be made in almost every case.Small duct primary sclerosing cholangitis is a variant of PSC in which affected individuals have abnormal blood tests and a liver biopsy that reveals features that are consistent with a diagnosis of PSC. However, these individuals have normal findings on more sensitive tests such as magnetic resonance cholangiopancreatography. This form of PSC is associated with fewer, milder symptoms than individuals with classic PSC. Individuals with small duct PSC often have IBD as well. Small duct PSC accounts for approximately 6%-16% of all cases of PSC. Some individuals will eventually develop classic PSC and end stage liver disease.Secondary sclerosing cholangitis (SSC) is a general term for a group of disorders characterized by sclerosing cholangitis, but that are caused by a known pathological process. The clinical features of SSC are extremely similar to those seen in PSC. Conditions that can cause SSC include those that result in obstruction of the bile ducts such as a tumor, gallstones or various congenital abnormalities. SSC can also develop as a consequence of surgery or injury due to lack of blood flow (ischemia) to the liver and bile ducts as may be associated with systemic vasculitis, radiation injury, or critically-ill patients. Infections can also cause SSC including cytomegalovirus, parasitic infections (e.g. liver flukes), or bacterial infections such as recurrent pyogenic cholangitis.IgG4-associated sclerosing cholangitis is a disorder characterized signs and symptoms that are extremely similar to classic PSC. However, these individuals have elevated levels of immunoglobulin G4 in blood serum. An immunoglobulin is a specialized protein of the immune system that functions as an antibody to protect the body from foreign substances such as bacteria. Unlike individuals with classic PSC, individuals with IgG4-associated sclerosing cholangitis respond to treatment with corticosteroids. In addition, IgG4-associated sclerosing cholangitis is rarely associated with IBD and is commonly associated with inflammation of the pancreas (pancreatitis). Some individuals with classic PSC also have elevated levels of immunoglobulin G4. Consequently, some physicians consider this disorder to be a variant of PSC, while others consider it a different and distinct disorder. Although IgG4-associated sclerosing cholangitis responds to treatment with corticosteroids, relapse is common.
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Related disorders of Primary Sclerosing Cholangitis. Symptoms of the following disorders can be similar to primary sclerosing cholangitis. Comparisons may be useful for a differential diagnosis:Primary biliary cholangitis (PBC) is a rare liver disorder that primarily affects females and typically becomes apparent during middle age. It is characterized by yellow discoloration of the skin (jaundice) associated with obstruction and inflammation of the bile ducts (cholestasis). Additional symptoms include fatigue, pain in the upper right portion of the abdomen, diarrhea, itching (pruritus), dry eyes, dry mouth, swelling of the feet and ankles, and the formation of small fatty deposits (xanthomas) on the skin around the eyes or in the skin creases of the palms, soles, elbows or knees. In some cases, serious complications can develop including cirrhosis, portal hypertension, osteoporosis, and vitamin deficiencies. Affected individuals are at risk of developing liver cancer. Although the exact cause of PBC is unknown, various factors including immunologic, genetic, and environmental ones are believed to play a role in the development of the disorder. (For more information on this disorder, choose “primary biliary cholangitis” as your search term in the Rare Disease Database.)Autoimmune hepatitis is a liver disease that occurs when the body’s immune system mistakenly attacks liver tissue. The reason why the body attacks healthy tissue is unknown. Symptoms can include those commonly associated with liver disease including fatigue, nausea, vomiting, itching, abdominal pain, jaundice, loss of appetite, dark urine, skin rashes, and an abnormally enlarged liver. Autoimmune hepatitis may be mild or severe and can develop slowly over time or rapidly. Untreated, the disorder can eventually progress to cirrhosis and liver failure. In many cases, if treated early enough, immunosuppressive drugs can manage the disorder. Although the exact cause of autoimmune hepatitis is unknown, multiple factors including environmental, immunologic and genetic ones are suspected to play a role.When features of autoimmune hepatitis occur with either PSC or PBC, this is defined as overlap. Some researchers believe that, despite overlapping symptoms, a primary diagnosis of one of the disorders should be made in almost every case.Small duct primary sclerosing cholangitis is a variant of PSC in which affected individuals have abnormal blood tests and a liver biopsy that reveals features that are consistent with a diagnosis of PSC. However, these individuals have normal findings on more sensitive tests such as magnetic resonance cholangiopancreatography. This form of PSC is associated with fewer, milder symptoms than individuals with classic PSC. Individuals with small duct PSC often have IBD as well. Small duct PSC accounts for approximately 6%-16% of all cases of PSC. Some individuals will eventually develop classic PSC and end stage liver disease.Secondary sclerosing cholangitis (SSC) is a general term for a group of disorders characterized by sclerosing cholangitis, but that are caused by a known pathological process. The clinical features of SSC are extremely similar to those seen in PSC. Conditions that can cause SSC include those that result in obstruction of the bile ducts such as a tumor, gallstones or various congenital abnormalities. SSC can also develop as a consequence of surgery or injury due to lack of blood flow (ischemia) to the liver and bile ducts as may be associated with systemic vasculitis, radiation injury, or critically-ill patients. Infections can also cause SSC including cytomegalovirus, parasitic infections (e.g. liver flukes), or bacterial infections such as recurrent pyogenic cholangitis.IgG4-associated sclerosing cholangitis is a disorder characterized signs and symptoms that are extremely similar to classic PSC. However, these individuals have elevated levels of immunoglobulin G4 in blood serum. An immunoglobulin is a specialized protein of the immune system that functions as an antibody to protect the body from foreign substances such as bacteria. Unlike individuals with classic PSC, individuals with IgG4-associated sclerosing cholangitis respond to treatment with corticosteroids. In addition, IgG4-associated sclerosing cholangitis is rarely associated with IBD and is commonly associated with inflammation of the pancreas (pancreatitis). Some individuals with classic PSC also have elevated levels of immunoglobulin G4. Consequently, some physicians consider this disorder to be a variant of PSC, while others consider it a different and distinct disorder. Although IgG4-associated sclerosing cholangitis responds to treatment with corticosteroids, relapse is common.
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Primary Sclerosing Cholangitis
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Diagnosis of Primary Sclerosing Cholangitis
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A diagnosis of primary sclerosing cholangitis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and a variety of specialized tests.Clinical Testing and Work-Up
Blood tests called liver function tests may be performed to measure the activity and levels of certain chemicals produced by the liver. Certain liver enzymes may be elevated including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltranspeptidase. Elevation of these enzymes is indicative of liver disease, but is nonspecific to PSC.Additional blood tests to detect other substances (e.g. autoantibodies) may also be performed to aid in diagnosing PSC or to rule out other conditions.
Specialized imaging tests may also be used to help obtain a diagnosis of PSC. A magnetic resonance cholangiopancreatography or MRCP is a noninvasive test used to evaluate both the intrahepatic and extrahepatic bile ducts. This exam employs MRI, an imaging technique that uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.In the past an exam called endoscopic retrograde cholangiopancreatography or ERCP was used to help diagnose PSC. This exam involves inserting a thin flexible tube (endoscope) into the mouth and down through the esophagus and stomach eventually reaching the bile ducts. A contrast dye is injected into the bile ducts and an x-ray is taken to evaluate the health and function of the bile ducts.A liver biopsy, which involves the surgical removal and microscopic examination, of a small sample of liver tissue, may be performed to evaluate the liver and determine how far PSC has progressed.Some physicians recommended a colonoscopy to evaluate the health and function of the bowels because of the high association of PSC with inflammatory bowel disease and colon cancer. Cross sectional imaging of the liver is recommended by some providers at 6 – 12 month intervals because of the high risk of hepatobiliary cancers.
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Diagnosis of Primary Sclerosing Cholangitis. A diagnosis of primary sclerosing cholangitis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and a variety of specialized tests.Clinical Testing and Work-Up
Blood tests called liver function tests may be performed to measure the activity and levels of certain chemicals produced by the liver. Certain liver enzymes may be elevated including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltranspeptidase. Elevation of these enzymes is indicative of liver disease, but is nonspecific to PSC.Additional blood tests to detect other substances (e.g. autoantibodies) may also be performed to aid in diagnosing PSC or to rule out other conditions.
Specialized imaging tests may also be used to help obtain a diagnosis of PSC. A magnetic resonance cholangiopancreatography or MRCP is a noninvasive test used to evaluate both the intrahepatic and extrahepatic bile ducts. This exam employs MRI, an imaging technique that uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.In the past an exam called endoscopic retrograde cholangiopancreatography or ERCP was used to help diagnose PSC. This exam involves inserting a thin flexible tube (endoscope) into the mouth and down through the esophagus and stomach eventually reaching the bile ducts. A contrast dye is injected into the bile ducts and an x-ray is taken to evaluate the health and function of the bile ducts.A liver biopsy, which involves the surgical removal and microscopic examination, of a small sample of liver tissue, may be performed to evaluate the liver and determine how far PSC has progressed.Some physicians recommended a colonoscopy to evaluate the health and function of the bowels because of the high association of PSC with inflammatory bowel disease and colon cancer. Cross sectional imaging of the liver is recommended by some providers at 6 – 12 month intervals because of the high risk of hepatobiliary cancers.
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Primary Sclerosing Cholangitis
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Therapies of Primary Sclerosing Cholangitis
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TreatmentThere is no specific, universal treatment for individuals with PSC. Treatment is directed toward the specific symptoms that are apparent in each individual and at slowing the progression of the disorder.Endoscopic surgery to remove blockages and enlarge narrowed bile ducts may be of benefit to help prevent liver deterioration in certain cases. Lost vitamins should be replaced when required to prevent complications related to these deficiencies. Antibiotics may be useful in controlling inflammation or infection. Individuals with PSC are encouraged to follow a normal healthy diet and to avoid alcohol or only have alcohol in small amounts.The drug cholestyramine may be effective in controlling itching. Cholestyramine may be given with or without antihistamines. If cholestyramine is ineffective, other medications may be recommended. Bisphosphonates, which are drugs that prevent the loss of bone mass, may be used to treat osteoporosis.Ultimately, individuals with PSC may require a liver transplant. Liver transplantation has proven effective at treating individuals with PSC. Generally, this procedure is reserved for individuals with advanced symptoms of PSC (e.g. intractable pruritus, recurrent bacterial cholangitis, end-stage liver disease). In some cases, the disorder has recurred after liver transplantation.
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Therapies of Primary Sclerosing Cholangitis. TreatmentThere is no specific, universal treatment for individuals with PSC. Treatment is directed toward the specific symptoms that are apparent in each individual and at slowing the progression of the disorder.Endoscopic surgery to remove blockages and enlarge narrowed bile ducts may be of benefit to help prevent liver deterioration in certain cases. Lost vitamins should be replaced when required to prevent complications related to these deficiencies. Antibiotics may be useful in controlling inflammation or infection. Individuals with PSC are encouraged to follow a normal healthy diet and to avoid alcohol or only have alcohol in small amounts.The drug cholestyramine may be effective in controlling itching. Cholestyramine may be given with or without antihistamines. If cholestyramine is ineffective, other medications may be recommended. Bisphosphonates, which are drugs that prevent the loss of bone mass, may be used to treat osteoporosis.Ultimately, individuals with PSC may require a liver transplant. Liver transplantation has proven effective at treating individuals with PSC. Generally, this procedure is reserved for individuals with advanced symptoms of PSC (e.g. intractable pruritus, recurrent bacterial cholangitis, end-stage liver disease). In some cases, the disorder has recurred after liver transplantation.
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Primary Sclerosing Cholangitis
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Overview of Primary Visual Agnosia
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Primary visual agnosia is a rare neurological disorder characterized by the total or partial loss of the ability to recognize and identify familiar objects and/or people by sight. This occurs without loss of the ability to actually see the object or person. The symptoms of visual agnosia occur as a result of damage to certain areas of the brain (primary) or in association with other disorders (secondary).
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Overview of Primary Visual Agnosia. Primary visual agnosia is a rare neurological disorder characterized by the total or partial loss of the ability to recognize and identify familiar objects and/or people by sight. This occurs without loss of the ability to actually see the object or person. The symptoms of visual agnosia occur as a result of damage to certain areas of the brain (primary) or in association with other disorders (secondary).
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Primary Visual Agnosia
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Symptoms of Primary Visual Agnosia
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People with primary visual agnosia may have one or several impairments in visual recognition without impairment of intelligence, motivation, and/or attention. Vision is almost always intact and the mind is clear. Some affected individuals do not have the ability to recognize familiar objects. They can see objects, but are unable to identify them by sight. However, objects may be identified by touch, sound, and/or smell. For example, affected individuals may not be able to identify a set of keys by sight, but can identify them upon holding them in their hands.Some researchers separate visual agnosia into two broad categories: apperceptive agnosia and associative agnosia. Apperceptive agnosia refers to individuals who cannot properly process what they see, meaning they have difficult identifying shapes or differentiating between different objects (visual stimuli). Affected individuals may not be able to recognize that pictures of the same object from different angles are of the same object. Affected individuals may be unable to copy (e.g., draw a picture) of an object.Associative agnosia refers to people who cannot match an object with their memory. They can accurately describe an object and even draw a picture of the object, but are unable to state what the object is or is used for. However, if told verbally what the object is, an affected individual will be able to describe what it is used for.In some cases, individuals with primary visual agnosia cannot identify familiar people (prosopagnosia). They can see the person clearly and can describe the person (e.g., hair and eye color), but cannot identify the person by name. People with prosopagnosia may identify people by touch, smell, speech, or the way that they walk (gait). In some rare cases, affected individuals cannot recognize their own face.Some people have a form of primary visual agnosia associated with the loss of the ability to identify their surroundings (loss of environmental familiarity agnosia). Symptoms include the inability to recognize familiar places or buildings. Affected individuals may be able to describe a familiar environment from memory and point to it on a map.Primary agnosia is associated with bilateral damage to the ventral visual stream, including the lingual and fusiform gyri.Primary visual agnosia can be distinguished from other visual disorders such as simultanagnosia that is a characterized by the inability to read and the inability to view one's surroundings as a whole. The affected individual can see parts of the surrounding scene, but not the whole. There is an inability to comprehend more than one part of a visual scene at a time or to coordinate the parts.In rare cases, people with primary visual agnosia may not be able to recognize or point to various parts of the body (autotopagnosia). Symptoms may also include loss of the ability to distinguish left from right.
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Symptoms of Primary Visual Agnosia. People with primary visual agnosia may have one or several impairments in visual recognition without impairment of intelligence, motivation, and/or attention. Vision is almost always intact and the mind is clear. Some affected individuals do not have the ability to recognize familiar objects. They can see objects, but are unable to identify them by sight. However, objects may be identified by touch, sound, and/or smell. For example, affected individuals may not be able to identify a set of keys by sight, but can identify them upon holding them in their hands.Some researchers separate visual agnosia into two broad categories: apperceptive agnosia and associative agnosia. Apperceptive agnosia refers to individuals who cannot properly process what they see, meaning they have difficult identifying shapes or differentiating between different objects (visual stimuli). Affected individuals may not be able to recognize that pictures of the same object from different angles are of the same object. Affected individuals may be unable to copy (e.g., draw a picture) of an object.Associative agnosia refers to people who cannot match an object with their memory. They can accurately describe an object and even draw a picture of the object, but are unable to state what the object is or is used for. However, if told verbally what the object is, an affected individual will be able to describe what it is used for.In some cases, individuals with primary visual agnosia cannot identify familiar people (prosopagnosia). They can see the person clearly and can describe the person (e.g., hair and eye color), but cannot identify the person by name. People with prosopagnosia may identify people by touch, smell, speech, or the way that they walk (gait). In some rare cases, affected individuals cannot recognize their own face.Some people have a form of primary visual agnosia associated with the loss of the ability to identify their surroundings (loss of environmental familiarity agnosia). Symptoms include the inability to recognize familiar places or buildings. Affected individuals may be able to describe a familiar environment from memory and point to it on a map.Primary agnosia is associated with bilateral damage to the ventral visual stream, including the lingual and fusiform gyri.Primary visual agnosia can be distinguished from other visual disorders such as simultanagnosia that is a characterized by the inability to read and the inability to view one's surroundings as a whole. The affected individual can see parts of the surrounding scene, but not the whole. There is an inability to comprehend more than one part of a visual scene at a time or to coordinate the parts.In rare cases, people with primary visual agnosia may not be able to recognize or point to various parts of the body (autotopagnosia). Symptoms may also include loss of the ability to distinguish left from right.
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Primary Visual Agnosia
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Causes of Primary Visual Agnosia
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Primary visual agnosia is a rare neurological disorder that occurs as a result of damage to the brain. Symptoms develop due to the inability to retrieve information from those damaged areas that are associated with visual memory. Lesions may occur as a result of traumatic brain injury, stroke, tumor, or overexposure to dangerous environmental toxins (e.g., carbon monoxide poisoning). In some cases, the cause of the brain damage may not be known. Symptoms may vary, according to the area of the brain that is affected.Visual agnosia may also occur in association with other underlying disorders (secondary visual agnosia) such as Alzheimer's disease, agenesis of the corpus callosum, MELAS, and other diseases that result in progressive dementia. (For more information on these disorders, choose “Alzheimer,” “Agenesis of the Corpus Callosum,” and “MELAS” as your search terms in the Rare Disease Database.)
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Causes of Primary Visual Agnosia. Primary visual agnosia is a rare neurological disorder that occurs as a result of damage to the brain. Symptoms develop due to the inability to retrieve information from those damaged areas that are associated with visual memory. Lesions may occur as a result of traumatic brain injury, stroke, tumor, or overexposure to dangerous environmental toxins (e.g., carbon monoxide poisoning). In some cases, the cause of the brain damage may not be known. Symptoms may vary, according to the area of the brain that is affected.Visual agnosia may also occur in association with other underlying disorders (secondary visual agnosia) such as Alzheimer's disease, agenesis of the corpus callosum, MELAS, and other diseases that result in progressive dementia. (For more information on these disorders, choose “Alzheimer,” “Agenesis of the Corpus Callosum,” and “MELAS” as your search terms in the Rare Disease Database.)
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Primary Visual Agnosia
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nord_1013_3
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Affects of Primary Visual Agnosia
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Primary visual agnosia is an extremely rare neurological disorder that affects males and females in equal numbers. The first detailed account of visual agnosia in the medical literature occurred in 1890.
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Affects of Primary Visual Agnosia. Primary visual agnosia is an extremely rare neurological disorder that affects males and females in equal numbers. The first detailed account of visual agnosia in the medical literature occurred in 1890.
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Primary Visual Agnosia
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Related disorders of Primary Visual Agnosia
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The following disorders may precede the development of primary visual agnosia. They can be useful in identifying an underlying cause of some forms of this disorder.Alzheimer's disease is a common, progressive, degenerative brain disorder affecting memory, thought, and language. Neurodegenerative changes lead to the formation of plaques or patches within the brain and the loss of cholinergic neurotransmitter function. The early behavioral changes may be subtle; however, as the disease progresses, memory losses increase and there are personality, mood, and behavioral changes. There may also be disturbances of judgment, concentration, and speech along with confusion and restlessness. (For more information on this disorder, choose “Alzheimer” as your search term in the Rare Disease Database.)Pick's disease is a degenerative neurological disorder that affects the frontal and temporal lobes of the brain. The symptoms of Pick's disease closely resemble those of Alzheimer's disease. In the early stages, memory is still intact and there is a high degree of disorientation. In the later stages of this disorder, there is a loss of motor control and language skills. Pick's disease usually begins between the ages of forty and sixty and appears to affect females more often than males, and the exact cause is not known. The area of the brain affected is the major different in Pick's disease from other forms of senile dementia. This disease involves atrophy limited to the lobes of the brain. Areas of degeneration are identified by the presence of Pick cells and Pick inclusion bodies instead of plaques and tangles. There may also be severe dementia. (For more information on this disorder, choose “Pick” as your search term in the Rare Disease Database.)Balint's syndrome is a rare neurological disorder associated with bilateral changes in posterior parietal cortex. It is characterized by the inability to voluntarily look at objects to the side (peripherally). An affected individual may also have trouble grasping objects due to difficulties with hand-to-eye coordination and may be unable to follow objects across the eyes' field of vision. Individuals often cannot read and the inability to view one's surroundings as a whole (simultanagnosia). Although the exact cause of Balint's syndrome is not known, it is thought that symptoms may be caused by improper development of part of the brain.
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Related disorders of Primary Visual Agnosia. The following disorders may precede the development of primary visual agnosia. They can be useful in identifying an underlying cause of some forms of this disorder.Alzheimer's disease is a common, progressive, degenerative brain disorder affecting memory, thought, and language. Neurodegenerative changes lead to the formation of plaques or patches within the brain and the loss of cholinergic neurotransmitter function. The early behavioral changes may be subtle; however, as the disease progresses, memory losses increase and there are personality, mood, and behavioral changes. There may also be disturbances of judgment, concentration, and speech along with confusion and restlessness. (For more information on this disorder, choose “Alzheimer” as your search term in the Rare Disease Database.)Pick's disease is a degenerative neurological disorder that affects the frontal and temporal lobes of the brain. The symptoms of Pick's disease closely resemble those of Alzheimer's disease. In the early stages, memory is still intact and there is a high degree of disorientation. In the later stages of this disorder, there is a loss of motor control and language skills. Pick's disease usually begins between the ages of forty and sixty and appears to affect females more often than males, and the exact cause is not known. The area of the brain affected is the major different in Pick's disease from other forms of senile dementia. This disease involves atrophy limited to the lobes of the brain. Areas of degeneration are identified by the presence of Pick cells and Pick inclusion bodies instead of plaques and tangles. There may also be severe dementia. (For more information on this disorder, choose “Pick” as your search term in the Rare Disease Database.)Balint's syndrome is a rare neurological disorder associated with bilateral changes in posterior parietal cortex. It is characterized by the inability to voluntarily look at objects to the side (peripherally). An affected individual may also have trouble grasping objects due to difficulties with hand-to-eye coordination and may be unable to follow objects across the eyes' field of vision. Individuals often cannot read and the inability to view one's surroundings as a whole (simultanagnosia). Although the exact cause of Balint's syndrome is not known, it is thought that symptoms may be caused by improper development of part of the brain.
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Primary Visual Agnosia
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Diagnosis of Primary Visual Agnosia
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A variety of psychophysical tests can be conducted to pinpoint the nature of the visual process that is disrupted in an individual. Brain damage that causes visual agnosia may be identified through imaging techniques, including computed tomography (CT scan) and magnetic resonance imaging (MRI).
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Diagnosis of Primary Visual Agnosia. A variety of psychophysical tests can be conducted to pinpoint the nature of the visual process that is disrupted in an individual. Brain damage that causes visual agnosia may be identified through imaging techniques, including computed tomography (CT scan) and magnetic resonance imaging (MRI).
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Primary Visual Agnosia
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nord_1013_6
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Therapies of Primary Visual Agnosia
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TreatmentTreatment of primary visual agnosia is symptomatic and supportive. Affected individuals may undergo exercises or rehabilitation to relearn about objects necessary for everyday living. Exercises and rehabilitation to help restore lost memories may also be helpful.In cases of secondary visual agnosia, treatment of an underlying disorder may reduce symptoms and help prevent further brain damage.
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Therapies of Primary Visual Agnosia. TreatmentTreatment of primary visual agnosia is symptomatic and supportive. Affected individuals may undergo exercises or rehabilitation to relearn about objects necessary for everyday living. Exercises and rehabilitation to help restore lost memories may also be helpful.In cases of secondary visual agnosia, treatment of an underlying disorder may reduce symptoms and help prevent further brain damage.
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Primary Visual Agnosia
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nord_1014_0
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Overview of Proctitis
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Proctitis is a chronic inflammatory disease arising in the rectum and characterized by bloody diarrhea. There are two types of proctitis, ulcerative and gonorrheal, which are differentiated by the means in which they are contracted. Gonorrheal proctitis is transmitted through sexual contact.
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Overview of Proctitis. Proctitis is a chronic inflammatory disease arising in the rectum and characterized by bloody diarrhea. There are two types of proctitis, ulcerative and gonorrheal, which are differentiated by the means in which they are contracted. Gonorrheal proctitis is transmitted through sexual contact.
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Proctitis
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nord_1014_1
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Symptoms of Proctitis
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Symptoms of proctitis are most frequently pain in the rectal area and a frequent desire to pass feces. Bloody diarrhea, painful defecation and bleeding in the rectal area are also common. Diarrhea may be followed by constipation with spasm and severe straining of the rectal muscles (tenesmus). In some cases, stools may be well formed but surrounded by blood and mucus.Proctitis usually runs a mild, intermittent course over many years. Occasionally there is neurological involvement with urinary bladder dysfunction, weakness and burning of the lower limbs (paresthesias) and pain in the thighs. Men may have difficulty maintaining penile erections. When a diagnosis of gonorrheal proctitis is confirmed, individuals also should be tested for other sexually transmitted organisms such as syphilis, amebiasis, chlamydia, campylobacter, shigella, and herpes simplex virus infections.Upon examination, individuals with ulcerative proctitis show ulcers in the rectum. Ulcerations are usually accompanied by rectal bleeding, straining of rectal muscles (tenesmus) and an anal discharge of bloody mucus. However, anal bleeding is seldom severe. Individuals with diarrhea often describe no increase in stool volume but rather frequent passage of small amounts of mucous or blood. Fever and weight loss are rare. Symptoms of ulcerative proctitis are very similar to ulcerative colitis. However, ulcerative proctitis is not as serious as colitis and is limited to the rectum. (See related disorder section for more information on Ulcerative Colitis.)
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Symptoms of Proctitis. Symptoms of proctitis are most frequently pain in the rectal area and a frequent desire to pass feces. Bloody diarrhea, painful defecation and bleeding in the rectal area are also common. Diarrhea may be followed by constipation with spasm and severe straining of the rectal muscles (tenesmus). In some cases, stools may be well formed but surrounded by blood and mucus.Proctitis usually runs a mild, intermittent course over many years. Occasionally there is neurological involvement with urinary bladder dysfunction, weakness and burning of the lower limbs (paresthesias) and pain in the thighs. Men may have difficulty maintaining penile erections. When a diagnosis of gonorrheal proctitis is confirmed, individuals also should be tested for other sexually transmitted organisms such as syphilis, amebiasis, chlamydia, campylobacter, shigella, and herpes simplex virus infections.Upon examination, individuals with ulcerative proctitis show ulcers in the rectum. Ulcerations are usually accompanied by rectal bleeding, straining of rectal muscles (tenesmus) and an anal discharge of bloody mucus. However, anal bleeding is seldom severe. Individuals with diarrhea often describe no increase in stool volume but rather frequent passage of small amounts of mucous or blood. Fever and weight loss are rare. Symptoms of ulcerative proctitis are very similar to ulcerative colitis. However, ulcerative proctitis is not as serious as colitis and is limited to the rectum. (See related disorder section for more information on Ulcerative Colitis.)
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Proctitis
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