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nord_1185_5
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Diagnosis of Systemic Capillary Leak Syndrome
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SCLS can be diagnosed with three parameters: low blood pressure, increased hematocrit and low protein in the blood (hypoalbuminemia). However, these three features are not absolutely conclusive of SCLS. Other tests must be done in order to rule out other possible causes of the symptoms such as infection and C-1 esterase inhibitor deficiency.To confirm the diagnosis, several key laboratory features are critical. The sudden and profound capillary leak causes a sharp decrease in serum albumin level (hypoalbuminemia) and a similarly sharp increase in the level of hemoglobin and hematocrit. The red blood cells which contribute to measurements of hemoglobin and hematocrit are not actually increased. Rather, the blood becomes concentrated due to the loss of fluid. This hemoconcentration is a classic feature of the syndrome and proof of hemoconcentration is essential for the diagnosis. Some patients are mistakenly diagnosed as having polycythemia, a condition in which the hematocrit is increased due to excessive marrow production of red blood cells.A search for an M protein should be undertaken but the absence of an M protein does not exclude the diagnosis.
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Diagnosis of Systemic Capillary Leak Syndrome. SCLS can be diagnosed with three parameters: low blood pressure, increased hematocrit and low protein in the blood (hypoalbuminemia). However, these three features are not absolutely conclusive of SCLS. Other tests must be done in order to rule out other possible causes of the symptoms such as infection and C-1 esterase inhibitor deficiency.To confirm the diagnosis, several key laboratory features are critical. The sudden and profound capillary leak causes a sharp decrease in serum albumin level (hypoalbuminemia) and a similarly sharp increase in the level of hemoglobin and hematocrit. The red blood cells which contribute to measurements of hemoglobin and hematocrit are not actually increased. Rather, the blood becomes concentrated due to the loss of fluid. This hemoconcentration is a classic feature of the syndrome and proof of hemoconcentration is essential for the diagnosis. Some patients are mistakenly diagnosed as having polycythemia, a condition in which the hematocrit is increased due to excessive marrow production of red blood cells.A search for an M protein should be undertaken but the absence of an M protein does not exclude the diagnosis.
| 1,185 |
Systemic Capillary Leak Syndrome
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nord_1185_6
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Therapies of Systemic Capillary Leak Syndrome
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Treatment
Currently, there is no known cure for SCLS. Treatment is directed at prevention of attacks using agents aimed at decreasing capillary leakage and aimed at interfering with hormone like cytokines that induce the leakage. Once an attack is underway, treatment is directed toward supportive care, specifically controlling blood pressure to maintain blood flow to vital organs as well as preventing excessive swelling and fluid accumulation.Treatment of a fully developed SCLS episode requires recognition that there are two phases of the acute attack. The first phase, which often lasts several days is called the resuscitation phase aimed at controlling the capillary leaks and maintaining blood pressure. In that phase, an albumin and fluid leak from the capillaries into the tissue spaces causes swelling. This loss of fluid has similar effects on the circulation as dehydration, which slows the flow of oxygen carrying blood to tissues. The blood pressure falls, and the red cells concentrate. Intravenous fluid replacement is usually required, but should be minimized due to its propensity to leak into tissues. Although the blood pressure may still be low, it is important to avoid overly aggressive intravenous fluid administration that could result in massive swelling of the extremities requiring surgical decompression. In this procedure, the skin of the arm of leg is cut to release the compressive pressure from the retained fluids and improve blood flow to and from the extremities. Excessive intravenous fluids may also cause accumulation of fluid in the lungs and around other vital organs. The goal during the acute phase is NOT to attempt to maintain absolutely normal blood pressure or urine flow but to maintain the blood pressure at just sufficiently high enough levels to avoid permanent damage to vital organs yet spare the patient from the risks of excess fluid administration. Measurement of central venous or arterial pressure in an intensive care unit is often necessary to achieve this delicate balance. Intravenous albumin and colloid may be used. Keeping up with the fluid loss is important because sustained low blood pressure can damage vital organs such as the kidneys.The second phase of treatment is sometimes called the recruitment phase as fluids and albumin are reabsorbed from the tissues. In this phase, the capillary leak has lessened and the main threat is fluid overload. Diuretics may be required for excess fluid overload.Glucocorticoids (steroids) are often used during the acute attack, especially early in the recruitment phase in an attempt to reduce the capillary leak, but their efficacy is unknown. Albumin and colloids administered with the intravenous fluids may have temporary benefit to increase blood flow to vital organs like the kidneys.Maintenance therapy is given in an attempt to reduce the frequency and severity of the acute attacks. Administrating immunoglobulins intravenously once per month for an indefinite period of time is currently the standard of care for SCLS. IVIG for prevention has been shown to significantly improve survival in patients with monoclonal gammopathy-associated SCLS, but it is also highly effective in cases of SCLS without monoclonal gammopathy.Secondary medications may include a combination of theophylline and terbutaline. These are administered by mouth. The level of theophylline must be maintained in the therapeutic range as determined by regular blood tests. Patients who do not tolerate these drugs may benefit by leukotriene inhibitors such as montelukast (Singulair). Occasionally, an ACE inhibitor such as lisinopril may be of benefit. The role of these secondary medications is uncertain.
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Therapies of Systemic Capillary Leak Syndrome. Treatment
Currently, there is no known cure for SCLS. Treatment is directed at prevention of attacks using agents aimed at decreasing capillary leakage and aimed at interfering with hormone like cytokines that induce the leakage. Once an attack is underway, treatment is directed toward supportive care, specifically controlling blood pressure to maintain blood flow to vital organs as well as preventing excessive swelling and fluid accumulation.Treatment of a fully developed SCLS episode requires recognition that there are two phases of the acute attack. The first phase, which often lasts several days is called the resuscitation phase aimed at controlling the capillary leaks and maintaining blood pressure. In that phase, an albumin and fluid leak from the capillaries into the tissue spaces causes swelling. This loss of fluid has similar effects on the circulation as dehydration, which slows the flow of oxygen carrying blood to tissues. The blood pressure falls, and the red cells concentrate. Intravenous fluid replacement is usually required, but should be minimized due to its propensity to leak into tissues. Although the blood pressure may still be low, it is important to avoid overly aggressive intravenous fluid administration that could result in massive swelling of the extremities requiring surgical decompression. In this procedure, the skin of the arm of leg is cut to release the compressive pressure from the retained fluids and improve blood flow to and from the extremities. Excessive intravenous fluids may also cause accumulation of fluid in the lungs and around other vital organs. The goal during the acute phase is NOT to attempt to maintain absolutely normal blood pressure or urine flow but to maintain the blood pressure at just sufficiently high enough levels to avoid permanent damage to vital organs yet spare the patient from the risks of excess fluid administration. Measurement of central venous or arterial pressure in an intensive care unit is often necessary to achieve this delicate balance. Intravenous albumin and colloid may be used. Keeping up with the fluid loss is important because sustained low blood pressure can damage vital organs such as the kidneys.The second phase of treatment is sometimes called the recruitment phase as fluids and albumin are reabsorbed from the tissues. In this phase, the capillary leak has lessened and the main threat is fluid overload. Diuretics may be required for excess fluid overload.Glucocorticoids (steroids) are often used during the acute attack, especially early in the recruitment phase in an attempt to reduce the capillary leak, but their efficacy is unknown. Albumin and colloids administered with the intravenous fluids may have temporary benefit to increase blood flow to vital organs like the kidneys.Maintenance therapy is given in an attempt to reduce the frequency and severity of the acute attacks. Administrating immunoglobulins intravenously once per month for an indefinite period of time is currently the standard of care for SCLS. IVIG for prevention has been shown to significantly improve survival in patients with monoclonal gammopathy-associated SCLS, but it is also highly effective in cases of SCLS without monoclonal gammopathy.Secondary medications may include a combination of theophylline and terbutaline. These are administered by mouth. The level of theophylline must be maintained in the therapeutic range as determined by regular blood tests. Patients who do not tolerate these drugs may benefit by leukotriene inhibitors such as montelukast (Singulair). Occasionally, an ACE inhibitor such as lisinopril may be of benefit. The role of these secondary medications is uncertain.
| 1,185 |
Systemic Capillary Leak Syndrome
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nord_1186_0
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Overview of Systemic Primary Carnitine Deficiency
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SummarySystemic primary carnitine deficiency (CDSP) is a rare metabolic disorder in which the body cannot properly process fats into energy. Carnitine functions to carry fatty acids obtained through diet to the energy centers in muscle cells (mitochondria). A deficiency of carnitine results in accumulation of fats in the liver, muscle, and heart. Symptoms of CDSP in infants can include poor feeding, tiredness, irritability and low blood sugar (hypoglycemia) but CDSP can also present later in childhood with heart and muscle abnormalities. Some people with CDSP are diagnosed as adults and have mild or no symptoms. CDSP is caused by mutations in the SLC22A5 gene and inherited as an autosomal recessive genetic condition.IntroductionCDSP is treatable by the daily use of L-carnitine supplements. Without early detection and treatment, an affected child may experience low blood sugar (hypoglycdemia), seizures, heart muscle weakness (cardiomyopathy) that can be life-threatening. Newborn screening is available for CDSP.
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Overview of Systemic Primary Carnitine Deficiency. SummarySystemic primary carnitine deficiency (CDSP) is a rare metabolic disorder in which the body cannot properly process fats into energy. Carnitine functions to carry fatty acids obtained through diet to the energy centers in muscle cells (mitochondria). A deficiency of carnitine results in accumulation of fats in the liver, muscle, and heart. Symptoms of CDSP in infants can include poor feeding, tiredness, irritability and low blood sugar (hypoglycemia) but CDSP can also present later in childhood with heart and muscle abnormalities. Some people with CDSP are diagnosed as adults and have mild or no symptoms. CDSP is caused by mutations in the SLC22A5 gene and inherited as an autosomal recessive genetic condition.IntroductionCDSP is treatable by the daily use of L-carnitine supplements. Without early detection and treatment, an affected child may experience low blood sugar (hypoglycdemia), seizures, heart muscle weakness (cardiomyopathy) that can be life-threatening. Newborn screening is available for CDSP.
| 1,186 |
Systemic Primary Carnitine Deficiency
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nord_1186_1
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Symptoms of Systemic Primary Carnitine Deficiency
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CDSP can present in three ways. Infants with the infantile metabolic (hepatic) type present in the first two years of life with episodes of irritability, tiredness and abnormal enlargement of the liver (hepatomegaly). Laboratory results show hypoglycemia with little to no ketones in urine (hypoketotic hypoglycemia), high levels of ammonia in the blood hyperammonemia), and elevated liver transaminases. Some children with the infantile presentation may also have symptoms of muscle disease.Children with the childhood myopathic (cardiac) type usually present between ages two to four with heart disease (cardiomyopathy), low muscle tone (hypotonia), skeletal muscle weakness, and elevated serum creatine kinase.The adulthood presentation of CDSP is much rarer and the most common symptom is fatigability.
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Symptoms of Systemic Primary Carnitine Deficiency. CDSP can present in three ways. Infants with the infantile metabolic (hepatic) type present in the first two years of life with episodes of irritability, tiredness and abnormal enlargement of the liver (hepatomegaly). Laboratory results show hypoglycemia with little to no ketones in urine (hypoketotic hypoglycemia), high levels of ammonia in the blood hyperammonemia), and elevated liver transaminases. Some children with the infantile presentation may also have symptoms of muscle disease.Children with the childhood myopathic (cardiac) type usually present between ages two to four with heart disease (cardiomyopathy), low muscle tone (hypotonia), skeletal muscle weakness, and elevated serum creatine kinase.The adulthood presentation of CDSP is much rarer and the most common symptom is fatigability.
| 1,186 |
Systemic Primary Carnitine Deficiency
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nord_1186_2
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Causes of Systemic Primary Carnitine Deficiency
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CDSP is caused by mutations in the CLC22A5 gene, resulting in absent or dysfunctional OCTN2 protein. Normally, this protein functions to reabsorb carnitine in kidneys and transport carnitine inside cells. If the protein is absent or abnormal, there is a shortage of carnitine in cells. Carnitine functions to carry fatty acids obtained through diet to the energy centers in muscle cells (mitochondria). A deficiency of carnitine results in an inability to utilize fat leading to hypoglycemia and the accumulation of fats in the liver, muscle, and heart.CDSP is inherited as an autosomal recessive genetic trait. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but will not show symptoms. The risk for two carrier parents to both pass the altered gene and 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 is 25%. The risk is the same for males and females.All individuals carry 4-5 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.
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Causes of Systemic Primary Carnitine Deficiency. CDSP is caused by mutations in the CLC22A5 gene, resulting in absent or dysfunctional OCTN2 protein. Normally, this protein functions to reabsorb carnitine in kidneys and transport carnitine inside cells. If the protein is absent or abnormal, there is a shortage of carnitine in cells. Carnitine functions to carry fatty acids obtained through diet to the energy centers in muscle cells (mitochondria). A deficiency of carnitine results in an inability to utilize fat leading to hypoglycemia and the accumulation of fats in the liver, muscle, and heart.CDSP is inherited as an autosomal recessive genetic trait. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but will not show symptoms. The risk for two carrier parents to both pass the altered gene and 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 is 25%. The risk is the same for males and females.All individuals carry 4-5 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.
| 1,186 |
Systemic Primary Carnitine Deficiency
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nord_1186_3
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Affects of Systemic Primary Carnitine Deficiency
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CDSP is a rare disorder that affects males and females in equal numbers. Based on newborn screening and reports in medical literature, the prevalence in the US is estimated to be 1:50,000.
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Affects of Systemic Primary Carnitine Deficiency. CDSP is a rare disorder that affects males and females in equal numbers. Based on newborn screening and reports in medical literature, the prevalence in the US is estimated to be 1:50,000.
| 1,186 |
Systemic Primary Carnitine Deficiency
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nord_1186_4
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Related disorders of Systemic Primary Carnitine Deficiency
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Symptoms of the following disorders can be similar to those of systemic primary carnitine deficiency. Comparisons may be useful for a differential diagnosis:Carnitine deficiency can occur as a result of other metabolic disorders (secondary carnitine deficiency) such as organic acidemias and fatty acid oxidation defects.Isovaleric acidemia is a rare inherited metabolic disorder of infancy characterized by attacks of vomiting, lack of appetite, and fatigue. Infants with this disorder become progressively weak and often have abnormally low body temperatures (hypothermia). A strong offensive body odor is also associated with this disorder. (For more information on this disorder, choose “Isovaleric Acidemia” as your search term in the Rare Disease Database.)Propionic acidemia is another form of organic acidemia that occurs in infancy. It is caused by a deficiency of the enzyme propionyl-CoA carboxylase (PCC). The initial symptoms of propionic acidemia include failure to thrive, vomiting, and extreme fatigue. (For more information on this disorder, choose “Propionic Acidemia” as your search term in the Rare Disease Database.)
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Related disorders of Systemic Primary Carnitine Deficiency. Symptoms of the following disorders can be similar to those of systemic primary carnitine deficiency. Comparisons may be useful for a differential diagnosis:Carnitine deficiency can occur as a result of other metabolic disorders (secondary carnitine deficiency) such as organic acidemias and fatty acid oxidation defects.Isovaleric acidemia is a rare inherited metabolic disorder of infancy characterized by attacks of vomiting, lack of appetite, and fatigue. Infants with this disorder become progressively weak and often have abnormally low body temperatures (hypothermia). A strong offensive body odor is also associated with this disorder. (For more information on this disorder, choose “Isovaleric Acidemia” as your search term in the Rare Disease Database.)Propionic acidemia is another form of organic acidemia that occurs in infancy. It is caused by a deficiency of the enzyme propionyl-CoA carboxylase (PCC). The initial symptoms of propionic acidemia include failure to thrive, vomiting, and extreme fatigue. (For more information on this disorder, choose “Propionic Acidemia” as your search term in the Rare Disease Database.)
| 1,186 |
Systemic Primary Carnitine Deficiency
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nord_1186_5
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Diagnosis of Systemic Primary Carnitine Deficiency
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Plasma carnitine levels are extremely reduced in CDSP. The diagnosis can be confirmed with molecular genetic testing to identify mutations in the SLC22A5 gene. Newborn screening is available to detect low carnitine levels in infants with CDSP.
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Diagnosis of Systemic Primary Carnitine Deficiency. Plasma carnitine levels are extremely reduced in CDSP. The diagnosis can be confirmed with molecular genetic testing to identify mutations in the SLC22A5 gene. Newborn screening is available to detect low carnitine levels in infants with CDSP.
| 1,186 |
Systemic Primary Carnitine Deficiency
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nord_1186_6
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Therapies of Systemic Primary Carnitine Deficiency
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The main treatment for CDSP is L-carnitine supplementation, which is very effective if started before organ damage occurs. Hypoglycemic episodes associated with carnitine deficiency are treated with intravenous dextrose infusion or proper feeding and diet. Maintaining normal carnitine levels through supplementation and preventing hypoglycemia through frequent feeding and diet can prevent the metabolic, hepatic, cardiac, and muscular complications of CDSP.Cardiomyopathy, if present, should be managed and treated by a cardiologist.
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Therapies of Systemic Primary Carnitine Deficiency. The main treatment for CDSP is L-carnitine supplementation, which is very effective if started before organ damage occurs. Hypoglycemic episodes associated with carnitine deficiency are treated with intravenous dextrose infusion or proper feeding and diet. Maintaining normal carnitine levels through supplementation and preventing hypoglycemia through frequent feeding and diet can prevent the metabolic, hepatic, cardiac, and muscular complications of CDSP.Cardiomyopathy, if present, should be managed and treated by a cardiologist.
| 1,186 |
Systemic Primary Carnitine Deficiency
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nord_1187_0
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Overview of Systemic Scleroderma
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Systemic scleroderma is a disease characterized by rapid growth of fibrous (connective) tissue that leads to scarring of skin and internal organs. Approximately one in 10,000 individuals is affected. It is more common in women and most often develops around age 30 to 50. Systemic scleroderma can affect almost any organ in the body, and there is a large variability of symptoms among affected individuals. One of the most common and earliest manifestations of the disease is Raynaud phenomenon, which involves blood vessel spasms (vasospasms) induced by cold temperature or stress. This can lead to temporary finger discoloration, numbness and pain and is also associated with the development of finger ulcers. Of note, Raynaud phenomenon also commonly occurs in healthy individuals. Other manifestations of systemic scleroderma include muscle and joint pain, skin tightening, and dilated blood vessels that can be seen through the skin (telangiectasias). Scarring of internal organs can also lead to gastrointestinal, pulmonary, cardiac, and renal disease. Although systemic scleroderma cannot be cured, many of the symptoms can be treated. A timely diagnosis is important to ensure appropriate management of the disease and associated complications.
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Overview of Systemic Scleroderma. Systemic scleroderma is a disease characterized by rapid growth of fibrous (connective) tissue that leads to scarring of skin and internal organs. Approximately one in 10,000 individuals is affected. It is more common in women and most often develops around age 30 to 50. Systemic scleroderma can affect almost any organ in the body, and there is a large variability of symptoms among affected individuals. One of the most common and earliest manifestations of the disease is Raynaud phenomenon, which involves blood vessel spasms (vasospasms) induced by cold temperature or stress. This can lead to temporary finger discoloration, numbness and pain and is also associated with the development of finger ulcers. Of note, Raynaud phenomenon also commonly occurs in healthy individuals. Other manifestations of systemic scleroderma include muscle and joint pain, skin tightening, and dilated blood vessels that can be seen through the skin (telangiectasias). Scarring of internal organs can also lead to gastrointestinal, pulmonary, cardiac, and renal disease. Although systemic scleroderma cannot be cured, many of the symptoms can be treated. A timely diagnosis is important to ensure appropriate management of the disease and associated complications.
| 1,187 |
Systemic Scleroderma
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nord_1187_1
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Symptoms of Systemic Scleroderma
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Systemic scleroderma can affect multiple organ systems and therefore lead to numerous symptoms and complications. The symptoms present, their severity, the rate of progression of the disease, the response to treatment, and overall survival vary widely depending on the affected individual. In most cases, people start to develop symptoms between age 30 and 50. Symptoms related to the different organs involved are described below. Skin
In most people, Raynaud phenomenon (RP) is the first manifestation of the disease. RP is characterized by blood vessel spams (vasospasm) in response to cold or stress. This most often occurs in the fingers and turns them white. Subsequently, as the vessels are occluded and cannot deliver oxygen, the fingers turn blue. This can also lead to severe pain and ulcers. After several minutes (usually 15 to 20), the vasospasms stop and the fingers become red as blood flows again. Another very common symptom of systemic scleroderma is rapid growth of connective tissue in the skin (skin fibrosis). The earliest involved areas are the fingers, hands and face. Symptoms associated with skin fibrosis include tight and dry skin, itching (pruritus), fluid accumulation (edema) and increased or decreased skin pigmentation. Another skin manifestation seen in most patients with scleroderma is telangiectasia. Telangiectasias are small dilated blood vessels that can appear as red lesions visible through the skin. Affected individuals can also develop accumulation of calcium nodules in the fingers, forearm, elbows, and knees. This condition is known as calcinosis cutis and can lead to pain if the nodules are large. Nerves, muscles, and joints
Many individuals living with systemic scleroderma develop muscle, joint, or nerve disease. Muscle involvement can lead to muscle pain, weakness, and muscle wasting (sarcopenia). Affected joints can be painful, stiff, and swollen. Nerve involvement is less common but can lead to burning or tingling sensation or numbness. In some individuals, the autonomic nervous system can be affected. This part of the nervous system is not under voluntarily control and is notably involved in self-regulation of the body. Dysfunction of the autonomic nervous system can lead to symptoms such as dizziness when standing up (orthostasis), inappropriate heart rate response to exertion, and inappropriate sweating.Lungs
The two main pulmonary manifestations of systemic scleroderma are pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). PAH is defined as increased pressure in the arteries of the lungs and can lead to shortness of breath (dyspnea), fatigue, and failure of the right ventricle of the heart, which in turn can cause chest pain, fluid accumulation (edema), and transient loss of consciousness upon exertion (exertional syncope). ILD corresponds to scarring (fibrosis) of lung tissue, which prevents lung expansion and gas exchange. The two main symptoms of ILD are progressive dyspnea and dry cough. PAH and ILD are progressive conditions and can eventually become life-threatening. Taken together, they account for about half of all deaths related to systemic scleroderma. Gastrointestinal tract
The most commonly involved part of the gastrointestinal tract in systemic scleroderma is the esophagus. In affected individuals, the esophagus is unable to contract efficiently (esophageal dismotility) to allow food to reach the stomach. In addition, the lower esophageal sphincter (LES), which is a circular muscle between the esophagus and the stomach, is not able to close properly. The combination of esophageal dismotility and LES incompetence can lead to heartburn due to acid reflux (a condition known as gastroesophageal reflux disease; GERD), choking on food, and difficulty swallowing (dysphagia). Fibrosis of the rest of the gastrointestinal can prevent food from moving through properly (pseudo-obstruction), which can promote bacterial growth and lead to pain, bloating, constipation, diarrhea, and fecal incontinence. Gastrointestinal bleeding also occurs in some patients due to dilation of veins in the stomach (gastric venous ectasias).Heart
Systemic scleroderma can affect many parts of the heart, including the heart muscle itself (myocardium), the sac in which it is contained (pericardium), the arteries feeding it (coronary arteries and arterioles), and its electrical conduction system. The manifestations of cardiac involvement vary depending on the affected part of the heart and can include chest pain, shortness of breath, hearth rhythm abnormalities (arrhythmias) and inability of the heart to pump blood forward optimally (heart failure). Kidneys
The most significant renal manifestation of systemic scleroderma is scleroderma renal crisis (SRC). It is characterized by abrupt onset on severe high blood pressure (hypertension), renal failure, and abnormal protein excretion in the urine (proteinuria). Another feature of SRC is microangiopathic hemolytic anemia (MAHA). In this condition, the platelets present in the blood excessively form clots in small vessels. When red blood cells travel in these vessels, they get sheared by the platelet clots (hemolysis). MAHA therefore leads to a decreased number of red blood cells (anemia) and platelets (thrombocytopenia). Others
In addition to symptoms described above, people living with systemic scleroderma commonly experience fatigue, anxiety, sexual dysfunction and concerns with body image. Although the disease is potentially fatal and is associated with an increased risk of mortality, many affected individuals can live long, productive lives. Clinical subsets
Systemic scleroderma is typically divided in four subsets with different clusters of symptoms. Limited cutaneous systemic sclerosis (lcSSc) is associated with skin fibrosis limited to the hands, forearm, feet and face, and usually prominent telangiectasias and calcinosis cutis. People with lcSSc can develop pulmonary arterial hypertension but very rarely develop scleroderma renal crisis and interstitial lung disease. Diffuse cutaneous systemic sclerosis is associated with rapid and diffuse skin fibrosis and early occurrence of renal, cardiac, and pulmonary complications. Systemic sclerosis sine scleroderma involves internal organ involvement of systemic scleroderma without the typical skin involvement. Systemic scleroderma overlap syndrome includes features of other connective tissue diseases such as rheumatoid arthritis or polymyositis and is notable for prominent joint and muscle involvement. Distinguishing the clinical subset of systemic scleroderma in an affected person is important as it can help predict the progression of the disease and the associated complications. However, not all patients fall within a specific subset and overlap between different categories is common.
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Symptoms of Systemic Scleroderma. Systemic scleroderma can affect multiple organ systems and therefore lead to numerous symptoms and complications. The symptoms present, their severity, the rate of progression of the disease, the response to treatment, and overall survival vary widely depending on the affected individual. In most cases, people start to develop symptoms between age 30 and 50. Symptoms related to the different organs involved are described below. Skin
In most people, Raynaud phenomenon (RP) is the first manifestation of the disease. RP is characterized by blood vessel spams (vasospasm) in response to cold or stress. This most often occurs in the fingers and turns them white. Subsequently, as the vessels are occluded and cannot deliver oxygen, the fingers turn blue. This can also lead to severe pain and ulcers. After several minutes (usually 15 to 20), the vasospasms stop and the fingers become red as blood flows again. Another very common symptom of systemic scleroderma is rapid growth of connective tissue in the skin (skin fibrosis). The earliest involved areas are the fingers, hands and face. Symptoms associated with skin fibrosis include tight and dry skin, itching (pruritus), fluid accumulation (edema) and increased or decreased skin pigmentation. Another skin manifestation seen in most patients with scleroderma is telangiectasia. Telangiectasias are small dilated blood vessels that can appear as red lesions visible through the skin. Affected individuals can also develop accumulation of calcium nodules in the fingers, forearm, elbows, and knees. This condition is known as calcinosis cutis and can lead to pain if the nodules are large. Nerves, muscles, and joints
Many individuals living with systemic scleroderma develop muscle, joint, or nerve disease. Muscle involvement can lead to muscle pain, weakness, and muscle wasting (sarcopenia). Affected joints can be painful, stiff, and swollen. Nerve involvement is less common but can lead to burning or tingling sensation or numbness. In some individuals, the autonomic nervous system can be affected. This part of the nervous system is not under voluntarily control and is notably involved in self-regulation of the body. Dysfunction of the autonomic nervous system can lead to symptoms such as dizziness when standing up (orthostasis), inappropriate heart rate response to exertion, and inappropriate sweating.Lungs
The two main pulmonary manifestations of systemic scleroderma are pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). PAH is defined as increased pressure in the arteries of the lungs and can lead to shortness of breath (dyspnea), fatigue, and failure of the right ventricle of the heart, which in turn can cause chest pain, fluid accumulation (edema), and transient loss of consciousness upon exertion (exertional syncope). ILD corresponds to scarring (fibrosis) of lung tissue, which prevents lung expansion and gas exchange. The two main symptoms of ILD are progressive dyspnea and dry cough. PAH and ILD are progressive conditions and can eventually become life-threatening. Taken together, they account for about half of all deaths related to systemic scleroderma. Gastrointestinal tract
The most commonly involved part of the gastrointestinal tract in systemic scleroderma is the esophagus. In affected individuals, the esophagus is unable to contract efficiently (esophageal dismotility) to allow food to reach the stomach. In addition, the lower esophageal sphincter (LES), which is a circular muscle between the esophagus and the stomach, is not able to close properly. The combination of esophageal dismotility and LES incompetence can lead to heartburn due to acid reflux (a condition known as gastroesophageal reflux disease; GERD), choking on food, and difficulty swallowing (dysphagia). Fibrosis of the rest of the gastrointestinal can prevent food from moving through properly (pseudo-obstruction), which can promote bacterial growth and lead to pain, bloating, constipation, diarrhea, and fecal incontinence. Gastrointestinal bleeding also occurs in some patients due to dilation of veins in the stomach (gastric venous ectasias).Heart
Systemic scleroderma can affect many parts of the heart, including the heart muscle itself (myocardium), the sac in which it is contained (pericardium), the arteries feeding it (coronary arteries and arterioles), and its electrical conduction system. The manifestations of cardiac involvement vary depending on the affected part of the heart and can include chest pain, shortness of breath, hearth rhythm abnormalities (arrhythmias) and inability of the heart to pump blood forward optimally (heart failure). Kidneys
The most significant renal manifestation of systemic scleroderma is scleroderma renal crisis (SRC). It is characterized by abrupt onset on severe high blood pressure (hypertension), renal failure, and abnormal protein excretion in the urine (proteinuria). Another feature of SRC is microangiopathic hemolytic anemia (MAHA). In this condition, the platelets present in the blood excessively form clots in small vessels. When red blood cells travel in these vessels, they get sheared by the platelet clots (hemolysis). MAHA therefore leads to a decreased number of red blood cells (anemia) and platelets (thrombocytopenia). Others
In addition to symptoms described above, people living with systemic scleroderma commonly experience fatigue, anxiety, sexual dysfunction and concerns with body image. Although the disease is potentially fatal and is associated with an increased risk of mortality, many affected individuals can live long, productive lives. Clinical subsets
Systemic scleroderma is typically divided in four subsets with different clusters of symptoms. Limited cutaneous systemic sclerosis (lcSSc) is associated with skin fibrosis limited to the hands, forearm, feet and face, and usually prominent telangiectasias and calcinosis cutis. People with lcSSc can develop pulmonary arterial hypertension but very rarely develop scleroderma renal crisis and interstitial lung disease. Diffuse cutaneous systemic sclerosis is associated with rapid and diffuse skin fibrosis and early occurrence of renal, cardiac, and pulmonary complications. Systemic sclerosis sine scleroderma involves internal organ involvement of systemic scleroderma without the typical skin involvement. Systemic scleroderma overlap syndrome includes features of other connective tissue diseases such as rheumatoid arthritis or polymyositis and is notable for prominent joint and muscle involvement. Distinguishing the clinical subset of systemic scleroderma in an affected person is important as it can help predict the progression of the disease and the associated complications. However, not all patients fall within a specific subset and overlap between different categories is common.
| 1,187 |
Systemic Scleroderma
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nord_1187_2
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Causes of Systemic Scleroderma
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Although the exact cause and disease mechanism of systemic scleroderma are not known, it is thought to occur in genetically predisposed individuals following a trigger, possibly exposure to virus or toxins. Systemic scleroderma is an autoimmune disease, which means that it involves a dysregulated immune system that attacks the affected individual’s own body. The first event to occur is possibly injury to small blood vessels (microvascular injury). In healthy individuals, response to injury leads to recruitment of inflammatory mediators that facilitate repair. In individuals with systemic scleroderma, microvascular injury leads to disproportionate inflammatory mediator recruitment and excessive fibrous tissue deposition. This fibrous tissue can replace healthy tissue and lead to symptoms of systemic scleroderma such as skin thickening, internal organ scarring and associated complications.
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Causes of Systemic Scleroderma. Although the exact cause and disease mechanism of systemic scleroderma are not known, it is thought to occur in genetically predisposed individuals following a trigger, possibly exposure to virus or toxins. Systemic scleroderma is an autoimmune disease, which means that it involves a dysregulated immune system that attacks the affected individual’s own body. The first event to occur is possibly injury to small blood vessels (microvascular injury). In healthy individuals, response to injury leads to recruitment of inflammatory mediators that facilitate repair. In individuals with systemic scleroderma, microvascular injury leads to disproportionate inflammatory mediator recruitment and excessive fibrous tissue deposition. This fibrous tissue can replace healthy tissue and lead to symptoms of systemic scleroderma such as skin thickening, internal organ scarring and associated complications.
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Affects of Systemic Scleroderma
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Systemic scleroderma affects between 38 and 341 individuals per million throughout the world (prevalence) and develops in 8 to 56 individuals per million each year (incidence). It is more common in populations from southern Europe, North America and Australia, and less common in populations from northern Europe and Japan. The disease most often starts to manifest in the fifth decade of life (age of onset). Although it most commonly occurs in women, men tend to have more severe disease. African American individuals tend to have a lower age of onset, higher rates of the diffuse cutaneous subtype, and overall more severe disease.
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Affects of Systemic Scleroderma. Systemic scleroderma affects between 38 and 341 individuals per million throughout the world (prevalence) and develops in 8 to 56 individuals per million each year (incidence). It is more common in populations from southern Europe, North America and Australia, and less common in populations from northern Europe and Japan. The disease most often starts to manifest in the fifth decade of life (age of onset). Although it most commonly occurs in women, men tend to have more severe disease. African American individuals tend to have a lower age of onset, higher rates of the diffuse cutaneous subtype, and overall more severe disease.
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Related disorders of Systemic Scleroderma
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Symptoms of the following disorders may be similar to those of systemic scleroderma. Comparisons may be useful for a differential diagnosis:Localized scleroderma (also known as morphea) is characterized by skin symptoms similar to those seen in systemic scleroderma but without internal organ involvement. It is considered a disease distinct from systemic scleroderma.Polymyositis is a type of inflammatory muscle disease (myopathy) characterized by inflammatory and degenerative changes in the muscles, leading to symmetric weakness and some degree of muscle wasting (atrophy). The areas principally affected include the muscles closest to and within the trunk of the body such as the hip, shoulders, arms, pharynx and neck. Polymyositis occurs most often in women over 20 years of age, but men can also be affected. Muscle weakness usually happens over days, weeks or months. Some affected people have muscle pain, breathing problems, and trouble swallowing. (For more information, choose “polymyositis” as your search term in the Rare Disease Database.) Dermatomyositis is characterized by muscle involvement similar to what is seen in polymyositis but also involves the skin. Associated skin abnormalities often include a distinctive reddish-purple rash (heliotrope rash) on the upper eyelid or across the cheeks and bridge of the nose in a “butterfly” distribution and on the forehead and scalp. Other characteristic rashes include scaling and redness of the knuckles, elbows, knees, and/or other extensor regions (Gottron papules and sign); an abnormal accumulation of fluid (edema) in body tissues surrounding the eyes; and/or other features. (For more information on this disorder choose “dermatomyositis” as your search term in the Rare Disease Database.)Systemic lupus erythematosus (SLE; lupus) is a chronic autoimmune disease affecting multiple organ systems. The symptoms are variable depending on the affected individual and can overlap with those seen in systemic scleroderma. Common disease manifestations include fatigue, joint pain (arthralgia), muscle pain (myalgia), facial (butterfly) rash, and kidney disease. The gastrointestinal tract, lungs, heart, and central nervous system can also be affected. Mixed connective tissue disease (MTCD) is an uncommon systemic inflammatory rheumatic disease. MCTD is a specific subset of the broader category of rheumatic “overlap syndromes”, a term used to describe when a patient has features of more than one classic inflammatory rheumatic disease. These classic rheumatic diseases include systemic lupus erythematosus, polymyositis, systemic scleroderma, and rheumatoid arthritis. Common symptoms seen in affected individuals include Raynaud phenomenon, joint pain (arthralgia) or inflammation (arthritis), muscle weakness and inflammation (myositis), and involvement of internal organs such as the gastrointestinal tract, lung, heart, and kidneys. (For more information on this disorder choose “mixed connective tissue disease” as your search term in the Rare Disease Database.)Amyloidosis is a group of disorders characterized by accumulation of abnormally folded protein (amyloid) that can occur throughout the body. It can occur as a disorder of its own or in the context of another predisposing disorder. Amyloid deposition in the skin can lead to swelling and easy bruising. Joint and muscle pain can also result from amyloid deposition. As with systemic scleroderma, internal organ involvement can occur and can notably lead to renal, cardiac, pulmonary, and nervous system disease. (For more information on this disorder choose “amyloidosis” as your search term in the Rare Disease Database.)
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Related disorders of Systemic Scleroderma. Symptoms of the following disorders may be similar to those of systemic scleroderma. Comparisons may be useful for a differential diagnosis:Localized scleroderma (also known as morphea) is characterized by skin symptoms similar to those seen in systemic scleroderma but without internal organ involvement. It is considered a disease distinct from systemic scleroderma.Polymyositis is a type of inflammatory muscle disease (myopathy) characterized by inflammatory and degenerative changes in the muscles, leading to symmetric weakness and some degree of muscle wasting (atrophy). The areas principally affected include the muscles closest to and within the trunk of the body such as the hip, shoulders, arms, pharynx and neck. Polymyositis occurs most often in women over 20 years of age, but men can also be affected. Muscle weakness usually happens over days, weeks or months. Some affected people have muscle pain, breathing problems, and trouble swallowing. (For more information, choose “polymyositis” as your search term in the Rare Disease Database.) Dermatomyositis is characterized by muscle involvement similar to what is seen in polymyositis but also involves the skin. Associated skin abnormalities often include a distinctive reddish-purple rash (heliotrope rash) on the upper eyelid or across the cheeks and bridge of the nose in a “butterfly” distribution and on the forehead and scalp. Other characteristic rashes include scaling and redness of the knuckles, elbows, knees, and/or other extensor regions (Gottron papules and sign); an abnormal accumulation of fluid (edema) in body tissues surrounding the eyes; and/or other features. (For more information on this disorder choose “dermatomyositis” as your search term in the Rare Disease Database.)Systemic lupus erythematosus (SLE; lupus) is a chronic autoimmune disease affecting multiple organ systems. The symptoms are variable depending on the affected individual and can overlap with those seen in systemic scleroderma. Common disease manifestations include fatigue, joint pain (arthralgia), muscle pain (myalgia), facial (butterfly) rash, and kidney disease. The gastrointestinal tract, lungs, heart, and central nervous system can also be affected. Mixed connective tissue disease (MTCD) is an uncommon systemic inflammatory rheumatic disease. MCTD is a specific subset of the broader category of rheumatic “overlap syndromes”, a term used to describe when a patient has features of more than one classic inflammatory rheumatic disease. These classic rheumatic diseases include systemic lupus erythematosus, polymyositis, systemic scleroderma, and rheumatoid arthritis. Common symptoms seen in affected individuals include Raynaud phenomenon, joint pain (arthralgia) or inflammation (arthritis), muscle weakness and inflammation (myositis), and involvement of internal organs such as the gastrointestinal tract, lung, heart, and kidneys. (For more information on this disorder choose “mixed connective tissue disease” as your search term in the Rare Disease Database.)Amyloidosis is a group of disorders characterized by accumulation of abnormally folded protein (amyloid) that can occur throughout the body. It can occur as a disorder of its own or in the context of another predisposing disorder. Amyloid deposition in the skin can lead to swelling and easy bruising. Joint and muscle pain can also result from amyloid deposition. As with systemic scleroderma, internal organ involvement can occur and can notably lead to renal, cardiac, pulmonary, and nervous system disease. (For more information on this disorder choose “amyloidosis” as your search term in the Rare Disease Database.)
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Diagnosis of Systemic Scleroderma
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Systemic scleroderma is a complex disorder that can be difficult to diagnose. In most cases, the diagnosis starts with a complete patient history and physical examination. If systemic scleroderma is suspected, laboratories test can be ordered. Notably, certain antibodies reacting against components of an individual’s body (autoantibodies) can be identified in systemic scleroderma. Antinuclear antibodies are present in approximately 95% of individuals. However, they are also present in other autoimmune conditions and in healthy individuals. Antitopoisomerase I (anti-Scl-70) antibodies and anti-RNA polymerase III antibodies are associated with dcSSc, while anticentromere antibodies can be seen in lcSSc. If antibodies titers are indicative of systemic scleroderma, specific tests will be performed to confirm the diagnosis and evaluate for internal organ involvement. Pulmonary function tests (PFTs) are breathing tests used to assess the lungs capacity to move air and diffuse it to the blood. They are often complemented by a computed tomography (CT) scan of the chest to visually assess the structure of the lungs. The heart and pulmonary arteries can be imaged with cardiac echocardiography, which uses ultrasound waves to reconstruct and visualize anatomical structures. Renal function can notably be evaluated by measuring creatinine levels in the blood and by urine analysis. Further testing might be indicated depending on the symptoms and characteristics of the affected individual.
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Diagnosis of Systemic Scleroderma. Systemic scleroderma is a complex disorder that can be difficult to diagnose. In most cases, the diagnosis starts with a complete patient history and physical examination. If systemic scleroderma is suspected, laboratories test can be ordered. Notably, certain antibodies reacting against components of an individual’s body (autoantibodies) can be identified in systemic scleroderma. Antinuclear antibodies are present in approximately 95% of individuals. However, they are also present in other autoimmune conditions and in healthy individuals. Antitopoisomerase I (anti-Scl-70) antibodies and anti-RNA polymerase III antibodies are associated with dcSSc, while anticentromere antibodies can be seen in lcSSc. If antibodies titers are indicative of systemic scleroderma, specific tests will be performed to confirm the diagnosis and evaluate for internal organ involvement. Pulmonary function tests (PFTs) are breathing tests used to assess the lungs capacity to move air and diffuse it to the blood. They are often complemented by a computed tomography (CT) scan of the chest to visually assess the structure of the lungs. The heart and pulmonary arteries can be imaged with cardiac echocardiography, which uses ultrasound waves to reconstruct and visualize anatomical structures. Renal function can notably be evaluated by measuring creatinine levels in the blood and by urine analysis. Further testing might be indicated depending on the symptoms and characteristics of the affected individual.
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Therapies of Systemic Scleroderma
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Treatment & Management As there is no cure for systemic scleroderma, management of the disease is mostly centered on symptom control and screening to detect and better control complications. Patients usually require long-term regular follow-up with numerous medical specialists. As systemic scleroderma is an autoimmune disease, medications that suppress the immune system (immunosuppressants) can be used, especially in severe cases with diffuse skin involvement, interstitial lung disease, inflammation of the heart muscle (myocarditis) and severe muscle or joint inflammation. Immunosuppressants used in systemic scleroderma include methotrexate, mycophenolate mofetil (MMF), and azathioprine. Glucocorticoids such as prednisone are also occasionally used in some patients, but their use is generally avoided if possible due to the risk of side effects. Skin, muscles, joints, and nerve
As mentioned above, patients with widespread skin involvement or severe muscle or joint inflammation might benefit from immunosuppressants. Those with Raynaud phenomenon are most commonly treated with calcium channel blockers such as Norvasc (amlodipine) and Procardia XL (nifedipine). Calcinosis cutis might be managed with a class of medications known as bisphosphonates, which are often used for the treatment of osteoporosis, while larger calcium deposits might need to be removed surgically. Pigmentary changes such as telangiectasias can be treated with laser therapy. Rheumatologists will be involved in the management of these symptoms, and dermatologists can contribute to the treatment of skin disease. Neurologists might also be involved to evaluate and treat neurologic complications of the disease. For instance, pain medication such as Lyrica (pregabalin) or Neurontin (gabapentin) can be prescribed in patient with burning pain because of nerve damage (neuropathic pain). Lungs
Early recognition of interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) with appropriate diagnostic methods (described in the “diagnosis” section) are crucial to initiate treatment as soon as possible. ILD has traditionally been treated with immunosuppressants. In 2019, Ofev (nintedanib) was approved by the Food and Drug Administration (FDA) to slow the rate of decline in pulmonary function in adults with ILD associated with systemic scleroderma (SSc-ILD). PAH is mainly treated with medication, such as Flolan (epoprostenol) or Tracleer (bosentan) that aims to decrease the constriction of pulmonary arteries. Respirologists are physicians that will manage the respiratory complications of individuals living with systemic scleroderma. Surgeons will also be part of the treating team in cases of very severe pulmonary disease, where lung transplantation can be considered. Gastrointestinal tract
The majority of patients with systemic scleroderma are treated with medication, such as Protonix (pantoprazole), that decreases acid production by the stomach. Some patients are also prescribed medication that increase gastrointestinal motility such as Reglan (metoclopramide) or Motilium (domperidone). Antibiotics can be used in patients with gastrointestinal bacterial overgrowth and associated symptoms. Gastroenterologists will often be involved, especially if other gastrointestinal manifestations that require more specific treatments are present. Heart
The treatment of systemic scleroderma-associated cardiac disease will depend on the specific cardiac manifestation that is present. Heart failure might require a specific kind of medication, known as ACE inhibitors (for instance, perindopril), that is used for high blood pressure, and medications that make the patient urinate (diuretics), such as Lasix (furosemide), to decrease fluid overload. As described above, immunosuppressants can be used in individuals with myocarditis. Cardiologists are the physician that will follow systemic scleroderma patients to manage potential cardiac complications. Kidneys
In addition to supportive management, ACE inhibitors are the mainstay of treatment for scleroderma renal crisis (SRC). Of note, chronic high doses of glucocorticoids are associated with an increased risk of SRC, which is another reason why their use is limited as much as possible in systemic scleroderma. In severe cases of SRC, dialysis and even renal transplantation might be required if renal function does not improve after the crisis. Nephrologists are physicians specialized in the diagnosis and management of kidney (renal) diseases. Others
Depending on the affected individual and their needs, other professionals will be involved such as nurses, social workers, physiotherapists, occupational therapists, and psychologists.
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Therapies of Systemic Scleroderma. Treatment & Management As there is no cure for systemic scleroderma, management of the disease is mostly centered on symptom control and screening to detect and better control complications. Patients usually require long-term regular follow-up with numerous medical specialists. As systemic scleroderma is an autoimmune disease, medications that suppress the immune system (immunosuppressants) can be used, especially in severe cases with diffuse skin involvement, interstitial lung disease, inflammation of the heart muscle (myocarditis) and severe muscle or joint inflammation. Immunosuppressants used in systemic scleroderma include methotrexate, mycophenolate mofetil (MMF), and azathioprine. Glucocorticoids such as prednisone are also occasionally used in some patients, but their use is generally avoided if possible due to the risk of side effects. Skin, muscles, joints, and nerve
As mentioned above, patients with widespread skin involvement or severe muscle or joint inflammation might benefit from immunosuppressants. Those with Raynaud phenomenon are most commonly treated with calcium channel blockers such as Norvasc (amlodipine) and Procardia XL (nifedipine). Calcinosis cutis might be managed with a class of medications known as bisphosphonates, which are often used for the treatment of osteoporosis, while larger calcium deposits might need to be removed surgically. Pigmentary changes such as telangiectasias can be treated with laser therapy. Rheumatologists will be involved in the management of these symptoms, and dermatologists can contribute to the treatment of skin disease. Neurologists might also be involved to evaluate and treat neurologic complications of the disease. For instance, pain medication such as Lyrica (pregabalin) or Neurontin (gabapentin) can be prescribed in patient with burning pain because of nerve damage (neuropathic pain). Lungs
Early recognition of interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) with appropriate diagnostic methods (described in the “diagnosis” section) are crucial to initiate treatment as soon as possible. ILD has traditionally been treated with immunosuppressants. In 2019, Ofev (nintedanib) was approved by the Food and Drug Administration (FDA) to slow the rate of decline in pulmonary function in adults with ILD associated with systemic scleroderma (SSc-ILD). PAH is mainly treated with medication, such as Flolan (epoprostenol) or Tracleer (bosentan) that aims to decrease the constriction of pulmonary arteries. Respirologists are physicians that will manage the respiratory complications of individuals living with systemic scleroderma. Surgeons will also be part of the treating team in cases of very severe pulmonary disease, where lung transplantation can be considered. Gastrointestinal tract
The majority of patients with systemic scleroderma are treated with medication, such as Protonix (pantoprazole), that decreases acid production by the stomach. Some patients are also prescribed medication that increase gastrointestinal motility such as Reglan (metoclopramide) or Motilium (domperidone). Antibiotics can be used in patients with gastrointestinal bacterial overgrowth and associated symptoms. Gastroenterologists will often be involved, especially if other gastrointestinal manifestations that require more specific treatments are present. Heart
The treatment of systemic scleroderma-associated cardiac disease will depend on the specific cardiac manifestation that is present. Heart failure might require a specific kind of medication, known as ACE inhibitors (for instance, perindopril), that is used for high blood pressure, and medications that make the patient urinate (diuretics), such as Lasix (furosemide), to decrease fluid overload. As described above, immunosuppressants can be used in individuals with myocarditis. Cardiologists are the physician that will follow systemic scleroderma patients to manage potential cardiac complications. Kidneys
In addition to supportive management, ACE inhibitors are the mainstay of treatment for scleroderma renal crisis (SRC). Of note, chronic high doses of glucocorticoids are associated with an increased risk of SRC, which is another reason why their use is limited as much as possible in systemic scleroderma. In severe cases of SRC, dialysis and even renal transplantation might be required if renal function does not improve after the crisis. Nephrologists are physicians specialized in the diagnosis and management of kidney (renal) diseases. Others
Depending on the affected individual and their needs, other professionals will be involved such as nurses, social workers, physiotherapists, occupational therapists, and psychologists.
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Overview of Takotsubo Cardiomyopathy
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SummaryTakotsubo cardiomyopathy is a heart disease characterized by transient dysfunction and ballooning of the left ventricle of the heart. It mostly affects elderly women and is often triggered by severe physical or emotional stress. The symptoms are similar to those of a heart attack (myocardial infarction) and include chest pain, difficulty breathing (dyspnea), and sometimes transient loss of consciousness (syncope). Although complications can occur, most individuals fully recover within one month. The treatment of takotsubo cardiomyopathy is focused on symptom control and the prevention and treatment of associated complications.IntroductionThe role of the heart is to act as a pump to make sure blood is appropriately oxygenated and able to feed the body. The heart as four chambers: two small atria (left and right), which are located on top of the heart, and two larger ventricles (also left and right), which are located below the atria and act as the main pump of the heart. Blood flows in the body the following way: 1) Blood in the left ventricle is ejected into the aorta, which redistributes oxygenated blood throughout the body 2) Oxygen in the blood is extracted by organs and deoxygenated blood comes back in the right atrium of the heart via the veins 3) Deoxygenated blood in the right atrium falls into the right ventricle 3) Deoxygenated blood is ejected from the right ventricle into the pulmonary arteries, where it will be able to take oxygen from the lungs 4) Oxygenated blood comes back to the left atrium via the pulmonary veins 5) Oxygenated blood in the left atrium falls into the left ventricle of the heart, where the cycle can start again.Takotsubo cardiomyopathy is a type of disease of cardiac muscle (cardiomyopathy) that is characterized by dysfunction and ballooning of a portion of the left ventricle of the heart, most often its tip (apex). It was first identified in Japan in the 1990s and was named after Japanese octopus traps (takotsubo) that are shaped similarly to the heart of affected individuals. Since that time, the condition has been recognized in individuals all over the world.
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Overview of Takotsubo Cardiomyopathy. SummaryTakotsubo cardiomyopathy is a heart disease characterized by transient dysfunction and ballooning of the left ventricle of the heart. It mostly affects elderly women and is often triggered by severe physical or emotional stress. The symptoms are similar to those of a heart attack (myocardial infarction) and include chest pain, difficulty breathing (dyspnea), and sometimes transient loss of consciousness (syncope). Although complications can occur, most individuals fully recover within one month. The treatment of takotsubo cardiomyopathy is focused on symptom control and the prevention and treatment of associated complications.IntroductionThe role of the heart is to act as a pump to make sure blood is appropriately oxygenated and able to feed the body. The heart as four chambers: two small atria (left and right), which are located on top of the heart, and two larger ventricles (also left and right), which are located below the atria and act as the main pump of the heart. Blood flows in the body the following way: 1) Blood in the left ventricle is ejected into the aorta, which redistributes oxygenated blood throughout the body 2) Oxygen in the blood is extracted by organs and deoxygenated blood comes back in the right atrium of the heart via the veins 3) Deoxygenated blood in the right atrium falls into the right ventricle 3) Deoxygenated blood is ejected from the right ventricle into the pulmonary arteries, where it will be able to take oxygen from the lungs 4) Oxygenated blood comes back to the left atrium via the pulmonary veins 5) Oxygenated blood in the left atrium falls into the left ventricle of the heart, where the cycle can start again.Takotsubo cardiomyopathy is a type of disease of cardiac muscle (cardiomyopathy) that is characterized by dysfunction and ballooning of a portion of the left ventricle of the heart, most often its tip (apex). It was first identified in Japan in the 1990s and was named after Japanese octopus traps (takotsubo) that are shaped similarly to the heart of affected individuals. Since that time, the condition has been recognized in individuals all over the world.
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Symptoms of Takotsubo Cardiomyopathy
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Takotsubo cardiomyopathy can occur in adults of any age, but most often develops in elderly women. The most common symptoms are the abrupt (acute) onset of crushing chest pain and difficulty breathing (dyspnea). Anxiety, sweating (diaphoresis), nausea, vomiting, palpitations, and transient loss of consciousness (syncope) can also occur.Most individuals that develop takotsubo cardiomyopathy fully recover within one month, and recurrence is rare. However, complications occur in about 20% of patients. In some individuals, the heart might be unable to pump blood efficiently (heart failure), which can lead to fatigue, dyspnea, and leg and abdomen swelling due to fluid accumulation (edema). In severe cases, cardiac dysfunction might prevent organs from receiving adequate oxygen supply (cardiogenic shock). Takotsubo cardiomyopathy can also lead to an irregular, too fast, or too slow heartbeat (arrhythmia). Another possible complication is pooling of blood in the heart, which promotes clot formation. These clots can be expulsed from the heart and lodge into arteries of the brain, which can lead to a stroke. Despite the possibility of complications, more than 90% of affected individuals survive takotsubo cardiomyopathy.
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Symptoms of Takotsubo Cardiomyopathy. Takotsubo cardiomyopathy can occur in adults of any age, but most often develops in elderly women. The most common symptoms are the abrupt (acute) onset of crushing chest pain and difficulty breathing (dyspnea). Anxiety, sweating (diaphoresis), nausea, vomiting, palpitations, and transient loss of consciousness (syncope) can also occur.Most individuals that develop takotsubo cardiomyopathy fully recover within one month, and recurrence is rare. However, complications occur in about 20% of patients. In some individuals, the heart might be unable to pump blood efficiently (heart failure), which can lead to fatigue, dyspnea, and leg and abdomen swelling due to fluid accumulation (edema). In severe cases, cardiac dysfunction might prevent organs from receiving adequate oxygen supply (cardiogenic shock). Takotsubo cardiomyopathy can also lead to an irregular, too fast, or too slow heartbeat (arrhythmia). Another possible complication is pooling of blood in the heart, which promotes clot formation. These clots can be expulsed from the heart and lodge into arteries of the brain, which can lead to a stroke. Despite the possibility of complications, more than 90% of affected individuals survive takotsubo cardiomyopathy.
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Causes of Takotsubo Cardiomyopathy
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The mechanism by which takotsubo cardiomyopathy develops in not entirely understood. In about 2/3 of cases, the disease is preceded by intense emotional stress (such as divorce, death of a loved one, or bankruptcy) or physical stress (such as a stroke, fracture, or infection). A hypothesis is that these stressors lead to the release of large amounts of adrenaline (epinephrine) and other stress-related hormones collectively known as catecholamines. This surge of hormones might lead to spasms of the blood vessels and disruption of the ventricles of the heart, which would be responsible for the ventricular dysfunction and ballooning seen in takotsubo cardiomyopathy.
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Causes of Takotsubo Cardiomyopathy. The mechanism by which takotsubo cardiomyopathy develops in not entirely understood. In about 2/3 of cases, the disease is preceded by intense emotional stress (such as divorce, death of a loved one, or bankruptcy) or physical stress (such as a stroke, fracture, or infection). A hypothesis is that these stressors lead to the release of large amounts of adrenaline (epinephrine) and other stress-related hormones collectively known as catecholamines. This surge of hormones might lead to spasms of the blood vessels and disruption of the ventricles of the heart, which would be responsible for the ventricular dysfunction and ballooning seen in takotsubo cardiomyopathy.
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Affects of Takotsubo Cardiomyopathy
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Takotsubo cardiomyopathy can develop in men and women of any age and ethnic background. However, about 90% of affected individuals are women, and 80% are women over the age of 50. The exact frequency of the disease is not known and might be underestimated, but is thought to comprise approximately 2% of all individuals (and up to 5% of women) with suspected ST-segment elevation myocardial infarction, which is the most severe type of heart attack. This represents more than 4000 individuals in the United States.
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Affects of Takotsubo Cardiomyopathy. Takotsubo cardiomyopathy can develop in men and women of any age and ethnic background. However, about 90% of affected individuals are women, and 80% are women over the age of 50. The exact frequency of the disease is not known and might be underestimated, but is thought to comprise approximately 2% of all individuals (and up to 5% of women) with suspected ST-segment elevation myocardial infarction, which is the most severe type of heart attack. This represents more than 4000 individuals in the United States.
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Related disorders of Takotsubo Cardiomyopathy
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Angina is a condition caused by limitation of blood flow to the heart. It is usually caused by partial obstruction of the arteries that feed the heart (coronary arteries) by a fatty plaque (atheroma), but can also rarely be caused by spasms of the arteries (vasospastic angina). Angina is usually triggered by exercise or stress and is relieved by rest, except in the case of vasospastic angina, which occurs at rest. The main symptom of angina is chest pain, which patients usually describe as a squeezing, pressure, or tightness. It is often accompanied by difficulty breathing (dyspnea), sweating (diaphoresis), nausea, and anxiety. Angina that occurs at rest, lasts longer than before, becomes more frequent, or becomes more intense is known as unstable angina.Acute myocardial infarction (MI) also called heart attack, often progresses from angina and is characterized by a total or almost total obstruction of a coronary artery, most commonly by a blood clot (thrombus) that forms after rupture of a fatty plaque. The clinical presentation of acute MI is undistinguishable from takotsubo cardiomyopathy and includes crushing chest pain, difficulty breathing (dyspnea), sweating (diaphoresis), nausea, and anxiety. As acute MI is a much more common condition than takotsubo cardiomyopathy, diagnostic testing (described in the following section) has to be performed to exclude the possibility of a myocardial infarction in all patients presenting with the symptoms described above.Myocarditis is a rare cause of cardiovascular disease that primarily manifests as sudden death, chest pain or heart failure. The symptoms of myocarditis are not specific to the disease and are similar to symptoms of more common heart disorders. A sensation of tightness or squeezing in the chest that is present with rest and with exertion is common. The cause of myocarditis is an inflammation of the heart muscle, most often following a viral infection. (For more information on this disorder, choose “myocarditis” as your search term in the Rare Disease Database.)Pheochromocytoma is a rare type of tumor that arises from certain cells known as chromaffin cells, which produce hormones necessary for the body to function properly. Most pheochromocytomas originate in one of the two adrenal glands located above the kidneys in the back of the upper abdomen. Symptoms associated with pheochromocytomas occur because of the release of catecholamines. Symptoms include high blood pressure (hypertension), pain in the chest or abdomen, nausea, vomiting, diarrhea, constipation, pallor, weakness, and weight loss. In addition, some cases of a takotsubo-like cardiomyopathy have been reported in individuals with a pheochromocytoma. (For more information on this disorder, choose “pheochromocytoma” as your search term in the Rare Disease Database.)
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Related disorders of Takotsubo Cardiomyopathy. Angina is a condition caused by limitation of blood flow to the heart. It is usually caused by partial obstruction of the arteries that feed the heart (coronary arteries) by a fatty plaque (atheroma), but can also rarely be caused by spasms of the arteries (vasospastic angina). Angina is usually triggered by exercise or stress and is relieved by rest, except in the case of vasospastic angina, which occurs at rest. The main symptom of angina is chest pain, which patients usually describe as a squeezing, pressure, or tightness. It is often accompanied by difficulty breathing (dyspnea), sweating (diaphoresis), nausea, and anxiety. Angina that occurs at rest, lasts longer than before, becomes more frequent, or becomes more intense is known as unstable angina.Acute myocardial infarction (MI) also called heart attack, often progresses from angina and is characterized by a total or almost total obstruction of a coronary artery, most commonly by a blood clot (thrombus) that forms after rupture of a fatty plaque. The clinical presentation of acute MI is undistinguishable from takotsubo cardiomyopathy and includes crushing chest pain, difficulty breathing (dyspnea), sweating (diaphoresis), nausea, and anxiety. As acute MI is a much more common condition than takotsubo cardiomyopathy, diagnostic testing (described in the following section) has to be performed to exclude the possibility of a myocardial infarction in all patients presenting with the symptoms described above.Myocarditis is a rare cause of cardiovascular disease that primarily manifests as sudden death, chest pain or heart failure. The symptoms of myocarditis are not specific to the disease and are similar to symptoms of more common heart disorders. A sensation of tightness or squeezing in the chest that is present with rest and with exertion is common. The cause of myocarditis is an inflammation of the heart muscle, most often following a viral infection. (For more information on this disorder, choose “myocarditis” as your search term in the Rare Disease Database.)Pheochromocytoma is a rare type of tumor that arises from certain cells known as chromaffin cells, which produce hormones necessary for the body to function properly. Most pheochromocytomas originate in one of the two adrenal glands located above the kidneys in the back of the upper abdomen. Symptoms associated with pheochromocytomas occur because of the release of catecholamines. Symptoms include high blood pressure (hypertension), pain in the chest or abdomen, nausea, vomiting, diarrhea, constipation, pallor, weakness, and weight loss. In addition, some cases of a takotsubo-like cardiomyopathy have been reported in individuals with a pheochromocytoma. (For more information on this disorder, choose “pheochromocytoma” as your search term in the Rare Disease Database.)
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Diagnosis of Takotsubo Cardiomyopathy
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Typically, individuals with takotsubo cardiomyopathy present with symptoms undistinguishable from a myocardial infarction and will therefore be considered to have a heart attack until proven otherwise. The two most common and useful initial tests for an individual with symptoms suggesting an acute MI is an electrocardiogram (ECG), which measures electrical activity of the heart, and blood troponin levels, which is a marker of damage to the heart. In takotsubo cardiomyopathy, the ECG shows changes that are typically seen in a ST-segment elevation myocardial infarction (the most severe type of heart attack), and troponin levels are elevated, as they also are in an MI. However, when coronary angiography (a medical imagining technique in which a dye is injected into the coronary arteries to visualize them with radiographs) is performed in individuals with takotsubo cardiomyopathy, no significant coronary artery occlusion is seen. Ventricular dysfunction and ballooning can be identified with ventriculography (which uses the same principles as coronary angiography but allows visualization of the ventricles), or echocardiography (which uses ultrasound waves to make visualization of the heart possible). Cardiac magnetic resonance imaging (MRI) is a specialized imaging technique that can occasionally be used to diagnose takotsubo cardiomyopathy and assess the extent of ventricular dysfunction and ballooning.
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Diagnosis of Takotsubo Cardiomyopathy. Typically, individuals with takotsubo cardiomyopathy present with symptoms undistinguishable from a myocardial infarction and will therefore be considered to have a heart attack until proven otherwise. The two most common and useful initial tests for an individual with symptoms suggesting an acute MI is an electrocardiogram (ECG), which measures electrical activity of the heart, and blood troponin levels, which is a marker of damage to the heart. In takotsubo cardiomyopathy, the ECG shows changes that are typically seen in a ST-segment elevation myocardial infarction (the most severe type of heart attack), and troponin levels are elevated, as they also are in an MI. However, when coronary angiography (a medical imagining technique in which a dye is injected into the coronary arteries to visualize them with radiographs) is performed in individuals with takotsubo cardiomyopathy, no significant coronary artery occlusion is seen. Ventricular dysfunction and ballooning can be identified with ventriculography (which uses the same principles as coronary angiography but allows visualization of the ventricles), or echocardiography (which uses ultrasound waves to make visualization of the heart possible). Cardiac magnetic resonance imaging (MRI) is a specialized imaging technique that can occasionally be used to diagnose takotsubo cardiomyopathy and assess the extent of ventricular dysfunction and ballooning.
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Therapies of Takotsubo Cardiomyopathy
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Treatment & Management
Although there is no standard treatment for takotsubo cardiomyopathy, most individuals fully recover within 1 month. Research has shown that the use of angiotensin-converting–enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARB), which are two class of medication used to treat high blood pressure, might improve survival after the condition has resolved. Many patients are prescribed beta-blockers, a class of medication that decreases the activating effects of catecholamines on the heart. However, there is no scientific evidence proving the use of beta-blockers improves survival in takotsubo cardiomyopathy. The management of the disease is mostly centered on symptom control and prevention and treatment of associated complications (supportive therapy). Patients that develop heart failure are usually treated with medication that stimulate the production of urine to eliminate excess fluid (diuretics) and medication that dilate blood vessels (vasodilators) to decrease the blood pressure the heart has to pump against. Fluid resuscitation might be required in those that develop cardiogenic shock. In some patients, blood thinners (anticoagulants) might be administered to prevent the formation of blood clots (thrombus). Pain control and addressing emotional and physical stressors that might have played a role in the development of the condition are two other important factors to consider.
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Therapies of Takotsubo Cardiomyopathy. Treatment & Management
Although there is no standard treatment for takotsubo cardiomyopathy, most individuals fully recover within 1 month. Research has shown that the use of angiotensin-converting–enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARB), which are two class of medication used to treat high blood pressure, might improve survival after the condition has resolved. Many patients are prescribed beta-blockers, a class of medication that decreases the activating effects of catecholamines on the heart. However, there is no scientific evidence proving the use of beta-blockers improves survival in takotsubo cardiomyopathy. The management of the disease is mostly centered on symptom control and prevention and treatment of associated complications (supportive therapy). Patients that develop heart failure are usually treated with medication that stimulate the production of urine to eliminate excess fluid (diuretics) and medication that dilate blood vessels (vasodilators) to decrease the blood pressure the heart has to pump against. Fluid resuscitation might be required in those that develop cardiogenic shock. In some patients, blood thinners (anticoagulants) might be administered to prevent the formation of blood clots (thrombus). Pain control and addressing emotional and physical stressors that might have played a role in the development of the condition are two other important factors to consider.
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Overview of TANC2-Related Disorders
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Summary
TANC2-related disorders are categorized as a neurodevelopmental syndrome with associated psychiatric findings. This condition is caused by changes (disease-causing variants) in the TANC2 gene. Characteristics of this disorder include autism, developmental delay, seizures, sleep disturbances, attention-deficit/hyperactivity disorder (ADHD) and intellectual disability. It is important to note that these features can also have different genetic causes.TANC2-related disorders are reported to have variable expressivity, meaning there is a range of symptoms that can occur in people affected with this genetic condition. In addition to the symptoms mentioned above, common symptoms include delayed motor development, delayed speech development and some patients have been reported with seizures (epilepsy). Additional features seen in patients affected with TANC2-related disorders are chronic constipation, distinct facial features that vary within a family and walking difficulties. The average age of onset for many symptoms begins in childhood. Introduction
TANC2-related disorders were first defined in 2019, therefore, this disorder has a wide and evolving spectrum of neurodevelopmental and psychiatric symptoms. The TANC2 gene holds instructions for creating (encoding) a protein called TANC2. This protein helps control connections between brain cells (synapse scaffold proteins). Having proper support for the synapse allows nerve cells to respond to stimuli. Genetic changes in the TANC2 gene lead to abnormally shaped proteins that cause the cells to not respond to stimuli. When nerve cells are not able to respond properly to signals, it can lead to the symptoms associated with TANC2-related disorders.
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Overview of TANC2-Related Disorders. Summary
TANC2-related disorders are categorized as a neurodevelopmental syndrome with associated psychiatric findings. This condition is caused by changes (disease-causing variants) in the TANC2 gene. Characteristics of this disorder include autism, developmental delay, seizures, sleep disturbances, attention-deficit/hyperactivity disorder (ADHD) and intellectual disability. It is important to note that these features can also have different genetic causes.TANC2-related disorders are reported to have variable expressivity, meaning there is a range of symptoms that can occur in people affected with this genetic condition. In addition to the symptoms mentioned above, common symptoms include delayed motor development, delayed speech development and some patients have been reported with seizures (epilepsy). Additional features seen in patients affected with TANC2-related disorders are chronic constipation, distinct facial features that vary within a family and walking difficulties. The average age of onset for many symptoms begins in childhood. Introduction
TANC2-related disorders were first defined in 2019, therefore, this disorder has a wide and evolving spectrum of neurodevelopmental and psychiatric symptoms. The TANC2 gene holds instructions for creating (encoding) a protein called TANC2. This protein helps control connections between brain cells (synapse scaffold proteins). Having proper support for the synapse allows nerve cells to respond to stimuli. Genetic changes in the TANC2 gene lead to abnormally shaped proteins that cause the cells to not respond to stimuli. When nerve cells are not able to respond properly to signals, it can lead to the symptoms associated with TANC2-related disorders.
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Symptoms of TANC2-Related Disorders
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Individuals with TANC2-related disorders have a spectrum of neurodevelopmental conditions. These can include autism, intellectual disability, language delays and motor delays. There have been reports of patients with a TANC2 genetic change having seizures. In these patients, brain imaging is typically normal. Some adult patients display psychiatric conditions such as schizophrenia, bipolar disorder and compulsive behavior. Dysregulation of non-voluntary body functions (dysautonomia) has also been documented. Low blood pressure, feeling faint, excessive or lack of sweating, fatigue, trouble swallowing, fast or slow heart rate, anxiety and drooling are all symptoms of dysautonomia. Other reported features of TANC2-related disorders include chronic constipation; walking difficulties; differences in facial features (widely spaced front teeth, large ears, thick eyebrows, large mouth); smaller head size (microcephaly) and sleep disturbances.
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Symptoms of TANC2-Related Disorders. Individuals with TANC2-related disorders have a spectrum of neurodevelopmental conditions. These can include autism, intellectual disability, language delays and motor delays. There have been reports of patients with a TANC2 genetic change having seizures. In these patients, brain imaging is typically normal. Some adult patients display psychiatric conditions such as schizophrenia, bipolar disorder and compulsive behavior. Dysregulation of non-voluntary body functions (dysautonomia) has also been documented. Low blood pressure, feeling faint, excessive or lack of sweating, fatigue, trouble swallowing, fast or slow heart rate, anxiety and drooling are all symptoms of dysautonomia. Other reported features of TANC2-related disorders include chronic constipation; walking difficulties; differences in facial features (widely spaced front teeth, large ears, thick eyebrows, large mouth); smaller head size (microcephaly) and sleep disturbances.
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Causes of TANC2-Related Disorders
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TANC2-related disorders are caused by changes (pathogenic variants) in the TANC2 gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working in the body. Depending on the function of the protein, it can affect different parts of the body. Typically, the genetic change in TANC2 is new in the patient (de novo). This means that it was not inherited from either parent. However, there have been rare instances of a patient inheriting a pathogenic variant in the TANC2 gene from a parent.The TANC2 gene holds instructions for creating (encoding) a protein called tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2 (TANC2). This protein interacts with postsynaptic density (PSD) proteins. PSD proteins are attached to the surface of the postsynaptic membrane that receives chemical signals and sends signals to target cells. Target cells can include nerve cells or muscle cells. Healthy PSD proteins facilitate sending signals constantly between cells. In short, the TANC2 protein helps the brain communicate within the brain and with other body parts. Genetic changes in the TANC2 gene lead to abnormally shaped TANC2 proteins that cause the cells to not respond to stimuli. When nerve cells are not able to respond properly to signals, it can lead to the symptoms associated with TANC2-related disorders.TANC2-related disorders follow an autosomal dominant pattern of inheritance. This means that an individual only needs a single pathogenic variant (referred to also as heterozygous) in the TANC2 gene to cause medical problems. The non-working gene can be inherited from either parent or can be the result of a new genetic change in the individual (known as de novo). Males and females have the same level of risk, and the risk of passing a non-working gene to offspring is 50% for each pregnancy.
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Causes of TANC2-Related Disorders. TANC2-related disorders are caused by changes (pathogenic variants) in the TANC2 gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working in the body. Depending on the function of the protein, it can affect different parts of the body. Typically, the genetic change in TANC2 is new in the patient (de novo). This means that it was not inherited from either parent. However, there have been rare instances of a patient inheriting a pathogenic variant in the TANC2 gene from a parent.The TANC2 gene holds instructions for creating (encoding) a protein called tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2 (TANC2). This protein interacts with postsynaptic density (PSD) proteins. PSD proteins are attached to the surface of the postsynaptic membrane that receives chemical signals and sends signals to target cells. Target cells can include nerve cells or muscle cells. Healthy PSD proteins facilitate sending signals constantly between cells. In short, the TANC2 protein helps the brain communicate within the brain and with other body parts. Genetic changes in the TANC2 gene lead to abnormally shaped TANC2 proteins that cause the cells to not respond to stimuli. When nerve cells are not able to respond properly to signals, it can lead to the symptoms associated with TANC2-related disorders.TANC2-related disorders follow an autosomal dominant pattern of inheritance. This means that an individual only needs a single pathogenic variant (referred to also as heterozygous) in the TANC2 gene to cause medical problems. The non-working gene can be inherited from either parent or can be the result of a new genetic change in the individual (known as de novo). Males and females have the same level of risk, and the risk of passing a non-working gene to offspring is 50% for each pregnancy.
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Affects of TANC2-Related Disorders
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In 2019, Hui Guo, et al reported the first 20 patients with known disease-causing (pathogenic) TANC2 variants. TANC2-related disorder is extremely rare. The number of people affected by these disorders is unknown. Rare disorders like TANC2-related disorders often go undiagnosed or misdiagnosed, making it extremely difficult to determine their true frequency in the general population.
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Affects of TANC2-Related Disorders. In 2019, Hui Guo, et al reported the first 20 patients with known disease-causing (pathogenic) TANC2 variants. TANC2-related disorder is extremely rare. The number of people affected by these disorders is unknown. Rare disorders like TANC2-related disorders often go undiagnosed or misdiagnosed, making it extremely difficult to determine their true frequency in the general population.
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Related disorders of TANC2-Related Disorders
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There are many neurodevelopmental disorders that can cause signs and symptoms similar to those seen in people with TANC2-related disorders. Genetic changes in TBR1 (intellectual developmental disorder with autism and speech delay), CNOT3 (intellectual developmental disorder with speech delay, autism and dysmorphic facies), and JARID2 (developmental delay with variable intellectual disability and dysmorphic facies) are just a few examples.
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Related disorders of TANC2-Related Disorders. There are many neurodevelopmental disorders that can cause signs and symptoms similar to those seen in people with TANC2-related disorders. Genetic changes in TBR1 (intellectual developmental disorder with autism and speech delay), CNOT3 (intellectual developmental disorder with speech delay, autism and dysmorphic facies), and JARID2 (developmental delay with variable intellectual disability and dysmorphic facies) are just a few examples.
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Diagnosis of TANC2-Related Disorders
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A diagnosis of TANC2-related disorder is based on molecular genetic testing results that show a disease-causing (pathogenic) variant in the TANC2 gene. A clinical diagnosis cannot be used for this disorder.
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Diagnosis of TANC2-Related Disorders. A diagnosis of TANC2-related disorder is based on molecular genetic testing results that show a disease-causing (pathogenic) variant in the TANC2 gene. A clinical diagnosis cannot be used for this disorder.
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Therapies of TANC2-Related Disorders
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There is currently no cure for TANC2-related disorders. Treatment is based on the medical problems that are present in an affected person. Due to the rarity of this condition, treatments have not been studied in a large group of patients. There are no standardized treatment protocols or guidelines for affected individuals. A multidisciplinary team of pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders (neurologists), speech pathologists, physical therapists and other healthcare professionals can be involved in care. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Management can include speech and language therapy; occupational therapy; physical therapy; neurodevelopmental assessments for academic ability; gastrointestinal evaluation to assess for constipation and prescription of antiepileptic medications.
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Therapies of TANC2-Related Disorders. There is currently no cure for TANC2-related disorders. Treatment is based on the medical problems that are present in an affected person. Due to the rarity of this condition, treatments have not been studied in a large group of patients. There are no standardized treatment protocols or guidelines for affected individuals. A multidisciplinary team of pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders (neurologists), speech pathologists, physical therapists and other healthcare professionals can be involved in care. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Management can include speech and language therapy; occupational therapy; physical therapy; neurodevelopmental assessments for academic ability; gastrointestinal evaluation to assess for constipation and prescription of antiepileptic medications.
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Overview of Tangier Disease
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Tangier disease is a rare inherited disorder characterized by significantly reduced levels of high-density lipoproteins (HDL) in the blood. HDL-cholesterol (HDL-C) is often referred to as the “good cholesterol” as it can facilitate the removal of cholesterol out of the walls of arteries, particularly the coronary (heart) arteries. Classic features of Tangier disease include fatty accumulations that present as enlarged and yellow- or orange-colored tonsils, or enlarged liver (hepatomegaly), spleen (splenomegaly), or lymph nodes. Tangier disease may also be associated with an increased risk of cardiovascular disease, moderate elevation in triglycerides (hypertriglyceridemia), nerve disturbances (neuropathy), and rarely an opaqueness in the covering of the eye (corneal clouding). This disorder was originally named after the location in which it was first discovered – Tangier Island in the Chesapeake Bay. Later, the disease was further characterized as more individuals were found to have the disease in other areas of the United States and around the globe.
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Overview of Tangier Disease. Tangier disease is a rare inherited disorder characterized by significantly reduced levels of high-density lipoproteins (HDL) in the blood. HDL-cholesterol (HDL-C) is often referred to as the “good cholesterol” as it can facilitate the removal of cholesterol out of the walls of arteries, particularly the coronary (heart) arteries. Classic features of Tangier disease include fatty accumulations that present as enlarged and yellow- or orange-colored tonsils, or enlarged liver (hepatomegaly), spleen (splenomegaly), or lymph nodes. Tangier disease may also be associated with an increased risk of cardiovascular disease, moderate elevation in triglycerides (hypertriglyceridemia), nerve disturbances (neuropathy), and rarely an opaqueness in the covering of the eye (corneal clouding). This disorder was originally named after the location in which it was first discovered – Tangier Island in the Chesapeake Bay. Later, the disease was further characterized as more individuals were found to have the disease in other areas of the United States and around the globe.
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Symptoms of Tangier Disease
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Symptoms of Tangier disease are variable and depend on which organs are involved and the severity of those manifestations. Tangier disease is most often characterized by enlarged orange- or yellow-colored tonsils. This discoloration is due to fatty deposits accumulating in the tonsils. Fatty deposits can also form in other organs causing enlargement of the throat, liver, spleen, or lymph nodes. Fat accumulations in nerves can cause disturbances and loss-of-sensation called peripheral neuropathy. Discoloration may also occur in the digestive system, particularly the rectum and large intestine. Cardiovascular disease has been reported in adults with Tangier disease. In rare cases, a clouding of the cornea of the eye can occur, but is generally mild and does not cause vision impairment.
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Symptoms of Tangier Disease. Symptoms of Tangier disease are variable and depend on which organs are involved and the severity of those manifestations. Tangier disease is most often characterized by enlarged orange- or yellow-colored tonsils. This discoloration is due to fatty deposits accumulating in the tonsils. Fatty deposits can also form in other organs causing enlargement of the throat, liver, spleen, or lymph nodes. Fat accumulations in nerves can cause disturbances and loss-of-sensation called peripheral neuropathy. Discoloration may also occur in the digestive system, particularly the rectum and large intestine. Cardiovascular disease has been reported in adults with Tangier disease. In rare cases, a clouding of the cornea of the eye can occur, but is generally mild and does not cause vision impairment.
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Causes of Tangier Disease
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Tangier disease is an autosomal recessive genetic disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for Tangier disease, the individual will be a carrier for the disease but will not show the classic characteristics. However, carriers of Tangier disease often are found to have relatively low levels of HDL-C.The risk for two carrier parents to both pass the altered gene and 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 is 25%. The risk is the same for males and females. 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. The gene that causes Tangier disease has been identified as ABCA1 (ATP-binding cassette transporter A1). ABCA1 codes for a cell surface protein that is important in the process of reverse cholesterol transport, which allows the movement of cholesterol from inside the cell to apolipoprotein AI (apoA-I), the major protein constituent of HDL. When two ABCA1 gene mutations are present, the cell is no longer able to efflux cholesterol out of the cell to ApoA-I. Cholesterol is a soft, waxy substance found among the lipids (fats) in the bloodstream and in all the cells in our body. Cholesterol is essential to the formation of cell membranes, hormones, and other cellular functions. Cholesterol and other fats cannot dissolve in the blood and have to be transported to and from the cells by special carriers called lipoproteins. There are several types of lipoproteins that vary in density, but the most clinically important types are low-density lipoprotein (LDL) and HDL. About one-third to one-fourth of blood cholesterol is carried by HDL. HDL is commonly called the “good” cholesterol because it may be involved with the removal of cholesterol from the artery walls and ultimate disposal to the liver. On the other hand, LDL deposits cholesterol in the artery walls, causing the formation of cholesterol plaque.Patients with Tangier disease have been found to have a severe reduction in HDL levels. Without sufficient HDL to help clear arteries of plaques, individuals are more susceptible to having excess lipid deposits on organs of the body such as liver, heart, spleen, lymph nodes, and brain.
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Causes of Tangier Disease. Tangier disease is an autosomal recessive genetic disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for Tangier disease, the individual will be a carrier for the disease but will not show the classic characteristics. However, carriers of Tangier disease often are found to have relatively low levels of HDL-C.The risk for two carrier parents to both pass the altered gene and 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 is 25%. The risk is the same for males and females. 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. The gene that causes Tangier disease has been identified as ABCA1 (ATP-binding cassette transporter A1). ABCA1 codes for a cell surface protein that is important in the process of reverse cholesterol transport, which allows the movement of cholesterol from inside the cell to apolipoprotein AI (apoA-I), the major protein constituent of HDL. When two ABCA1 gene mutations are present, the cell is no longer able to efflux cholesterol out of the cell to ApoA-I. Cholesterol is a soft, waxy substance found among the lipids (fats) in the bloodstream and in all the cells in our body. Cholesterol is essential to the formation of cell membranes, hormones, and other cellular functions. Cholesterol and other fats cannot dissolve in the blood and have to be transported to and from the cells by special carriers called lipoproteins. There are several types of lipoproteins that vary in density, but the most clinically important types are low-density lipoprotein (LDL) and HDL. About one-third to one-fourth of blood cholesterol is carried by HDL. HDL is commonly called the “good” cholesterol because it may be involved with the removal of cholesterol from the artery walls and ultimate disposal to the liver. On the other hand, LDL deposits cholesterol in the artery walls, causing the formation of cholesterol plaque.Patients with Tangier disease have been found to have a severe reduction in HDL levels. Without sufficient HDL to help clear arteries of plaques, individuals are more susceptible to having excess lipid deposits on organs of the body such as liver, heart, spleen, lymph nodes, and brain.
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Affects of Tangier Disease
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Tangier disease is a rare disorder with only approximately 100 cases diagnosed worldwide. Tangier disease is thought to be present at birth, but the age of diagnosis can be highly variable (from infancy through 7th decade) due to the nature of symptoms.
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Affects of Tangier Disease. Tangier disease is a rare disorder with only approximately 100 cases diagnosed worldwide. Tangier disease is thought to be present at birth, but the age of diagnosis can be highly variable (from infancy through 7th decade) due to the nature of symptoms.
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Related disorders of Tangier Disease
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Symptoms of the following disorders can be similar to those of multiple sclerosis. Comparisons may be useful for a differential diagnosis:Familial hypoalphalipoproteinemia
LCAT deficiency
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Related disorders of Tangier Disease. Symptoms of the following disorders can be similar to those of multiple sclerosis. Comparisons may be useful for a differential diagnosis:Familial hypoalphalipoproteinemia
LCAT deficiency
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Diagnosis of Tangier Disease
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Diagnosis of Tangier disease is achieved through clinical evaluation and can be confirmed through genetic testing involving the sequencing of the ABCA1 gene. HDL-C deficiency and an extremely low apolipoprotein A1 (ApoA1) level are typical diagnostic criteria.
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Diagnosis of Tangier Disease. Diagnosis of Tangier disease is achieved through clinical evaluation and can be confirmed through genetic testing involving the sequencing of the ABCA1 gene. HDL-C deficiency and an extremely low apolipoprotein A1 (ApoA1) level are typical diagnostic criteria.
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Therapies of Tangier Disease
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Treatment
Treatment of Tangier disease is supportive and based on specific disease manifestations in a given individual. There are no known specific treatments for Tangier disease. Surgical removal of the spleen, tonsils, or other enlarged tissues may become necessary in some patients. It is suggested that management of Tangier disease should include regular assessment of cardiovascular risk and neurological and ophthalmological examination.Genetic counseling is recommended for families of patients with Tangier disease.
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Therapies of Tangier Disease. Treatment
Treatment of Tangier disease is supportive and based on specific disease manifestations in a given individual. There are no known specific treatments for Tangier disease. Surgical removal of the spleen, tonsils, or other enlarged tissues may become necessary in some patients. It is suggested that management of Tangier disease should include regular assessment of cardiovascular risk and neurological and ophthalmological examination.Genetic counseling is recommended for families of patients with Tangier disease.
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Overview of TANGO2 Deficiency Disorder
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TANGO2 deficiency disorder is a rare genetic disorder caused by disease causing changes in the TANGO2 gene. Affected individuals experience episodes of acute illness called metabolic crises. These episodes can be triggered, often by a preceding infection or from decreased oral intake or fasting for an extended period of time. Irregularities in the rhythm of the heart (arrhythmias), the breakdown of muscle tissue (rhabdomyolysis) and other complications can occur during an episode. The term encephalopathy is a general term for brain disease. Neurological problems including intellectual disability and delays in reaching developmental milestones can occur. Additional signs and symptoms can occur both within and outside of metabolic crisis. TANGO2 deficiency can affect people very differently. There is no cure for the disorder, but research is underway to better understand and treat this disease. Current treatment is aimed at the specific symptoms present in each individual.
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Overview of TANGO2 Deficiency Disorder. TANGO2 deficiency disorder is a rare genetic disorder caused by disease causing changes in the TANGO2 gene. Affected individuals experience episodes of acute illness called metabolic crises. These episodes can be triggered, often by a preceding infection or from decreased oral intake or fasting for an extended period of time. Irregularities in the rhythm of the heart (arrhythmias), the breakdown of muscle tissue (rhabdomyolysis) and other complications can occur during an episode. The term encephalopathy is a general term for brain disease. Neurological problems including intellectual disability and delays in reaching developmental milestones can occur. Additional signs and symptoms can occur both within and outside of metabolic crisis. TANGO2 deficiency can affect people very differently. There is no cure for the disorder, but research is underway to better understand and treat this disease. Current treatment is aimed at the specific symptoms present in each individual.
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Symptoms of TANGO2 Deficiency Disorder
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Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the basis of these symptoms remains unclear. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.TANGO2 deficiency is a variable disorder. This means that how the disorder affects people can vary greatly from one affected individual to another. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals can first experience episodes of acute illness called metabolic crisis. Affected individuals often present with symptoms before a metabolic crisis is apparent. These symptoms can include delays in reaching developmental milestones (developmental delays) and regression, poor gait coordination, clumsiness, low functioning thyroid gland (hypothyroidism) or seizures. Episodic symptoms termed as TANGO2 spells can be seen in many individuals characterized by sudden onset of head tilt, body tilt, inability to walk properly, loss of coordination, significant leg tightness and extreme fatigue.During a metabolic crisis there can be low blood sugar (hypoglycemia, elevated liver enzymes (transaminitis), elevated creatinine kinase and troponin (enzymes found in skeletal and heart muscle) and a buildup of toxic substances including ammonia (hyperammonemia) and lactic acid in the blood (lactic acidosis). A metabolic crisis is often triggered, usually by illness or from eating poorly or fasting for an extended period of time. Stress or dehydration can also trigger an episode. A metabolic crisis may develop rapidly (acutely) and can cause profound muscle weakness, loss of coordination (ataxia), disorientation and, in severe instances, unconsciousness (comatose state).During a metabolic crisis, individuals develop a condition called rhabdomyolysis, in which muscle tissue breaks down. Muscle pain (myalgia), muscle weakness and fatigue can develop. When muscle tissue breaks down, it produces substances that are released into the body including creatinine kinase (CK) and a protein called myoglobulin. Myoglobin can build up in the urine (myoglobinuria). This can cause the urine to appear dark brown. Myoglobinuria can potentially lead to damage of the kidneys. The kidneys have several functions in the body including filtering waste products from the blood. Myoglobulins can cause obstruction of tiny structures in the kidneys called tubules, which damages the kidney. Kidney damage can cause decreased kidney function and eventually kidney failure.During an acute illness, affected individuals may develop irregular heart rhythms (arrhythmias), abnormalities in the resting electrocardiogram (ECG), and decreased ability for the heart to pump (cardiac dysfunction). All children should have a baseline ECG and echocardiogram which should be followed and repeated during crisis. The most common abnormality during an acute crisis is QT prolongation. Prolongation of the QT interval refers to a change seen on the ECG. QT prolongation predisposes affected individuals to an increased risk of life-threatening rhythm disturbances, specifically ventricular tachycardia or torsade de pointes. These abnormal rhythms originate from the bottom pumping chamber of the heart. In addition to the QT prolongation, some affected individuals also develop Brugada type I changes in their ECG, which is a specific pattern in the ECG that also predisposes the individuals to life-threatening heart rhythm problems (ventricular tachycardia and ventricular fibrillation). While QT prolongation persists until the crisis has resolved, Brugada changes can come and go and thus ECGs and telemetry (which is active bedside monitoring of the electrical activity of the heart during hospitalization) should be monitored throughout the crisis. These arrhythmias can lead to sudden loss of consciousness (syncope), cardiac arrest, and potentially cause sudden cardiac death.Arrhythmias that occur during metabolic crisis develop rapidly and can be extremely difficult to manage. Arrhythmias are the leading cause of death among children affected by TANGO2 gene alterations. In addition to arrhythmias, the heart muscle can develop dysfunction (cardiomyopathy). This means the heart can develop heart failure, meaning the heart cannot pump well. It is therefore important that all children in crisis be followed by specialists, who have expertise in heart arrhythmia and cardiomyopathy disorders.Affected individuals will also have neurodevelopmental problems including intellectual disability, seizures and problems coordinating voluntary movements (ataxia) causing clumsiness and an unsteady way of walking (unsteady gait) and difficulty with speech (dysarthria). Intellectual disability can range in severity from mild to moderate to severe.. Many affected individuals experience developmental delay, or they experience the loss of developmental milestones that they have already reached (regression). About half of the affected individuals have seizures that usually respond to medications. In a subset of children, these can be difficult to control. In addition, muscle weakness can result in sporadic head or body tilting and difficulty opening the eyelids and drooling and difficulty swallowing. These episodes can come and go within hours. Some individuals have increased muscle tone in their legs, which can cause muscles to be tight even at rest. Some children are noted to walk on their toes. Some children may have a reduced ability to stretch. Increased muscle tone can lead to spasticity. Some individuals have low function of the thyroid (hypothyroidism). The thyroid is a butterfly-shaped gland located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities such as the heart rate, body temperature and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. Symptoms of hypothyroidism in children can include fatigue, constipation, low muscle tone and growth delay.Additional symptoms that have been reported include exaggerated or heightened reflexes (hyperreflexia) and temporary misalignment of the eyes where one or both eyes are turned outward away from the nose (exotropia). In rare instances, affected children have developed sensorineural hearing loss. Sensorineural hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain.
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Symptoms of TANGO2 Deficiency Disorder. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the basis of these symptoms remains unclear. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.TANGO2 deficiency is a variable disorder. This means that how the disorder affects people can vary greatly from one affected individual to another. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals can first experience episodes of acute illness called metabolic crisis. Affected individuals often present with symptoms before a metabolic crisis is apparent. These symptoms can include delays in reaching developmental milestones (developmental delays) and regression, poor gait coordination, clumsiness, low functioning thyroid gland (hypothyroidism) or seizures. Episodic symptoms termed as TANGO2 spells can be seen in many individuals characterized by sudden onset of head tilt, body tilt, inability to walk properly, loss of coordination, significant leg tightness and extreme fatigue.During a metabolic crisis there can be low blood sugar (hypoglycemia, elevated liver enzymes (transaminitis), elevated creatinine kinase and troponin (enzymes found in skeletal and heart muscle) and a buildup of toxic substances including ammonia (hyperammonemia) and lactic acid in the blood (lactic acidosis). A metabolic crisis is often triggered, usually by illness or from eating poorly or fasting for an extended period of time. Stress or dehydration can also trigger an episode. A metabolic crisis may develop rapidly (acutely) and can cause profound muscle weakness, loss of coordination (ataxia), disorientation and, in severe instances, unconsciousness (comatose state).During a metabolic crisis, individuals develop a condition called rhabdomyolysis, in which muscle tissue breaks down. Muscle pain (myalgia), muscle weakness and fatigue can develop. When muscle tissue breaks down, it produces substances that are released into the body including creatinine kinase (CK) and a protein called myoglobulin. Myoglobin can build up in the urine (myoglobinuria). This can cause the urine to appear dark brown. Myoglobinuria can potentially lead to damage of the kidneys. The kidneys have several functions in the body including filtering waste products from the blood. Myoglobulins can cause obstruction of tiny structures in the kidneys called tubules, which damages the kidney. Kidney damage can cause decreased kidney function and eventually kidney failure.During an acute illness, affected individuals may develop irregular heart rhythms (arrhythmias), abnormalities in the resting electrocardiogram (ECG), and decreased ability for the heart to pump (cardiac dysfunction). All children should have a baseline ECG and echocardiogram which should be followed and repeated during crisis. The most common abnormality during an acute crisis is QT prolongation. Prolongation of the QT interval refers to a change seen on the ECG. QT prolongation predisposes affected individuals to an increased risk of life-threatening rhythm disturbances, specifically ventricular tachycardia or torsade de pointes. These abnormal rhythms originate from the bottom pumping chamber of the heart. In addition to the QT prolongation, some affected individuals also develop Brugada type I changes in their ECG, which is a specific pattern in the ECG that also predisposes the individuals to life-threatening heart rhythm problems (ventricular tachycardia and ventricular fibrillation). While QT prolongation persists until the crisis has resolved, Brugada changes can come and go and thus ECGs and telemetry (which is active bedside monitoring of the electrical activity of the heart during hospitalization) should be monitored throughout the crisis. These arrhythmias can lead to sudden loss of consciousness (syncope), cardiac arrest, and potentially cause sudden cardiac death.Arrhythmias that occur during metabolic crisis develop rapidly and can be extremely difficult to manage. Arrhythmias are the leading cause of death among children affected by TANGO2 gene alterations. In addition to arrhythmias, the heart muscle can develop dysfunction (cardiomyopathy). This means the heart can develop heart failure, meaning the heart cannot pump well. It is therefore important that all children in crisis be followed by specialists, who have expertise in heart arrhythmia and cardiomyopathy disorders.Affected individuals will also have neurodevelopmental problems including intellectual disability, seizures and problems coordinating voluntary movements (ataxia) causing clumsiness and an unsteady way of walking (unsteady gait) and difficulty with speech (dysarthria). Intellectual disability can range in severity from mild to moderate to severe.. Many affected individuals experience developmental delay, or they experience the loss of developmental milestones that they have already reached (regression). About half of the affected individuals have seizures that usually respond to medications. In a subset of children, these can be difficult to control. In addition, muscle weakness can result in sporadic head or body tilting and difficulty opening the eyelids and drooling and difficulty swallowing. These episodes can come and go within hours. Some individuals have increased muscle tone in their legs, which can cause muscles to be tight even at rest. Some children are noted to walk on their toes. Some children may have a reduced ability to stretch. Increased muscle tone can lead to spasticity. Some individuals have low function of the thyroid (hypothyroidism). The thyroid is a butterfly-shaped gland located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities such as the heart rate, body temperature and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. Symptoms of hypothyroidism in children can include fatigue, constipation, low muscle tone and growth delay.Additional symptoms that have been reported include exaggerated or heightened reflexes (hyperreflexia) and temporary misalignment of the eyes where one or both eyes are turned outward away from the nose (exotropia). In rare instances, affected children have developed sensorineural hearing loss. Sensorineural hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain.
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Causes of TANGO2 Deficiency Disorder
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TANGO2 deficiency is caused by variations in the TANGO) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When alteration 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. Researchers are not sure what the protein produced (encoded) by the TANGO2 gene does. It may have a role in secretory protein loading within the endoplasmic reticulum, which is an extensive membrane network found within certain cells where proteins are processed. Studies also indicate that it may play a role in synthesis of lipids, important for cell functions. The penetrance of disease-causing variations in the TANGO2 gene is believed to be 100%. That means everyone who has disease causing changes in both copies of the TANGO2 gene will eventually develop some type of associated sign or symptom of the disorder. Variations in this gene also have variable expressivity, which means the signs and symptoms can differ among affected individuals. Consequently, the severity of the disorder may vary among affected individuals.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. 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 gene variant 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 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 TANGO2 Deficiency Disorder. TANGO2 deficiency is caused by variations in the TANGO) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When alteration 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. Researchers are not sure what the protein produced (encoded) by the TANGO2 gene does. It may have a role in secretory protein loading within the endoplasmic reticulum, which is an extensive membrane network found within certain cells where proteins are processed. Studies also indicate that it may play a role in synthesis of lipids, important for cell functions. The penetrance of disease-causing variations in the TANGO2 gene is believed to be 100%. That means everyone who has disease causing changes in both copies of the TANGO2 gene will eventually develop some type of associated sign or symptom of the disorder. Variations in this gene also have variable expressivity, which means the signs and symptoms can differ among affected individuals. Consequently, the severity of the disorder may vary among affected individuals.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. 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 gene variant 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
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Affects of TANGO2 Deficiency Disorder
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TANGO2 deficiency is a rare disorder that was first reported in the medical literature in 2016. According to the TANGO2 Research Foundation, as of January 2023, over 100 individuals have been identified with the disorder worldwide. Based on the known carrier frequency of TANGO2 changes in different populations, it is likely that over 8,000 individuals are affected with TANGO2 deficiency in the world. Rare diseases often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Affects of TANGO2 Deficiency Disorder. TANGO2 deficiency is a rare disorder that was first reported in the medical literature in 2016. According to the TANGO2 Research Foundation, as of January 2023, over 100 individuals have been identified with the disorder worldwide. Based on the known carrier frequency of TANGO2 changes in different populations, it is likely that over 8,000 individuals are affected with TANGO2 deficiency in the world. Rare diseases often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Related disorders of TANGO2 Deficiency Disorder
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Symptoms of the following disorders can be similar to those of TANGO2-deficiency. Comparisons may be useful for a differential diagnosis.Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism that is inherited in an autosomal recessive pattern. It occurs when an enzyme needed to break down certain very long-chain fatty acids is missing or not working properly. VLCADD is one of the metabolic diseases known as fatty acid oxidation (FOD) diseases. The breakdown of fatty acids takes place in the mitochondria found in each cell. The mitochondria are small, well-defined bodies that are found in the cytoplasm of cells and in which energy is generated from the breakdown of complex substances into simpler ones (mitochondrial oxidation). Classically, three forms of VLCADD have been described: an early-onset, severe form which, if unrecognized and undiagnosed, may lead to extreme weakness of the heart muscles (cardiomyopathy) and may be life-threatening, a later-onset, milder form that is characterized by repeated bouts of low blood sugar (hypoglycemia), and a later-onset, milder form that is characterized by breakdown of muscle tissue (e.g., rhabdomyolysis). Patients may present with a combination of symptoms and the disorder is best thought of as being a continuum. Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, most VLCADD infants in the United States are being detected in the neonatal period. (For more information on this disorder, choose “VLCADD” as your search term in the Rare Disease Database.)Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprint for essential components of the respiratory chain is mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Additional disorders include that can be mistaken for TANGO2 deficiency include carnitine palmitotyltransferase II deficiency, carnitine acylcarnitine translocase deficiency, acute recurrent myoglobinuria, LPIN1 deficiency, multiple acyl-coenzyme A dehydrogenase deficiency, trifunctional protein deficiency, LCHAD deficiency and various disorders of glycogen/glucose metabolism. (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 TANGO2 Deficiency Disorder. Symptoms of the following disorders can be similar to those of TANGO2-deficiency. Comparisons may be useful for a differential diagnosis.Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism that is inherited in an autosomal recessive pattern. It occurs when an enzyme needed to break down certain very long-chain fatty acids is missing or not working properly. VLCADD is one of the metabolic diseases known as fatty acid oxidation (FOD) diseases. The breakdown of fatty acids takes place in the mitochondria found in each cell. The mitochondria are small, well-defined bodies that are found in the cytoplasm of cells and in which energy is generated from the breakdown of complex substances into simpler ones (mitochondrial oxidation). Classically, three forms of VLCADD have been described: an early-onset, severe form which, if unrecognized and undiagnosed, may lead to extreme weakness of the heart muscles (cardiomyopathy) and may be life-threatening, a later-onset, milder form that is characterized by repeated bouts of low blood sugar (hypoglycemia), and a later-onset, milder form that is characterized by breakdown of muscle tissue (e.g., rhabdomyolysis). Patients may present with a combination of symptoms and the disorder is best thought of as being a continuum. Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, most VLCADD infants in the United States are being detected in the neonatal period. (For more information on this disorder, choose “VLCADD” as your search term in the Rare Disease Database.)Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprint for essential components of the respiratory chain is mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Additional disorders include that can be mistaken for TANGO2 deficiency include carnitine palmitotyltransferase II deficiency, carnitine acylcarnitine translocase deficiency, acute recurrent myoglobinuria, LPIN1 deficiency, multiple acyl-coenzyme A dehydrogenase deficiency, trifunctional protein deficiency, LCHAD deficiency and various disorders of glycogen/glucose metabolism. (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 TANGO2 Deficiency Disorder
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A diagnosis of TANGO2 deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Diagnostic criteria for this disorder have not yet been established.Clinical Testing and Workup
Most individuals are diagnosed through molecular genetic testing. Molecular genetic testing can detect a variation in the TANGO2 gene known to cause TANGO2 deficiency but is available only as a diagnostic service at specialized laboratories.
Advanced imaging techniques such as magnetic resonance imaging (MRI) of the brain may also be performed. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues, including the brain. Physicians use an MRI to obtain a detailed image of a major region of the brain called the cerebrum. Some affected individuals have shown reduced size of the cerebrum within the skull (cerebral volume loss).Other tests may be performed to assess specific symptoms. For example, if seizure activity is seen or suspected – body shaking or staring spells, physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and help to detect seizures. During health the cardiac ECG and echocardiogram are typically normal.
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Diagnosis of TANGO2 Deficiency Disorder. A diagnosis of TANGO2 deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Diagnostic criteria for this disorder have not yet been established.Clinical Testing and Workup
Most individuals are diagnosed through molecular genetic testing. Molecular genetic testing can detect a variation in the TANGO2 gene known to cause TANGO2 deficiency but is available only as a diagnostic service at specialized laboratories.
Advanced imaging techniques such as magnetic resonance imaging (MRI) of the brain may also be performed. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues, including the brain. Physicians use an MRI to obtain a detailed image of a major region of the brain called the cerebrum. Some affected individuals have shown reduced size of the cerebrum within the skull (cerebral volume loss).Other tests may be performed to assess specific symptoms. For example, if seizure activity is seen or suspected – body shaking or staring spells, physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and help to detect seizures. During health the cardiac ECG and echocardiogram are typically normal.
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Therapies of TANGO2 Deficiency Disorder
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Treatment
The treatment of TANGO2 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of metabolic disease in children (pediatric metabolic physicians and geneticists), heart arrhythmias in children (pediatric cardiologists and electrophysiologists), intensive care physicians who specialize in taking care of children in intensive care units, physicians who are experts in the diagnosis and treatment of the brain and central nervous system in children (pediatric neurologists), physicians who specialize in the diagnosis and treatment of hypothyroidism (pediatric endocrinologists), specialists who asses and treat hearing problems (audiologists) 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.Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. However, natural history study data shows that vitamin B complex or multivitamins including all 8 vitamin Bs at the recommended dietary allowance (RDA) may reduce the risk of metabolic crises in children. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with TANGO2 deficiency. A metabolic crisis is a medical emergency that requires prompt treatment. This can include hydration to treat rhabdomyolysis. During a metabolic crisis, physicians should monitor electrolyte levels. Electrolytes are certain salts and minerals that may be found in the body. Affected individuals should be monitored for normal levels of potassium, magnesium and glucose.During a metabolic crisis, treatment of heart rhythm abnormalities can differ depending on the specific type of ECG abnormality that is present. Because nearly all children in crisis have QT prolongation, all drugs that prolong the QT interval should be avoided during crises. Magnesium should be used to maintain levels above 2.2 mg/dl. However, arrhythmias develop rapidly and any child with marked QTc prolongation or premature ventricular contractions (PVCs) should be immediately transferred to an intensive care unit. Single PVCs can be treated with IV magnesium, but any higher-grade arrhythmias or ventricular tachycardia appears to respond best to isoproterenol. Atrial pacing can also be used.Recurrent ventricular tachycardia or torsade de pointes can be treated by cardioversion but will typically recur. As soon as ventricular tachycardia or torsade de pointes is seen, isoproterenol should be considered and quickly administered if possible. Cardiac dysfunction may limit the use of this drug. Cardioversion is a method of restoring heart rhythm to normal, either through electrical shock or with specific medications. Direct current cardioversion is a procedure in which a small electrical charge is delivered to the heart to “shock” it back to normal rhythm. Although currently isoproterenol appears to be the most effective drug choice for ventricular tachycardia, death has occurred despite its use. Because researchers do not completely understand the underlying reason that arrhythmias occur in this disorder, the ideal treatments for heart rhythm problems are not known. Extracorporeal membrane oxygenation (ECMO) is a life support system that can be used as a last resort for arrhythmia management during crises. Some but not all individuals who have had ventricular arrhythmias receive an implantable cardioverter defibrillator (ICD) and its use should be decided by the team and family. Because arrhythmias appear to only occur during metabolic crisis and because these medications can cause hypoglycemia, prophylactic or daily antiarrhythmic medications are not recommended. Some individuals have undergone a cardiac sympathectomy, a surgical procedure in which certain nerves going to the heart are cut or clamped. Whether or not this is a long-term effective treatment is unclear. Hypothyroidism may be treated with a medication called levothyroxine. This medication replaces or provides more of the thyroid hormone that affected individuals are lacking. Seizures may be treated with anti-seizure medications called anticonvulsants or anti-epileptics.Affected children may benefit from occupational, physical and speech therapy. Additional medical, social and/or vocational services including specialized learning programs may be necessary.
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Therapies of TANGO2 Deficiency Disorder. Treatment
The treatment of TANGO2 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of metabolic disease in children (pediatric metabolic physicians and geneticists), heart arrhythmias in children (pediatric cardiologists and electrophysiologists), intensive care physicians who specialize in taking care of children in intensive care units, physicians who are experts in the diagnosis and treatment of the brain and central nervous system in children (pediatric neurologists), physicians who specialize in the diagnosis and treatment of hypothyroidism (pediatric endocrinologists), specialists who asses and treat hearing problems (audiologists) 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.Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. However, natural history study data shows that vitamin B complex or multivitamins including all 8 vitamin Bs at the recommended dietary allowance (RDA) may reduce the risk of metabolic crises in children. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with TANGO2 deficiency. A metabolic crisis is a medical emergency that requires prompt treatment. This can include hydration to treat rhabdomyolysis. During a metabolic crisis, physicians should monitor electrolyte levels. Electrolytes are certain salts and minerals that may be found in the body. Affected individuals should be monitored for normal levels of potassium, magnesium and glucose.During a metabolic crisis, treatment of heart rhythm abnormalities can differ depending on the specific type of ECG abnormality that is present. Because nearly all children in crisis have QT prolongation, all drugs that prolong the QT interval should be avoided during crises. Magnesium should be used to maintain levels above 2.2 mg/dl. However, arrhythmias develop rapidly and any child with marked QTc prolongation or premature ventricular contractions (PVCs) should be immediately transferred to an intensive care unit. Single PVCs can be treated with IV magnesium, but any higher-grade arrhythmias or ventricular tachycardia appears to respond best to isoproterenol. Atrial pacing can also be used.Recurrent ventricular tachycardia or torsade de pointes can be treated by cardioversion but will typically recur. As soon as ventricular tachycardia or torsade de pointes is seen, isoproterenol should be considered and quickly administered if possible. Cardiac dysfunction may limit the use of this drug. Cardioversion is a method of restoring heart rhythm to normal, either through electrical shock or with specific medications. Direct current cardioversion is a procedure in which a small electrical charge is delivered to the heart to “shock” it back to normal rhythm. Although currently isoproterenol appears to be the most effective drug choice for ventricular tachycardia, death has occurred despite its use. Because researchers do not completely understand the underlying reason that arrhythmias occur in this disorder, the ideal treatments for heart rhythm problems are not known. Extracorporeal membrane oxygenation (ECMO) is a life support system that can be used as a last resort for arrhythmia management during crises. Some but not all individuals who have had ventricular arrhythmias receive an implantable cardioverter defibrillator (ICD) and its use should be decided by the team and family. Because arrhythmias appear to only occur during metabolic crisis and because these medications can cause hypoglycemia, prophylactic or daily antiarrhythmic medications are not recommended. Some individuals have undergone a cardiac sympathectomy, a surgical procedure in which certain nerves going to the heart are cut or clamped. Whether or not this is a long-term effective treatment is unclear. Hypothyroidism may be treated with a medication called levothyroxine. This medication replaces or provides more of the thyroid hormone that affected individuals are lacking. Seizures may be treated with anti-seizure medications called anticonvulsants or anti-epileptics.Affected children may benefit from occupational, physical and speech therapy. Additional medical, social and/or vocational services including specialized learning programs may be necessary.
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Overview of Tardive Dyskinesia
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Tardive dyskinesia (TD) is an involuntary neurological movement disorder caused by the use of dopamine receptor blocking drugs that are prescribed to treat certain psychiatric or gastrointestinal conditions. Long-term use of these drugs may produce biochemical abnormalities in the area of the brain known as the striatum. The reasons that some people who take these drugs may get tardive dyskinesia, and some people do not, is unknown. Tardive dystonia is a more severe form of tardive dyskinesia in which slower twisting movements of the neck and trunk muscles are prominent.
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Overview of Tardive Dyskinesia. Tardive dyskinesia (TD) is an involuntary neurological movement disorder caused by the use of dopamine receptor blocking drugs that are prescribed to treat certain psychiatric or gastrointestinal conditions. Long-term use of these drugs may produce biochemical abnormalities in the area of the brain known as the striatum. The reasons that some people who take these drugs may get tardive dyskinesia, and some people do not, is unknown. Tardive dystonia is a more severe form of tardive dyskinesia in which slower twisting movements of the neck and trunk muscles are prominent.
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Symptoms of Tardive Dyskinesia
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Tardive dyskinesia is characterized by involuntary and abnormal movements of the jaw, lips and tongue. Typical symptoms include facial grimacing, sticking out the tongue, sucking or fish-like movements of the mouth. In some cases, the arms and/or legs may also be affected by involuntary rapid, jerking movements (chorea), or slow, writhing movements (athetosis). Symptoms of tardive dystonia include slower, twisting movements of larger muscles of the neck and trunk as well as the face.
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Symptoms of Tardive Dyskinesia. Tardive dyskinesia is characterized by involuntary and abnormal movements of the jaw, lips and tongue. Typical symptoms include facial grimacing, sticking out the tongue, sucking or fish-like movements of the mouth. In some cases, the arms and/or legs may also be affected by involuntary rapid, jerking movements (chorea), or slow, writhing movements (athetosis). Symptoms of tardive dystonia include slower, twisting movements of larger muscles of the neck and trunk as well as the face.
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Causes of Tardive Dyskinesia
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Tardive dyskinesia is caused by long-term use of a class of drugs known as neuroleptics. Neuroleptic drugs are often prescribed for management of certain mental, neurological, or gastrointestinal disorders. Metoclopramide and prochlorperazine are drugs used for chronic gastrointestinal conditions that may cause tardive dyskinesia. Neuroleptic drugs block dopamine receptors in the brain. Dopamine is a neurotransmitter which is a chemical that helps brain cells to communicate. Although most cases occur after a person has taken these drugs for several years, some cases may occur with shorter use of neuroleptic drugs.
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Causes of Tardive Dyskinesia. Tardive dyskinesia is caused by long-term use of a class of drugs known as neuroleptics. Neuroleptic drugs are often prescribed for management of certain mental, neurological, or gastrointestinal disorders. Metoclopramide and prochlorperazine are drugs used for chronic gastrointestinal conditions that may cause tardive dyskinesia. Neuroleptic drugs block dopamine receptors in the brain. Dopamine is a neurotransmitter which is a chemical that helps brain cells to communicate. Although most cases occur after a person has taken these drugs for several years, some cases may occur with shorter use of neuroleptic drugs.
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Affects of Tardive Dyskinesia
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Tardive dyskinesia affects individuals who have been taking neuroleptic drugs for a long period of time. A high percentage of schizophrenic people who have spent long periods of time taking these drugs have a high risk of developing TD. However, neuroleptic drugs are also prescribed for depression, some digestive disorders, and other neurologic illnesses.
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Affects of Tardive Dyskinesia. Tardive dyskinesia affects individuals who have been taking neuroleptic drugs for a long period of time. A high percentage of schizophrenic people who have spent long periods of time taking these drugs have a high risk of developing TD. However, neuroleptic drugs are also prescribed for depression, some digestive disorders, and other neurologic illnesses.
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Related disorders of Tardive Dyskinesia
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Symptoms of the following disorders can be similar to those of Tardive dyskinesia. Comparisons may be useful for a differential diagnosis:Huntington’s Disease (also known as Huntington’s Chorea) is an inherited neurological illness. Those affected experience involuntary movements, loss of motor control, changes in gait, loss of memory, and in some cases, dementia. In general, the first symptoms of HD appear between thirty and fifty years of age. HD runs a progressive course, severely weakening patients usually over a ten to twenty-year period, whereas there is no degeneration in Tardive Dyskinesia. (For more information on this disorder, choose “Huntington” as your search term in the Rare Disease Database.)Cerebral Palsy is a disorder characterized by impaired muscle control or coordination (motor output system) resulting from injury to the brain during its early stages of development (the fetal, perinatal, or early childhood stages). There may be associated problems with sensory input, such as vision or hearing defects, central processing (such as communication), intellectual or perceptual deficits, and/or seizures. People with CP can have slow facial and tongue movements, which may resemble TD. (For more information on this disorder, choose “Cerebral Palsy” as your search term in the Rare Disease Database.)Tourette Syndrome is a neurological movement disorder which begins in childhood between the ages of two and sixteen. The disorder is characterized by involuntary muscular movements called “tics”, and uncontrollable vocal sounds. Sometimes inappropriate words may unavoidably be spoken. Tourette Syndrome is not a degenerative disorder and those affected can expect to live a normal life span. Neuroleptic drugs such as haloperidol and pimozide can be prescribed as treatments for TS, so it may sometimes be difficult to determine whether facial and tongue movements in TS patients are caused by the disorder or the drugs. (For more information on this disorder, choose “Tourette” as your search term in the Rare Disease Database.)Dystonia is a group of complex movement disorders with various causes, treatments, progression, and symptoms. These neurological conditions are characterized by involuntary muscle contractions, which force certain parts of the body into abnormal, sometimes painful movements and positions. Dystonia is not a single disease, but a set of symptoms that often cannot be attributed to a single cause. Both genetic and non-genetic factors contribute to different forms of dystonia. The major characteristics of all forms of dystonia are twisting, repetitive writhing movements affecting particular parts of the body (for example, the neck, trunk, or arm). Tardive dystonia is a particularly severe form of tardive dyskinesia. (For more information on this disorder, choose “Dystonia” as your search term in the Rare Disease Database.)
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Related disorders of Tardive Dyskinesia. Symptoms of the following disorders can be similar to those of Tardive dyskinesia. Comparisons may be useful for a differential diagnosis:Huntington’s Disease (also known as Huntington’s Chorea) is an inherited neurological illness. Those affected experience involuntary movements, loss of motor control, changes in gait, loss of memory, and in some cases, dementia. In general, the first symptoms of HD appear between thirty and fifty years of age. HD runs a progressive course, severely weakening patients usually over a ten to twenty-year period, whereas there is no degeneration in Tardive Dyskinesia. (For more information on this disorder, choose “Huntington” as your search term in the Rare Disease Database.)Cerebral Palsy is a disorder characterized by impaired muscle control or coordination (motor output system) resulting from injury to the brain during its early stages of development (the fetal, perinatal, or early childhood stages). There may be associated problems with sensory input, such as vision or hearing defects, central processing (such as communication), intellectual or perceptual deficits, and/or seizures. People with CP can have slow facial and tongue movements, which may resemble TD. (For more information on this disorder, choose “Cerebral Palsy” as your search term in the Rare Disease Database.)Tourette Syndrome is a neurological movement disorder which begins in childhood between the ages of two and sixteen. The disorder is characterized by involuntary muscular movements called “tics”, and uncontrollable vocal sounds. Sometimes inappropriate words may unavoidably be spoken. Tourette Syndrome is not a degenerative disorder and those affected can expect to live a normal life span. Neuroleptic drugs such as haloperidol and pimozide can be prescribed as treatments for TS, so it may sometimes be difficult to determine whether facial and tongue movements in TS patients are caused by the disorder or the drugs. (For more information on this disorder, choose “Tourette” as your search term in the Rare Disease Database.)Dystonia is a group of complex movement disorders with various causes, treatments, progression, and symptoms. These neurological conditions are characterized by involuntary muscle contractions, which force certain parts of the body into abnormal, sometimes painful movements and positions. Dystonia is not a single disease, but a set of symptoms that often cannot be attributed to a single cause. Both genetic and non-genetic factors contribute to different forms of dystonia. The major characteristics of all forms of dystonia are twisting, repetitive writhing movements affecting particular parts of the body (for example, the neck, trunk, or arm). Tardive dystonia is a particularly severe form of tardive dyskinesia. (For more information on this disorder, choose “Dystonia” as your search term in the Rare Disease Database.)
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Diagnosis of Tardive Dyskinesia
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Diagnosis of Tardive Dyskinesia.
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Therapies of Tardive Dyskinesia
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Treatment
Treatment of tardive dyskinesia initially consists of discontinuing the neuroleptic drug as soon as involuntary facial, neck, trunk, or extremity movements are identified in people taking neuroleptic drugs if this is felt to be safe psychiatrically. Use of an “atypical” neuroleptic drug is often used in place of traditional neuroleptics if felt to be psychiatrically appropriate. However, the “atypical” neuroleptic drugs are also capable of causing or perpetuating tardive dyskinesia. In some cases, physicians may be forced to reinstitute a neuroleptic drug if the tardive dyskinesia symptoms do not disappear and become very severe after medication is discontinued.In 2017, Ingrezza (valbenazine) was FDA approved to treat adults with tardive dyskinesia. Ingrezza is manufactured by Neurocrine Biosciences, Inc.In 2017, Austedo (deutetrabenazine) was FDA approved for the treatment of tardive dyskinesia in adults. Austedo is manufactured by Teva Pharmaceutical Industries Ltd.
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Therapies of Tardive Dyskinesia. Treatment
Treatment of tardive dyskinesia initially consists of discontinuing the neuroleptic drug as soon as involuntary facial, neck, trunk, or extremity movements are identified in people taking neuroleptic drugs if this is felt to be safe psychiatrically. Use of an “atypical” neuroleptic drug is often used in place of traditional neuroleptics if felt to be psychiatrically appropriate. However, the “atypical” neuroleptic drugs are also capable of causing or perpetuating tardive dyskinesia. In some cases, physicians may be forced to reinstitute a neuroleptic drug if the tardive dyskinesia symptoms do not disappear and become very severe after medication is discontinued.In 2017, Ingrezza (valbenazine) was FDA approved to treat adults with tardive dyskinesia. Ingrezza is manufactured by Neurocrine Biosciences, Inc.In 2017, Austedo (deutetrabenazine) was FDA approved for the treatment of tardive dyskinesia in adults. Austedo is manufactured by Teva Pharmaceutical Industries Ltd.
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Overview of Tarlov Cysts
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Tarlov cysts are fluid-filled sacs that affect the nerve roots of the spine, especially near the base of the spine (sacral region). Individuals may be affected by multiple cysts of varying size. Symptoms can occur depending upon the size and specific location of the cyst. Generally, the larger a Tarlov cyst is, the more likely it is to cause symptoms. Symptoms sometimes caused by Tarlov cysts include pain in the area served by the affected nerves, numbness and altered sensation, an inability to control bladder and bowel movements (incontinence), impotence, and, rarely, weakness in the legs. Small, asymptomatic cysts can slowly increase in size eventually causing symptoms. The exact cause of Tarlov cysts is unknown, but they may occur due to variation in normal development of the nerve sheath. Tarlov cysts were first described in the medical literature in 1938.
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Overview of Tarlov Cysts. Tarlov cysts are fluid-filled sacs that affect the nerve roots of the spine, especially near the base of the spine (sacral region). Individuals may be affected by multiple cysts of varying size. Symptoms can occur depending upon the size and specific location of the cyst. Generally, the larger a Tarlov cyst is, the more likely it is to cause symptoms. Symptoms sometimes caused by Tarlov cysts include pain in the area served by the affected nerves, numbness and altered sensation, an inability to control bladder and bowel movements (incontinence), impotence, and, rarely, weakness in the legs. Small, asymptomatic cysts can slowly increase in size eventually causing symptoms. The exact cause of Tarlov cysts is unknown, but they may occur due to variation in normal development of the nerve sheath. Tarlov cysts were first described in the medical literature in 1938.
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Symptoms of Tarlov Cysts
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Many cases of Tarlov cysts are not associated with symptoms (asymptomatic). However, Tarlov cysts can grow in size eventually compressing or damaging adjacent nerve roots or nerves contained within the cyst (radiculopathy). The specific symptoms and their severity vary from one individual to another and with location along the spinal column.Chronic pain is a common with symptomatic Tarlov cysts. Pain from lumbo-sacral cysts may affect the lower back, especially below the waist, and spread to the buttocks and legs. Pain may be worsened by walking (neurogenic claudication). Symptoms may become progressively worse. In some individuals sitting or standing may worsen pain; recumbency may relieve pain. In some cases, pain can also affect the upper back, neck, arms and hands if the cysts are located in the upper spine. Pain may worsen when coughing or sneezing. Affected individuals have also reported vulvar, testicular, rectal, pelvic and abdominal pain.Because Tarlov cysts can affect the nerves, symptoms relating to loss of neurological function can also develop including leg weakness, diminished reflexes, loss of sensation on the skin, and changes in bowel or bladder function such as incontinence or painful urination (dysuria). Some individuals may have difficulty empting the bladder and constipation has also been reported. Changes in sexual function such as impotence can also occur.Affected individuals may also develop abnormal burning or prickling sensations (paresthesias) or numbness and decreased sensitivity (dysesthesia), especially in the legs or feet. Tenderness or soreness may be present around the involved area of the spine.Additional symptoms have been reported in the medical literature including chronic headaches, blurred vision, pressure behind the eyes, dizziness, and dragging of the foot when walking due to weakness of the muscles in the ankles and feet (foot drop). Some individuals demonstrate progressive thinning (erosion) of the spinal bone overlying the cyst.
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Symptoms of Tarlov Cysts. Many cases of Tarlov cysts are not associated with symptoms (asymptomatic). However, Tarlov cysts can grow in size eventually compressing or damaging adjacent nerve roots or nerves contained within the cyst (radiculopathy). The specific symptoms and their severity vary from one individual to another and with location along the spinal column.Chronic pain is a common with symptomatic Tarlov cysts. Pain from lumbo-sacral cysts may affect the lower back, especially below the waist, and spread to the buttocks and legs. Pain may be worsened by walking (neurogenic claudication). Symptoms may become progressively worse. In some individuals sitting or standing may worsen pain; recumbency may relieve pain. In some cases, pain can also affect the upper back, neck, arms and hands if the cysts are located in the upper spine. Pain may worsen when coughing or sneezing. Affected individuals have also reported vulvar, testicular, rectal, pelvic and abdominal pain.Because Tarlov cysts can affect the nerves, symptoms relating to loss of neurological function can also develop including leg weakness, diminished reflexes, loss of sensation on the skin, and changes in bowel or bladder function such as incontinence or painful urination (dysuria). Some individuals may have difficulty empting the bladder and constipation has also been reported. Changes in sexual function such as impotence can also occur.Affected individuals may also develop abnormal burning or prickling sensations (paresthesias) or numbness and decreased sensitivity (dysesthesia), especially in the legs or feet. Tenderness or soreness may be present around the involved area of the spine.Additional symptoms have been reported in the medical literature including chronic headaches, blurred vision, pressure behind the eyes, dizziness, and dragging of the foot when walking due to weakness of the muscles in the ankles and feet (foot drop). Some individuals demonstrate progressive thinning (erosion) of the spinal bone overlying the cyst.
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Causes of Tarlov Cysts
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The exact cause of Tarlov cysts is unknown. Several theories exist including that the cysts result from an inflammatory process within the nerve root sheath or that trauma injures the nerve root sheath and causes leaking of cerebrospinal fluid (CSF) into the area where a cyst forms. Some researchers believe that an abnormal congenital connection (communication) exists between the subarachnoid space, which contains cerebrospinal fluid, and the area surrounding the affected nerves (perineural region). The connection may remain or eventually close, after allowing cerebrospinal fluid to leak out and cause a cyst. Because Tarlov cysts contain cerebrospinal fluid, researchers have speculated that normal fluctuations in CSF pressure may lead to an increase in cyst size and a greater likelihood of developing symptoms.In many cases, individuals with asymptomatic Tarlov cysts developed symptoms following trauma or activities that raise cerebrospinal fluid pressure such as heavy lifting. Some reports suggest that individuals with connective tissue disorders are at a greater risk of developing Tarlov cysts than the general population.More research is necessary to understand the underlying mechanisms that ultimately cause the development of Tarlov cysts or the onset of their symptoms.
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Causes of Tarlov Cysts. The exact cause of Tarlov cysts is unknown. Several theories exist including that the cysts result from an inflammatory process within the nerve root sheath or that trauma injures the nerve root sheath and causes leaking of cerebrospinal fluid (CSF) into the area where a cyst forms. Some researchers believe that an abnormal congenital connection (communication) exists between the subarachnoid space, which contains cerebrospinal fluid, and the area surrounding the affected nerves (perineural region). The connection may remain or eventually close, after allowing cerebrospinal fluid to leak out and cause a cyst. Because Tarlov cysts contain cerebrospinal fluid, researchers have speculated that normal fluctuations in CSF pressure may lead to an increase in cyst size and a greater likelihood of developing symptoms.In many cases, individuals with asymptomatic Tarlov cysts developed symptoms following trauma or activities that raise cerebrospinal fluid pressure such as heavy lifting. Some reports suggest that individuals with connective tissue disorders are at a greater risk of developing Tarlov cysts than the general population.More research is necessary to understand the underlying mechanisms that ultimately cause the development of Tarlov cysts or the onset of their symptoms.
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Affects of Tarlov Cysts
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Women are at a higher risk of developing Tarlov cysts than men. The exact incidence or prevalence of symptomatic Tarlov cysts in the general population is unknown. Because these cysts often go unrecognized or misdiagnosed, determining their true frequency in the general population is difficult. However, the total number of Tarlov cyst patients (symptomatic and asymptomatic) is estimated at 4.6 to 9 percent of the adult population.
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Affects of Tarlov Cysts. Women are at a higher risk of developing Tarlov cysts than men. The exact incidence or prevalence of symptomatic Tarlov cysts in the general population is unknown. Because these cysts often go unrecognized or misdiagnosed, determining their true frequency in the general population is difficult. However, the total number of Tarlov cyst patients (symptomatic and asymptomatic) is estimated at 4.6 to 9 percent of the adult population.
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Related disorders of Tarlov Cysts
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Symptoms of the following disorders can be similar to those of Tarlov cysts. Comparison of symptoms may be useful for a differential diagnosis.Various cysts and tumors may have similar symptoms to those associated with Tarlov cysts. This group includes meningeal diverticula, meningoceles, neurofibromas, schwannoma, and arachnoid cysts. These cysts and tumors may cause compression of the spinal cord or nerve roots. (For more information on these conditions, choose the specific cyst or tumor name in the Rare Disease Database.)Arachnoid cysts are fluid-filled sacs that occur on the arachnoid membrane that covers the brain (intracranial) and the spinal cord (spinal). There are three membranes covering these components of the central nervous system: dura mater, arachnoid, and pia mater. Arachnoid cysts appear on the arachnoid membrane, and they may also expand into the space between the pia mater and arachnoid membranes (subarachnoid space). The most common locations for intracranial arachnoid cysts are near the temporal lobe (the middle fossa), near the third ventricle (the suprasellar region), and the area that contains the cerebellum, pons, and medulla oblongata (the posterior fossa). In many cases, arachnoid cysts do not cause symptoms (asymptomatic). In cases in which symptoms occur, headaches, seizures and abnormal accumulation of excessive cerebrospinal fluid in the brain (hydrocephalus) are common. The exact cause of arachnoid cysts is unknown. (For more information on this disorder, choose “arachnoid cysts” as your search term in the Rare Disease Database.)
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Related disorders of Tarlov Cysts. Symptoms of the following disorders can be similar to those of Tarlov cysts. Comparison of symptoms may be useful for a differential diagnosis.Various cysts and tumors may have similar symptoms to those associated with Tarlov cysts. This group includes meningeal diverticula, meningoceles, neurofibromas, schwannoma, and arachnoid cysts. These cysts and tumors may cause compression of the spinal cord or nerve roots. (For more information on these conditions, choose the specific cyst or tumor name in the Rare Disease Database.)Arachnoid cysts are fluid-filled sacs that occur on the arachnoid membrane that covers the brain (intracranial) and the spinal cord (spinal). There are three membranes covering these components of the central nervous system: dura mater, arachnoid, and pia mater. Arachnoid cysts appear on the arachnoid membrane, and they may also expand into the space between the pia mater and arachnoid membranes (subarachnoid space). The most common locations for intracranial arachnoid cysts are near the temporal lobe (the middle fossa), near the third ventricle (the suprasellar region), and the area that contains the cerebellum, pons, and medulla oblongata (the posterior fossa). In many cases, arachnoid cysts do not cause symptoms (asymptomatic). In cases in which symptoms occur, headaches, seizures and abnormal accumulation of excessive cerebrospinal fluid in the brain (hydrocephalus) are common. The exact cause of arachnoid cysts is unknown. (For more information on this disorder, choose “arachnoid cysts” as your search term in the Rare Disease Database.)
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Diagnosis of Tarlov Cysts
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Diagnosis
A diagnosis of Tarlov cysts may be suspected based upon a thorough clinical evaluation, a detailed patient history with identification of characteristic symptoms and a neurological examination. A diagnosis may be confirmed by a variety of specialized tests. In some cases, a diagnosis of a Tarlov cyst is made incidentally through x-ray or MRI scan investigation undertaken for other reasons.Clinical Testing and Work-Up
Magnetic resonance imaging (MRI) of the lumbar region and computed tomography (CT) can both reveal Tarlov cysts. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the organ being studied. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the organ's tissue structure.Another test, known as a myelogram, uses a special dye called contrast material and x-rays as well as a CT scan to create a picture of the subarachnoid space. During this test, the contrast fluid is injected under local anesthesia into the spinal canal through a thin needle. The dye allows certain structures such as the nerve roots and spinal canal to be seen more clearly on x-ray. The size and location of the connection between the cyst and the normal spinal fluid containing space can be demonstrated by CT scan performed after the myelogram. Erosion of the sacrum or vertebral bone by the cyst can also be shown.
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Diagnosis of Tarlov Cysts. Diagnosis
A diagnosis of Tarlov cysts may be suspected based upon a thorough clinical evaluation, a detailed patient history with identification of characteristic symptoms and a neurological examination. A diagnosis may be confirmed by a variety of specialized tests. In some cases, a diagnosis of a Tarlov cyst is made incidentally through x-ray or MRI scan investigation undertaken for other reasons.Clinical Testing and Work-Up
Magnetic resonance imaging (MRI) of the lumbar region and computed tomography (CT) can both reveal Tarlov cysts. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the organ being studied. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the organ's tissue structure.Another test, known as a myelogram, uses a special dye called contrast material and x-rays as well as a CT scan to create a picture of the subarachnoid space. During this test, the contrast fluid is injected under local anesthesia into the spinal canal through a thin needle. The dye allows certain structures such as the nerve roots and spinal canal to be seen more clearly on x-ray. The size and location of the connection between the cyst and the normal spinal fluid containing space can be demonstrated by CT scan performed after the myelogram. Erosion of the sacrum or vertebral bone by the cyst can also be shown.
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Therapies of Tarlov Cysts
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TreatmentTarlov cysts that do not cause symptoms should be monitored periodically to see whether cysts increase in size or whether symptoms develop. There is no specific, accepted therapy for individuals with symptomatic Tarlov cysts. Treatment is directed toward the specific symptoms that are apparent in each individual and may include drugs, surgery and other techniques. The response to various therapeutic options is highly individualized; what works for one person may be ineffective for another.Non-steroidal anti-inflammatory drugs (NSAIDs) may be prescribed to treat nerve irritation and inflammation. A procedure known as transcutaneous electrical nerve stimulation or TENS may also be used to relieve nerve pain. During this procedure, electrical impulses are sent through the skin to help control pain.Tarlov cysts have been treated by procedures in which cerebrospinal fluid is drained from the cyst (aspiration). Results from such procedures vary and, in most cases, the cysts eventually fill up with cerebrospinal fluid again. In some cases, symptoms can return within hours.Several different procedures, both surgical and nonsurgical, have been used that involve draining a Tarlov cyst and then filling the cyst with another substance such as fibrin glue, fat, or muscle. This prevents cerebrospinal fluid from refilling the cysts and reduces pressure on the surrounding nerves.A nonsurgical procedure used to treat individuals with symptomatic Tarlov cysts uses a combination of substances that mimic blood clotting (fibrin glue). Fibrin glue injection is a minimally invasive procedure that has benefited some individuals with symptomatic Tarlov cysts. After the cysts are drained, fibrin glue is used to seal or “glue” the cyst closed preventing the cysts from filling up again. Some individuals have experienced immediate relief after this procedure; others reported delayed benefit. This procedure has led to short-term and long-term relief of symptoms in some cases. Complications have been reported in cases where the cyst communicates readily with the spinal fluid containing space.Surgical removal of Tarlov cysts may be used to treat symptomatic individuals who do not respond to other forms of therapy. Debate exists in the medical literature as to the most appropriate surgical technique to treat individuals with symptomatic Tarlov cysts. Various techniques have been used with different success rates and side effects. Surgical intervention depends upon numerous factors such as the progression of the disorder; the degree of nerve root compression; the size of the connection between the subarachnoid space and the cyst; an individual’s age and general health; and/or other factors. Decisions concerning the use of particular interventions 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, patient preference and other appropriate factors is needed.Very large cysts may require direct surgical intervention to drain and then obliterate the cyst. One surgical technique that has been used to treat symptomatic Tarlov cysts is an operation that exposes the region of the spine where the cyst is located by removal of overlying vertebral bone. The cyst is then sliced open with one or more thin cuts (fenestrations) and drained of fluid. The cyst wall is collapsed, circumferentially reinforced and sutured closed or the cavity is packed full of another substance such as fat or tissue adhesive to prevent it from refilling with cerebrospinal fluid.In another procedure, after surgery to expose and drain the cysts, a flap of nearby muscle tissue is used to fill the cyst in order to prevent recurrence. A muscle flap is a portion of muscle that can be transferred along with its blood supply to an adjacent part of the body. The muscle flap is use to fill the decompressed cyst and to prevent it from refilling with cerebrospinal fluid. Results of treatment may be disappointing if irreversible nerve damage has already occurred.
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Therapies of Tarlov Cysts. TreatmentTarlov cysts that do not cause symptoms should be monitored periodically to see whether cysts increase in size or whether symptoms develop. There is no specific, accepted therapy for individuals with symptomatic Tarlov cysts. Treatment is directed toward the specific symptoms that are apparent in each individual and may include drugs, surgery and other techniques. The response to various therapeutic options is highly individualized; what works for one person may be ineffective for another.Non-steroidal anti-inflammatory drugs (NSAIDs) may be prescribed to treat nerve irritation and inflammation. A procedure known as transcutaneous electrical nerve stimulation or TENS may also be used to relieve nerve pain. During this procedure, electrical impulses are sent through the skin to help control pain.Tarlov cysts have been treated by procedures in which cerebrospinal fluid is drained from the cyst (aspiration). Results from such procedures vary and, in most cases, the cysts eventually fill up with cerebrospinal fluid again. In some cases, symptoms can return within hours.Several different procedures, both surgical and nonsurgical, have been used that involve draining a Tarlov cyst and then filling the cyst with another substance such as fibrin glue, fat, or muscle. This prevents cerebrospinal fluid from refilling the cysts and reduces pressure on the surrounding nerves.A nonsurgical procedure used to treat individuals with symptomatic Tarlov cysts uses a combination of substances that mimic blood clotting (fibrin glue). Fibrin glue injection is a minimally invasive procedure that has benefited some individuals with symptomatic Tarlov cysts. After the cysts are drained, fibrin glue is used to seal or “glue” the cyst closed preventing the cysts from filling up again. Some individuals have experienced immediate relief after this procedure; others reported delayed benefit. This procedure has led to short-term and long-term relief of symptoms in some cases. Complications have been reported in cases where the cyst communicates readily with the spinal fluid containing space.Surgical removal of Tarlov cysts may be used to treat symptomatic individuals who do not respond to other forms of therapy. Debate exists in the medical literature as to the most appropriate surgical technique to treat individuals with symptomatic Tarlov cysts. Various techniques have been used with different success rates and side effects. Surgical intervention depends upon numerous factors such as the progression of the disorder; the degree of nerve root compression; the size of the connection between the subarachnoid space and the cyst; an individual’s age and general health; and/or other factors. Decisions concerning the use of particular interventions 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, patient preference and other appropriate factors is needed.Very large cysts may require direct surgical intervention to drain and then obliterate the cyst. One surgical technique that has been used to treat symptomatic Tarlov cysts is an operation that exposes the region of the spine where the cyst is located by removal of overlying vertebral bone. The cyst is then sliced open with one or more thin cuts (fenestrations) and drained of fluid. The cyst wall is collapsed, circumferentially reinforced and sutured closed or the cavity is packed full of another substance such as fat or tissue adhesive to prevent it from refilling with cerebrospinal fluid.In another procedure, after surgery to expose and drain the cysts, a flap of nearby muscle tissue is used to fill the cyst in order to prevent recurrence. A muscle flap is a portion of muscle that can be transferred along with its blood supply to an adjacent part of the body. The muscle flap is use to fill the decompressed cyst and to prevent it from refilling with cerebrospinal fluid. Results of treatment may be disappointing if irreversible nerve damage has already occurred.
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Overview of Tarsal Carpal Coalition Syndrome
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Summary
Tarsal carpal coalition syndrome (TCC) is a rare genetic condition that is primarily characterized by fusion of the bones of the hands, wrists, feet and ankles, but may involve other areas such as the elbow. The most common symptoms are worsening stiffness, pain, immobility and deformity of the affected joints. TCC is caused by changes (pathogenic variants or mutations) in the NOG gene leading to overgrowth of bone or other tissues in the affected joints. Treatment options include physical therapy, occupational therapy and surgery aimed at reducing pain, improving joint mobility, correcting joint deformity and maintaining patient independence. Early diagnosis can lead to improved patient outcomes and better quality of life. Introduction
TCC was first described in 1985 in a family with multiple affected members. In 2001, multiple genetic pathogenic variants of the NOG gene were reported to be associated with this disorder. Since then, additional pathogenic variants have been identified in this gene and have been associated with a range of similar conditions. Some scientists suggest classifying these conditions as NOG gene-related symphalangism spectrum disorders, where symphalangism refers to the fusion of finger or toe joints. Tarsal carpal coalition syndrome can be differentiated from other NOG gene-related symphalangism spectrum disorders by the absence of conductive hearing loss, abnormal facial features, or asymmetry of spinal curvature and the chest.
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Overview of Tarsal Carpal Coalition Syndrome. Summary
Tarsal carpal coalition syndrome (TCC) is a rare genetic condition that is primarily characterized by fusion of the bones of the hands, wrists, feet and ankles, but may involve other areas such as the elbow. The most common symptoms are worsening stiffness, pain, immobility and deformity of the affected joints. TCC is caused by changes (pathogenic variants or mutations) in the NOG gene leading to overgrowth of bone or other tissues in the affected joints. Treatment options include physical therapy, occupational therapy and surgery aimed at reducing pain, improving joint mobility, correcting joint deformity and maintaining patient independence. Early diagnosis can lead to improved patient outcomes and better quality of life. Introduction
TCC was first described in 1985 in a family with multiple affected members. In 2001, multiple genetic pathogenic variants of the NOG gene were reported to be associated with this disorder. Since then, additional pathogenic variants have been identified in this gene and have been associated with a range of similar conditions. Some scientists suggest classifying these conditions as NOG gene-related symphalangism spectrum disorders, where symphalangism refers to the fusion of finger or toe joints. Tarsal carpal coalition syndrome can be differentiated from other NOG gene-related symphalangism spectrum disorders by the absence of conductive hearing loss, abnormal facial features, or asymmetry of spinal curvature and the chest.
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Symptoms of Tarsal Carpal Coalition Syndrome
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The most common initial signs and symptoms of tarsal carpal coalition syndrome are worsening joint stiffness, joint pain and joint deformity. Common complaints include pain with walking and abnormal walking pattern (gait). Tarsal-carpal coalition syndrome is a progressive disease that is characterized by abnormal development that leads to the fusion of bones in the distal joints. The wrists/hands (carpals, phalanges/fingers) and ankles/feet (tarsals, phalanges/toes) are most affected. Involvement of the hand often is most noticeable in the pinky finger and spreads towards the thumb, but the thumb is often spared. Progressive fusion of the bones in these regions that may cause deformities such as inward or outward twisting of the feet, flat feet, shortening of the fingers or toes (brachydactyly), abnormal curvature of the fingers (clinodactyly) or partial to near complete fusion of the fingers or toes (syndactyly). These deformities may be detected while a patient is still in the womb, and symptoms such as reduced range of motion in the fingers/toes, elbows and ankles may be seen at birth. There is often a family history of the condition and older family members may have similar but more advanced symptoms such as fixed flexion of joints, fusion of fingers and fusion of many small bones in the hands and/or feet.If diagnosed at birth, babies with TCC may show stiffness or decreased/absent movement of finger joints, wrists, and elbows, shortening of fingers/toes, and fixed joint deformities such as clubfoot (inward deviation of the foot). In adults, symptoms are often more severe (since symptoms have had a longer time to progress) and may include fixed flexion deformities of the elbows, fusion of the fingers/toes, shortening of the fingers/toes, extensive fusion of the small bones of the hands and feet (carpal & tarsal bones) and limited range of motion in joints such as the fingers/toes, wrist, ankles and elbows. If not initially detected, adults with tarsal carpal coalition syndrome may have a history of delayed fine and gross motor development such as inability to bring things to their mouth, impaired ability to form a fist, difficulty raising their arms above their shoulders or fully straightening or supinating the forearms, trouble placing their thighs on floor when seated with folded legs and a history of abnormal walking gait. This is due to overgrowth of tissues in the affected joints leading to stiffness. Patients with TCC may have low-to-normal height and weight, but normal intelligence and lifespan.
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Symptoms of Tarsal Carpal Coalition Syndrome. The most common initial signs and symptoms of tarsal carpal coalition syndrome are worsening joint stiffness, joint pain and joint deformity. Common complaints include pain with walking and abnormal walking pattern (gait). Tarsal-carpal coalition syndrome is a progressive disease that is characterized by abnormal development that leads to the fusion of bones in the distal joints. The wrists/hands (carpals, phalanges/fingers) and ankles/feet (tarsals, phalanges/toes) are most affected. Involvement of the hand often is most noticeable in the pinky finger and spreads towards the thumb, but the thumb is often spared. Progressive fusion of the bones in these regions that may cause deformities such as inward or outward twisting of the feet, flat feet, shortening of the fingers or toes (brachydactyly), abnormal curvature of the fingers (clinodactyly) or partial to near complete fusion of the fingers or toes (syndactyly). These deformities may be detected while a patient is still in the womb, and symptoms such as reduced range of motion in the fingers/toes, elbows and ankles may be seen at birth. There is often a family history of the condition and older family members may have similar but more advanced symptoms such as fixed flexion of joints, fusion of fingers and fusion of many small bones in the hands and/or feet.If diagnosed at birth, babies with TCC may show stiffness or decreased/absent movement of finger joints, wrists, and elbows, shortening of fingers/toes, and fixed joint deformities such as clubfoot (inward deviation of the foot). In adults, symptoms are often more severe (since symptoms have had a longer time to progress) and may include fixed flexion deformities of the elbows, fusion of the fingers/toes, shortening of the fingers/toes, extensive fusion of the small bones of the hands and feet (carpal & tarsal bones) and limited range of motion in joints such as the fingers/toes, wrist, ankles and elbows. If not initially detected, adults with tarsal carpal coalition syndrome may have a history of delayed fine and gross motor development such as inability to bring things to their mouth, impaired ability to form a fist, difficulty raising their arms above their shoulders or fully straightening or supinating the forearms, trouble placing their thighs on floor when seated with folded legs and a history of abnormal walking gait. This is due to overgrowth of tissues in the affected joints leading to stiffness. Patients with TCC may have low-to-normal height and weight, but normal intelligence and lifespan.
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Causes of Tarsal Carpal Coalition Syndrome
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Tarsal carpal coalition syndrome is caused by changes (pathogenic variants) in the NOG gene. These variants result in a loss of the noggin protein which normally forms a receptor that decreases the concentration of proteins associated with bone and cartilage growth. This excess of bone-forming and cartilage-forming proteins or cells (osteoblasts) leads to oversized growth plates and excess cartilage and bone formation. This causes failure of joint formation and fusion of adjacent bones. Multiple pathogenic variants have been identified that lead to various presentations of TCC with overlapping symptoms. These variants cause abnormal cartilage formation but do not affect the overall shape or length of limbs. Most cases run in families, but some have been isolated (sporadic, non-familial). Different families with similar/identical pathogenic variants may have different symptoms, different severity, or even different NOG gene-related disorders due to differences in gene expression. Though there is variation in presentation, it appears that everyone with a pathogenic variant in the NOG gene has some form of disease with similar findings in males and females. Additionally, it is important to note that people with a larger deletion of the NOG gene often have more severe symptoms due to loss or deletion of other genes in addition to NOG. Tarsal carpal coalition syndrome is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Tarsal Carpal Coalition Syndrome. Tarsal carpal coalition syndrome is caused by changes (pathogenic variants) in the NOG gene. These variants result in a loss of the noggin protein which normally forms a receptor that decreases the concentration of proteins associated with bone and cartilage growth. This excess of bone-forming and cartilage-forming proteins or cells (osteoblasts) leads to oversized growth plates and excess cartilage and bone formation. This causes failure of joint formation and fusion of adjacent bones. Multiple pathogenic variants have been identified that lead to various presentations of TCC with overlapping symptoms. These variants cause abnormal cartilage formation but do not affect the overall shape or length of limbs. Most cases run in families, but some have been isolated (sporadic, non-familial). Different families with similar/identical pathogenic variants may have different symptoms, different severity, or even different NOG gene-related disorders due to differences in gene expression. Though there is variation in presentation, it appears that everyone with a pathogenic variant in the NOG gene has some form of disease with similar findings in males and females. Additionally, it is important to note that people with a larger deletion of the NOG gene often have more severe symptoms due to loss or deletion of other genes in addition to NOG. Tarsal carpal coalition syndrome is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
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Affects of Tarsal Carpal Coalition Syndrome
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Tarsal carpal coalition syndrome is a rare condition with a prevalence of 1/1,000,000 in the general population.
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Affects of Tarsal Carpal Coalition Syndrome. Tarsal carpal coalition syndrome is a rare condition with a prevalence of 1/1,000,000 in the general population.
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Related disorders of Tarsal Carpal Coalition Syndrome
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● unspecified congenital synostosis syndromeOther NOG-related symphalangism spectrum disorders (NOG-SSD):● Proximal symphalangism and multiple synostoses syndrome 1
● Stapes ankylosis with broad thumbs and toes
● Brachydactyly type B2
● Radioulnar synostosis
● brachydactyly type B (BDB)
● multiple synostoses syndrome 1 (SYNS1)
● Teunissen–Cremers syndrome (TCS)
● symphalangism-brachydactyly syndrome
● WL syndrome
● deafness-symphalangism syndrome of Herrmann
● facioaudiosymphalangism syndromeTarsal carpal coalition syndrome is one of several NOG-related symphalangism spectrum disorders (NOG-SSD) that share similarities in their pattern of joint involvement but can vary in other features such as stature, hearing loss, fusion of the humerus and radius (upper and lower arm bones) and presence of short fingers or toes. For example, patients with multiple synostoses syndrome-1 and proximal symphalangism have conductive hearing loss unlike TCC. Also, multiple synostoses syndrome-1 can be differentiated from proximal symphalangism because it consistently involves the hips and cervical spine (neck level). These conditions are also caused by pathogenic variants in the NOG gene, but the pathogenic variants are at different spots on the gene, or the gene expression is different so these patients may have different symptoms. This further suggests that only certain joints are affected by pathogenic variants in certain areas of the NOG gene. Therefore, the pathogenic variants that cause TCC affect joint formation in the limbs but do not affect formation of joints in the middle ear and spine. This means that unlike similar conditions, TCC is not associated with hearing loss or deformities of the spine and chest. It is important to note that in all these conditions, the severity of the disease is related to the degree/size of pathogenic variants /deletion in the NOG gene.
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Related disorders of Tarsal Carpal Coalition Syndrome. ● unspecified congenital synostosis syndromeOther NOG-related symphalangism spectrum disorders (NOG-SSD):● Proximal symphalangism and multiple synostoses syndrome 1
● Stapes ankylosis with broad thumbs and toes
● Brachydactyly type B2
● Radioulnar synostosis
● brachydactyly type B (BDB)
● multiple synostoses syndrome 1 (SYNS1)
● Teunissen–Cremers syndrome (TCS)
● symphalangism-brachydactyly syndrome
● WL syndrome
● deafness-symphalangism syndrome of Herrmann
● facioaudiosymphalangism syndromeTarsal carpal coalition syndrome is one of several NOG-related symphalangism spectrum disorders (NOG-SSD) that share similarities in their pattern of joint involvement but can vary in other features such as stature, hearing loss, fusion of the humerus and radius (upper and lower arm bones) and presence of short fingers or toes. For example, patients with multiple synostoses syndrome-1 and proximal symphalangism have conductive hearing loss unlike TCC. Also, multiple synostoses syndrome-1 can be differentiated from proximal symphalangism because it consistently involves the hips and cervical spine (neck level). These conditions are also caused by pathogenic variants in the NOG gene, but the pathogenic variants are at different spots on the gene, or the gene expression is different so these patients may have different symptoms. This further suggests that only certain joints are affected by pathogenic variants in certain areas of the NOG gene. Therefore, the pathogenic variants that cause TCC affect joint formation in the limbs but do not affect formation of joints in the middle ear and spine. This means that unlike similar conditions, TCC is not associated with hearing loss or deformities of the spine and chest. It is important to note that in all these conditions, the severity of the disease is related to the degree/size of pathogenic variants /deletion in the NOG gene.
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Diagnosis of Tarsal Carpal Coalition Syndrome
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Diagnosis of tarsal carpal coalition syndrome begins with recognizing the symptoms of joint stiffness, pain and deformity which are highly suspicious for this condition. Often these suspicions are confirmed by imaging such as CT or MRI which show the characteristic joint fusion, shortening of fingers/toes, deformity of bones and joint deformity. It should be noted that on plain imaging such as x-rays, children under 8 years old may not have enough bone formation to show bone fusion, and instead the cartilage fusion is still causing them to have symptoms. A definitive diagnosis can be made through genetic testing showing characteristic pathogenic variants in the NOG gene.
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Diagnosis of Tarsal Carpal Coalition Syndrome. Diagnosis of tarsal carpal coalition syndrome begins with recognizing the symptoms of joint stiffness, pain and deformity which are highly suspicious for this condition. Often these suspicions are confirmed by imaging such as CT or MRI which show the characteristic joint fusion, shortening of fingers/toes, deformity of bones and joint deformity. It should be noted that on plain imaging such as x-rays, children under 8 years old may not have enough bone formation to show bone fusion, and instead the cartilage fusion is still causing them to have symptoms. A definitive diagnosis can be made through genetic testing showing characteristic pathogenic variants in the NOG gene.
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Therapies of Tarsal Carpal Coalition Syndrome
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Treatment
Treatment is mostly aimed at controlling pain and preserving function with physical therapy followed by regular surgeries that involve cutting and reshaping bones to improve alignment or function. Patients diagnosed as infants may need physical therapy once or twice a month to support range of motion and development of gross motor patterns. They may need casts to stabilize the joints as they grow followed by fitted orthotics for significant joint deformities such as clubfoot. Occupational therapy may be used to help with daily activities and creation of custom assistance devices to help perform daily activities. In all patients, long-term follow-up is recommended due to the progressive nature of this condition and tendency for symptoms to worsen or recur. Microfractures and progressive ossification (formation or conversion of tissues to bone) lead to pain and can restrict mobility. Physical and occupational therapy can help maintain range of motion, reduce pain and preserve independence and function. When conservative treatments no longer work, surgery is the next option. Surgery involves removal of excess bone and soft-tissue or arthrodesis (surgical immobilization via fusion of adjacent joints). The size of the coalitions (fusion) is the main factor in predicting patient outcomes. Surgical options are divided into a few main categories: excision (cutting out), arthrodesis (surgical immobilization of a joint by fusion) and osteotomy (cutting and reshaping of bones). All of these options focus on reducing symptoms, correcting deformities and/or improving functionality and appearance. After surgery, the joint is often placed in a plaster cast to allow healing of the bones for approximately 6 weeks. If multiple surgeries are required, there may be a period of up to 8 weeks between surgeries to allow for the initial joint to heal and regain function prior to a second surgery on the contralateral joint, such as the left knee being operated on 8 weeks after surgery on the right knee. Physical therapy may use electrical stimulation to retain strength in the muscles of the affected limb and may conduct training for proper joint utilization if the patient has been affected since infancy (i.e., they never had a normal walking gait due to stiffness of joints in the foot or legs). Patients may need to have frequent or repeated surgeries due to the progressive nature of this condition.
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Therapies of Tarsal Carpal Coalition Syndrome. Treatment
Treatment is mostly aimed at controlling pain and preserving function with physical therapy followed by regular surgeries that involve cutting and reshaping bones to improve alignment or function. Patients diagnosed as infants may need physical therapy once or twice a month to support range of motion and development of gross motor patterns. They may need casts to stabilize the joints as they grow followed by fitted orthotics for significant joint deformities such as clubfoot. Occupational therapy may be used to help with daily activities and creation of custom assistance devices to help perform daily activities. In all patients, long-term follow-up is recommended due to the progressive nature of this condition and tendency for symptoms to worsen or recur. Microfractures and progressive ossification (formation or conversion of tissues to bone) lead to pain and can restrict mobility. Physical and occupational therapy can help maintain range of motion, reduce pain and preserve independence and function. When conservative treatments no longer work, surgery is the next option. Surgery involves removal of excess bone and soft-tissue or arthrodesis (surgical immobilization via fusion of adjacent joints). The size of the coalitions (fusion) is the main factor in predicting patient outcomes. Surgical options are divided into a few main categories: excision (cutting out), arthrodesis (surgical immobilization of a joint by fusion) and osteotomy (cutting and reshaping of bones). All of these options focus on reducing symptoms, correcting deformities and/or improving functionality and appearance. After surgery, the joint is often placed in a plaster cast to allow healing of the bones for approximately 6 weeks. If multiple surgeries are required, there may be a period of up to 8 weeks between surgeries to allow for the initial joint to heal and regain function prior to a second surgery on the contralateral joint, such as the left knee being operated on 8 weeks after surgery on the right knee. Physical therapy may use electrical stimulation to retain strength in the muscles of the affected limb and may conduct training for proper joint utilization if the patient has been affected since infancy (i.e., they never had a normal walking gait due to stiffness of joints in the foot or legs). Patients may need to have frequent or repeated surgeries due to the progressive nature of this condition.
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Overview of Tarsal Tunnel Syndrome
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Tarsal tunnel syndrome is a rare disorder caused by damage to the tibial nerve or its branches, usually due to compression as it passes through the tarsal tunnel (entrapment neuropathy). The tarsal tunnel is a narrow passageway bound by bone and soft tissue that lies on the inside of the ankle. The tibial nerve (as well as certain blood vessels and tendons) passes through the tarsal tunnel. However, the term tarsal tunnel syndrome is often broadly applied to any pain along the tibial nerve, which can result from a multitude of causes. Individuals with tarsal tunnel syndrome may experience pain, burning, or a tingling sensation along the tibial nerve.
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Overview of Tarsal Tunnel Syndrome. Tarsal tunnel syndrome is a rare disorder caused by damage to the tibial nerve or its branches, usually due to compression as it passes through the tarsal tunnel (entrapment neuropathy). The tarsal tunnel is a narrow passageway bound by bone and soft tissue that lies on the inside of the ankle. The tibial nerve (as well as certain blood vessels and tendons) passes through the tarsal tunnel. However, the term tarsal tunnel syndrome is often broadly applied to any pain along the tibial nerve, which can result from a multitude of causes. Individuals with tarsal tunnel syndrome may experience pain, burning, or a tingling sensation along the tibial nerve.
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Symptoms of Tarsal Tunnel Syndrome
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The specific symptoms of tarsal tunnel syndrome can vary from one person to another. In some cases, symptoms can develop suddenly, and in others gradually. Some affected individuals may experience a sharp, shooting pain along the tibial nerve. This nerve branches off from the sciatic nerve and runs down the lower leg to the ankle and then the foot. Pain can be severe enough to cause a person to limp. Affected individuals may describe a radiating pain that cannot be localized to one spot. In addition to or instead of pain, affected individuals may experience numbness of the affected area or a burning or tingling sensation (paresthesia), which is often described as similar to “pins and needles”.In some individuals, symptoms may affect one spot such as the inside of the ankle. In other individuals, symptoms can affect the ankle, heel and foot. For example, pain may radiate from the ankle down to the heel or even the foot, depending on which section of the nerve is affected. Less frequently, pain may radiate up from the ankle to the calf.The symptoms of tarsal tunnel syndrome are often worsened by activity such as prolonged standing or walking. Consequently, pain may worsen throughout an active day. Symptoms are usually relieved by rest. However, as the disorder progresses, some affected individuals have reported pain that occurs during rest or at night when attempting to sleep.
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Symptoms of Tarsal Tunnel Syndrome. The specific symptoms of tarsal tunnel syndrome can vary from one person to another. In some cases, symptoms can develop suddenly, and in others gradually. Some affected individuals may experience a sharp, shooting pain along the tibial nerve. This nerve branches off from the sciatic nerve and runs down the lower leg to the ankle and then the foot. Pain can be severe enough to cause a person to limp. Affected individuals may describe a radiating pain that cannot be localized to one spot. In addition to or instead of pain, affected individuals may experience numbness of the affected area or a burning or tingling sensation (paresthesia), which is often described as similar to “pins and needles”.In some individuals, symptoms may affect one spot such as the inside of the ankle. In other individuals, symptoms can affect the ankle, heel and foot. For example, pain may radiate from the ankle down to the heel or even the foot, depending on which section of the nerve is affected. Less frequently, pain may radiate up from the ankle to the calf.The symptoms of tarsal tunnel syndrome are often worsened by activity such as prolonged standing or walking. Consequently, pain may worsen throughout an active day. Symptoms are usually relieved by rest. However, as the disorder progresses, some affected individuals have reported pain that occurs during rest or at night when attempting to sleep.
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Causes of Tarsal Tunnel Syndrome
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Tarsal tunnel syndrome can be caused by any condition that causes compression of the tibial nerve or its branches as it passes through the tarsal tunnel. A wide variety of conditions can cause tarsal tunnel syndrome including space-occupying lesions or masses, which may increase pressure in the tunnel. Such lesions include tumors consisting mainly of fat tissue (lipomas), tumors consisting of nerve fibers and ganglion cells (gangliomas) and tumors of the nerve sheath (schwannomas).Additional conditions that can cause tarsal tunnel syndrome include a benign bony growth in the tarsal tunnel (exostosis), enlarged (varicose) veins and inflammation of the synovial membrane (proliferative synovitis). Certain injuries or trauma such as an ankle sprain, fracture or valgus foot deformity may cause inflammation and swelling that can lead to tarsal tunnel syndrome. In addition, certain disorders such as diabetes and arthritis can also cause inflammation and swelling that can lead to tarsal tunnel syndrome.Individuals who have severely flat feet (pes planus) are at a greater risk of developing tarsal tunnel syndrome than the general population because the flattened “fallen” arches can stretch the tibial nerve.
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Causes of Tarsal Tunnel Syndrome. Tarsal tunnel syndrome can be caused by any condition that causes compression of the tibial nerve or its branches as it passes through the tarsal tunnel. A wide variety of conditions can cause tarsal tunnel syndrome including space-occupying lesions or masses, which may increase pressure in the tunnel. Such lesions include tumors consisting mainly of fat tissue (lipomas), tumors consisting of nerve fibers and ganglion cells (gangliomas) and tumors of the nerve sheath (schwannomas).Additional conditions that can cause tarsal tunnel syndrome include a benign bony growth in the tarsal tunnel (exostosis), enlarged (varicose) veins and inflammation of the synovial membrane (proliferative synovitis). Certain injuries or trauma such as an ankle sprain, fracture or valgus foot deformity may cause inflammation and swelling that can lead to tarsal tunnel syndrome. In addition, certain disorders such as diabetes and arthritis can also cause inflammation and swelling that can lead to tarsal tunnel syndrome.Individuals who have severely flat feet (pes planus) are at a greater risk of developing tarsal tunnel syndrome than the general population because the flattened “fallen” arches can stretch the tibial nerve.
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Affects of Tarsal Tunnel Syndrome
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The incidence and prevalence of tarsal tunnel syndrome is unknown. The disorder is believed to affect males and females in equal numbers.
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Affects of Tarsal Tunnel Syndrome. The incidence and prevalence of tarsal tunnel syndrome is unknown. The disorder is believed to affect males and females in equal numbers.
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Related disorders of Tarsal Tunnel Syndrome
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Symptoms of the following disorders can be similar to those of tarsal tunnel syndrome. Comparisons may be useful for a differential diagnosis.Plantar fasciitis is a common condition characterized by inflammation of the thick band of tissue which runs along the bottom of the foot (plantar fascia). The plantar fascia supports the arch of the foot and acts as a shock absorber. Plantar fasciitis is a common cause of heel pain and is often described as a sharp pain in the heel. Pain associated with plantar fasciitis tends to develop gradually and tends to be worse in the morning and may improve throughout the day and with stretching exercises. Additionally, the pain is unlike the shooting and tingling pain associated with tarsal tunnel syndrome.A wide variety of conditions can cause pain in the foot or ankle including diabetes (diabetic neuropathy), posterior tibial tendinosis, stress fractures, certain rare disorders such as reflex sympathetic dystrophy and certain disorders that affect the nerves outside of the central nervous system (peripheral neuropathy).
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Related disorders of Tarsal Tunnel Syndrome. Symptoms of the following disorders can be similar to those of tarsal tunnel syndrome. Comparisons may be useful for a differential diagnosis.Plantar fasciitis is a common condition characterized by inflammation of the thick band of tissue which runs along the bottom of the foot (plantar fascia). The plantar fascia supports the arch of the foot and acts as a shock absorber. Plantar fasciitis is a common cause of heel pain and is often described as a sharp pain in the heel. Pain associated with plantar fasciitis tends to develop gradually and tends to be worse in the morning and may improve throughout the day and with stretching exercises. Additionally, the pain is unlike the shooting and tingling pain associated with tarsal tunnel syndrome.A wide variety of conditions can cause pain in the foot or ankle including diabetes (diabetic neuropathy), posterior tibial tendinosis, stress fractures, certain rare disorders such as reflex sympathetic dystrophy and certain disorders that affect the nerves outside of the central nervous system (peripheral neuropathy).
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Diagnosis of Tarsal Tunnel Syndrome
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A diagnosis of tarsal tunnel syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A specific finding that can detect an irritated nerve is Tinel’s sign. During a Tinel’s sign test, a doctor will tap or apply pressure to the tibial nerve. If this causes a tingling or a “pins and needles” sensation in the foot or toes, it is considered positive and is indicative of tarsal tunnel syndrome.Additional tests that may be performed include electromyography and magnetic resonance imaging (MRI). Electromyography is a test that can determine the health of muscles and nerves and can detect nerve dysfunction. An MRI uses a magnetic field and radio waves to produce cross-sectional images particular organs and bodily tissues and may be used if a space-occupying is the suspected cause of tarsal tunnel syndrome or to detect if the nerve is irritated.
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Diagnosis of Tarsal Tunnel Syndrome. A diagnosis of tarsal tunnel syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A specific finding that can detect an irritated nerve is Tinel’s sign. During a Tinel’s sign test, a doctor will tap or apply pressure to the tibial nerve. If this causes a tingling or a “pins and needles” sensation in the foot or toes, it is considered positive and is indicative of tarsal tunnel syndrome.Additional tests that may be performed include electromyography and magnetic resonance imaging (MRI). Electromyography is a test that can determine the health of muscles and nerves and can detect nerve dysfunction. An MRI uses a magnetic field and radio waves to produce cross-sectional images particular organs and bodily tissues and may be used if a space-occupying is the suspected cause of tarsal tunnel syndrome or to detect if the nerve is irritated.
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Therapies of Tarsal Tunnel Syndrome
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Treatment
The treatment of tarsal tunnel syndrome is directed toward the specific symptoms that are apparent in each individual. Physicians may recommend conservative treatment, which can include rest, contrast baths, nonsteroidal anti-inflammatory drugs (NSAIDs), and nonrigid orthotics. Orthotics refers to devices such as splints or braces that are used to protect or correct the position of the foot. In some cases, changing to looser or larger footwear to reduce tightness can relieve pain associated with tarsal tunnel syndrome.Some individuals may benefit from a local injection of certain medications (anesthetics) to reduce pain or corticosteroids to reduce inflammation. This may also prove to be diagnostic, as relief brought on by an injection of an anesthetic around the affected nerve confirms the diagnosis. Immobilization such as through the use of a cast can also be beneficial in some cases. Physical therapy may also be recommended.Individuals with tarsal tunnel syndrome due to flat feet may be treated with orthotics designed to provide support or restore the natural arch of the foot.Surgery is recommended for individuals with severe symptoms who do not respond to conservative treatment. The purpose of the surgery is to decompress the nerve from within the tarsal tunnel and/or removal of any space-occupying lesion.
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Therapies of Tarsal Tunnel Syndrome. Treatment
The treatment of tarsal tunnel syndrome is directed toward the specific symptoms that are apparent in each individual. Physicians may recommend conservative treatment, which can include rest, contrast baths, nonsteroidal anti-inflammatory drugs (NSAIDs), and nonrigid orthotics. Orthotics refers to devices such as splints or braces that are used to protect or correct the position of the foot. In some cases, changing to looser or larger footwear to reduce tightness can relieve pain associated with tarsal tunnel syndrome.Some individuals may benefit from a local injection of certain medications (anesthetics) to reduce pain or corticosteroids to reduce inflammation. This may also prove to be diagnostic, as relief brought on by an injection of an anesthetic around the affected nerve confirms the diagnosis. Immobilization such as through the use of a cast can also be beneficial in some cases. Physical therapy may also be recommended.Individuals with tarsal tunnel syndrome due to flat feet may be treated with orthotics designed to provide support or restore the natural arch of the foot.Surgery is recommended for individuals with severe symptoms who do not respond to conservative treatment. The purpose of the surgery is to decompress the nerve from within the tarsal tunnel and/or removal of any space-occupying lesion.
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Overview of Tatton Brown Rahman Syndrome
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SummaryTatton Brown Rahman Syndrome (TBRS), also known as DNMT3A overgrowth syndrome, was first identified in 2014. TBRS is a complex multisystem disorder involving many different tissues including the nervous system, muscle and blood. It is associated with tall stature, increased weight and/or large head circumference (macrocephaly). Individuals typically have mild to severe intellectual disability, as well as subtle but distinctive facial characteristics. There are a variety of other symptoms associated with TBRS, such as low muscle tone, behavioral and mental health issues, orthopedic problems, heart defects and autism, but not all individuals have every clinical finding reported and the syndrome varies considerably in its severity.TBRS is caused by germline/constitutional variants (pathogenic variants) in the DNMT3A gene. Germline/constitutional refers to a variant that is present in all cells. Most DNMT3A gene variants occur spontaneously (de novo) which means they are not inherited from a parent. Some individuals have inherited the disorder from an affected parent in an autosomal dominant pattern. As of 2022, approximately 300 individuals have been diagnosed with TBRS, though the number of individuals with TBRS is likely much higher.
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Overview of Tatton Brown Rahman Syndrome. SummaryTatton Brown Rahman Syndrome (TBRS), also known as DNMT3A overgrowth syndrome, was first identified in 2014. TBRS is a complex multisystem disorder involving many different tissues including the nervous system, muscle and blood. It is associated with tall stature, increased weight and/or large head circumference (macrocephaly). Individuals typically have mild to severe intellectual disability, as well as subtle but distinctive facial characteristics. There are a variety of other symptoms associated with TBRS, such as low muscle tone, behavioral and mental health issues, orthopedic problems, heart defects and autism, but not all individuals have every clinical finding reported and the syndrome varies considerably in its severity.TBRS is caused by germline/constitutional variants (pathogenic variants) in the DNMT3A gene. Germline/constitutional refers to a variant that is present in all cells. Most DNMT3A gene variants occur spontaneously (de novo) which means they are not inherited from a parent. Some individuals have inherited the disorder from an affected parent in an autosomal dominant pattern. As of 2022, approximately 300 individuals have been diagnosed with TBRS, though the number of individuals with TBRS is likely much higher.
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Symptoms of Tatton Brown Rahman Syndrome
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The severity and symptoms of TBRS vary from person to person. Patients and parents should consult with their physician to determine risks for specific symptoms and a plan for medical management.Distinctive Facial Appearance
Individuals with TBRS tend to have facial characteristics that include low-set, heavy, horizontal eyebrows, prominent upper central incisors, rounded face and a reduction in the vertical space between the upper and lower eyelids (narrow palpebral fissures).Overgrowth
Most individuals with TBRS have a larger head circumference than average at birth (macrocephaly) and/or tall stature.Obesity
Many individuals with TBRS are overweight and may be diagnosed with obesity.Intellectual Disability and Developmental Delay
Intellectual disability (ID) can vary across patients, with a spectrum of mild to severe ID. Patients also experience developmental delays (DD), which may be present in motor function, speech, language, cognitive abilities and social skills. Severity of DD varies among patients, though nonverbal and spatial reasoning skills appear to be more significantly affected in these individuals than verbal reasoning.Psychiatric and Behavioral Disorders
Psychiatric and behavioral disorders are common in individuals with TBRS and may take different forms. The most common behavioral diagnosis in TBRS patients is autism spectrum disorder. Other psychiatric and behavioral problems that have been identified in TBRS patients include anxiety, aggression, psychotic disorders, bipolar disorder, obsessive behaviors and compulsive eating.
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Symptoms of Tatton Brown Rahman Syndrome. The severity and symptoms of TBRS vary from person to person. Patients and parents should consult with their physician to determine risks for specific symptoms and a plan for medical management.Distinctive Facial Appearance
Individuals with TBRS tend to have facial characteristics that include low-set, heavy, horizontal eyebrows, prominent upper central incisors, rounded face and a reduction in the vertical space between the upper and lower eyelids (narrow palpebral fissures).Overgrowth
Most individuals with TBRS have a larger head circumference than average at birth (macrocephaly) and/or tall stature.Obesity
Many individuals with TBRS are overweight and may be diagnosed with obesity.Intellectual Disability and Developmental Delay
Intellectual disability (ID) can vary across patients, with a spectrum of mild to severe ID. Patients also experience developmental delays (DD), which may be present in motor function, speech, language, cognitive abilities and social skills. Severity of DD varies among patients, though nonverbal and spatial reasoning skills appear to be more significantly affected in these individuals than verbal reasoning.Psychiatric and Behavioral Disorders
Psychiatric and behavioral disorders are common in individuals with TBRS and may take different forms. The most common behavioral diagnosis in TBRS patients is autism spectrum disorder. Other psychiatric and behavioral problems that have been identified in TBRS patients include anxiety, aggression, psychotic disorders, bipolar disorder, obsessive behaviors and compulsive eating.
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Causes of Tatton Brown Rahman Syndrome
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TBRS is caused by pathogenic variants in the DNMT3A (DNA methyltransferase 3 alpha) gene, which produces the DNMT3A enzyme. The function of DNMT3A is not completely understood, but it is believed that this enzyme is responsible for methylating DNA. Methylation is a process involving the addition of methyl groups to DNA: methylation results in transcriptional repression. Patients with TBRS have pathogenic variants in the DNMT3A gene that prevent the DNMT3A enzyme from functioning properly, causing a suspected decreased methylation (hypomethylation).Many of the identified gene variants are unique to the individual. Most of these variants are not inherited but arise for the first time in the affected individual (de novo inheritance), though inherited variants do occur as well. DNMT3A variants are autosomal dominant. Autosomal dominant genetic conditions occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Tatton Brown Rahman Syndrome. TBRS is caused by pathogenic variants in the DNMT3A (DNA methyltransferase 3 alpha) gene, which produces the DNMT3A enzyme. The function of DNMT3A is not completely understood, but it is believed that this enzyme is responsible for methylating DNA. Methylation is a process involving the addition of methyl groups to DNA: methylation results in transcriptional repression. Patients with TBRS have pathogenic variants in the DNMT3A gene that prevent the DNMT3A enzyme from functioning properly, causing a suspected decreased methylation (hypomethylation).Many of the identified gene variants are unique to the individual. Most of these variants are not inherited but arise for the first time in the affected individual (de novo inheritance), though inherited variants do occur as well. DNMT3A variants are autosomal dominant. Autosomal dominant genetic conditions occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Affects of Tatton Brown Rahman Syndrome
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The incidence and prevalence of TBRS are unknown. Since 2014, the TBRS Community is aware of more than 300 individuals with TBRS. Individuals have been diagnosed at different ages. This syndrome seems to affect males and females equally.
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Affects of Tatton Brown Rahman Syndrome. The incidence and prevalence of TBRS are unknown. Since 2014, the TBRS Community is aware of more than 300 individuals with TBRS. Individuals have been diagnosed at different ages. This syndrome seems to affect males and females equally.
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Related disorders of Tatton Brown Rahman Syndrome
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Genetically Related DisordersThere are several disorders that are genetically similar to TBRS. Heyn-Sproul-Jackson syndrome is one such disorder. This disorder is characterized by pathogenic variants in DNMT3A as well. However, these pathogenic variants cause a gain-of-function in DNMT3A, resulting in symptoms that have been described as the opposite of TBRS. These symptoms include a small head (microcephaly) and short stature (dwarfism).Sporadic tumors, like those in acute myeloid leukemia and myelodysplastic syndrome, result from a sporadic mutation – i.e., these are not caused by germline variants, meaning the variant occurred later in life and is not heritable. These somatic variants in DNMT3A can be related to clonal hematopoesis and hematologic malignancies.Phenotypically (Symptomatic) Related DisordersPrior to the discovery of TBRS, many patients were misdiagnosed with Sotos syndrome due to the similarities between the conditions, including overgrowth and developmental disabilities. Commonalities also include behavioral issues, intellectual disability and neurological issues. Sotos syndrome presents with craniofacial features that are similar but distinct from TBRS. Sotos syndrome is caused by a pathogenic variant in the NSD1 gene. Sotos syndrome and TBRS can be differentiated by genetic testing. (For more information on this condition, choose “Sotos” as your search term in the Rare Disease Database.)Weaver syndrome, as known as Weaver-Smith syndrome, is another disorder similar to TBRS. This condition is also characterized by overgrowth, intellectual disability and low muscle tone (hypotonia). Joint problems may also be common in this disorder. Affected individuals have craniofacial features that are similar but distinct from those present in TBRS. Weaver syndrome is caused by a variant in the EZH2 gene. (For more information on this condition, choose “Weaver” as your search term in the Rare Disease Database.)Individuals with Marfan syndrome have similar characteristics to those diagnosed with TBRS. Marfan syndrome is characterized by tall stature and lax joints. These individuals may also present with scoliosis, eye and heart problems and chest wall differences. However, intellectual disability is not usually associated with Marfan syndrome. Marfan syndrome is caused by a variant in the FBN1 gene and can be inherited in an autosomal dominant pattern. (For more information on this condition, choose “Marfan” as your search term in the Rare Disease Database.)
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Related disorders of Tatton Brown Rahman Syndrome. Genetically Related DisordersThere are several disorders that are genetically similar to TBRS. Heyn-Sproul-Jackson syndrome is one such disorder. This disorder is characterized by pathogenic variants in DNMT3A as well. However, these pathogenic variants cause a gain-of-function in DNMT3A, resulting in symptoms that have been described as the opposite of TBRS. These symptoms include a small head (microcephaly) and short stature (dwarfism).Sporadic tumors, like those in acute myeloid leukemia and myelodysplastic syndrome, result from a sporadic mutation – i.e., these are not caused by germline variants, meaning the variant occurred later in life and is not heritable. These somatic variants in DNMT3A can be related to clonal hematopoesis and hematologic malignancies.Phenotypically (Symptomatic) Related DisordersPrior to the discovery of TBRS, many patients were misdiagnosed with Sotos syndrome due to the similarities between the conditions, including overgrowth and developmental disabilities. Commonalities also include behavioral issues, intellectual disability and neurological issues. Sotos syndrome presents with craniofacial features that are similar but distinct from TBRS. Sotos syndrome is caused by a pathogenic variant in the NSD1 gene. Sotos syndrome and TBRS can be differentiated by genetic testing. (For more information on this condition, choose “Sotos” as your search term in the Rare Disease Database.)Weaver syndrome, as known as Weaver-Smith syndrome, is another disorder similar to TBRS. This condition is also characterized by overgrowth, intellectual disability and low muscle tone (hypotonia). Joint problems may also be common in this disorder. Affected individuals have craniofacial features that are similar but distinct from those present in TBRS. Weaver syndrome is caused by a variant in the EZH2 gene. (For more information on this condition, choose “Weaver” as your search term in the Rare Disease Database.)Individuals with Marfan syndrome have similar characteristics to those diagnosed with TBRS. Marfan syndrome is characterized by tall stature and lax joints. These individuals may also present with scoliosis, eye and heart problems and chest wall differences. However, intellectual disability is not usually associated with Marfan syndrome. Marfan syndrome is caused by a variant in the FBN1 gene and can be inherited in an autosomal dominant pattern. (For more information on this condition, choose “Marfan” as your search term in the Rare Disease Database.)
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Diagnosis of Tatton Brown Rahman Syndrome
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Clinical features that may lead to suspicion of TBRS include:
– Generalized overgrowth in infancy, adolescence or childhood
– Intellectual disability or developmental delay
– Distinctive facial features
– Joint hypermobility
– Low muscle tone (hypotonia)
– Behavioral problems including autism spectrum disorder and a variety of other characteristicsDiagnosis is confirmed by genetic testing revealing a pathogenic variant in the DNMT3A gene. Variants that disrupt the function of DNMT3A cause TBRS, so the specific variant is necessary for diagnosis. Due to the similarities between this syndrome and other overgrowth syndromes, genetic testing may include a gene panel consisting of many genes that cause different overgrowth syndromes.
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Diagnosis of Tatton Brown Rahman Syndrome. Clinical features that may lead to suspicion of TBRS include:
– Generalized overgrowth in infancy, adolescence or childhood
– Intellectual disability or developmental delay
– Distinctive facial features
– Joint hypermobility
– Low muscle tone (hypotonia)
– Behavioral problems including autism spectrum disorder and a variety of other characteristicsDiagnosis is confirmed by genetic testing revealing a pathogenic variant in the DNMT3A gene. Variants that disrupt the function of DNMT3A cause TBRS, so the specific variant is necessary for diagnosis. Due to the similarities between this syndrome and other overgrowth syndromes, genetic testing may include a gene panel consisting of many genes that cause different overgrowth syndromes.
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Therapies of Tatton Brown Rahman Syndrome
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Current therapies for TBRS involve management of symptoms. Genetic counseling may help to inform affected individuals and caregivers of the implications of TBRS, the risks associated with the syndrome and medical actions that may be needed. Creation of a treatment plan may aid in this process.Clinical and developmental assessment can aid in motor, speech, language, cognitive and adaptive evaluation, evaluation for early intervention and risk for continued overgrowth beyond a healthy threshold. Neuropsychiatric evaluation may aid in screening for behavioral health or mental health concerns. Evaluation by a neurologist may be recommended if the patient experiences seizures, as well as to identify new neurological manifestations. Similarly, if sleep apnea is diagnosed and obstructive, a respiratory physician will likely need to be involved.Speech therapy may be useful for individuals following evaluation. Occupational therapy is frequently utilized by these patients as well to develop necessary skills. Behavioral therapy may also be utilized for individuals with TBRS. Physical therapy may be useful for low muscle tone and orthopedic problems.Routine cardiovascular screening is suggested due to the increased frequency of heart conditions in patients with TBRS. Monitoring by a hematologist may be suggested due to the potential increased risk for acute myeloid leukemia (AML) and other blood conditions.Family support and resources are available for individuals affected by TBRS and their families/caregivers from TBRS Community via Facebook or the following link: https://tbrsyndrome.org.
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Therapies of Tatton Brown Rahman Syndrome. Current therapies for TBRS involve management of symptoms. Genetic counseling may help to inform affected individuals and caregivers of the implications of TBRS, the risks associated with the syndrome and medical actions that may be needed. Creation of a treatment plan may aid in this process.Clinical and developmental assessment can aid in motor, speech, language, cognitive and adaptive evaluation, evaluation for early intervention and risk for continued overgrowth beyond a healthy threshold. Neuropsychiatric evaluation may aid in screening for behavioral health or mental health concerns. Evaluation by a neurologist may be recommended if the patient experiences seizures, as well as to identify new neurological manifestations. Similarly, if sleep apnea is diagnosed and obstructive, a respiratory physician will likely need to be involved.Speech therapy may be useful for individuals following evaluation. Occupational therapy is frequently utilized by these patients as well to develop necessary skills. Behavioral therapy may also be utilized for individuals with TBRS. Physical therapy may be useful for low muscle tone and orthopedic problems.Routine cardiovascular screening is suggested due to the increased frequency of heart conditions in patients with TBRS. Monitoring by a hematologist may be suggested due to the potential increased risk for acute myeloid leukemia (AML) and other blood conditions.Family support and resources are available for individuals affected by TBRS and their families/caregivers from TBRS Community via Facebook or the following link: https://tbrsyndrome.org.
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Overview of Tay Sachs Disease
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Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. Tay-Sachs disease is categorized as a lysosomal storage disease. Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or “digest” nutrients, including certain complex carbohydrates and fats (like glycosphingolipids). When one of these lysosomal enzymes (such as hexosaminidase A) is missing or ineffective, glycosphingolipids start to build up in the lysosome. If there is too much accumulation of these materials in the lysosome, the cells in the nervous system degenerate and die, triggering an inflammatory response that amplifies damage in surrounding tissue.The most common form of Tay-Sachs disease is the Infantile form, which can present around 6 months of age as reduced vision and an exaggerated startle response and eventually progress to a gradual loss of skills and seizures by age 2 and early death, usually by the age of 5. There is also a juvenile version of the disease beginning at about the age of 5 years of age and adult forms of Tay-Sachs disease also known as late-onset Tay Sachs disease (LOTS) beginning in the late teens and beyond. All three forms of Tay-Sachs disease are inherited in an autosomal recessive manner and the age of onset is a function of the amount, if any, of residual enzyme activity.
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Overview of Tay Sachs Disease. Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. Tay-Sachs disease is categorized as a lysosomal storage disease. Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or “digest” nutrients, including certain complex carbohydrates and fats (like glycosphingolipids). When one of these lysosomal enzymes (such as hexosaminidase A) is missing or ineffective, glycosphingolipids start to build up in the lysosome. If there is too much accumulation of these materials in the lysosome, the cells in the nervous system degenerate and die, triggering an inflammatory response that amplifies damage in surrounding tissue.The most common form of Tay-Sachs disease is the Infantile form, which can present around 6 months of age as reduced vision and an exaggerated startle response and eventually progress to a gradual loss of skills and seizures by age 2 and early death, usually by the age of 5. There is also a juvenile version of the disease beginning at about the age of 5 years of age and adult forms of Tay-Sachs disease also known as late-onset Tay Sachs disease (LOTS) beginning in the late teens and beyond. All three forms of Tay-Sachs disease are inherited in an autosomal recessive manner and the age of onset is a function of the amount, if any, of residual enzyme activity.
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Symptoms of Tay Sachs Disease
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Infantile Tay-Sachs Disease
The infantile form of Tay-Sachs disease is characterized by complete or almost complete lack of hexosaminidase A enzyme activity. The disorder often progresses rapidly, resulting in significant cognitive and physical deterioration.Infants may appear completely unaffected at birth. Initial symptoms, which usually develop between 3 and 6 months, can include mild muscle weakness, twitching or jerking of muscles (myoclonic jerks) and an exaggerated startle response, such as when there is a sudden or unexpected noise. The startle response may be partly due to an increased sensitivity to sound (acoustic hypersensitivity).Between six and 10 months, affected infants may fail to gain new motor skills. They may no longer make eye contact and there may be unusual eye movements. They may be listlessness and irritable. As affected infants age, they may experience slow growth, progressive muscle weakness and diminished muscle tone (hypotonia). Affected infants may also exhibit gradual loss of vision, involuntary muscle spasms (myoclonus), slow, stiff movements (spasticity) and the loss of previously acquired skills (i.e., psychomotor regression) such as crawling or sitting up.A characteristic symptom of Tay-Sachs disease is the development of a macular “cherry red” spot. This ophthalmological finding emerges from abnormal accumulation of pale undigested material in the macula which contrasts to the thin foveal transparent background exposing the normal rich choroidal vasculature. This characteristic finding occurs is approximately 90% of individuals with infantile Tay-Sachs disease.As affected infants age, more serious complications may develop including seizures, difficulty swallowing, loss of vision, paralysis and progressive hearing loss. Additional cognitive deficits may include confusion, disorientation and/or deterioration of intellectual abilities. Eventually, infants may become unresponsive to their environment and surroundings. By three to five years of age, life-threatening complications begin to occur such as aspiration pneumonia leading to respiratory failure.Juvenile (Subacute) Tay-Sachs Disease
The onset of juvenile Tay-Sachs disease can be anywhere between 2 and 10 years of age. One of the first signs is often clumsiness and incoordination. This occurs because affected children have issues controlling their body’s movements (ataxia). Children tend to experience a progressive loss of speech, life skills and intellectual abilities. Affected individuals may or may not develop a cherry-red spot in the eyes. Degeneration of the optic nerves (optic atrophy) may occur. Some children may have retinitis pigmentosa, a progressive loss and degeneration of the cells in the retina where shapes and colors are first encoded. Affected children become less responsive to their environment and surroundings. Life-threatening complications usually occur around 15 years of age.Late-Onset Tay-Sachs Disease
The presentation and symptoms associated with late-onset Tay-Sachs disease vary greatly. Onset of the disease may vary from the late teens to any time in adulthood. This variability may occur even within affected members of the same family. For example, in a given family one person may have symptoms in their 20s, while another reaches into their 60s or 70s with relatively milder minor symptoms. The disorder progresses much slower than the infantile or juvenile forms of the disease.Initial symptoms associated with late-onset Tay-Sachs disease may include progressive muscle weakness and wasting (neurogenic atrophy), incoordination and clumsiness from cerebellar dysfunction (ataxia) or acute psychiatric presentation. As affected individuals age, muscle twitching (fasciculation), cramps, weakness and muscle wasting progresses affecting preferentially the quadriceps and hip flexor muscles, and later, the triceps muscles. Patients need to lock their knees in hyperextension to be able to stand and support their weight. Failure to do so results in falls and eventually leads to the need for a device to assist with walking. Patients may exhibit tremors and progressive slurred speech (dysarthria). Difficulties swallowing (dysphagia) may emerge late in the disease. Some affected individuals experience acute psychiatric manifestations (mania, acute depression or psychosis) that may require emergency psychiatric care. Over time, cognitive difficulties including executive dysfunction and some memory difficulties might emerge.
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Symptoms of Tay Sachs Disease. Infantile Tay-Sachs Disease
The infantile form of Tay-Sachs disease is characterized by complete or almost complete lack of hexosaminidase A enzyme activity. The disorder often progresses rapidly, resulting in significant cognitive and physical deterioration.Infants may appear completely unaffected at birth. Initial symptoms, which usually develop between 3 and 6 months, can include mild muscle weakness, twitching or jerking of muscles (myoclonic jerks) and an exaggerated startle response, such as when there is a sudden or unexpected noise. The startle response may be partly due to an increased sensitivity to sound (acoustic hypersensitivity).Between six and 10 months, affected infants may fail to gain new motor skills. They may no longer make eye contact and there may be unusual eye movements. They may be listlessness and irritable. As affected infants age, they may experience slow growth, progressive muscle weakness and diminished muscle tone (hypotonia). Affected infants may also exhibit gradual loss of vision, involuntary muscle spasms (myoclonus), slow, stiff movements (spasticity) and the loss of previously acquired skills (i.e., psychomotor regression) such as crawling or sitting up.A characteristic symptom of Tay-Sachs disease is the development of a macular “cherry red” spot. This ophthalmological finding emerges from abnormal accumulation of pale undigested material in the macula which contrasts to the thin foveal transparent background exposing the normal rich choroidal vasculature. This characteristic finding occurs is approximately 90% of individuals with infantile Tay-Sachs disease.As affected infants age, more serious complications may develop including seizures, difficulty swallowing, loss of vision, paralysis and progressive hearing loss. Additional cognitive deficits may include confusion, disorientation and/or deterioration of intellectual abilities. Eventually, infants may become unresponsive to their environment and surroundings. By three to five years of age, life-threatening complications begin to occur such as aspiration pneumonia leading to respiratory failure.Juvenile (Subacute) Tay-Sachs Disease
The onset of juvenile Tay-Sachs disease can be anywhere between 2 and 10 years of age. One of the first signs is often clumsiness and incoordination. This occurs because affected children have issues controlling their body’s movements (ataxia). Children tend to experience a progressive loss of speech, life skills and intellectual abilities. Affected individuals may or may not develop a cherry-red spot in the eyes. Degeneration of the optic nerves (optic atrophy) may occur. Some children may have retinitis pigmentosa, a progressive loss and degeneration of the cells in the retina where shapes and colors are first encoded. Affected children become less responsive to their environment and surroundings. Life-threatening complications usually occur around 15 years of age.Late-Onset Tay-Sachs Disease
The presentation and symptoms associated with late-onset Tay-Sachs disease vary greatly. Onset of the disease may vary from the late teens to any time in adulthood. This variability may occur even within affected members of the same family. For example, in a given family one person may have symptoms in their 20s, while another reaches into their 60s or 70s with relatively milder minor symptoms. The disorder progresses much slower than the infantile or juvenile forms of the disease.Initial symptoms associated with late-onset Tay-Sachs disease may include progressive muscle weakness and wasting (neurogenic atrophy), incoordination and clumsiness from cerebellar dysfunction (ataxia) or acute psychiatric presentation. As affected individuals age, muscle twitching (fasciculation), cramps, weakness and muscle wasting progresses affecting preferentially the quadriceps and hip flexor muscles, and later, the triceps muscles. Patients need to lock their knees in hyperextension to be able to stand and support their weight. Failure to do so results in falls and eventually leads to the need for a device to assist with walking. Patients may exhibit tremors and progressive slurred speech (dysarthria). Difficulties swallowing (dysphagia) may emerge late in the disease. Some affected individuals experience acute psychiatric manifestations (mania, acute depression or psychosis) that may require emergency psychiatric care. Over time, cognitive difficulties including executive dysfunction and some memory difficulties might emerge.
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Causes of Tay Sachs Disease
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Tay-Sachs disease is caused by a change (mutation) in the hexosaminidase subunit alpha (HEXA) gene. Genes provide the instructions for the basic structure of proteins, all of which that play a critical role in many functions and structure of the body. When a mutation occurs in a gene, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.The HEXA gene encodes the structure of the protein HEXA which is a subunit of the enzyme hexosaminidase A. More than 80 different mutations of the HEXA gene have been identified in individuals with the disease. Inheriting two mutated copies of the HEXA gene (homozygotes) causes deficiency of the hexosaminidase A enzyme, which is necessary to breakdown GM2-ganglioside (a glycosphingolipids) within cells of the body. Failure to breakdown GM2-ganglioside results in its abnormal accumulation in brain and nerve cells eventually resulting in the progressive deterioration of the central nervous system.In infantile Tay-Sachs disease, there is a complete lack of hexosaminidase A. In juvenile and late-onset Tay-Sachs disease, there minimal but still some residual hexosaminidase A enzyme activity which explains why these disorders might be less severe and progress at a slower pace than infantile Tay-Sachs disease.Tay-Sachs disease is inherited as an autosomal recessive disease. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene, one from each parent. If an individual inherits one normal copy of the gene from one parent and an abnormal (mutated) copy of the gene from the other parent, that person will be a carrier for the disease but will not develop the disease. The risk for two carrier parents to both pass the altered gene and 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 the normal genes from each parent is 25%. The risk is the same for males and females.
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Causes of Tay Sachs Disease. Tay-Sachs disease is caused by a change (mutation) in the hexosaminidase subunit alpha (HEXA) gene. Genes provide the instructions for the basic structure of proteins, all of which that play a critical role in many functions and structure of the body. When a mutation occurs in a gene, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.The HEXA gene encodes the structure of the protein HEXA which is a subunit of the enzyme hexosaminidase A. More than 80 different mutations of the HEXA gene have been identified in individuals with the disease. Inheriting two mutated copies of the HEXA gene (homozygotes) causes deficiency of the hexosaminidase A enzyme, which is necessary to breakdown GM2-ganglioside (a glycosphingolipids) within cells of the body. Failure to breakdown GM2-ganglioside results in its abnormal accumulation in brain and nerve cells eventually resulting in the progressive deterioration of the central nervous system.In infantile Tay-Sachs disease, there is a complete lack of hexosaminidase A. In juvenile and late-onset Tay-Sachs disease, there minimal but still some residual hexosaminidase A enzyme activity which explains why these disorders might be less severe and progress at a slower pace than infantile Tay-Sachs disease.Tay-Sachs disease is inherited as an autosomal recessive disease. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene, one from each parent. If an individual inherits one normal copy of the gene from one parent and an abnormal (mutated) copy of the gene from the other parent, that person will be a carrier for the disease but will not develop the disease. The risk for two carrier parents to both pass the altered gene and 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 the normal genes from each parent is 25%. The risk is the same for males and females.
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Affects of Tay Sachs Disease
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Tay-Sachs disease affects males and females in equal numbers. Tay-Sachs disease used to be considered a prototypical disease of Jewish people of Ashkenazi descent. Community counselling and carrier screening efforts in these communities have succeeded in reducing disease prevalence to figures roughly equivalent to those of non-Jewish populations. Increased prevalence of Tay Sachs disease is also reported in other ethnic groups including those living in the Cajun community of Louisiana and southeastern Quebec. In the general population, the carrier rate for Tay-Sacks disease is approximately 1 in 250-300 people.
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Affects of Tay Sachs Disease. Tay-Sachs disease affects males and females in equal numbers. Tay-Sachs disease used to be considered a prototypical disease of Jewish people of Ashkenazi descent. Community counselling and carrier screening efforts in these communities have succeeded in reducing disease prevalence to figures roughly equivalent to those of non-Jewish populations. Increased prevalence of Tay Sachs disease is also reported in other ethnic groups including those living in the Cajun community of Louisiana and southeastern Quebec. In the general population, the carrier rate for Tay-Sacks disease is approximately 1 in 250-300 people.
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Related disorders of Tay Sachs Disease
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Symptoms of the following disorders can share similarities to those of Tay-Sachs disease. Comparisons may be useful for a differential diagnosis:Sandhoff disease is closely related and shares many clinical and biochemical features to Tay-Sachs. Like Tay-Sachs disease, Sandhoff disease affects the function of the enzyme Hexosaminidase A. It does so by disruption of the beta subunit (HEXB subunit) of hexosaminidase A encoded by the gene HEXB. Like Tay-Sachs, Sandhoff disease is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Sandhoff” as your search term in the Rare Disease Database.)Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system. The symptoms of Leigh syndrome usually begin between the ages of three months and two years, but some patients do not exhibit signs and symptoms until several years later. Symptoms are associated with progressive or stepwise neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia) and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of proteins of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most people, Leigh syndrome is inherited as an autosomal recessive disease. However, X-linked recessive inheritance and inheritance from the mother via a mitochondrial DNA (mtDNA) mutation are also possible. (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)The neuronal ceroid lipofuscinoses (NCLs) are a group of progressive degenerative neurometabolic diseases. These diseases share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Two forms occur during infancy: classic infantile CLN1 disease (Santavuori disease) and CLN2 disease (late infantile type). The NCLs are characterized by abnormal accumulation of certain fatty, granular substances such as ceroid and lipofuscin within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment and other characteristic symptoms and physical findings. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)There are many other lysosomal storage diseases that can share symptoms like those seen in Tay-Sachs disease. Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various materials inside lysosomes as a result of deficiencies in enzymes involved in the degradation of large molecules. These disorders may affect different parts of the body, including the skeleton, brain, skin, heart. liver, spleen and peripheral nervous system. (For more information on this disorder, choose “lysosomal” as your search term in the Rare Disease Database.)Symptoms of the following disorders can be similar to those of Late-onset Tay-Sachs disease. Comparisons may be useful for a differential diagnosis:Milder or late -onset forms of spinal muscular atrophy (SMA) shares may similarities with the neuromuscular presentation of adult of late-onset Tay-Sachs disease. SMA results in progressive degeneration of the motor neurons in the spinal cord and leads to muscle weakness, fasciculations and muscle wasting. SMA is typically due to deletions or mutations of the gene SMN1 and its severity is modified by the number of copies of the related gene SMN2. (For more information on this disorder, choose “Spinal Muscular Atrophy” as your search term in the Rare Disease Database.)Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, resulting degeneration of the upper (motor cortex) and lower (spinal cord) motor neurons. Muscle wasting and spasticity are common. Weakness in the arms and hands results in loss of dexterity and weakness in legs may lead to incapacity to ambulate and falling. ALS may also involve swallowing (dysphagia), weakness of the tongue, vocal cords, and diaphragm and can cause speech and respiratory difficulties. As weakness progresses patients are at increased risk for respiratory complications. There are familial and sporadic forms of ALS. (For more information on this disorder, choose “Amyotrophic Lateral Sclerosis” as your search term in the Rare Disease Database.)Progressive hereditary spinal cerebellar degenerations represent a large group of inherited disorders characterized by cerebellar deficits including incoordination, ataxia tremor and dysarthria along with combination of dysfunction of various spinal tracts. Their presentation may not be unlike those of patients with cerebellar dysfunction in the context of adult or late-onset Tay Sachs disease.
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Related disorders of Tay Sachs Disease. Symptoms of the following disorders can share similarities to those of Tay-Sachs disease. Comparisons may be useful for a differential diagnosis:Sandhoff disease is closely related and shares many clinical and biochemical features to Tay-Sachs. Like Tay-Sachs disease, Sandhoff disease affects the function of the enzyme Hexosaminidase A. It does so by disruption of the beta subunit (HEXB subunit) of hexosaminidase A encoded by the gene HEXB. Like Tay-Sachs, Sandhoff disease is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Sandhoff” as your search term in the Rare Disease Database.)Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system. The symptoms of Leigh syndrome usually begin between the ages of three months and two years, but some patients do not exhibit signs and symptoms until several years later. Symptoms are associated with progressive or stepwise neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia) and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of proteins of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most people, Leigh syndrome is inherited as an autosomal recessive disease. However, X-linked recessive inheritance and inheritance from the mother via a mitochondrial DNA (mtDNA) mutation are also possible. (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)The neuronal ceroid lipofuscinoses (NCLs) are a group of progressive degenerative neurometabolic diseases. These diseases share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Two forms occur during infancy: classic infantile CLN1 disease (Santavuori disease) and CLN2 disease (late infantile type). The NCLs are characterized by abnormal accumulation of certain fatty, granular substances such as ceroid and lipofuscin within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment and other characteristic symptoms and physical findings. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)There are many other lysosomal storage diseases that can share symptoms like those seen in Tay-Sachs disease. Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various materials inside lysosomes as a result of deficiencies in enzymes involved in the degradation of large molecules. These disorders may affect different parts of the body, including the skeleton, brain, skin, heart. liver, spleen and peripheral nervous system. (For more information on this disorder, choose “lysosomal” as your search term in the Rare Disease Database.)Symptoms of the following disorders can be similar to those of Late-onset Tay-Sachs disease. Comparisons may be useful for a differential diagnosis:Milder or late -onset forms of spinal muscular atrophy (SMA) shares may similarities with the neuromuscular presentation of adult of late-onset Tay-Sachs disease. SMA results in progressive degeneration of the motor neurons in the spinal cord and leads to muscle weakness, fasciculations and muscle wasting. SMA is typically due to deletions or mutations of the gene SMN1 and its severity is modified by the number of copies of the related gene SMN2. (For more information on this disorder, choose “Spinal Muscular Atrophy” as your search term in the Rare Disease Database.)Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, resulting degeneration of the upper (motor cortex) and lower (spinal cord) motor neurons. Muscle wasting and spasticity are common. Weakness in the arms and hands results in loss of dexterity and weakness in legs may lead to incapacity to ambulate and falling. ALS may also involve swallowing (dysphagia), weakness of the tongue, vocal cords, and diaphragm and can cause speech and respiratory difficulties. As weakness progresses patients are at increased risk for respiratory complications. There are familial and sporadic forms of ALS. (For more information on this disorder, choose “Amyotrophic Lateral Sclerosis” as your search term in the Rare Disease Database.)Progressive hereditary spinal cerebellar degenerations represent a large group of inherited disorders characterized by cerebellar deficits including incoordination, ataxia tremor and dysarthria along with combination of dysfunction of various spinal tracts. Their presentation may not be unlike those of patients with cerebellar dysfunction in the context of adult or late-onset Tay Sachs disease.
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Diagnosis of Tay Sachs Disease
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The diagnosis of Tay-Sachs disease may be confirmed by a thorough clinical evaluation and specialized tests such as blood tests that measure the enzyme activity levels of hexosaminidase A. Molecular genetic testing for mutations in the HEXA gene can confirm a diagnosis of Tay-Sachs disease. With the advent of more widely available gene panels and exome and whole genome sequencing, more patients are initially diagnosed by molecular testing followed by enzymatic confirmation.It is possible that a diagnosis of Tay-Sachs disease may be suspected before birth (prenatally) based upon specialized tests, such as amniocentesis and chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed, while CVS involves the removal of tissue samples from a portion of the placenta. These samples are studied to determine hexosaminidase A activity. Absence or greatly reduced activity suggests a diagnosis. Prenatal diagnosis is also possible through molecular genetic testing of tissue samples obtained through CVS or amniocentesis, particularly if the disease-causing mutation(s) in the HEXA gene are known in the family.Carrier testing for Tay-Sachs disease can be accomplished from a blood sample and determines whether an individual carries one disease-causing copy of the HEXA gene. Relatives of individuals with Tay-Sachs disease can be tested to determine whether they are carriers. Couples who are planning to have a child and have any Jewish ancestry (not just Ashkenazi) are encouraged to undergo carrier screening before proceeding with a pregnancy. For couples that find that they are carriers, there are several options available for starting a family. These options include assisted reproductive technologies (ART) such as in vitro fertilization (IVF) and adoption. Couples are encouraged to consult with a genetic counselor to discuss these options.Genetic counseling is available to assist families in testing decisions, interpreting test results and understanding health insurance coverage. Families are strongly encouraged to seek out a genetic counselor, particularly before carrier screening, to be most informed when making genetics healthcare decisions. For assistance finding a genetic counselor, visit: https://findageneticcounselor.nsgc.org/?reload=timezone
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Diagnosis of Tay Sachs Disease. The diagnosis of Tay-Sachs disease may be confirmed by a thorough clinical evaluation and specialized tests such as blood tests that measure the enzyme activity levels of hexosaminidase A. Molecular genetic testing for mutations in the HEXA gene can confirm a diagnosis of Tay-Sachs disease. With the advent of more widely available gene panels and exome and whole genome sequencing, more patients are initially diagnosed by molecular testing followed by enzymatic confirmation.It is possible that a diagnosis of Tay-Sachs disease may be suspected before birth (prenatally) based upon specialized tests, such as amniocentesis and chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed, while CVS involves the removal of tissue samples from a portion of the placenta. These samples are studied to determine hexosaminidase A activity. Absence or greatly reduced activity suggests a diagnosis. Prenatal diagnosis is also possible through molecular genetic testing of tissue samples obtained through CVS or amniocentesis, particularly if the disease-causing mutation(s) in the HEXA gene are known in the family.Carrier testing for Tay-Sachs disease can be accomplished from a blood sample and determines whether an individual carries one disease-causing copy of the HEXA gene. Relatives of individuals with Tay-Sachs disease can be tested to determine whether they are carriers. Couples who are planning to have a child and have any Jewish ancestry (not just Ashkenazi) are encouraged to undergo carrier screening before proceeding with a pregnancy. For couples that find that they are carriers, there are several options available for starting a family. These options include assisted reproductive technologies (ART) such as in vitro fertilization (IVF) and adoption. Couples are encouraged to consult with a genetic counselor to discuss these options.Genetic counseling is available to assist families in testing decisions, interpreting test results and understanding health insurance coverage. Families are strongly encouraged to seek out a genetic counselor, particularly before carrier screening, to be most informed when making genetics healthcare decisions. For assistance finding a genetic counselor, visit: https://findageneticcounselor.nsgc.org/?reload=timezone
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Therapies of Tay Sachs Disease
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TreatmentThere is no approved treatment for Tay-Sachs disease. Treatment is directed toward the individual symptom management. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, speech pathologists, specialists who assess and treat hearing problems (audiologists), eye specialists and other health care professionals may need to collaborate to develop a plan for an affected child’s treatment. Because of the potential for feeding difficulties, infants should be monitored for nutritional status and proper hydration. Nutritional support and supplementation may be necessary. Occasionally, the insertion of a feeding tube may be required to help prevent food, liquid or other foreign material from accidently going into the lungs (aspiration).Anticonvulsants may be used to treat seizures in some people with Tay-Sachs disease, but may not be effective in all people. The types and frequency of seizures can change over time in some individuals which will require a change in medication type or dosage.Genetic counseling is recommended for affected individuals and their families. Psychosocial support is recommended for the entire family.
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Therapies of Tay Sachs Disease. TreatmentThere is no approved treatment for Tay-Sachs disease. Treatment is directed toward the individual symptom management. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, speech pathologists, specialists who assess and treat hearing problems (audiologists), eye specialists and other health care professionals may need to collaborate to develop a plan for an affected child’s treatment. Because of the potential for feeding difficulties, infants should be monitored for nutritional status and proper hydration. Nutritional support and supplementation may be necessary. Occasionally, the insertion of a feeding tube may be required to help prevent food, liquid or other foreign material from accidently going into the lungs (aspiration).Anticonvulsants may be used to treat seizures in some people with Tay-Sachs disease, but may not be effective in all people. The types and frequency of seizures can change over time in some individuals which will require a change in medication type or dosage.Genetic counseling is recommended for affected individuals and their families. Psychosocial support is recommended for the entire family.
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Overview of TCF7L2-Related Neurodevelopmental Disorder
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TCF7L2-related neurodevelopmental disorder (TRND) is a newly discovered disorder caused by a change (variant or mutation) in the TCF7L2 gene. This mutation may be responsible for developmental delays in childhood, intellectual disability, autism, myopia, ADHD, abnormal physical features and other problems. There is a wide spectrum of severity for individuals affected with TRND. Many of the symptoms of TRND overlap with other neurodevelopmental disorders. TRND must be diagnosed with a genetic test and cannot be diagnosed by symptoms alone.
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Overview of TCF7L2-Related Neurodevelopmental Disorder. TCF7L2-related neurodevelopmental disorder (TRND) is a newly discovered disorder caused by a change (variant or mutation) in the TCF7L2 gene. This mutation may be responsible for developmental delays in childhood, intellectual disability, autism, myopia, ADHD, abnormal physical features and other problems. There is a wide spectrum of severity for individuals affected with TRND. Many of the symptoms of TRND overlap with other neurodevelopmental disorders. TRND must be diagnosed with a genetic test and cannot be diagnosed by symptoms alone.
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Symptoms of TCF7L2-Related Neurodevelopmental Disorder
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There is a wide spectrum of severity for individuals affected with TRND. Affected children tend to have developmental delays such as delayed speech and motor milestones. Some children may grow up to have average intellectual abilities, while others may have mild/moderate intellectual disability. Some individuals with TRND may also have autism spectrum disorder (ASD), social communication deficits, speech-language impairment and/or attention-deficit/hyperactivity disorder (ADHD). About half of those with the mutation may have nearsightedness (myopia) or vision impairments. Some children have been reported to have abnormal physical features such as a curved spine (scoliosis) and abnormal chest shape. However, the significance of these findings is still unknown. Many of the symptoms of TRND overlap with other neurodevelopmental disorders. Autism spectrum disorder (ASD) is characterized by lack of interest, repetitive behaviors and issues with social interaction and communication. Patients may also have problems with eye contact and other nonverbal social communications, as well as difficulty making and maintaining relationships with peers. Early symptoms of ASD (at about 1-2 years) are poor eye contact, limited response to name, little gesturing and regression of language skills. Toddlers may demonstrate little pretend play and very intense interests. Children may have trouble with literal thinking and emotions.
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Symptoms of TCF7L2-Related Neurodevelopmental Disorder. There is a wide spectrum of severity for individuals affected with TRND. Affected children tend to have developmental delays such as delayed speech and motor milestones. Some children may grow up to have average intellectual abilities, while others may have mild/moderate intellectual disability. Some individuals with TRND may also have autism spectrum disorder (ASD), social communication deficits, speech-language impairment and/or attention-deficit/hyperactivity disorder (ADHD). About half of those with the mutation may have nearsightedness (myopia) or vision impairments. Some children have been reported to have abnormal physical features such as a curved spine (scoliosis) and abnormal chest shape. However, the significance of these findings is still unknown. Many of the symptoms of TRND overlap with other neurodevelopmental disorders. Autism spectrum disorder (ASD) is characterized by lack of interest, repetitive behaviors and issues with social interaction and communication. Patients may also have problems with eye contact and other nonverbal social communications, as well as difficulty making and maintaining relationships with peers. Early symptoms of ASD (at about 1-2 years) are poor eye contact, limited response to name, little gesturing and regression of language skills. Toddlers may demonstrate little pretend play and very intense interests. Children may have trouble with literal thinking and emotions.
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Causes of TCF7L2-Related Neurodevelopmental Disorder
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TCF7L2-related neurodevelopmental disorder is caused by a change (variant or mutation) in the TCF7L2 gene. Mutations are nearly always de novo, which means that the mutation is present in the child but not in the parents. Because of the mutation in this gene, the protein product of the gene (a transcription factor) is either made incorrectly or not formed at all. Transcription factors are DNA-binding factors that regulate the amount of protein made in cells. Due to the lack of this protein, which is critical for brain development, patients develop the symptoms of TRND. There is currently no understood link between the mutation and the specific symptoms of TRND. TRND follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
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Causes of TCF7L2-Related Neurodevelopmental Disorder. TCF7L2-related neurodevelopmental disorder is caused by a change (variant or mutation) in the TCF7L2 gene. Mutations are nearly always de novo, which means that the mutation is present in the child but not in the parents. Because of the mutation in this gene, the protein product of the gene (a transcription factor) is either made incorrectly or not formed at all. Transcription factors are DNA-binding factors that regulate the amount of protein made in cells. Due to the lack of this protein, which is critical for brain development, patients develop the symptoms of TRND. There is currently no understood link between the mutation and the specific symptoms of TRND. TRND follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
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Affects of TCF7L2-Related Neurodevelopmental Disorder
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There are no known risk factors or populations that are affected at increased rates. It appears that TRND may be more common in males.
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Affects of TCF7L2-Related Neurodevelopmental Disorder. There are no known risk factors or populations that are affected at increased rates. It appears that TRND may be more common in males.
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Related disorders of TCF7L2-Related Neurodevelopmental Disorder
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Many other neurodevelopmental disorders can cause signs and symptoms that are similar to TRND.
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Related disorders of TCF7L2-Related Neurodevelopmental Disorder. Many other neurodevelopmental disorders can cause signs and symptoms that are similar to TRND.
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Diagnosis of TCF7L2-Related Neurodevelopmental Disorder
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A diagnosis of TRND may be suspected based on clinical signs and symptoms such as delayed development and/or difficulty with speech, motor skills, behavior, learning or other neurological functions, as well as autism, ADHD, intellectual disability and vision/hearing impairments. A diagnosis of TRND is confirmed by genetic testing that shows a likely pathogenic mutation in the TCF7L2 gene. The TCF7L2 gene is not included in most targeted gene panels for autism or myopia, so whole exome or whole genome testing is usually required to make a diagnosis. Genetic testing may be warranted if a child has diagnoses of autism and myopia.
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Diagnosis of TCF7L2-Related Neurodevelopmental Disorder. A diagnosis of TRND may be suspected based on clinical signs and symptoms such as delayed development and/or difficulty with speech, motor skills, behavior, learning or other neurological functions, as well as autism, ADHD, intellectual disability and vision/hearing impairments. A diagnosis of TRND is confirmed by genetic testing that shows a likely pathogenic mutation in the TCF7L2 gene. The TCF7L2 gene is not included in most targeted gene panels for autism or myopia, so whole exome or whole genome testing is usually required to make a diagnosis. Genetic testing may be warranted if a child has diagnoses of autism and myopia.
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Therapies of TCF7L2-Related Neurodevelopmental Disorder
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There are currently no established medical treatments for TCF7L2-related neurodevelopmental disorder. Behavioral therapies may be helpful for some patients. A multidisciplinary team of care providers for children with TRND may include a genetic counselor or geneticist, developmental psychologist, speech and physical therapists and learning specialists.
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Therapies of TCF7L2-Related Neurodevelopmental Disorder. There are currently no established medical treatments for TCF7L2-related neurodevelopmental disorder. Behavioral therapies may be helpful for some patients. A multidisciplinary team of care providers for children with TRND may include a genetic counselor or geneticist, developmental psychologist, speech and physical therapists and learning specialists.
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Overview of Tenosynovial Giant Cell Tumor
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SummaryTenosynovial giant cell tumors (TGCTs) are a group of rare, typically non-life-threatening tumors that involve the synovium, bursae and tendon sheath. Synovium is the thin layer of tissue or membrane that covers the inner surface of the joint spaces and the bursae and tendon sheaths. The bursae are small fluid-filled sacs that cushion bones, tendons and muscles around the joints. A tendon sheath is a layer membrane that covers a tendon. Tendons are fibrous tissue that connects muscle to bone.These tumors cause the affected synovium, bursae or tendon sheaths to thicken and overgrow. They are benign, which means they are not cancerous and do not spread to other areas of the body (metastasize). However, they can grow and cause damage to the surrounding tissue and structures of the affected limb. Symptoms can include pain, swelling, tenderness, warmth at the location and limitation of movement of the joint. Large or small joints can be affected depending upon the tumor subtype. In localized TGCT, smaller joints tend to be affected, such as digits and parts of the foot. In diffuse TGCT, large joints tend to be involved, most commonly the knee. Surgery is often the initial treatment option. However, depending on the subtype, the tumor can recur, particularly in diffuse TGCT which was previously known as pigmented villonodular synovitis (PVNS). If untreated or if the tumor continually recurs, they can result in damage and degeneration of the affected joint and surrounding tissues or structures. Sometimes, they can cause significant disability. In rare cases, amputation is warranted.Introduction
The terminology used to describe these tumors in medical literature is varied and confusing. The World Health Organization (WHO) classified these tumors in 2013 with the nomenclature “tenosynovial giant cell tumor”. This classification defines two distinct types of tenosynovial giant cell tumor: localized and diffuse. Localized TGCT encompassed the previously known giant cell tumor of the tendon sheath (GCTTS), tenosynovitis and nodular synovitis. Diffuse TGCT encompasses formerly known pigmented villonodular synovitis (PVNS). Diffuse TGCT was also called diffuse-type PVNS or diffuse-type giant cell tumor.
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Overview of Tenosynovial Giant Cell Tumor. SummaryTenosynovial giant cell tumors (TGCTs) are a group of rare, typically non-life-threatening tumors that involve the synovium, bursae and tendon sheath. Synovium is the thin layer of tissue or membrane that covers the inner surface of the joint spaces and the bursae and tendon sheaths. The bursae are small fluid-filled sacs that cushion bones, tendons and muscles around the joints. A tendon sheath is a layer membrane that covers a tendon. Tendons are fibrous tissue that connects muscle to bone.These tumors cause the affected synovium, bursae or tendon sheaths to thicken and overgrow. They are benign, which means they are not cancerous and do not spread to other areas of the body (metastasize). However, they can grow and cause damage to the surrounding tissue and structures of the affected limb. Symptoms can include pain, swelling, tenderness, warmth at the location and limitation of movement of the joint. Large or small joints can be affected depending upon the tumor subtype. In localized TGCT, smaller joints tend to be affected, such as digits and parts of the foot. In diffuse TGCT, large joints tend to be involved, most commonly the knee. Surgery is often the initial treatment option. However, depending on the subtype, the tumor can recur, particularly in diffuse TGCT which was previously known as pigmented villonodular synovitis (PVNS). If untreated or if the tumor continually recurs, they can result in damage and degeneration of the affected joint and surrounding tissues or structures. Sometimes, they can cause significant disability. In rare cases, amputation is warranted.Introduction
The terminology used to describe these tumors in medical literature is varied and confusing. The World Health Organization (WHO) classified these tumors in 2013 with the nomenclature “tenosynovial giant cell tumor”. This classification defines two distinct types of tenosynovial giant cell tumor: localized and diffuse. Localized TGCT encompassed the previously known giant cell tumor of the tendon sheath (GCTTS), tenosynovitis and nodular synovitis. Diffuse TGCT encompasses formerly known pigmented villonodular synovitis (PVNS). Diffuse TGCT was also called diffuse-type PVNS or diffuse-type giant cell tumor.
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Symptoms of Tenosynovial Giant Cell Tumor
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The signs and symptoms of tenosynovial giant cell tumors (TGCTs) can vary depending upon the exact location involved and the subtype present. Symptoms tend to be non-specific, and most patients report pain and swelling as a symptom of the disease. Other symptoms include limitation in range of motion, tenderness to the touch, warmth coming from the joint, clicking or popping of the joint and stiffness. Diffuse TGCT
(also known as diffuse-type giant cell tumor; formerly, PVNS)Diffuse TGCT usually affects a large joint; the tumor is widespread (diffuse) and affects the entire or most of the joint. TGCT is a monoarticular disease, meaning only one joint is involved. The knee is most often affected, followed by the ankle and hip. The elbow or shoulder can also be affected. In rare instances, the two joints that connect the jaw bones to the skull (temporomandibular joints) or the joints that connect vertebrae together (spinal facet joints) can be affected.The initial symptoms are usually pain and swelling of the affected joint. Stiffness of the joint and reduction in range of motion can also occur. Usually, these symptoms have a gradual onset. There may be a feeling of warmth or tenderness on the skin of the affected joint. A painless swelling of the joint is sometimes the first sign. Sometimes, swelling can be significant. Affected individuals may have a sensation of the affected joint ‘locking’ or ‘catching.’ There may be a popping sound on occasion and the joint may feel unstable. Symptoms can occur suddenly and intermittently and are often referred to as a “flare”.Diffuse TGCT can progress to cause arthritic damage and degeneration to the joint and damage to the surrounding cartilage and bone. If untreated, diffuse TGCT can potentially cause chronic, debilitating disease and significant functional impairment of the affected joint. Surgery is the main form of initial treatment, but the disease often recurs. With the discovery of drug options, the initial treatment may not always be surgery if the disease cannot be removed in its entirety. More often, drug options are used following recurrence or when patients have high risk of recurrence or morbidity (complications or consequences) from surgery. In asymptomatic patients, an active surveillance approach may be taken due to the high recurrence rate. Active surveillance includes MRIs to monitor disease and evaluation of symptoms.Localized TGCT
(Intraarticular GCTTS, formerly localized PVNS; extraarticular GCTTS; formerly nodular tenosynovitis)Localized TGCT usually presents as a growth or mass of abnormal tissue (nodules) or as a small growth that is connected to the affected area with a stalk of abnormal tissue (pedunculated mass). These tumors are usually limited to a specific area of the joint (localized), are well-defined (encapsulated) and typically affect smaller joints such as those of the hands and toes. However, localized TGCT can impact other joints such as the knee. The initial sign is often a swelling. The tumor grows slowly over time. Sometimes they cause pain. Eventually, affected individuals may have a sensation of the affected joint ‘locking’ or ‘catching.’ The affected joint may become unstable. Unlike the diffuse form, these tumors are unlikely to cause destructive changes to the joint or surrounding areas and are less likely to recur after treatment. Surgery is the main form of treatment and is often curative.
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Symptoms of Tenosynovial Giant Cell Tumor. The signs and symptoms of tenosynovial giant cell tumors (TGCTs) can vary depending upon the exact location involved and the subtype present. Symptoms tend to be non-specific, and most patients report pain and swelling as a symptom of the disease. Other symptoms include limitation in range of motion, tenderness to the touch, warmth coming from the joint, clicking or popping of the joint and stiffness. Diffuse TGCT
(also known as diffuse-type giant cell tumor; formerly, PVNS)Diffuse TGCT usually affects a large joint; the tumor is widespread (diffuse) and affects the entire or most of the joint. TGCT is a monoarticular disease, meaning only one joint is involved. The knee is most often affected, followed by the ankle and hip. The elbow or shoulder can also be affected. In rare instances, the two joints that connect the jaw bones to the skull (temporomandibular joints) or the joints that connect vertebrae together (spinal facet joints) can be affected.The initial symptoms are usually pain and swelling of the affected joint. Stiffness of the joint and reduction in range of motion can also occur. Usually, these symptoms have a gradual onset. There may be a feeling of warmth or tenderness on the skin of the affected joint. A painless swelling of the joint is sometimes the first sign. Sometimes, swelling can be significant. Affected individuals may have a sensation of the affected joint ‘locking’ or ‘catching.’ There may be a popping sound on occasion and the joint may feel unstable. Symptoms can occur suddenly and intermittently and are often referred to as a “flare”.Diffuse TGCT can progress to cause arthritic damage and degeneration to the joint and damage to the surrounding cartilage and bone. If untreated, diffuse TGCT can potentially cause chronic, debilitating disease and significant functional impairment of the affected joint. Surgery is the main form of initial treatment, but the disease often recurs. With the discovery of drug options, the initial treatment may not always be surgery if the disease cannot be removed in its entirety. More often, drug options are used following recurrence or when patients have high risk of recurrence or morbidity (complications or consequences) from surgery. In asymptomatic patients, an active surveillance approach may be taken due to the high recurrence rate. Active surveillance includes MRIs to monitor disease and evaluation of symptoms.Localized TGCT
(Intraarticular GCTTS, formerly localized PVNS; extraarticular GCTTS; formerly nodular tenosynovitis)Localized TGCT usually presents as a growth or mass of abnormal tissue (nodules) or as a small growth that is connected to the affected area with a stalk of abnormal tissue (pedunculated mass). These tumors are usually limited to a specific area of the joint (localized), are well-defined (encapsulated) and typically affect smaller joints such as those of the hands and toes. However, localized TGCT can impact other joints such as the knee. The initial sign is often a swelling. The tumor grows slowly over time. Sometimes they cause pain. Eventually, affected individuals may have a sensation of the affected joint ‘locking’ or ‘catching.’ The affected joint may become unstable. Unlike the diffuse form, these tumors are unlikely to cause destructive changes to the joint or surrounding areas and are less likely to recur after treatment. Surgery is the main form of treatment and is often curative.
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Causes of Tenosynovial Giant Cell Tumor
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A minority of the cells that make up a TGCT (2-16%) carry a specific chromosomal translocation. Chromosomes, which are present in the nucleus of all human cells, carry genetic information for each individual, like the blueprint of the body. Each human body cell normally has 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.A chromosomal translocation is when a piece or region of certain chromosomes break off and are rearranged, resulting in shifting of genes and an altered set of chromosomes. In these tumors, there is a translocation involving specific regions on chromosome 1 and chromosome 2. This is written as [t (1;2) (p13;q37)]. Cells containing this translocation overproduce a type of protein called colony stimulating factor-1 or CSF-1. These cells only make up a small portion of the cells in the tumor. However, because they overproduce CSF-1, they attract other cells in the body, specifically cells that have a CSF-1 receptor. A receptor is a protein molecule on the surface of the cell that receives chemical signals from outside the cell. CSF-1 binds to a CSF-1 receptor, like a baseball to a glove. Cells that have CSF-1 receptors include a type of white blood cell called macrophages and several other cells. It is these other cells that make up the bulk of a tenosynovial giant cell tumor. The TGCT cells use CSF-1 to recruit the white blood cells to incorporate into the tumor. These other cells most likely cause the inflammatory changes that are associated with these tumors.It is not known what causes the translocation involving chromosomes 1 and 2. It may occur randomly, for no apparent reason. There are no environmental, genetic, occupational, lifestyle, demographic or regional risk factors that have been conclusively shown to be involved with the development of these tumors.
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Causes of Tenosynovial Giant Cell Tumor. A minority of the cells that make up a TGCT (2-16%) carry a specific chromosomal translocation. Chromosomes, which are present in the nucleus of all human cells, carry genetic information for each individual, like the blueprint of the body. Each human body cell normally has 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.A chromosomal translocation is when a piece or region of certain chromosomes break off and are rearranged, resulting in shifting of genes and an altered set of chromosomes. In these tumors, there is a translocation involving specific regions on chromosome 1 and chromosome 2. This is written as [t (1;2) (p13;q37)]. Cells containing this translocation overproduce a type of protein called colony stimulating factor-1 or CSF-1. These cells only make up a small portion of the cells in the tumor. However, because they overproduce CSF-1, they attract other cells in the body, specifically cells that have a CSF-1 receptor. A receptor is a protein molecule on the surface of the cell that receives chemical signals from outside the cell. CSF-1 binds to a CSF-1 receptor, like a baseball to a glove. Cells that have CSF-1 receptors include a type of white blood cell called macrophages and several other cells. It is these other cells that make up the bulk of a tenosynovial giant cell tumor. The TGCT cells use CSF-1 to recruit the white blood cells to incorporate into the tumor. These other cells most likely cause the inflammatory changes that are associated with these tumors.It is not known what causes the translocation involving chromosomes 1 and 2. It may occur randomly, for no apparent reason. There are no environmental, genetic, occupational, lifestyle, demographic or regional risk factors that have been conclusively shown to be involved with the development of these tumors.
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Affects of Tenosynovial Giant Cell Tumor
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Tenosynovial giant cell tumors mainly affect individuals between 25-50 years of age, with a median age of diagnosis of 40. However, these tumors can affect the elderly and younger children as well. Slightly more females than males are affected with localized TGCT. For diffuse TGCT, males and females are equally affected. Based on a 2017 Dutch study, the global incidence has been estimated to be 43 cases of TGCT per 1 million people in the general population. For localized TGCT, 39 cases per 1 million are estimated, whereas for diffuse TGCT, 4 cases per 1 million are estimated. Incidence refers to the number of new cases in a population in a specific time period. A Dutch study reported that the prevalence of TGCT is 11 per 100,000 people for diffuse TGCT and 44 per 100,000 people for localized TGCT. Prevalence refers to all cases diagnosed, regardless of when they were diagnosed. More people live with TGCT long-term than are newly diagnosed, thus, the prevalence of the disease is higher than the incidence.
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Affects of Tenosynovial Giant Cell Tumor. Tenosynovial giant cell tumors mainly affect individuals between 25-50 years of age, with a median age of diagnosis of 40. However, these tumors can affect the elderly and younger children as well. Slightly more females than males are affected with localized TGCT. For diffuse TGCT, males and females are equally affected. Based on a 2017 Dutch study, the global incidence has been estimated to be 43 cases of TGCT per 1 million people in the general population. For localized TGCT, 39 cases per 1 million are estimated, whereas for diffuse TGCT, 4 cases per 1 million are estimated. Incidence refers to the number of new cases in a population in a specific time period. A Dutch study reported that the prevalence of TGCT is 11 per 100,000 people for diffuse TGCT and 44 per 100,000 people for localized TGCT. Prevalence refers to all cases diagnosed, regardless of when they were diagnosed. More people live with TGCT long-term than are newly diagnosed, thus, the prevalence of the disease is higher than the incidence.
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Related disorders of Tenosynovial Giant Cell Tumor
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Symptoms of the following disorders can be similar to those of tenosynovial giant cell tumors (TGCTs). Comparisons may be useful for a differential diagnosis.There are several other tumors and conditions that may need to be differentiated from TGCTs including synovial hemangiomas, synovial chondromatosis, sports injuries such as labrum and meniscus tears, fibromas, tophaceous gout, hemorrhagic synovitis, ganglion cysts and malignant sarcomas. Certain disorders can cause changes in a joint that can resemble tenosynovial giant cell tumors including tuberculosis (tuberculous arthritis), amyloidosis and hemophilia (hemophilic arthropathy).
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Related disorders of Tenosynovial Giant Cell Tumor. Symptoms of the following disorders can be similar to those of tenosynovial giant cell tumors (TGCTs). Comparisons may be useful for a differential diagnosis.There are several other tumors and conditions that may need to be differentiated from TGCTs including synovial hemangiomas, synovial chondromatosis, sports injuries such as labrum and meniscus tears, fibromas, tophaceous gout, hemorrhagic synovitis, ganglion cysts and malignant sarcomas. Certain disorders can cause changes in a joint that can resemble tenosynovial giant cell tumors including tuberculosis (tuberculous arthritis), amyloidosis and hemophilia (hemophilic arthropathy).
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Diagnosis of Tenosynovial Giant Cell Tumor
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A diagnosis of TGCT is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The initial symptoms of these tumors are often vague and may go unrecognized. Consequently, there is usually a significant delay, 3-4 years on average, from the onset of symptoms until a diagnosis is made.Clinical Testing and Workup
X-rays can help with a diagnosis of the damage resulting from the tumors. Plain x-rays, called radiographs, can help to rule out other conditions and can sometimes show damage or degeneration to the surrounding bone or cartilage. X-rays will not be effective in helping to diagnose all patients with these tumors, especially if the tumors have not caused damage to surrounding bone or cartilage. X-rays may be useful to rule out other diseases but do not establish a diagnosis of TGCT. A specialized imaging technique called magnetic resonance imaging, or MRI, is the most frequently used and this examination can be very effective in helping to diagnose these tumors. MRI is the preferred technique for the detection and characterization of TGCT. An MRI uses a magnetic field and radio waves to produce cross-sectional images of certain organs and bodily tissues. MRI can be used with and without a contrasting dye, allowing the radiologist more insight into blood vessels and other vasculature specific to the joint and tumor growth. An MRI can reveal distinctive changes that indicate a tenosynovial giant cell tumor, such as hemosiderin (iron-containing compound that stains the tumors a rusty color) deposits that become apparent on MRI.Sometimes, doctors will take a sample of synovial fluid; this is a viscous fluid found in synovial joints that reduces friction between cartilage of the joint during movement. With TGCTs, synovial fluid is often bloody and will indicate a need for further testing. Sometimes, surgical removal and microscopic examination of affected tissue (biopsy), may be necessary to confirm a diagnosis. A biopsy allows doctors to see what kind of cells make up a tumor. However, many patients are diagnosed with MRI alone due to advancements in imaging resolution.It is important to differentiate between diffuse TGCT and localized TGCT as the prognosis and treatment of these conditions can be different. There is no microscopic difference between the features of these two subtypes, however, through imaging, cell behavioral changes can be identified. Imaging is the sole way the cell behavior and subtype is established.
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Diagnosis of Tenosynovial Giant Cell Tumor. A diagnosis of TGCT is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The initial symptoms of these tumors are often vague and may go unrecognized. Consequently, there is usually a significant delay, 3-4 years on average, from the onset of symptoms until a diagnosis is made.Clinical Testing and Workup
X-rays can help with a diagnosis of the damage resulting from the tumors. Plain x-rays, called radiographs, can help to rule out other conditions and can sometimes show damage or degeneration to the surrounding bone or cartilage. X-rays will not be effective in helping to diagnose all patients with these tumors, especially if the tumors have not caused damage to surrounding bone or cartilage. X-rays may be useful to rule out other diseases but do not establish a diagnosis of TGCT. A specialized imaging technique called magnetic resonance imaging, or MRI, is the most frequently used and this examination can be very effective in helping to diagnose these tumors. MRI is the preferred technique for the detection and characterization of TGCT. An MRI uses a magnetic field and radio waves to produce cross-sectional images of certain organs and bodily tissues. MRI can be used with and without a contrasting dye, allowing the radiologist more insight into blood vessels and other vasculature specific to the joint and tumor growth. An MRI can reveal distinctive changes that indicate a tenosynovial giant cell tumor, such as hemosiderin (iron-containing compound that stains the tumors a rusty color) deposits that become apparent on MRI.Sometimes, doctors will take a sample of synovial fluid; this is a viscous fluid found in synovial joints that reduces friction between cartilage of the joint during movement. With TGCTs, synovial fluid is often bloody and will indicate a need for further testing. Sometimes, surgical removal and microscopic examination of affected tissue (biopsy), may be necessary to confirm a diagnosis. A biopsy allows doctors to see what kind of cells make up a tumor. However, many patients are diagnosed with MRI alone due to advancements in imaging resolution.It is important to differentiate between diffuse TGCT and localized TGCT as the prognosis and treatment of these conditions can be different. There is no microscopic difference between the features of these two subtypes, however, through imaging, cell behavioral changes can be identified. Imaging is the sole way the cell behavior and subtype is established.
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Therapies of Tenosynovial Giant Cell Tumor
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Treatment
Surgery is often the initial treatment option. However, there is no current consensus on the standard of care or the optimal surgical technique. Surgery for localized TGCT tends to be curative. However, there is a risk of recurrence around 10-15%. Diffuse TGCT tends to slowly get worse (progressive disease) and often recurs after surgery at a higher rate around 50-70%. Following the first recurrence, subsequent recurrence rate can be as high as 88%. It has been shown in a single nationwide study that patients initially treated at an expert cancer center have lower recurrence rates (42%) compared to patients initially treated at community centers (92%). Therefore, patients should be seen at multidisciplinary expert centers when possible.The specific surgical techniques a surgeon will use depend on several factors including the location and extent of the disease. TGCT is typically treated with synovectomy, removing the involved area of the lining. There is no consensus on the optimal synovectomy technique, whether arthroscopic or open surgery. Synovectomy involves the complete removal of the affected synovium (the membrane lining the inside of a joint). Completely removing the diseased synovium may not always be possible. During open surgery, a surgeon will create an incision (large opening) that allows them full access to the affected joint. This will allow the surgeon to remove the diseased tissue. Arthroscopic surgery involves creating a much smaller incision through which very small instruments are placed. These instruments include a tiny camera that allows the surgeon to see within the diseased joint and surgically remove the diseased tissue.There have not been formal randomized studies comparing open surgery versus arthroscopic surgery. According to reports in the medical literature, some physicians have had better experiences with open surgery, while others have had better results with arthroscopic surgery. This is based on surgeon’s preference. Sometimes, a combination of arthroscopic and open surgery may be used, especially in the knee. In severe, resistant cases, total joint replacement has been tried to repair the extensive damage to the bone. However, the replacement does not address the tumor itself and is used in combination with a synovectomy to address the tumors and improve joint health. Joint replacements have similar recurrence rates as open surgeries.
The surgical removal of part of the disease, and not the entirety of it, is known as debulk surgery. The adequacy of this approach is controversial as symptoms may not be correlated to the extent of disease.Historically, radiation therapy has been used as an adjunct treatment to surgery, particularly in cases where there is incomplete removal (resection) of the tumor. An adjunct therapy is one that is used alongside the main (or primary) therapy. There are two types of radiation, external beam radiation and intraarticular radiation, or isotopic synoviorthesis. Intraarticular radiation therapy alone (radiation therapy as a primary treatment) has also been attempted but has had inconclusive and variable results. Information on radiation therapy as a primary or adjuvant therapy is limited to small, poor-quality, single institution reports and, therefore, has not yet been conclusively established. Additionally, there is a risk of secondary radiation-induced sarcoma. Due to this risk and the lack of established efficacy, radiation treatment is not recommended and should not be used to substitute suboptimal treatment.In 2019, a medicine that targets the disease, specifically CSF-1, was approved. Pexidartinib (Turalio), the first CSF-1 inhibitor, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with symptomatic tenosynovial giant cell tumor associated with severe disease or functional limitations and not amenable to improvement with surgery. Turalio showed over 50% response in TGCT patients, 39% of TGCT patients having partial response and 18% having complete response. Imatinib (Gleevec) and nilotinib (Tasigna) are often used off-label to treat TGCT. Imatinib has shown that 33% of patients have a significant reduction in tumor size, with 27% having partial shrinkage and 4% having unmeasurable disease. Other medicines are now being investigated for their inhibition of CSF-1 and tumor shrinkage.
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Therapies of Tenosynovial Giant Cell Tumor. Treatment
Surgery is often the initial treatment option. However, there is no current consensus on the standard of care or the optimal surgical technique. Surgery for localized TGCT tends to be curative. However, there is a risk of recurrence around 10-15%. Diffuse TGCT tends to slowly get worse (progressive disease) and often recurs after surgery at a higher rate around 50-70%. Following the first recurrence, subsequent recurrence rate can be as high as 88%. It has been shown in a single nationwide study that patients initially treated at an expert cancer center have lower recurrence rates (42%) compared to patients initially treated at community centers (92%). Therefore, patients should be seen at multidisciplinary expert centers when possible.The specific surgical techniques a surgeon will use depend on several factors including the location and extent of the disease. TGCT is typically treated with synovectomy, removing the involved area of the lining. There is no consensus on the optimal synovectomy technique, whether arthroscopic or open surgery. Synovectomy involves the complete removal of the affected synovium (the membrane lining the inside of a joint). Completely removing the diseased synovium may not always be possible. During open surgery, a surgeon will create an incision (large opening) that allows them full access to the affected joint. This will allow the surgeon to remove the diseased tissue. Arthroscopic surgery involves creating a much smaller incision through which very small instruments are placed. These instruments include a tiny camera that allows the surgeon to see within the diseased joint and surgically remove the diseased tissue.There have not been formal randomized studies comparing open surgery versus arthroscopic surgery. According to reports in the medical literature, some physicians have had better experiences with open surgery, while others have had better results with arthroscopic surgery. This is based on surgeon’s preference. Sometimes, a combination of arthroscopic and open surgery may be used, especially in the knee. In severe, resistant cases, total joint replacement has been tried to repair the extensive damage to the bone. However, the replacement does not address the tumor itself and is used in combination with a synovectomy to address the tumors and improve joint health. Joint replacements have similar recurrence rates as open surgeries.
The surgical removal of part of the disease, and not the entirety of it, is known as debulk surgery. The adequacy of this approach is controversial as symptoms may not be correlated to the extent of disease.Historically, radiation therapy has been used as an adjunct treatment to surgery, particularly in cases where there is incomplete removal (resection) of the tumor. An adjunct therapy is one that is used alongside the main (or primary) therapy. There are two types of radiation, external beam radiation and intraarticular radiation, or isotopic synoviorthesis. Intraarticular radiation therapy alone (radiation therapy as a primary treatment) has also been attempted but has had inconclusive and variable results. Information on radiation therapy as a primary or adjuvant therapy is limited to small, poor-quality, single institution reports and, therefore, has not yet been conclusively established. Additionally, there is a risk of secondary radiation-induced sarcoma. Due to this risk and the lack of established efficacy, radiation treatment is not recommended and should not be used to substitute suboptimal treatment.In 2019, a medicine that targets the disease, specifically CSF-1, was approved. Pexidartinib (Turalio), the first CSF-1 inhibitor, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with symptomatic tenosynovial giant cell tumor associated with severe disease or functional limitations and not amenable to improvement with surgery. Turalio showed over 50% response in TGCT patients, 39% of TGCT patients having partial response and 18% having complete response. Imatinib (Gleevec) and nilotinib (Tasigna) are often used off-label to treat TGCT. Imatinib has shown that 33% of patients have a significant reduction in tumor size, with 27% having partial shrinkage and 4% having unmeasurable disease. Other medicines are now being investigated for their inhibition of CSF-1 and tumor shrinkage.
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