id
stringlengths 8
11
| title
stringlengths 14
124
| content
stringlengths 0
34k
| contents
stringlengths 20
34k
| nordid
int64 0
1.32k
| rare-disease
stringlengths 4
103
|
|---|---|---|---|---|---|
nord_71_3 | Affects of Amniotic Band Syndrome | Amniotic band syndrome is estimated to occur in anywhere from 1 in 1,200 to 15,000 live births. No gender or ethnic predispositions have been identified with amniotic band syndrome.In the surveillance of almost 300,000 births in a Boston hospital over many years, 40 infants (1 in 7,500) with amniotic band syndrome were identified, including several with recognized causes. | Affects of Amniotic Band Syndrome. Amniotic band syndrome is estimated to occur in anywhere from 1 in 1,200 to 15,000 live births. No gender or ethnic predispositions have been identified with amniotic band syndrome.In the surveillance of almost 300,000 births in a Boston hospital over many years, 40 infants (1 in 7,500) with amniotic band syndrome were identified, including several with recognized causes. | 71 | Amniotic Band Syndrome |
nord_71_4 | Related disorders of Amniotic Band Syndrome | Symptoms of the following disorders can be similar to those of amniotic band syndrome. Comparisons may be useful for a differential diagnosis.Adams-Oliver syndrome (AOS) is a rare inherited disorder characterized by defects of the scalp and abnormalities of the fingers, toes, arms, and/or legs. The physical abnormalities associated with this disorder vary greatly among affected individuals. In infants with AOS, scalp defects are present at birth (congenital) and may include one or multiple hairless scarred areas that may have abnormally wide (dilated) blood vessels directly under the affected skin. In severe cases, an underlying defect of the bones of the skull may also be present. In addition, infants with this disorder typically have malformations of the hands, arms, feet, and/or legs. These range from abnormally short (hypoplastic) fingers and toes to absent hands and/or lower legs. In some cases, abnormalities of the heart may also be present. AOS is due to a spontaneous genetic change (i.e., new mutation) or can be inherited from an affected parent. Inheritance is autosomal dominant. (For more information on this disorder, choose “Adams Oliver” as your search term in the Rare Disease Database.)There are a few, rare “familial” disorders that have reported in the medical literature in which symptoms similar to amniotic band syndrome occur in conjunction with symptoms unrelated to the limb defects. Such recurrent symptoms include cleft lip and cleft palate, extra fingers or toes (polydactyly), congenital heart defects or kidney (renal abnormalities). Some of these reports of the limb abnormalities associated with amniotic band syndrome occurring with additional symptoms have been found in multiple generations of one family. These cases may represent distinct, unrecognized rare syndromes, and they add support to the theory that some cases of amniotic band syndrome have a genetic basis. | Related disorders of Amniotic Band Syndrome. Symptoms of the following disorders can be similar to those of amniotic band syndrome. Comparisons may be useful for a differential diagnosis.Adams-Oliver syndrome (AOS) is a rare inherited disorder characterized by defects of the scalp and abnormalities of the fingers, toes, arms, and/or legs. The physical abnormalities associated with this disorder vary greatly among affected individuals. In infants with AOS, scalp defects are present at birth (congenital) and may include one or multiple hairless scarred areas that may have abnormally wide (dilated) blood vessels directly under the affected skin. In severe cases, an underlying defect of the bones of the skull may also be present. In addition, infants with this disorder typically have malformations of the hands, arms, feet, and/or legs. These range from abnormally short (hypoplastic) fingers and toes to absent hands and/or lower legs. In some cases, abnormalities of the heart may also be present. AOS is due to a spontaneous genetic change (i.e., new mutation) or can be inherited from an affected parent. Inheritance is autosomal dominant. (For more information on this disorder, choose “Adams Oliver” as your search term in the Rare Disease Database.)There are a few, rare “familial” disorders that have reported in the medical literature in which symptoms similar to amniotic band syndrome occur in conjunction with symptoms unrelated to the limb defects. Such recurrent symptoms include cleft lip and cleft palate, extra fingers or toes (polydactyly), congenital heart defects or kidney (renal abnormalities). Some of these reports of the limb abnormalities associated with amniotic band syndrome occurring with additional symptoms have been found in multiple generations of one family. These cases may represent distinct, unrecognized rare syndromes, and they add support to the theory that some cases of amniotic band syndrome have a genetic basis. | 71 | Amniotic Band Syndrome |
nord_71_5 | Diagnosis of Amniotic Band Syndrome | Amniotic band syndrome is typically diagnosed at or soon after birth based upon characteristic physical findings. The minimal diagnostic criteria consist of the detection of certain abnormalities of the arms, legs, fingers, and/or toes, i.e., ring-like constriction or amputation defects, fusion (syndactyly) between some digits and/or strands of tissue attached to the ends of affected fingers.In some cases, the condition may be suspected before birth (prenatally), based upon the results of certain specialized imaging techniques, such as fetal ultrasonography, which may reveal the characteristic defects. During fetal ultrasonography, reflected high-frequency sound waves are used to create an image of the developing fetus. | Diagnosis of Amniotic Band Syndrome. Amniotic band syndrome is typically diagnosed at or soon after birth based upon characteristic physical findings. The minimal diagnostic criteria consist of the detection of certain abnormalities of the arms, legs, fingers, and/or toes, i.e., ring-like constriction or amputation defects, fusion (syndactyly) between some digits and/or strands of tissue attached to the ends of affected fingers.In some cases, the condition may be suspected before birth (prenatally), based upon the results of certain specialized imaging techniques, such as fetal ultrasonography, which may reveal the characteristic defects. During fetal ultrasonography, reflected high-frequency sound waves are used to create an image of the developing fetus. | 71 | Amniotic Band Syndrome |
nord_71_6 | Therapies of Amniotic Band Syndrome | Treatment
The treatment of infants and children with amniotic band syndrome is symptomatic and supportive. For example, in infants with incomplete development of the lungs and associated respiratory insufficiency, treatment may include oxygen support measures and other supportive therapies as required. Reconstructive surgery or other surgical techniques may be recommended to help correct or repair associated malformations, such as ring-like constrictions of the limbs, webbed fingers and toes, cleft lip or club foot. Physical and occupational therapy may also be necessary to ensure infants can attain the optimal use of affected fingers, toes, arms and legs. | Therapies of Amniotic Band Syndrome. Treatment
The treatment of infants and children with amniotic band syndrome is symptomatic and supportive. For example, in infants with incomplete development of the lungs and associated respiratory insufficiency, treatment may include oxygen support measures and other supportive therapies as required. Reconstructive surgery or other surgical techniques may be recommended to help correct or repair associated malformations, such as ring-like constrictions of the limbs, webbed fingers and toes, cleft lip or club foot. Physical and occupational therapy may also be necessary to ensure infants can attain the optimal use of affected fingers, toes, arms and legs. | 71 | Amniotic Band Syndrome |
nord_72_0 | Overview of Amniotic Fluid Embolism | Amniotic fluid embolism (AFE) is an extremely rare, but life-threatening complication that affects pregnant women shortly before, during, or immediately following labor and childbirth. Most instances occur during labor. In this disorder, it is hypothesized that a pregnant woman has a severe, allergic reaction to amniotic fluid or other fetal material such as fetal cells, which enter the mother’s bloodstream. Amniotic fluid is contained within the amniotic sac. This fluid supports, cushions, and protects a developing fetus. Amniotic fluid embolism is unpredictable and no risk factors have been identified. AFE can cause a severe, rapid decline in the mother’s health. For years, some researchers believed that the amniotic fluid and fetal cells cause obstruction within the mother’s blood vessels, but now most researchers believe that the mother’s immune system reacts to the amniotic fluid and fetal cells causing an overwhelming immune system response, which ends up harming the mother and the fetus. Breathing problems, cardiac arrest, and excessive bleeding are some of the life-threatening complications that can occur. Researchers and physicians do not fully understand why amniotic fluid or fetal cells entering the mother’s bloodstream causes this reaction in some women. Amniotic fluid embolism is a medical emergency that develops suddenly and rapidly and can be fatal. Early recognition and prompt supportive treatment are essential. | Overview of Amniotic Fluid Embolism. Amniotic fluid embolism (AFE) is an extremely rare, but life-threatening complication that affects pregnant women shortly before, during, or immediately following labor and childbirth. Most instances occur during labor. In this disorder, it is hypothesized that a pregnant woman has a severe, allergic reaction to amniotic fluid or other fetal material such as fetal cells, which enter the mother’s bloodstream. Amniotic fluid is contained within the amniotic sac. This fluid supports, cushions, and protects a developing fetus. Amniotic fluid embolism is unpredictable and no risk factors have been identified. AFE can cause a severe, rapid decline in the mother’s health. For years, some researchers believed that the amniotic fluid and fetal cells cause obstruction within the mother’s blood vessels, but now most researchers believe that the mother’s immune system reacts to the amniotic fluid and fetal cells causing an overwhelming immune system response, which ends up harming the mother and the fetus. Breathing problems, cardiac arrest, and excessive bleeding are some of the life-threatening complications that can occur. Researchers and physicians do not fully understand why amniotic fluid or fetal cells entering the mother’s bloodstream causes this reaction in some women. Amniotic fluid embolism is a medical emergency that develops suddenly and rapidly and can be fatal. Early recognition and prompt supportive treatment are essential. | 72 | Amniotic Fluid Embolism |
nord_72_1 | Symptoms of Amniotic Fluid Embolism | The signs and symptoms of amniotic fluid embolism often develop rapidly. Nonspecific symptoms including headaches, chest pain, cough, sweating, nausea, and vomiting have been reported as early signs. Other common initial symptoms include difficulty breathing or shortness of breath (dyspnea), abnormally rapid breathing (tachypnea), low blood pressure (hypotension), an abnormally rapid heartbeat (tachycardia), bluish discoloration of the skin and mucous membranes due to a lack of oxygen (cyanosis) in the blood, and a deficiency in the amount of oxygen reaching the tissues of the body (hypoxia). There may be rapidly high blood pressure in the blood vessels of the lungs (pulmonary hypertension) and sudden narrowing of blood vessels (vasospasm). Breathing problems can progress to acute respiratory failure a severe, life-threatening complication where damage and fluid leakage into the lungs makes breathing difficult or impossible. Some affected women experience increasing cardiac rhythm abnormalities, low blood pressure, shock, and/or the abrupt loss of heat function despite no underlying heart disease (cardiac arrest). Cardiac arrest can cause gasping breath, no breathing, or complete unresponsiveness in the affected individual. Affected women may experience an altered mental status including anxiety or confusion, seizures, or coma.Most women develop a condition called disseminated intravascular coagulation (DIC). In DIC, blood clotting factors, specialized proteins that help the blood to clot, are used up or broken down. Without these clotting factors, an affected woman cannot create blood clots to stop bleeding. There may be bleeding from the uterus and from puncture sites, such as the site of an intravenous needle or an epidural catheter. In rare instances, severe bleeding (hemorrhaging) may be the first sign of amniotic fluid embolism. Doctors may note a condition called nonreassuring fetal status. This term means that the fetus is not doing as well as would normally be expected. The fetus may not be getting enough oxygen and there may be an abnormally slow heart rate. Nonreassuring fetal status is an assessment of fetal health given late in the pregnancy or during delivery. In the event that an AFE occurs during pregnancy, the infant must be expeditiously delivered as a life saving measure for both the mother and fetus. | Symptoms of Amniotic Fluid Embolism. The signs and symptoms of amniotic fluid embolism often develop rapidly. Nonspecific symptoms including headaches, chest pain, cough, sweating, nausea, and vomiting have been reported as early signs. Other common initial symptoms include difficulty breathing or shortness of breath (dyspnea), abnormally rapid breathing (tachypnea), low blood pressure (hypotension), an abnormally rapid heartbeat (tachycardia), bluish discoloration of the skin and mucous membranes due to a lack of oxygen (cyanosis) in the blood, and a deficiency in the amount of oxygen reaching the tissues of the body (hypoxia). There may be rapidly high blood pressure in the blood vessels of the lungs (pulmonary hypertension) and sudden narrowing of blood vessels (vasospasm). Breathing problems can progress to acute respiratory failure a severe, life-threatening complication where damage and fluid leakage into the lungs makes breathing difficult or impossible. Some affected women experience increasing cardiac rhythm abnormalities, low blood pressure, shock, and/or the abrupt loss of heat function despite no underlying heart disease (cardiac arrest). Cardiac arrest can cause gasping breath, no breathing, or complete unresponsiveness in the affected individual. Affected women may experience an altered mental status including anxiety or confusion, seizures, or coma.Most women develop a condition called disseminated intravascular coagulation (DIC). In DIC, blood clotting factors, specialized proteins that help the blood to clot, are used up or broken down. Without these clotting factors, an affected woman cannot create blood clots to stop bleeding. There may be bleeding from the uterus and from puncture sites, such as the site of an intravenous needle or an epidural catheter. In rare instances, severe bleeding (hemorrhaging) may be the first sign of amniotic fluid embolism. Doctors may note a condition called nonreassuring fetal status. This term means that the fetus is not doing as well as would normally be expected. The fetus may not be getting enough oxygen and there may be an abnormally slow heart rate. Nonreassuring fetal status is an assessment of fetal health given late in the pregnancy or during delivery. In the event that an AFE occurs during pregnancy, the infant must be expeditiously delivered as a life saving measure for both the mother and fetus. | 72 | Amniotic Fluid Embolism |
nord_72_2 | Causes of Amniotic Fluid Embolism | Amniotic fluid embolism is a condition that occurs because there is systemic reaction similar to that found in an allergic response to amniotic fluid or fetal cells or fetal tissue debris by the pregnant mother. The amniotic fluid and other material enters the mother’s bloodstream, most likely due to small tears in the lower part of the uterus, the part of the cervix that forms a canal connecting the vagina to the uterus (endocervix), or because of damage or abnormality affecting the placenta. The cervix is the narrow passage that forms the lower end of the uterus. The placenta is the organ that joins or connects the developing fetus to the mother. The placenta allows the transfer of oxygen and nutrients from the mother to the fetus. How amniotic fluid or fetal cells cause an allergic reaction in some women and not others is not completely understood. Originally, researchers believed that amniotic fluid had an embolic effect, which means that the amniotic fluid formed clots (emboli) in the mother’s blood vessels, most likely the blood vessels of the lungs. That is where the disorder’s name, amniotic fluid embolism, came from. While amniotic fluid or fetal cells may contribute to some mechanical obstruction, amniotic fluid dissolves in fluid (soluble) and the fetal cells or tissue debris that can also enter the mother’s blood are usually too small an amount to cause a clot to form. Researchers now believe that this is an immune-mediated disorder, and that the symptoms are caused by the mother’s immune system, which reacts to the amniotic fluid or fetal cells as foreign substances. This immune response causes an overwhelming inflammatory response in the mother’s body that damages healthy tissue and structures, which ultimately is believed to cause the signs and symptoms. The process more closely resembles anaphylactic shock than it does an embolic event. Although many potential risk factors have been discussed, no risk factors for amniotic fluid embolization have been conclusively proven to increase a woman’s risk of developing this disorder. Most studies have been inconsistent or contradictive in regard to risk factors. The onset of amniotic fluid embolism cannot be predicted or anticipated by doctors nor can the disorder be prevented | Causes of Amniotic Fluid Embolism. Amniotic fluid embolism is a condition that occurs because there is systemic reaction similar to that found in an allergic response to amniotic fluid or fetal cells or fetal tissue debris by the pregnant mother. The amniotic fluid and other material enters the mother’s bloodstream, most likely due to small tears in the lower part of the uterus, the part of the cervix that forms a canal connecting the vagina to the uterus (endocervix), or because of damage or abnormality affecting the placenta. The cervix is the narrow passage that forms the lower end of the uterus. The placenta is the organ that joins or connects the developing fetus to the mother. The placenta allows the transfer of oxygen and nutrients from the mother to the fetus. How amniotic fluid or fetal cells cause an allergic reaction in some women and not others is not completely understood. Originally, researchers believed that amniotic fluid had an embolic effect, which means that the amniotic fluid formed clots (emboli) in the mother’s blood vessels, most likely the blood vessels of the lungs. That is where the disorder’s name, amniotic fluid embolism, came from. While amniotic fluid or fetal cells may contribute to some mechanical obstruction, amniotic fluid dissolves in fluid (soluble) and the fetal cells or tissue debris that can also enter the mother’s blood are usually too small an amount to cause a clot to form. Researchers now believe that this is an immune-mediated disorder, and that the symptoms are caused by the mother’s immune system, which reacts to the amniotic fluid or fetal cells as foreign substances. This immune response causes an overwhelming inflammatory response in the mother’s body that damages healthy tissue and structures, which ultimately is believed to cause the signs and symptoms. The process more closely resembles anaphylactic shock than it does an embolic event. Although many potential risk factors have been discussed, no risk factors for amniotic fluid embolization have been conclusively proven to increase a woman’s risk of developing this disorder. Most studies have been inconsistent or contradictive in regard to risk factors. The onset of amniotic fluid embolism cannot be predicted or anticipated by doctors nor can the disorder be prevented | 72 | Amniotic Fluid Embolism |
nord_72_3 | Affects of Amniotic Fluid Embolism | Amniotic fluid embolism is a rare complication that occurs just before, during, or immediately after birth. The number of women who have experienced this complication is unknown. Amniotic fluid embolism is a rare disorder. Rare disorders often go unrecognized or misdiagnosed, making it difficult to determine their true frequency in the general population. Estimates have ranged from 1 in 8,000 to 1 in 80,000 pregnancies. | Affects of Amniotic Fluid Embolism. Amniotic fluid embolism is a rare complication that occurs just before, during, or immediately after birth. The number of women who have experienced this complication is unknown. Amniotic fluid embolism is a rare disorder. Rare disorders often go unrecognized or misdiagnosed, making it difficult to determine their true frequency in the general population. Estimates have ranged from 1 in 8,000 to 1 in 80,000 pregnancies. | 72 | Amniotic Fluid Embolism |
nord_72_4 | Related disorders of Amniotic Fluid Embolism | Symptoms of the following disorders can be similar to those of amniotic fluid embolism. Comparisons may be useful for a differential diagnosis.There are many different conditions or disorders that can cause symptoms or signs that are similar to those seen in amniotic fluid embolism. These include seizures during pregnancy due to high blood pressure (eclampsia); separation of the placenta from the uterine wall (placental abruption); heart failure during the last few months before or after birth (peripartum cardiomyopathy); anaphylaxis, a blood clot (embolus) in the lungs; an air embolism; the entry of material such as the contents of the stomach into the lungs or lower respiratory tract (pulmonary aspiration); shock due to extremely rapid low blood pressure because of widespread infection (septic shock); the loss of more than 20% of the blood supply (hemorrhagic shock), which can be caused by several events including a ruptured or inverted uterus; a heart attack (myocardial infarction); and the toxic effects of certain drugs such as a toxic reaction to anesthesia drugs. | Related disorders of Amniotic Fluid Embolism. Symptoms of the following disorders can be similar to those of amniotic fluid embolism. Comparisons may be useful for a differential diagnosis.There are many different conditions or disorders that can cause symptoms or signs that are similar to those seen in amniotic fluid embolism. These include seizures during pregnancy due to high blood pressure (eclampsia); separation of the placenta from the uterine wall (placental abruption); heart failure during the last few months before or after birth (peripartum cardiomyopathy); anaphylaxis, a blood clot (embolus) in the lungs; an air embolism; the entry of material such as the contents of the stomach into the lungs or lower respiratory tract (pulmonary aspiration); shock due to extremely rapid low blood pressure because of widespread infection (septic shock); the loss of more than 20% of the blood supply (hemorrhagic shock), which can be caused by several events including a ruptured or inverted uterus; a heart attack (myocardial infarction); and the toxic effects of certain drugs such as a toxic reaction to anesthesia drugs. | 72 | Amniotic Fluid Embolism |
nord_72_5 | Diagnosis of Amniotic Fluid Embolism | A diagnosis of amniotic fluid embolism is based upon identification of characteristic clinical symptoms only. To date, there are no diagnostic assays, imaging studies or pathologic markers that have been validated for the diagnosis of AFE. Prompt diagnosis and early, aggressive advanced life support techniques are essential in assuring the best possible outcomes in amniotic fluid embolism. There is a lack of internal consensus in the medical community as to diagnostic criteria for this disorder, although there have been proposed diagnostic criteria for the research reporting of AFE (Clark SL, 2016). The diagnosis is made by identifying characteristic symptoms and excluding other possible causes of the signs and symptoms (diagnosis of exclusion). Clinical Testing and Workup
A variety of different tests can be ordered to assist in the management of amniotic fluid embolism. These tests include a full blood count, which can reveal low levels of hemoglobin or high levels of certain heart enzymes. Blood coagulation tests can be run that will show low platelet and fibrinogen levels and increased prothrombin time and activated partial thromboplastin time (APTT). Platelets are specialized red blood cells that help the blood to clot. Fibrinogen is a specialized protein found in blood. It is a type of clotting factor that is essential in helping the blood to clot. Prothrombin time and APTT are tests that determine how long it takes the blood to clot. Prothrombin and APTT times are prolonged, which means the blood is taking longer to clot than normal. This happens because in amniotic fluid embolism the clotting factors are used up or broken down rapidly and a woman’s blood cannot clot.Two different tests may be used to show low oxygen levels – continuous pulse oximetry and arterial blood gas (ARG). Continuous pulse oximetry is a simple test in which a small sensor is attached to a person’s fingertip or an earlobe to measure how much oxygen is in a person’s blood. A doctor may take a small blood sample to perform an ARG, which can assess both oxygen and carbon dioxide levels. A chest x-ray may show fluid in the lungs, a prominent pulmonary artery, or enlargement of the heart (cardiomegaly). An electrocardiogram, an echo or echocardiography, is a test that uses high frequency sound waves to create pictures of the heart. This test can show right heart strain and abnormalities of the heart rhythm as well as dysfunction of the right or left upper chamber of the heart (ventricular dysfunction). A finding on echocardiography that is specifically characteristic of AFE is right heart strain followed by elevated pulmonary pressures and resultant left sided failure. An electrocardiogram can also measure the electrical activity of the heart and can reveal abnormal electrical patterns. Sometimes, doctors would take a sample of pulmonary blood to look for the fetal squamous cells, which were believed to be covered with white blood cells called neutrophils and fetal debris like fetal tissue or cells. This was once considered diagnostic of amniotic fluid embolism, but is no longer considered conclusive evidence of the disorder as this finding is not specific to this disorder. | Diagnosis of Amniotic Fluid Embolism. A diagnosis of amniotic fluid embolism is based upon identification of characteristic clinical symptoms only. To date, there are no diagnostic assays, imaging studies or pathologic markers that have been validated for the diagnosis of AFE. Prompt diagnosis and early, aggressive advanced life support techniques are essential in assuring the best possible outcomes in amniotic fluid embolism. There is a lack of internal consensus in the medical community as to diagnostic criteria for this disorder, although there have been proposed diagnostic criteria for the research reporting of AFE (Clark SL, 2016). The diagnosis is made by identifying characteristic symptoms and excluding other possible causes of the signs and symptoms (diagnosis of exclusion). Clinical Testing and Workup
A variety of different tests can be ordered to assist in the management of amniotic fluid embolism. These tests include a full blood count, which can reveal low levels of hemoglobin or high levels of certain heart enzymes. Blood coagulation tests can be run that will show low platelet and fibrinogen levels and increased prothrombin time and activated partial thromboplastin time (APTT). Platelets are specialized red blood cells that help the blood to clot. Fibrinogen is a specialized protein found in blood. It is a type of clotting factor that is essential in helping the blood to clot. Prothrombin time and APTT are tests that determine how long it takes the blood to clot. Prothrombin and APTT times are prolonged, which means the blood is taking longer to clot than normal. This happens because in amniotic fluid embolism the clotting factors are used up or broken down rapidly and a woman’s blood cannot clot.Two different tests may be used to show low oxygen levels – continuous pulse oximetry and arterial blood gas (ARG). Continuous pulse oximetry is a simple test in which a small sensor is attached to a person’s fingertip or an earlobe to measure how much oxygen is in a person’s blood. A doctor may take a small blood sample to perform an ARG, which can assess both oxygen and carbon dioxide levels. A chest x-ray may show fluid in the lungs, a prominent pulmonary artery, or enlargement of the heart (cardiomegaly). An electrocardiogram, an echo or echocardiography, is a test that uses high frequency sound waves to create pictures of the heart. This test can show right heart strain and abnormalities of the heart rhythm as well as dysfunction of the right or left upper chamber of the heart (ventricular dysfunction). A finding on echocardiography that is specifically characteristic of AFE is right heart strain followed by elevated pulmonary pressures and resultant left sided failure. An electrocardiogram can also measure the electrical activity of the heart and can reveal abnormal electrical patterns. Sometimes, doctors would take a sample of pulmonary blood to look for the fetal squamous cells, which were believed to be covered with white blood cells called neutrophils and fetal debris like fetal tissue or cells. This was once considered diagnostic of amniotic fluid embolism, but is no longer considered conclusive evidence of the disorder as this finding is not specific to this disorder. | 72 | Amniotic Fluid Embolism |
nord_72_6 | Therapies of Amniotic Fluid Embolism | Amniotic fluid embolism is a medical emergency. Treatment is aggressive and supportive. A team of specialists is required to treat affected individuals. This team will include specialists in treating pain and in managing care of a patient before, during and after surgery (anesthesiologists); physicians who specialize in pregnancy, childbirth and a woman’s reproductive system (obstetricians); obstetricians who specialize in maternal and fetal health (maternal-fetal medicine specialists); physicians who specialize in the diagnosis and treatment of blood disorders (hematologists); and physicians who specialize in the treatment of critically ill patients (intensivists).Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the severity of the disorder; the presence or absence of certain symptoms; whether the patient is conscious, breathing, etc.; an individual’s age and general health; the health and status of the fetus; and/or other elements. The Society for Maternal-Fetal Medicine has published recommendations for the treatment of amniotic fluid embolism (Society for Maternal-Fetal Medicine, 2016 et al.). Initially, physicians will work to stabilize a woman’s breathing and heart function. If an affected woman is unconscious, they may receive cardiopulmonary resuscitation (CPR). An affected woman may receive supplemental oxygen to make up for a lack of oxygen in the blood or tissues. This can require the insertion of a breathing tube to help with breathing and the use of a machine to assist with breathing (mechanical ventilation). Sometimes, doctors will insert a small, thin tube called a catheter into the main artery of the lungs (pulmonary artery catheter). This catheter can be used to monitor blood pressure. A central venous catheter may be placed into a large vein and used to deliver medications, draw blood, given blood transfusions, or give fluids or nutrients. Some women may receive medications to help the heart function better, or to help reduce fluid accumulation in the lungs or around the heart. Medications that cause the blood vessels to narrow, called vasopressors may be given to treat low blood pressure (hypotension) and improve the amount of blood the heart pumps out (cardiac output). Medications that change the speed or force of muscle contractions, called inotropic medications, may also be given to help improve cardiac output. Medications may also be given to help maintain the muscle tone of the uterus. Sometimes, there is a loss of muscle tone called uterine atony. Some women will require blood transfusions to replace lost blood and to replace clotting factors that are essential to help the blood clot. Most patients require activation of hospital specific massive transfusion protocols as women who have suffered an AFE require multiple component therapy.Immediate delivery of the fetus is required for the health of the fetus. Decreasing the aorto-caval compression may improve maternal resuscitation. Psychosocial support for the entire family is essential as well. Some women survive amniotic fluid embolism with no long-term complications of the condition. However, there is a risk of long-term complications including neurological problems because of a lack of oxygen to the brain. | Therapies of Amniotic Fluid Embolism. Amniotic fluid embolism is a medical emergency. Treatment is aggressive and supportive. A team of specialists is required to treat affected individuals. This team will include specialists in treating pain and in managing care of a patient before, during and after surgery (anesthesiologists); physicians who specialize in pregnancy, childbirth and a woman’s reproductive system (obstetricians); obstetricians who specialize in maternal and fetal health (maternal-fetal medicine specialists); physicians who specialize in the diagnosis and treatment of blood disorders (hematologists); and physicians who specialize in the treatment of critically ill patients (intensivists).Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the severity of the disorder; the presence or absence of certain symptoms; whether the patient is conscious, breathing, etc.; an individual’s age and general health; the health and status of the fetus; and/or other elements. The Society for Maternal-Fetal Medicine has published recommendations for the treatment of amniotic fluid embolism (Society for Maternal-Fetal Medicine, 2016 et al.). Initially, physicians will work to stabilize a woman’s breathing and heart function. If an affected woman is unconscious, they may receive cardiopulmonary resuscitation (CPR). An affected woman may receive supplemental oxygen to make up for a lack of oxygen in the blood or tissues. This can require the insertion of a breathing tube to help with breathing and the use of a machine to assist with breathing (mechanical ventilation). Sometimes, doctors will insert a small, thin tube called a catheter into the main artery of the lungs (pulmonary artery catheter). This catheter can be used to monitor blood pressure. A central venous catheter may be placed into a large vein and used to deliver medications, draw blood, given blood transfusions, or give fluids or nutrients. Some women may receive medications to help the heart function better, or to help reduce fluid accumulation in the lungs or around the heart. Medications that cause the blood vessels to narrow, called vasopressors may be given to treat low blood pressure (hypotension) and improve the amount of blood the heart pumps out (cardiac output). Medications that change the speed or force of muscle contractions, called inotropic medications, may also be given to help improve cardiac output. Medications may also be given to help maintain the muscle tone of the uterus. Sometimes, there is a loss of muscle tone called uterine atony. Some women will require blood transfusions to replace lost blood and to replace clotting factors that are essential to help the blood clot. Most patients require activation of hospital specific massive transfusion protocols as women who have suffered an AFE require multiple component therapy.Immediate delivery of the fetus is required for the health of the fetus. Decreasing the aorto-caval compression may improve maternal resuscitation. Psychosocial support for the entire family is essential as well. Some women survive amniotic fluid embolism with no long-term complications of the condition. However, there is a risk of long-term complications including neurological problems because of a lack of oxygen to the brain. | 72 | Amniotic Fluid Embolism |
nord_73_0 | Overview of Amyloidosis | General DiscussionAmyloidosis is a systemic disorder that is classified into several types based on the precursor protein. The different types of amyloidosis are classified as systemic or localized. AL (immunoglobulin light chain, historically known as primary) amyloidosis is the most common type of systemic amyloidosis. AL amyloidosis results from an abnormality (dyscrasia) of a type of white blood cell called plasma cells in the bone marrow and is closely related to multiple myeloma. AA (historically known at secondary) amyloidosis is derived from the inflammatory protein serum amyloid A. AA amyloidosis occurs in association with chronic inflammatory diseases such as the rheumatic diseases, familial Mediterranean fever, chronic inflammatory bowel disease, tuberculosis or empyema. Hereditary amyloidosis is a rare type of amyloidosis that is caused by an abnormal gene. There are several abnormal genes that can cause hereditary amyloidosis, but the most common type of hereditary amyloidosis is called ATTR and caused by changes (pathogenic variants or mutations) in the transthyretin (TTR) gene. Age related amyloidosis, in which the amyloid is derived from wild-type (normal) transthyretin, is a slowly progressive disease that affects the hearts of elderly individuals, usually men and less commonly women, and is called ATTRwt amyloidosis. Amyloid deposits may occasionally occur in isolation without evidence of a systemic disease; isolated bladder or tracheal amyloidosis are the most common such presentations. Dialysis-related beta2-microglobulin amyloidosis is a type of systemic amyloidosis that can occur in individuals who have experienced long-term kidney dialysis to remove accumulated impurities or wastes in the blood by mechanical filtration. This form of amyloidosis, also known as AB2MG (amyloid associated with the beta-2m protein), is associated with the aggregation of beta2-microglobulin, a type of amyloid protein that is cleared by the normally functioning kidney. Dialysis-related beta2-microglobulin amyloidosis occurs in patients with near end-stage renal disease. It does not affect individuals with normal or mildly reduced renal function or patients with a functioning renal transplant. | Overview of Amyloidosis. General DiscussionAmyloidosis is a systemic disorder that is classified into several types based on the precursor protein. The different types of amyloidosis are classified as systemic or localized. AL (immunoglobulin light chain, historically known as primary) amyloidosis is the most common type of systemic amyloidosis. AL amyloidosis results from an abnormality (dyscrasia) of a type of white blood cell called plasma cells in the bone marrow and is closely related to multiple myeloma. AA (historically known at secondary) amyloidosis is derived from the inflammatory protein serum amyloid A. AA amyloidosis occurs in association with chronic inflammatory diseases such as the rheumatic diseases, familial Mediterranean fever, chronic inflammatory bowel disease, tuberculosis or empyema. Hereditary amyloidosis is a rare type of amyloidosis that is caused by an abnormal gene. There are several abnormal genes that can cause hereditary amyloidosis, but the most common type of hereditary amyloidosis is called ATTR and caused by changes (pathogenic variants or mutations) in the transthyretin (TTR) gene. Age related amyloidosis, in which the amyloid is derived from wild-type (normal) transthyretin, is a slowly progressive disease that affects the hearts of elderly individuals, usually men and less commonly women, and is called ATTRwt amyloidosis. Amyloid deposits may occasionally occur in isolation without evidence of a systemic disease; isolated bladder or tracheal amyloidosis are the most common such presentations. Dialysis-related beta2-microglobulin amyloidosis is a type of systemic amyloidosis that can occur in individuals who have experienced long-term kidney dialysis to remove accumulated impurities or wastes in the blood by mechanical filtration. This form of amyloidosis, also known as AB2MG (amyloid associated with the beta-2m protein), is associated with the aggregation of beta2-microglobulin, a type of amyloid protein that is cleared by the normally functioning kidney. Dialysis-related beta2-microglobulin amyloidosis occurs in patients with near end-stage renal disease. It does not affect individuals with normal or mildly reduced renal function or patients with a functioning renal transplant. | 73 | Amyloidosis |
nord_73_1 | Symptoms of Amyloidosis | Amyloidosis is usually a multisystem disease resulting in a wide spectrum of clinical presentations. Consequently, a patient may present to, or be referred to, one of several subspecialists, most commonly a nephrologist, cardiologist or neurologist. Recent advances in therapy have rendered early and precise diagnosis critical if the patient is to fully benefit. Most patients have more than one organ involved and therefore the finding of a combination of any of the features below should heighten the suspicion of amyloidosis:The kidney is the organ most commonly involved in AL amyloidosis and AA amyloidosis, however, rarely involved in hereditary (familial) amyloidosis. An excessive amount of protein in the urine (proteinuria) is the usual manifestation of renal involvement and is commonly heavy, resulting in the nephrotic syndrome. Less commonly, amyloid causes an excess of urea and other nitrogenous wastes in the blood (progressive azotemia) as the initial manifestation of renal disease. An abnormal accumulation of fluid such as swelling of the legs and abdomen, in the absence of heart failure is a feature of nephrotic syndrome, as is the presence of excess cholesterol in the blood (hypercholesterolemia) that may be profound. The kidneys often become small, pale and hard, but in amyloidosis, large kidneys are commonly seen as well.Amyloidosis frequently involves the heart. The heart is commonly involved in AL and ATTRv amyloidosis and is the most common phenotype of ATTRwt amyloidosis. Amyloid infiltration of the heart results in ventricular wall thickening and the development of heart failure. Rapidly progressive congestive heart failure with thick ventricular walls is the classical presentation of AL cardiac amyloidosis. The heart is invariably involved in ATTRwt amyloidosis, often in ATTR amyloidosis and rarely in AA amyloidosis. Common symptoms of heart involvement include: an enlarged heart (cardiomegaly); an irregular heartbeat (arrhythmias); and abnormalities of the heart seen on electrocardiograms (for example: low voltage). Congestive heart failure is the most common cardiac complication of amyloidosis. Nodular deposits of amyloid may be present on the membranous sac that surrounds the heart (pericardium) and on the lining of the heart chambers or heart valves (endocardium).Although less common than renal or cardiac involvement, neuropathy may be a significant problem in amyloidosis. Occasionally, it is the presenting and predominant feature of AL amyloidosis. In specific variants of hereditary amyloidosis (particularly V30M ATTR originally known as familial amyloid polyneuropathy), it is the primary feature of the disease. The neuropathy is often painful and sensorimotor in nature although neuropathic pain may be occasionally significant. These symptoms may include sensory neuropathy with numbness and tingling sensations in the feet that progresses to the legs and eventually the upper extremities; motor neuropathy with loss of motion beginning in the feet and extending upward. Carpal tunnel syndrome is commonly seen, not due to direct nerve involvement, but rather to soft tissue infiltration causing median nerve compression. In ATTRv amyloidosis, the peripheral neuropathy is frequently accompanied by an autonomic neuropathy characterized by constipation and a decrease in the amount of sweat production (hypohidrosis), a sudden drop in blood pressure when the patient stands up (postural hypotension) and, in the male, erectile dysfunction. Postural hypotension may be profound and result in recurrent fainting (syncopal) episodes. Systemic amyloidosis does not involve the central nervous system and is unrelated to Alzheimer disease.Amyloidosis may affect the liver and the spleen. Amyloid involvement in the spleen increases the risk of spontaneous rupture of that organ. Some degree of hepatic involvement is common in AL amyloidosis. It is also common in AA amyloidosis but is not seen in ATTRv amyloidosis. In most patients, hepatic involvement is asymptomatic. An enlarged liver (hepatomegaly) and an enlarged spleen (splenomegaly) are the most notable signs. Generally, the amyloid-infiltrated liver feels very hard, and elevated liver enzymes (particularly alkaline phosphatase) and other liver function abnormalities may be detected early. Generally, the function of the liver is not significantly affected until late in the course of the disease. Elevation of bilirubin is an ominous sign and may portend hepatic failure. Hepatic amyloidosis rarely occurs in isolation and is usually associated with organ involvement elsewhere.Amyloidosis may also affect the gastrointestinal (digestive) system. Amyloid accumulation in the gastrointestinal tract may cause a lack of movement (motility) in the esophagus and the small and large intestines. Malabsorption, ulceration, bleeding, weak gastric activity, pseudo-obstruction of the gastrointestinal tract, protein loss and diarrhea may also occur. Loss of taste, and a difficulty eating solid foods because of enlargement of the tongue (macroglossia) from amyloid infiltration, may contribute to weight loss, or weight loss may be a non-specific manifestation of the systemic disease. In patients with autonomic neuropathy, gastric emptying is impaired, resulting in a sensation of early satiety.The skin is frequently involved in primary amyloidosis. Dermatologic involvement is almost exclusively limited to AL amyloidosis and consists of soft tissue, skin and vascular abnormalities. Periorbital purpura is a result of capillary fragility and may appear after coughing, sneezing, or straining for a bowel movement. Not infrequently, purpuric lesions may arise after such simple actions as rubbing the eyelids. Soft tissue infiltration may cause macroglossia and hoarseness, although examination of the vocal cords may appear normal. Lesions of the skin may be visible or may be so small that they may be seen only with a microscope. Waxy looking papular lesions may appear on the face and the neck. They may also occur under the arms (axillary region), near the anus and the groin. Other areas that may be affected are the mucous areas such as the ear canal or tongue. Areas of swelling, hemorrhages under the skin (purpura), hair loss (alopecia), inflammation of the tongue (glossitis) and a dry mouth (xerostomia) may also be present.Problems with the respiratory system that are associated with amyloidosis often parallel cardiac symptoms. In the localized form of amyloidosis, air passages and ducts may be obstructed by amyloid deposits in the nasal sinuses, voice box (larynx) and throat (trachea) and bronchial tree. Fluid collecting in the pleural space (pleural effusion) is quite common in patients with congestive heart failure due to amyloidosis, but large recurrent pleural effusions disproportionate to the degree of heart failure suggest pleural amyloidosis.Joint abnormalities (arthropathy) occur in amyloidosis due to the accumulation of amyloid deposits in the lining of joints (synovial membranes). This occurs in AL amyloidosis and occasionally in dialysis-related amyloidosis. Articular cartilage or the synovial membrane and fluid may become involved as well. Symptoms are similar to those of rheumatoid arthritis. Amyloid deposits in muscle tissue may cause muscle weakness and muscle changes (pseudomyopathy). Symptoms of amyloidosis may also be manifested by bleeding disorders. These may result from deficiency of certain clotting factors or small amyloid deposits in blood vessels within the skin.
Dialysis-related beta2-microglobulin amyloidosis usually affects the bones and joints. Initial symptoms include carpal tunnel syndrome, shoulder pain and inflammation of the tendon sheaths of the hands. Case reports of severe pulmonary hypertension and heart failure also exist. | Symptoms of Amyloidosis. Amyloidosis is usually a multisystem disease resulting in a wide spectrum of clinical presentations. Consequently, a patient may present to, or be referred to, one of several subspecialists, most commonly a nephrologist, cardiologist or neurologist. Recent advances in therapy have rendered early and precise diagnosis critical if the patient is to fully benefit. Most patients have more than one organ involved and therefore the finding of a combination of any of the features below should heighten the suspicion of amyloidosis:The kidney is the organ most commonly involved in AL amyloidosis and AA amyloidosis, however, rarely involved in hereditary (familial) amyloidosis. An excessive amount of protein in the urine (proteinuria) is the usual manifestation of renal involvement and is commonly heavy, resulting in the nephrotic syndrome. Less commonly, amyloid causes an excess of urea and other nitrogenous wastes in the blood (progressive azotemia) as the initial manifestation of renal disease. An abnormal accumulation of fluid such as swelling of the legs and abdomen, in the absence of heart failure is a feature of nephrotic syndrome, as is the presence of excess cholesterol in the blood (hypercholesterolemia) that may be profound. The kidneys often become small, pale and hard, but in amyloidosis, large kidneys are commonly seen as well.Amyloidosis frequently involves the heart. The heart is commonly involved in AL and ATTRv amyloidosis and is the most common phenotype of ATTRwt amyloidosis. Amyloid infiltration of the heart results in ventricular wall thickening and the development of heart failure. Rapidly progressive congestive heart failure with thick ventricular walls is the classical presentation of AL cardiac amyloidosis. The heart is invariably involved in ATTRwt amyloidosis, often in ATTR amyloidosis and rarely in AA amyloidosis. Common symptoms of heart involvement include: an enlarged heart (cardiomegaly); an irregular heartbeat (arrhythmias); and abnormalities of the heart seen on electrocardiograms (for example: low voltage). Congestive heart failure is the most common cardiac complication of amyloidosis. Nodular deposits of amyloid may be present on the membranous sac that surrounds the heart (pericardium) and on the lining of the heart chambers or heart valves (endocardium).Although less common than renal or cardiac involvement, neuropathy may be a significant problem in amyloidosis. Occasionally, it is the presenting and predominant feature of AL amyloidosis. In specific variants of hereditary amyloidosis (particularly V30M ATTR originally known as familial amyloid polyneuropathy), it is the primary feature of the disease. The neuropathy is often painful and sensorimotor in nature although neuropathic pain may be occasionally significant. These symptoms may include sensory neuropathy with numbness and tingling sensations in the feet that progresses to the legs and eventually the upper extremities; motor neuropathy with loss of motion beginning in the feet and extending upward. Carpal tunnel syndrome is commonly seen, not due to direct nerve involvement, but rather to soft tissue infiltration causing median nerve compression. In ATTRv amyloidosis, the peripheral neuropathy is frequently accompanied by an autonomic neuropathy characterized by constipation and a decrease in the amount of sweat production (hypohidrosis), a sudden drop in blood pressure when the patient stands up (postural hypotension) and, in the male, erectile dysfunction. Postural hypotension may be profound and result in recurrent fainting (syncopal) episodes. Systemic amyloidosis does not involve the central nervous system and is unrelated to Alzheimer disease.Amyloidosis may affect the liver and the spleen. Amyloid involvement in the spleen increases the risk of spontaneous rupture of that organ. Some degree of hepatic involvement is common in AL amyloidosis. It is also common in AA amyloidosis but is not seen in ATTRv amyloidosis. In most patients, hepatic involvement is asymptomatic. An enlarged liver (hepatomegaly) and an enlarged spleen (splenomegaly) are the most notable signs. Generally, the amyloid-infiltrated liver feels very hard, and elevated liver enzymes (particularly alkaline phosphatase) and other liver function abnormalities may be detected early. Generally, the function of the liver is not significantly affected until late in the course of the disease. Elevation of bilirubin is an ominous sign and may portend hepatic failure. Hepatic amyloidosis rarely occurs in isolation and is usually associated with organ involvement elsewhere.Amyloidosis may also affect the gastrointestinal (digestive) system. Amyloid accumulation in the gastrointestinal tract may cause a lack of movement (motility) in the esophagus and the small and large intestines. Malabsorption, ulceration, bleeding, weak gastric activity, pseudo-obstruction of the gastrointestinal tract, protein loss and diarrhea may also occur. Loss of taste, and a difficulty eating solid foods because of enlargement of the tongue (macroglossia) from amyloid infiltration, may contribute to weight loss, or weight loss may be a non-specific manifestation of the systemic disease. In patients with autonomic neuropathy, gastric emptying is impaired, resulting in a sensation of early satiety.The skin is frequently involved in primary amyloidosis. Dermatologic involvement is almost exclusively limited to AL amyloidosis and consists of soft tissue, skin and vascular abnormalities. Periorbital purpura is a result of capillary fragility and may appear after coughing, sneezing, or straining for a bowel movement. Not infrequently, purpuric lesions may arise after such simple actions as rubbing the eyelids. Soft tissue infiltration may cause macroglossia and hoarseness, although examination of the vocal cords may appear normal. Lesions of the skin may be visible or may be so small that they may be seen only with a microscope. Waxy looking papular lesions may appear on the face and the neck. They may also occur under the arms (axillary region), near the anus and the groin. Other areas that may be affected are the mucous areas such as the ear canal or tongue. Areas of swelling, hemorrhages under the skin (purpura), hair loss (alopecia), inflammation of the tongue (glossitis) and a dry mouth (xerostomia) may also be present.Problems with the respiratory system that are associated with amyloidosis often parallel cardiac symptoms. In the localized form of amyloidosis, air passages and ducts may be obstructed by amyloid deposits in the nasal sinuses, voice box (larynx) and throat (trachea) and bronchial tree. Fluid collecting in the pleural space (pleural effusion) is quite common in patients with congestive heart failure due to amyloidosis, but large recurrent pleural effusions disproportionate to the degree of heart failure suggest pleural amyloidosis.Joint abnormalities (arthropathy) occur in amyloidosis due to the accumulation of amyloid deposits in the lining of joints (synovial membranes). This occurs in AL amyloidosis and occasionally in dialysis-related amyloidosis. Articular cartilage or the synovial membrane and fluid may become involved as well. Symptoms are similar to those of rheumatoid arthritis. Amyloid deposits in muscle tissue may cause muscle weakness and muscle changes (pseudomyopathy). Symptoms of amyloidosis may also be manifested by bleeding disorders. These may result from deficiency of certain clotting factors or small amyloid deposits in blood vessels within the skin.
Dialysis-related beta2-microglobulin amyloidosis usually affects the bones and joints. Initial symptoms include carpal tunnel syndrome, shoulder pain and inflammation of the tendon sheaths of the hands. Case reports of severe pulmonary hypertension and heart failure also exist. | 73 | Amyloidosis |
nord_73_2 | Causes of Amyloidosis | Amyloidosis is caused by abnormal folding of normal soluble proteins leading to fibril formation in one or more body organs, systems or soft tissues. These clumps of protein are called amyloid deposits and the accumulation of amyloid deposits causes the progressive malfunction and eventual failure of the affected organ. Normally, proteins are broken down at about the same rate as they are produced, but these unusually stable amyloid deposits are deposited more rapidly than they can be broken down.The cause of AL amyloidosis is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (part of an antibody). Usually, an excess amount of antibody protein is produced and the abnormal light chain portion or the whole antibody molecule accumulates in the body tissues in the form of amyloid deposits.AA amyloidosis is caused by the inflammatory disease process that is part of the underlying disease. Approximately 50% of the people with secondary amyloidosis have rheumatoid arthritis as the underlying disease.Familial amyloidosis is caused by an abnormality in the gene for one of several proteins. The most common form of hereditary amyloidosis is caused by a pathogenic variant in the gene for transthyretin (TTR) leading to ATTRv amyloidosis. More than 100 different variants in the transthyretin gene have been reported and the most common variant has been termed V30M. Different TTR gene variants are associated with amyloidosis that affects different organ systems. Rarely, variants in genes for proteins that cause amyloidosis are fibrinogen A alpha chain, apolipoprotein A1 and A2, gelsolin, LECT2 and cystatin C.All the hereditary amyloidoses follow autosomal dominant inheritance. 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. Not every person getting the gene, however, will ultimately get sick with amyloidosis.The exact cause of dialysis-related beta2-microglobulin amyloidosis is not fully understood. A normally functioning kidney can clear out beta 2-microglobulin. In some individuals on long-term dialysis or some individuals on continuous ambulatory peritoneal dialysis (CAPD), the kidneys’ inability to function properly leads to the abnormal retention and accumulation of the beta2-microglobulin protein. Some individuals with near end-stage renal failure have also developed this form of amyloidosis. Although this retention and accumulation is believed to be the main underlying factor, additional factors are required for the disorder to develop, which is why only a percentage of individuals on dialysis develop dialysis-related beta2-microglobuin amyloidosis. | Causes of Amyloidosis. Amyloidosis is caused by abnormal folding of normal soluble proteins leading to fibril formation in one or more body organs, systems or soft tissues. These clumps of protein are called amyloid deposits and the accumulation of amyloid deposits causes the progressive malfunction and eventual failure of the affected organ. Normally, proteins are broken down at about the same rate as they are produced, but these unusually stable amyloid deposits are deposited more rapidly than they can be broken down.The cause of AL amyloidosis is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (part of an antibody). Usually, an excess amount of antibody protein is produced and the abnormal light chain portion or the whole antibody molecule accumulates in the body tissues in the form of amyloid deposits.AA amyloidosis is caused by the inflammatory disease process that is part of the underlying disease. Approximately 50% of the people with secondary amyloidosis have rheumatoid arthritis as the underlying disease.Familial amyloidosis is caused by an abnormality in the gene for one of several proteins. The most common form of hereditary amyloidosis is caused by a pathogenic variant in the gene for transthyretin (TTR) leading to ATTRv amyloidosis. More than 100 different variants in the transthyretin gene have been reported and the most common variant has been termed V30M. Different TTR gene variants are associated with amyloidosis that affects different organ systems. Rarely, variants in genes for proteins that cause amyloidosis are fibrinogen A alpha chain, apolipoprotein A1 and A2, gelsolin, LECT2 and cystatin C.All the hereditary amyloidoses follow autosomal dominant inheritance. 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. Not every person getting the gene, however, will ultimately get sick with amyloidosis.The exact cause of dialysis-related beta2-microglobulin amyloidosis is not fully understood. A normally functioning kidney can clear out beta 2-microglobulin. In some individuals on long-term dialysis or some individuals on continuous ambulatory peritoneal dialysis (CAPD), the kidneys’ inability to function properly leads to the abnormal retention and accumulation of the beta2-microglobulin protein. Some individuals with near end-stage renal failure have also developed this form of amyloidosis. Although this retention and accumulation is believed to be the main underlying factor, additional factors are required for the disorder to develop, which is why only a percentage of individuals on dialysis develop dialysis-related beta2-microglobuin amyloidosis. | 73 | Amyloidosis |
nord_73_3 | Affects of Amyloidosis | It is estimated that there are approximately 4,000 new cases of AL amyloidosis annually in the United States, though actual incidence may be somewhat higher as a result of under-diagnosis and/or misdiagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. AL amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65.Individuals at risk for AA amyloidosis include those with chronic inflammatory diseases such as rheumatic arthritis, psoriatic arthritis, chronic juvenile arthritis, ankylosing spondylitis in children, inflammatory bowel disease and familial Mediterranean fever. People with chronic infectious diseases such as tuberculosis, leprosy, bronchiectasis, chronic osteomyelitis and chronic pyelonephritis are also at risk. AA amyloidosis occurs in less than 5% of individuals with these conditions.Familial amyloidosis caused by a transthyretin gene variant occurs in approximately 1 in 100,000 Caucasians in the U.S, and more commonly in African Americans (approximately 4% in that population). This condition is prevalent in Portugal, Sweden, Japan, Ireland, Spain, France, Finland, Germany and Greece. Symptoms usually begin between 40 and 65 years of age.Though both familial and AA amyloidosis are probably less common than AL amyloidosis, ATTRwt amyloidosis is probably more common, but considerably underdiagnosed. | Affects of Amyloidosis. It is estimated that there are approximately 4,000 new cases of AL amyloidosis annually in the United States, though actual incidence may be somewhat higher as a result of under-diagnosis and/or misdiagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. AL amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65.Individuals at risk for AA amyloidosis include those with chronic inflammatory diseases such as rheumatic arthritis, psoriatic arthritis, chronic juvenile arthritis, ankylosing spondylitis in children, inflammatory bowel disease and familial Mediterranean fever. People with chronic infectious diseases such as tuberculosis, leprosy, bronchiectasis, chronic osteomyelitis and chronic pyelonephritis are also at risk. AA amyloidosis occurs in less than 5% of individuals with these conditions.Familial amyloidosis caused by a transthyretin gene variant occurs in approximately 1 in 100,000 Caucasians in the U.S, and more commonly in African Americans (approximately 4% in that population). This condition is prevalent in Portugal, Sweden, Japan, Ireland, Spain, France, Finland, Germany and Greece. Symptoms usually begin between 40 and 65 years of age.Though both familial and AA amyloidosis are probably less common than AL amyloidosis, ATTRwt amyloidosis is probably more common, but considerably underdiagnosed. | 73 | Amyloidosis |
nord_73_4 | Related disorders of Amyloidosis | The following disorders may be associated with amyloidosis. Amyloidosis may appear in conjunction with or as a result of the following disorders:Multiple myeloma, Hodgkin lymphoma, lymphoma, medullary carcinoma of the thyroid, Whipple disease, Crohn disease, osteomyelitis, rheumatoid arthritis, ankylosing spondylitis, Reiter syndrome, psoriatic arthritis, tuberculosis, leprosy, familial Mediterranean fever, early onset Alzheimer disease and Waldenstrom macroglobulinemia (For more information on these disorders, search for them in the Rare Disease Database.) | Related disorders of Amyloidosis. The following disorders may be associated with amyloidosis. Amyloidosis may appear in conjunction with or as a result of the following disorders:Multiple myeloma, Hodgkin lymphoma, lymphoma, medullary carcinoma of the thyroid, Whipple disease, Crohn disease, osteomyelitis, rheumatoid arthritis, ankylosing spondylitis, Reiter syndrome, psoriatic arthritis, tuberculosis, leprosy, familial Mediterranean fever, early onset Alzheimer disease and Waldenstrom macroglobulinemia (For more information on these disorders, search for them in the Rare Disease Database.) | 73 | Amyloidosis |
nord_73_5 | Diagnosis of Amyloidosis | Particularly in the case of AL amyloidosis, early diagnosis is the key to survival and post treatment regaining of quality of life. The diagnosis of amyloidosis is suspected following a detailed patient history and clinical evaluation but requires aspiration of abdominal fat pad and/or biopsy of the involved organ. If the disease is suspected on clinical grounds, a biopsy of the involved organ will give the highest yield. The biopsy material is examined microscopically and is stained with a dye called Congo red that will produce a green color when looked at in a polarizing microscope if amyloid is present. When amyloidosis is diagnosed on a tissue biopsy it is essential that the affected individual be further evaluated to determine what organs are affected.Once a tissue biopsy of amyloidosis has been established, it is crucial to determine the type of amyloidosis. In AL amyloidosis, manifestations of a plasma cell dyscrasia will be found in 98% of the time. In 2% of cases, a B-cell lymphoma is identified as the cause of AL amyloidosis. The specific tests that are used to make a diagnosis of the plasma cell dyscrasia or B-cell clone are immunofixation and protein electrophoresis of the blood and urine, bone marrow biopsy with immunochemical staining of plasma cells for kappa and lambda light chains and a serum free light chain assay. The diagnosis of TTR hereditary amyloidosis can be confirmed by performing molecular genetic testing for variants in the TTR gene on a blood sample. In the absence of variants of transthyretin, very rare forms of familial amyloidosis may be present.If the patient is an elderly man with clinically isolated cardiac involvement, the most likely diagnosis is ATTRwt amyloidosis a condition in which normal transthyretin is deposited in the heart.Specific immunostaining (for example, immunogold electron microscopy) of appropriately preserved tissue is available at specialized centers and offers a high specificity for determining the accurate type of amyloid. In difficult diagnostic cases, mass spectrometry is able to determine precisely the molecular structure of the amyloid deposits– this technique is being used more and more frequently. A technique called radiolabeled serum amyloid P (SAP) scanning is available in a few centers in Europe that specialize in amyloidosis. This test is used to monitor and evaluate the extent of accumulation of amyloid deposits.In individuals on long-term dialysis or with end stage renal failure, lab tests may be performed that can analyze blood or urine samples to detect increased levels B2M protein. | Diagnosis of Amyloidosis. Particularly in the case of AL amyloidosis, early diagnosis is the key to survival and post treatment regaining of quality of life. The diagnosis of amyloidosis is suspected following a detailed patient history and clinical evaluation but requires aspiration of abdominal fat pad and/or biopsy of the involved organ. If the disease is suspected on clinical grounds, a biopsy of the involved organ will give the highest yield. The biopsy material is examined microscopically and is stained with a dye called Congo red that will produce a green color when looked at in a polarizing microscope if amyloid is present. When amyloidosis is diagnosed on a tissue biopsy it is essential that the affected individual be further evaluated to determine what organs are affected.Once a tissue biopsy of amyloidosis has been established, it is crucial to determine the type of amyloidosis. In AL amyloidosis, manifestations of a plasma cell dyscrasia will be found in 98% of the time. In 2% of cases, a B-cell lymphoma is identified as the cause of AL amyloidosis. The specific tests that are used to make a diagnosis of the plasma cell dyscrasia or B-cell clone are immunofixation and protein electrophoresis of the blood and urine, bone marrow biopsy with immunochemical staining of plasma cells for kappa and lambda light chains and a serum free light chain assay. The diagnosis of TTR hereditary amyloidosis can be confirmed by performing molecular genetic testing for variants in the TTR gene on a blood sample. In the absence of variants of transthyretin, very rare forms of familial amyloidosis may be present.If the patient is an elderly man with clinically isolated cardiac involvement, the most likely diagnosis is ATTRwt amyloidosis a condition in which normal transthyretin is deposited in the heart.Specific immunostaining (for example, immunogold electron microscopy) of appropriately preserved tissue is available at specialized centers and offers a high specificity for determining the accurate type of amyloid. In difficult diagnostic cases, mass spectrometry is able to determine precisely the molecular structure of the amyloid deposits– this technique is being used more and more frequently. A technique called radiolabeled serum amyloid P (SAP) scanning is available in a few centers in Europe that specialize in amyloidosis. This test is used to monitor and evaluate the extent of accumulation of amyloid deposits.In individuals on long-term dialysis or with end stage renal failure, lab tests may be performed that can analyze blood or urine samples to detect increased levels B2M protein. | 73 | Amyloidosis |
nord_73_6 | Therapies of Amyloidosis | TreatmentThe type of treatment available is driven by the type of amyloidosis and the clinical state of the patient. In AL amyloidosis, the cause is the abnormal plasma cells and as such, chemotherapy aimed at eradicating those cells forms the cornerstone of treatment. Various regimens have been studied but the ones with the most historical evidence are melphalan and dexamethasone given orally or high dose melphalan given intravenously with autologous stem cell transplantation. Both are equally effective, but the treatments and side effects are different. High dose melphalan with stem cell transplantation is an involved treatment that often involves a 2–3-week hospital stay and a few months of additional recovery time. The use of oral melphalan on a monthly basis is less toxic but is associated with a higher risk of treatment-related leukemia. Newer agents active in multiple myeloma (another disease of abnormal plasma cells), such as Velcade (bortezomib) or Revlimid (lenalidomide), are also very effective in AL amyloidosis and have been shown to provide a benefit in patients with relapsed disease. Often, these drugs are incorporated into upfront treatment. The combination of bortezomib, Cytoxan (cyclophosphamide) and dexamethasone is associated with good tolerability and rapid responses. Recently, regulatory agencies approved of combination of CyBorD and Daratumumab for the treatment of AL amyloidosis and this is now the standard of care for patients with new diagnosis. The specific treatment for any individual has to be personalized to their unique situation.The two most important determinants of long-term survival with AL are the presence and extent of cardiac involvement and hematologic response to therapy.Supportive therapy (treatment of congestive heart failure, attention to nutrition, treatment of autonomic neuropathy etc.) is a very important concomitant measure. Given the complexity of the disease, it is recommended that treatment be performed in a center with experience in amyloidosis, or at least that the patient should have an initial evaluation at such a center, with continued communication during treatment in the local community.Hereditary TTR amyloidosis is treated, if possible, by removal of the source of the abnormal TTR production. Since the dominant source is the liver, liver transplantation is performed in carefully selected patients whose disease is not too far advanced. Onpattro (patisiran) and Tegsedi (inoteresen) are TTR gene silencers and have been approved by the Food and Drug Administration (FDA) for treatment of ATTRv amyloidosis with peripheral neuropathy. In 2019, the FDA approved Vyndaqel (tafamidis meglumine) to treat the cardiomyopathy (heart disease) caused by ATTR (ATTR-CM).Genetic counseling is recommended for individuals with hereditary amyloidosis and their family members.In ATTRwt amyloidosis, therapy is supportive, but both for this disease and for ATTR, pharmacologic therapies aimed at stabilizing the transthyretin molecule and thus preventing amyloid formation are being actively investigated.The mainstay of AA amyloidosis treatment is therapy of the underlying disease. Renal transplantation has been performed successfully for renal disease due to AA amyloidosis.In 2015, the FDA authorized the use of a medical device called Lixelle Beta 2-microglobulin apheresis column to treat dialysis-related beta2-microglobulin amyloidosis. The device works by removing the beta 2m protein from the blood.Amyloidosis Treatment CentersMedical centers that provide diagnosis and treatment for amyloidosis and conduct research and clinical trials can be located here:
https://www.amyloidosissupport.org/International Amyloid Centers
Italian center for the Study and Cure of Systemic Amyloidosis (Pavia, Italy)
www.amiloidosi.itNational Amyloidosis Center, London, UK.
https://www.ucl.ac.uk/amyloidosis/national-amyloidosis-centre | Therapies of Amyloidosis. TreatmentThe type of treatment available is driven by the type of amyloidosis and the clinical state of the patient. In AL amyloidosis, the cause is the abnormal plasma cells and as such, chemotherapy aimed at eradicating those cells forms the cornerstone of treatment. Various regimens have been studied but the ones with the most historical evidence are melphalan and dexamethasone given orally or high dose melphalan given intravenously with autologous stem cell transplantation. Both are equally effective, but the treatments and side effects are different. High dose melphalan with stem cell transplantation is an involved treatment that often involves a 2–3-week hospital stay and a few months of additional recovery time. The use of oral melphalan on a monthly basis is less toxic but is associated with a higher risk of treatment-related leukemia. Newer agents active in multiple myeloma (another disease of abnormal plasma cells), such as Velcade (bortezomib) or Revlimid (lenalidomide), are also very effective in AL amyloidosis and have been shown to provide a benefit in patients with relapsed disease. Often, these drugs are incorporated into upfront treatment. The combination of bortezomib, Cytoxan (cyclophosphamide) and dexamethasone is associated with good tolerability and rapid responses. Recently, regulatory agencies approved of combination of CyBorD and Daratumumab for the treatment of AL amyloidosis and this is now the standard of care for patients with new diagnosis. The specific treatment for any individual has to be personalized to their unique situation.The two most important determinants of long-term survival with AL are the presence and extent of cardiac involvement and hematologic response to therapy.Supportive therapy (treatment of congestive heart failure, attention to nutrition, treatment of autonomic neuropathy etc.) is a very important concomitant measure. Given the complexity of the disease, it is recommended that treatment be performed in a center with experience in amyloidosis, or at least that the patient should have an initial evaluation at such a center, with continued communication during treatment in the local community.Hereditary TTR amyloidosis is treated, if possible, by removal of the source of the abnormal TTR production. Since the dominant source is the liver, liver transplantation is performed in carefully selected patients whose disease is not too far advanced. Onpattro (patisiran) and Tegsedi (inoteresen) are TTR gene silencers and have been approved by the Food and Drug Administration (FDA) for treatment of ATTRv amyloidosis with peripheral neuropathy. In 2019, the FDA approved Vyndaqel (tafamidis meglumine) to treat the cardiomyopathy (heart disease) caused by ATTR (ATTR-CM).Genetic counseling is recommended for individuals with hereditary amyloidosis and their family members.In ATTRwt amyloidosis, therapy is supportive, but both for this disease and for ATTR, pharmacologic therapies aimed at stabilizing the transthyretin molecule and thus preventing amyloid formation are being actively investigated.The mainstay of AA amyloidosis treatment is therapy of the underlying disease. Renal transplantation has been performed successfully for renal disease due to AA amyloidosis.In 2015, the FDA authorized the use of a medical device called Lixelle Beta 2-microglobulin apheresis column to treat dialysis-related beta2-microglobulin amyloidosis. The device works by removing the beta 2m protein from the blood.Amyloidosis Treatment CentersMedical centers that provide diagnosis and treatment for amyloidosis and conduct research and clinical trials can be located here:
https://www.amyloidosissupport.org/International Amyloid Centers
Italian center for the Study and Cure of Systemic Amyloidosis (Pavia, Italy)
www.amiloidosi.itNational Amyloidosis Center, London, UK.
https://www.ucl.ac.uk/amyloidosis/national-amyloidosis-centre | 73 | Amyloidosis |
nord_74_0 | Overview of Amyotrophic Lateral Sclerosis | Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration and eventual death of nerve cells (neurons) in the brain, brainstem and spinal cord. The neurons involved in ALS facilitate communication between the nervous system and voluntary muscles of the body (motor neurons). Normally, motor neurons in the brain (upper motor neurons) send messages to motor neurons in the spinal cord and brainstem (lower motor neurons), which then relay the message to various muscles. ALS affects both the upper and lower motor neurons so that the transmission of messages is interrupted and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. ALS affects the muscles needed to move the arms and legs, to speak and swallow, to support the neck and trunk, and to breathe. The symptoms of ALS progress over time and, ultimately, the disease leads to ventilatory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. Although two therapies are approved to slow the progression of the disease by a small amount (disease-modifying therapy) in the United States, the mainstay of therapy for ALS is centered on symptom control and supportive care. | Overview of Amyotrophic Lateral Sclerosis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration and eventual death of nerve cells (neurons) in the brain, brainstem and spinal cord. The neurons involved in ALS facilitate communication between the nervous system and voluntary muscles of the body (motor neurons). Normally, motor neurons in the brain (upper motor neurons) send messages to motor neurons in the spinal cord and brainstem (lower motor neurons), which then relay the message to various muscles. ALS affects both the upper and lower motor neurons so that the transmission of messages is interrupted and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. ALS affects the muscles needed to move the arms and legs, to speak and swallow, to support the neck and trunk, and to breathe. The symptoms of ALS progress over time and, ultimately, the disease leads to ventilatory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. Although two therapies are approved to slow the progression of the disease by a small amount (disease-modifying therapy) in the United States, the mainstay of therapy for ALS is centered on symptom control and supportive care. | 74 | Amyotrophic Lateral Sclerosis |
nord_74_1 | Symptoms of Amyotrophic Lateral Sclerosis | ALS causes a combination of upper and lower motor neuron disease, and the symptoms vary depending on the muscle controlled by the affected neurons and whether upper or lower motor neurons are predominantly affected. The main manifestations of upper motor neuron disease are muscle weakness, increased muscle tone and stiffness (spasticity), increased reflexes (hyperreflexia), and abnormal speech and swallowing. Lower motor neuron disease causes muscle weakness and wasting (atrophy), decreased muscle tone, decreased reflexes (hyporeflexia), twitching of muscle fibers (fasciculations), muscle cramps, and abnormalities of speech, swallowing, and breathing. When ALS affects the limb and trunk muscles, it leads to symptoms such as difficulty walking or falls and difficulty performing activities of daily living. When ALS affects nerves of the head and neck (cranial nerves), it can leads to bulbar symptoms, which include difficulty swallowing (dysphagia) or speaking (dysarthria) and weakness of the muscles of the face or tongue. Dysphagia can lead to complications such as difficulty feeding, choking, excess saliva or drooling, and weight loss. Dysphagia can also lead to pneumonia because of aspiration of food contents (aspiration pneumonia), when food or liquids enter the airway due to dysfunctional swallowing. Bulbar symptoms can also include emotional lability characterized by episodes of sudden, uncontrollable, and inappropriate laughing or crying (pseudobulbar affect).Although the symptoms of ALS can begin at any time in adulthood, they most commonly manifest in individuals between 55 and 75 years old. Genetic forms of ALS with childhood onset are very rare. Early in the disease, patients can present with either or both upper and lower motor neuron symptoms. Symptoms most commonly begin in the extremities (spinal-onset ALS). Symptoms that develop in the limbs can affect either or both the upper and lower extremities and are typically more pronounced on one side (asymmetric) initially. Early on, the symptoms of ALS can be subtle and include slight muscle weakness, clumsy hand movements, and/or difficulty performing tasks that require delicate movements of the fingers and/or hands. Muscle weakness in the legs may cause tripping and falling. About a third of patients initially present with predominant bulbar symptoms (bulbar-onset ALS). More rarely, patients might initially present with breathing symptoms such as shortness of breath (dyspnea) because of weakness of the ventilatory muscles. ALS is a neurodegenerative disease, so the symptoms progress and become worse over time; muscles become more severely affected and additional muscles become involved. The disease may progress quickly or slowly. As ALS progresses, typically over the course of three to five years, the individual will gradually lose the ability to stand or walk. In time, many patients will require mechanical assistance to breath and are at increased risk for ventilatory failure. A small percentage of people with ALS experience a gradual stabilization of symptoms and may maintain that level (plateau) for a few months or rarely years.Although ALS is predominantly seen as a disease affecting motor neurons, non-motor symptoms can be observed in up to half of affected individuals. In fact, about 10% of patients are concurrently affected by a disease known as behavioral variant frontotemporal dementia (bvFTD) and can develop cognitive impairment and behavioral symptoms such as disinhibition, overeating and compulsive or inappropriate behavior (for more information on this disorder, choose “frontotemporal degeneration” as your search term in the Rare Disease Database). Other non-motor symptoms that can be seen in ALS include cognitive impairment and behavioral changes that are typically less marked than in patients with FTD, mood alterations such as depression and pseudobulbar affect (as described above). In addition, patients with ALS might be at an increased risk of developing blood clots due to decreased mobility. | Symptoms of Amyotrophic Lateral Sclerosis. ALS causes a combination of upper and lower motor neuron disease, and the symptoms vary depending on the muscle controlled by the affected neurons and whether upper or lower motor neurons are predominantly affected. The main manifestations of upper motor neuron disease are muscle weakness, increased muscle tone and stiffness (spasticity), increased reflexes (hyperreflexia), and abnormal speech and swallowing. Lower motor neuron disease causes muscle weakness and wasting (atrophy), decreased muscle tone, decreased reflexes (hyporeflexia), twitching of muscle fibers (fasciculations), muscle cramps, and abnormalities of speech, swallowing, and breathing. When ALS affects the limb and trunk muscles, it leads to symptoms such as difficulty walking or falls and difficulty performing activities of daily living. When ALS affects nerves of the head and neck (cranial nerves), it can leads to bulbar symptoms, which include difficulty swallowing (dysphagia) or speaking (dysarthria) and weakness of the muscles of the face or tongue. Dysphagia can lead to complications such as difficulty feeding, choking, excess saliva or drooling, and weight loss. Dysphagia can also lead to pneumonia because of aspiration of food contents (aspiration pneumonia), when food or liquids enter the airway due to dysfunctional swallowing. Bulbar symptoms can also include emotional lability characterized by episodes of sudden, uncontrollable, and inappropriate laughing or crying (pseudobulbar affect).Although the symptoms of ALS can begin at any time in adulthood, they most commonly manifest in individuals between 55 and 75 years old. Genetic forms of ALS with childhood onset are very rare. Early in the disease, patients can present with either or both upper and lower motor neuron symptoms. Symptoms most commonly begin in the extremities (spinal-onset ALS). Symptoms that develop in the limbs can affect either or both the upper and lower extremities and are typically more pronounced on one side (asymmetric) initially. Early on, the symptoms of ALS can be subtle and include slight muscle weakness, clumsy hand movements, and/or difficulty performing tasks that require delicate movements of the fingers and/or hands. Muscle weakness in the legs may cause tripping and falling. About a third of patients initially present with predominant bulbar symptoms (bulbar-onset ALS). More rarely, patients might initially present with breathing symptoms such as shortness of breath (dyspnea) because of weakness of the ventilatory muscles. ALS is a neurodegenerative disease, so the symptoms progress and become worse over time; muscles become more severely affected and additional muscles become involved. The disease may progress quickly or slowly. As ALS progresses, typically over the course of three to five years, the individual will gradually lose the ability to stand or walk. In time, many patients will require mechanical assistance to breath and are at increased risk for ventilatory failure. A small percentage of people with ALS experience a gradual stabilization of symptoms and may maintain that level (plateau) for a few months or rarely years.Although ALS is predominantly seen as a disease affecting motor neurons, non-motor symptoms can be observed in up to half of affected individuals. In fact, about 10% of patients are concurrently affected by a disease known as behavioral variant frontotemporal dementia (bvFTD) and can develop cognitive impairment and behavioral symptoms such as disinhibition, overeating and compulsive or inappropriate behavior (for more information on this disorder, choose “frontotemporal degeneration” as your search term in the Rare Disease Database). Other non-motor symptoms that can be seen in ALS include cognitive impairment and behavioral changes that are typically less marked than in patients with FTD, mood alterations such as depression and pseudobulbar affect (as described above). In addition, patients with ALS might be at an increased risk of developing blood clots due to decreased mobility. | 74 | Amyotrophic Lateral Sclerosis |
nord_74_2 | Causes of Amyotrophic Lateral Sclerosis | The underlying cause of sporadic ALS is not known. It is thought that dysfunction in a variety of interconnected molecular mechanisms contribute to the disease. These mechanisms include dysfunction of protein balance, folding and transport, excessive neuron stimulation (excitotoxicity), oxidative stress, neuroinflammation and dysfunction of mitochondria (the “powerhouse of the cell”). Ultimately, these anomalies lead to damage and death of motor neurons, hence leading to the symptoms of ALS. Only age and family history are clearly established risk factors for ALS.Approximately 10 percent of all cases of ALS are familial (hereditary). More than 25 genes have been associated with the disease. Most familial cases follow a dominant pattern of inheritance, although recessive or X-linked patterns of inheritance are also possible. However, some individuals with a disease-causing (pathogenic) genetic mutation will not develop the disease (incomplete penetrance). Age of onset and disease characteristics often cannot be precisely predicted based on the presence of a known genetic mutation.Familial ALS is most commonly caused by mutations in the C9ORF72 gene. This mutation can cause ALS, frontotemporal dementia (FTD), or both. The second most common cause of familial ALS is due to mutations in the SOD1 gene. Almost half of familial ALS cases are caused by mutations in SOD1 and C9ORF72 genes, and another 20% are caused by mutations in genes known as TARDBP and FUS. Mutations in these genes are all associated with dominant forms of familial ALS.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | Causes of Amyotrophic Lateral Sclerosis. The underlying cause of sporadic ALS is not known. It is thought that dysfunction in a variety of interconnected molecular mechanisms contribute to the disease. These mechanisms include dysfunction of protein balance, folding and transport, excessive neuron stimulation (excitotoxicity), oxidative stress, neuroinflammation and dysfunction of mitochondria (the “powerhouse of the cell”). Ultimately, these anomalies lead to damage and death of motor neurons, hence leading to the symptoms of ALS. Only age and family history are clearly established risk factors for ALS.Approximately 10 percent of all cases of ALS are familial (hereditary). More than 25 genes have been associated with the disease. Most familial cases follow a dominant pattern of inheritance, although recessive or X-linked patterns of inheritance are also possible. However, some individuals with a disease-causing (pathogenic) genetic mutation will not develop the disease (incomplete penetrance). Age of onset and disease characteristics often cannot be precisely predicted based on the presence of a known genetic mutation.Familial ALS is most commonly caused by mutations in the C9ORF72 gene. This mutation can cause ALS, frontotemporal dementia (FTD), or both. The second most common cause of familial ALS is due to mutations in the SOD1 gene. Almost half of familial ALS cases are caused by mutations in SOD1 and C9ORF72 genes, and another 20% are caused by mutations in genes known as TARDBP and FUS. Mutations in these genes are all associated with dominant forms of familial ALS.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | 74 | Amyotrophic Lateral Sclerosis |
nord_74_3 | Affects of Amyotrophic Lateral Sclerosis | ALS is a rare disorder that develops in 1.5 to 3 per 100,000 people every year in North American and European populations. Approximately 30,000 people are affected in the United States, with an estimated 5,000 new cases diagnosed each year. ALS affects more males than females, as about 60% of affected individuals are males. Further research on the epidemiology of ALS needs to be done, as the vast majority of epidemiologic research is centered on North American and European populations. | Affects of Amyotrophic Lateral Sclerosis. ALS is a rare disorder that develops in 1.5 to 3 per 100,000 people every year in North American and European populations. Approximately 30,000 people are affected in the United States, with an estimated 5,000 new cases diagnosed each year. ALS affects more males than females, as about 60% of affected individuals are males. Further research on the epidemiology of ALS needs to be done, as the vast majority of epidemiologic research is centered on North American and European populations. | 74 | Amyotrophic Lateral Sclerosis |
nord_74_4 | Related disorders of Amyotrophic Lateral Sclerosis | ALS VariantsThere are several subtypes of motor neuron disease that share some overlapping features and pathology with ALS. These motor neuron disease phenotypes are typically associated with a better prognosis compared to classical ALS. Biologically, it is unclear whether or not these entities exist on a continuum with ALS or if they represent distinctly different diseases.Primary lateral sclerosis (PLS) is a rare neurological disorder characterized by progressive loss of upper motor neurons. Upper motor neuron loss causes spasticity and weakness in the muscles of the arms and legs, which can present as unsteady walking, tripping, or difficulty using the hands or arms. Upper motor neuron loss in the bulbar muscles causes abnormalities of speech and swallowing, although bulbar symptoms are not typically the initial presenting symptom of PLS. PLS leads to progressive disability, but typically progresses much slower than ALS. Unlike in ALS, lower motor neurons are not affected in PLS. (For more information on this disorder, choose “Primary Lateral Sclerosis” as your search term in the Rare Disease Database.)Progressive muscular atrophy (PMA) involves progressive loss of lower motor neurons only. This disease is characterized by weakness and atrophy of the muscles, particularly the legs. Decreased tone and reflexes are noted on exam. If upper motor neuron symptoms do not occur within two years, then it is less likely that ALS will develop in the future.Focal or monomelic amyotrophy affects lower motor neurons in only one area of the body, most commonly in the muscles of the hand and arm. Affected muscles develop atrophy and weakness. Onset usually occurs in early adulthood. The disease often progresses over several months then leaves the patient with a fixed impairment of function.Other Related DisordersSymptoms of the following disorders can at times present with similar features to ALS. Comparisons may be useful for a differential diagnosis.Spinal muscular atrophy (SMA) is a group of rare inherited neurological disorders most often occurring in infancy and characterized by the progressive degeneration of lower motor neurons. SMA most commonly presents in infancy or childhood, but adult onset SMA may be considered in the differential diagnosis for patients presenting with predominantly lower motor neuron disease in the limbs. (For more information on this disorder, choose “Spinal Muscular Atrophy” as your search in the Rare Disease Database.)Multifocal motor neuropathy (MMN) is a rare disorder characterized by lower motor neuron dysfunction, primarily of the arms and legs. The disorder is considered to be immune-mediated, which means there is inflammation resulting from abnormal functioning of the immune system and the presence of specific autoantibodies that target a specific protein in the body. The term multifocal means “arising from two or more anatomical locations”. The disorder is acquired at some point during a person’s life; a person is not born with the disorder. Multifocal motor neuropathy usually responds to treatment with intravenous immunoglobulin (IVIG). MMN is considered in the differential diagnosis for patients presenting with limb weakness, particularly in the hands, and findings consistent with lower motor neuron dysfunction on exam. (For more information on this disorder, choose “Multifocal Motor Neuropathy” as your search in the Rare Disease Database.)The hereditary spastic paraplegias (HSP) are a large group of inherited disorders that primarily affect upper motor neurons. The primary symptom of HSP is difficulty walking due to muscle weakness and spasticity in the legs. There are more than 80 different genetic types of HSP. There may be significant variation in the severity of leg weakness (varying from none to marked), the degree of spasticity (varying from minimal to severe) and the occurrence of other neurologic symptoms between different genetic types of HSP, as well differences in the nature and severity of symptoms between individuals who have exactly the same genetic type of HSP. HSP is considered in the differential diagnosis for a patient presenting with a predominance of upper motor neuron symptoms, particularly in legs. (For more information on this disorder, choose “Hereditary Spastic Paraplegia” as your search in the Rare Disease Database.)Kennedy Disease or spinal bulbar muscular atrophy is a rare X-linked disorder causing progressive lower motor neuron disease and symptoms of androgen dysfunction in adult males. (For more information on this disorder, choose “Kennedy Disease” as your search in the Rare Disease Database.) | Related disorders of Amyotrophic Lateral Sclerosis. ALS VariantsThere are several subtypes of motor neuron disease that share some overlapping features and pathology with ALS. These motor neuron disease phenotypes are typically associated with a better prognosis compared to classical ALS. Biologically, it is unclear whether or not these entities exist on a continuum with ALS or if they represent distinctly different diseases.Primary lateral sclerosis (PLS) is a rare neurological disorder characterized by progressive loss of upper motor neurons. Upper motor neuron loss causes spasticity and weakness in the muscles of the arms and legs, which can present as unsteady walking, tripping, or difficulty using the hands or arms. Upper motor neuron loss in the bulbar muscles causes abnormalities of speech and swallowing, although bulbar symptoms are not typically the initial presenting symptom of PLS. PLS leads to progressive disability, but typically progresses much slower than ALS. Unlike in ALS, lower motor neurons are not affected in PLS. (For more information on this disorder, choose “Primary Lateral Sclerosis” as your search term in the Rare Disease Database.)Progressive muscular atrophy (PMA) involves progressive loss of lower motor neurons only. This disease is characterized by weakness and atrophy of the muscles, particularly the legs. Decreased tone and reflexes are noted on exam. If upper motor neuron symptoms do not occur within two years, then it is less likely that ALS will develop in the future.Focal or monomelic amyotrophy affects lower motor neurons in only one area of the body, most commonly in the muscles of the hand and arm. Affected muscles develop atrophy and weakness. Onset usually occurs in early adulthood. The disease often progresses over several months then leaves the patient with a fixed impairment of function.Other Related DisordersSymptoms of the following disorders can at times present with similar features to ALS. Comparisons may be useful for a differential diagnosis.Spinal muscular atrophy (SMA) is a group of rare inherited neurological disorders most often occurring in infancy and characterized by the progressive degeneration of lower motor neurons. SMA most commonly presents in infancy or childhood, but adult onset SMA may be considered in the differential diagnosis for patients presenting with predominantly lower motor neuron disease in the limbs. (For more information on this disorder, choose “Spinal Muscular Atrophy” as your search in the Rare Disease Database.)Multifocal motor neuropathy (MMN) is a rare disorder characterized by lower motor neuron dysfunction, primarily of the arms and legs. The disorder is considered to be immune-mediated, which means there is inflammation resulting from abnormal functioning of the immune system and the presence of specific autoantibodies that target a specific protein in the body. The term multifocal means “arising from two or more anatomical locations”. The disorder is acquired at some point during a person’s life; a person is not born with the disorder. Multifocal motor neuropathy usually responds to treatment with intravenous immunoglobulin (IVIG). MMN is considered in the differential diagnosis for patients presenting with limb weakness, particularly in the hands, and findings consistent with lower motor neuron dysfunction on exam. (For more information on this disorder, choose “Multifocal Motor Neuropathy” as your search in the Rare Disease Database.)The hereditary spastic paraplegias (HSP) are a large group of inherited disorders that primarily affect upper motor neurons. The primary symptom of HSP is difficulty walking due to muscle weakness and spasticity in the legs. There are more than 80 different genetic types of HSP. There may be significant variation in the severity of leg weakness (varying from none to marked), the degree of spasticity (varying from minimal to severe) and the occurrence of other neurologic symptoms between different genetic types of HSP, as well differences in the nature and severity of symptoms between individuals who have exactly the same genetic type of HSP. HSP is considered in the differential diagnosis for a patient presenting with a predominance of upper motor neuron symptoms, particularly in legs. (For more information on this disorder, choose “Hereditary Spastic Paraplegia” as your search in the Rare Disease Database.)Kennedy Disease or spinal bulbar muscular atrophy is a rare X-linked disorder causing progressive lower motor neuron disease and symptoms of androgen dysfunction in adult males. (For more information on this disorder, choose “Kennedy Disease” as your search in the Rare Disease Database.) | 74 | Amyotrophic Lateral Sclerosis |
nord_74_5 | Diagnosis of Amyotrophic Lateral Sclerosis | ALS is a clinical diagnosis. This means that no single test can reliably diagnose the disease. The diagnosis of ALS is therefore centered on a careful patient history and neurologic examination. Laboratory and imaging tests may be helpful to exclude other conditions depending on the clinical presentation. The diagnosis of ALS requires a history of progressive muscle weakness spreading to one or more anatomical regions and clinical evidence of upper and lower motor neuron disease, although only one type of motor neuron dysfunction might be predominant early in the disease course (see the Signs & Symptoms section above for more details on the clinical manifestations of upper and lower motor neuron disease). Electrodiagnostic studies such as electromyography (EMG) and nerve conduction studies (NCS), which evaluate transmission of nerve impulse to muscles and conduction of nerve impulse across neurons, can complement the physical examination and show further evidence of motor neuron dysfunction. Brain imaging, such as magnetic resonance imaging (MRI), is often performed in patients with suspected ALS. Although some level of brain atrophy can be seen in ALS, imaging is mostly performed to rule out other causes of motor neuron disease. Genetic testing is particularly helpful in cases of suspected familial ALS. Diagnostic delay is a common problem with ALS, with an average diagnostic delay of 1 year from symptom onset. | Diagnosis of Amyotrophic Lateral Sclerosis. ALS is a clinical diagnosis. This means that no single test can reliably diagnose the disease. The diagnosis of ALS is therefore centered on a careful patient history and neurologic examination. Laboratory and imaging tests may be helpful to exclude other conditions depending on the clinical presentation. The diagnosis of ALS requires a history of progressive muscle weakness spreading to one or more anatomical regions and clinical evidence of upper and lower motor neuron disease, although only one type of motor neuron dysfunction might be predominant early in the disease course (see the Signs & Symptoms section above for more details on the clinical manifestations of upper and lower motor neuron disease). Electrodiagnostic studies such as electromyography (EMG) and nerve conduction studies (NCS), which evaluate transmission of nerve impulse to muscles and conduction of nerve impulse across neurons, can complement the physical examination and show further evidence of motor neuron dysfunction. Brain imaging, such as magnetic resonance imaging (MRI), is often performed in patients with suspected ALS. Although some level of brain atrophy can be seen in ALS, imaging is mostly performed to rule out other causes of motor neuron disease. Genetic testing is particularly helpful in cases of suspected familial ALS. Diagnostic delay is a common problem with ALS, with an average diagnostic delay of 1 year from symptom onset. | 74 | Amyotrophic Lateral Sclerosis |
nord_74_6 | Therapies of Amyotrophic Lateral Sclerosis | TreatmentThe treatment of ALS generally requires a multidisciplinary team approach and should notably include neurologists, physical therapists, speech pathologists, pulmonologists, pulmonary therapists, medical social workers, nutritionists, psychologists and specialized nurses. Multidisciplinary care for ALS is associated with improved survival and patient satisfaction.There are two main components to ALS treatment: therapy that slows the progression of the disease (disease-modifying therapy) and therapy that helps manage symptoms and improve quality of life (supportive therapy). Unfortunately, there is no cure for ALS.Disease-modifying therapyThe drug riluzole (Rilutek) was the first drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALS. In clinical trials, riluzole was shown to prolong survival by an average of three to five months, although it did not substantially delay muscle deterioration. The other FDA approved disease-modifying therapy for ALS is edaravone (Radicava). It was shown to slow the rate of functional decline in certain patients with ALS. The benefits seem to be more pronounced in those with early ALS.In 2022, sodium phenylbutyrate/taurursodiol (Relyvrio) was FDA approved to treat patients with ALS. Symptomatic therapySymptomatic therapy of ALS has two main components: medications and non-pharmacological management.Several drugs may be used to help alleviate the symptoms of ALS. Muscle spasticity and fasciculations can be managed with muscle relaxants such as baclofen, tizanidine or diazepam. In some patients with severe and disabling spasticity, baclofen might be administered directly into the spinal canal (intrathecal administration) with a device known as an intrathecal pump. Some individuals with spasticity might also benefit from treatment with cannabinoids. Muscle cramps, which may be painful, can be treated with medications such as quinine sulfate, levetiracetam or mexiletine. Some patients with ALS might develop hypersalivation (sialorrhea) and be unable to manage pooling of secretions; this can be managed with medications such as atropine, scopolamine, amitriptyline, glycopyrrolate, or botulinum toxin injections. Oral suction devices can also be of benefit. Mood alterations such as depression or behavioral symptoms related to frontotemporal dementia can be managed with antidepressants such as selective serotonin reuptake inhibitors (SSRIs). Some patients with ALS may experience pain for different reasons, which can be managed with several medications depending on the type of pain.Physical and occupational therapy is very important and should consist of daily range-of- motion exercises. These exercises can help maintain the flexibility of affected joints and prevent the fixation of muscles (contractures). It is also essential that people with ALS maintain proper nutrition. Weight loss is an independent predictor of poor prognosis in ALS. Soft foods should be carefully chosen for patients who have dysphagia. When adequate nutrition and fluids cannot be maintained because of dysphagia, a gastric feeding tube can be considered. Speech therapy and augmentative communication devices can be useful for individuals with dysarthria.Once individuals develop ventilatory muscle weakness, non-invasive positive pressure ventilation (NIPPV) is beneficial to assist breathing. Cough assist devices are also useful to clear secretions. Eventually, ventilatory weakness progresses to the point where patients cannot breathe on their own and some patients will choose to pursue tracheostomy and permanent mechanical ventilation. For patients who decide against mechanical ventilation, home hospice services can provide supportive care and assist with comfort measures. | Therapies of Amyotrophic Lateral Sclerosis. TreatmentThe treatment of ALS generally requires a multidisciplinary team approach and should notably include neurologists, physical therapists, speech pathologists, pulmonologists, pulmonary therapists, medical social workers, nutritionists, psychologists and specialized nurses. Multidisciplinary care for ALS is associated with improved survival and patient satisfaction.There are two main components to ALS treatment: therapy that slows the progression of the disease (disease-modifying therapy) and therapy that helps manage symptoms and improve quality of life (supportive therapy). Unfortunately, there is no cure for ALS.Disease-modifying therapyThe drug riluzole (Rilutek) was the first drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALS. In clinical trials, riluzole was shown to prolong survival by an average of three to five months, although it did not substantially delay muscle deterioration. The other FDA approved disease-modifying therapy for ALS is edaravone (Radicava). It was shown to slow the rate of functional decline in certain patients with ALS. The benefits seem to be more pronounced in those with early ALS.In 2022, sodium phenylbutyrate/taurursodiol (Relyvrio) was FDA approved to treat patients with ALS. Symptomatic therapySymptomatic therapy of ALS has two main components: medications and non-pharmacological management.Several drugs may be used to help alleviate the symptoms of ALS. Muscle spasticity and fasciculations can be managed with muscle relaxants such as baclofen, tizanidine or diazepam. In some patients with severe and disabling spasticity, baclofen might be administered directly into the spinal canal (intrathecal administration) with a device known as an intrathecal pump. Some individuals with spasticity might also benefit from treatment with cannabinoids. Muscle cramps, which may be painful, can be treated with medications such as quinine sulfate, levetiracetam or mexiletine. Some patients with ALS might develop hypersalivation (sialorrhea) and be unable to manage pooling of secretions; this can be managed with medications such as atropine, scopolamine, amitriptyline, glycopyrrolate, or botulinum toxin injections. Oral suction devices can also be of benefit. Mood alterations such as depression or behavioral symptoms related to frontotemporal dementia can be managed with antidepressants such as selective serotonin reuptake inhibitors (SSRIs). Some patients with ALS may experience pain for different reasons, which can be managed with several medications depending on the type of pain.Physical and occupational therapy is very important and should consist of daily range-of- motion exercises. These exercises can help maintain the flexibility of affected joints and prevent the fixation of muscles (contractures). It is also essential that people with ALS maintain proper nutrition. Weight loss is an independent predictor of poor prognosis in ALS. Soft foods should be carefully chosen for patients who have dysphagia. When adequate nutrition and fluids cannot be maintained because of dysphagia, a gastric feeding tube can be considered. Speech therapy and augmentative communication devices can be useful for individuals with dysarthria.Once individuals develop ventilatory muscle weakness, non-invasive positive pressure ventilation (NIPPV) is beneficial to assist breathing. Cough assist devices are also useful to clear secretions. Eventually, ventilatory weakness progresses to the point where patients cannot breathe on their own and some patients will choose to pursue tracheostomy and permanent mechanical ventilation. For patients who decide against mechanical ventilation, home hospice services can provide supportive care and assist with comfort measures. | 74 | Amyotrophic Lateral Sclerosis |
nord_75_0 | Overview of Anaplastic Astrocytoma | Anaplastic astrocytoma is a rare malignant brain tumor. Astrocytomas are tumors that develop from certain star-shaped brain cells called astrocytes. Astrocytes and similar cells form tissue that surrounds and protects other nerve cells found within the brain and spinal cord. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from glial tissue, including astrocytomas, are collectively referred to as gliomas. The symptoms of anaplastic astrocytomas vary depending upon the specific location and size of the tumor. The specific cause of this tumor is unknown.Astrocytomas are classified according to a grading system developed by the World Health Organization (WHO). Astrocytomas come in four grades based upon how fast the cells are reproducing and that likelihood that they will spread (infiltrate) nearby tissue. Grades I or II astrocytomas are nonmalignant and may be referred to as low-grade. Grades III and IV astrocytomas are malignant and may be referred to as high-grade astrocytomas. Anaplastic astrocytomas are grade III astrocytomas. Grade IV astrocytomas are known as glioblastoma multiforme. Lower grade astrocytomas can change into higher grade astrocytomas over time. | Overview of Anaplastic Astrocytoma. Anaplastic astrocytoma is a rare malignant brain tumor. Astrocytomas are tumors that develop from certain star-shaped brain cells called astrocytes. Astrocytes and similar cells form tissue that surrounds and protects other nerve cells found within the brain and spinal cord. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from glial tissue, including astrocytomas, are collectively referred to as gliomas. The symptoms of anaplastic astrocytomas vary depending upon the specific location and size of the tumor. The specific cause of this tumor is unknown.Astrocytomas are classified according to a grading system developed by the World Health Organization (WHO). Astrocytomas come in four grades based upon how fast the cells are reproducing and that likelihood that they will spread (infiltrate) nearby tissue. Grades I or II astrocytomas are nonmalignant and may be referred to as low-grade. Grades III and IV astrocytomas are malignant and may be referred to as high-grade astrocytomas. Anaplastic astrocytomas are grade III astrocytomas. Grade IV astrocytomas are known as glioblastoma multiforme. Lower grade astrocytomas can change into higher grade astrocytomas over time. | 75 | Anaplastic Astrocytoma |
nord_75_1 | Symptoms of Anaplastic Astrocytoma | The symptoms of anaplastic astrocytoma vary depending upon the exact location and size of the tumor. Most symptoms result from increased pressure within the brain. An anaplastic astrocytoma usually develops slowly over time, but may develop rapidly.Increased pressure within the brain may be caused by the tumor itself or by blockage of the fluid-filled spaces in the brain called ventricles, which results in the abnormal accumulation of cerebrospinal fluid (CSF) in the brain. Symptoms commonly associated with anaplastic astrocytomas include headaches, lethargy or drowsiness, vomiting, and changes in personality or mental status. In some cases, seizures, vision problems, weakness of the arms and legs resulting in coordination difficulties may also occur.More specific symptoms relate to the area of brain where the tumor is located. Anaplastic astrocytomas may develop in any area of the central nervous system, although there is a strong preference for the large rounded portion of the brain (cerebrum) that occupies most of the skull. The cerebrum is divided into two halves known as the cerebral hemispheres. Anaplastic astrocytomas may develop in the frontal, temporal, parietal and occipital lobes of the cerebrum.A tumor in the frontal lobe may cause memory problems, changes in personality and mood, and paralysis (hemiplegia) on the side of the body opposite of the tumor. Tumors in the temporal lobe may cause seizures, memory problems, and problems with coordination and speech. Tumors in the parietal lobe may cause difficulties with communication through writing (agraphia), problems with fine motor skills, or sensory abnormalities such as tingling or burning sensations (paresthesias). Tumors in the occipital lobe can cause visual loss.Other common sites for anaplastic astrocytomas include the part of the brain that contains the thalamus and hypothalamus (diencephalon), the lower area of brain near the back of the neck that controls movement and balance (cerebellum), and the spinal cord. Tumors in the diencephalon region may cause headaches, fatigue, weakness of the arms and legs, vision problems, and hormonal imbalances. Tumors in the cerebellum may cause headaches, changes in personality or behavior, and balance problems. Tumors of spinal cord may cause back pain, sensory abnormalities such as tingling or burning sensations (paresthesias), weakness, and gait disturbances. | Symptoms of Anaplastic Astrocytoma. The symptoms of anaplastic astrocytoma vary depending upon the exact location and size of the tumor. Most symptoms result from increased pressure within the brain. An anaplastic astrocytoma usually develops slowly over time, but may develop rapidly.Increased pressure within the brain may be caused by the tumor itself or by blockage of the fluid-filled spaces in the brain called ventricles, which results in the abnormal accumulation of cerebrospinal fluid (CSF) in the brain. Symptoms commonly associated with anaplastic astrocytomas include headaches, lethargy or drowsiness, vomiting, and changes in personality or mental status. In some cases, seizures, vision problems, weakness of the arms and legs resulting in coordination difficulties may also occur.More specific symptoms relate to the area of brain where the tumor is located. Anaplastic astrocytomas may develop in any area of the central nervous system, although there is a strong preference for the large rounded portion of the brain (cerebrum) that occupies most of the skull. The cerebrum is divided into two halves known as the cerebral hemispheres. Anaplastic astrocytomas may develop in the frontal, temporal, parietal and occipital lobes of the cerebrum.A tumor in the frontal lobe may cause memory problems, changes in personality and mood, and paralysis (hemiplegia) on the side of the body opposite of the tumor. Tumors in the temporal lobe may cause seizures, memory problems, and problems with coordination and speech. Tumors in the parietal lobe may cause difficulties with communication through writing (agraphia), problems with fine motor skills, or sensory abnormalities such as tingling or burning sensations (paresthesias). Tumors in the occipital lobe can cause visual loss.Other common sites for anaplastic astrocytomas include the part of the brain that contains the thalamus and hypothalamus (diencephalon), the lower area of brain near the back of the neck that controls movement and balance (cerebellum), and the spinal cord. Tumors in the diencephalon region may cause headaches, fatigue, weakness of the arms and legs, vision problems, and hormonal imbalances. Tumors in the cerebellum may cause headaches, changes in personality or behavior, and balance problems. Tumors of spinal cord may cause back pain, sensory abnormalities such as tingling or burning sensations (paresthesias), weakness, and gait disturbances. | 75 | Anaplastic Astrocytoma |
nord_75_2 | Causes of Anaplastic Astrocytoma | The exact cause of anaplastic astrocytomas is unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.Astrocytomas occur with greater frequency in certain genetic disorders including neurofibromatosis type I, Li-Fraumeni syndrome, and tuberous sclerosis. Except in these rare disorders, the vast majority of astrocytomas are not passed on to offspring with greater frequency. Researchers believe that some individuals may have a genetic predisposition to developing an astrocytoma. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. | Causes of Anaplastic Astrocytoma. The exact cause of anaplastic astrocytomas is unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.Astrocytomas occur with greater frequency in certain genetic disorders including neurofibromatosis type I, Li-Fraumeni syndrome, and tuberous sclerosis. Except in these rare disorders, the vast majority of astrocytomas are not passed on to offspring with greater frequency. Researchers believe that some individuals may have a genetic predisposition to developing an astrocytoma. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. | 75 | Anaplastic Astrocytoma |
nord_75_3 | Affects of Anaplastic Astrocytoma | Anaplastic astrocytomas affect males slightly more often than females. The exact incidence of these tumors is unknown. Anaplastic astrocytoma and glioblastoma multiforme are estimated to affect 5-8 people per 100,000 in the general population. Anaplastic astrocytomas are more common in adults than children. In adults, anaplastic astrocytomas usually develop between 30 and 50 years of age. Astrocytomas and a related tumor (oligodendroglioma) are the most common primary brain tumors in adults.In children, anaplastic astrocytomas usually develop between 5 and 9 years of age. Malignant astrocytomas (i.e., anaplastic astrocytoma and glioblastoma multiforme) account for approximately 10 percent of childhood central nervous stem tumors. Astrocytomas as a whole account for more than half of all primary childhood tumors of the central nervous system. Most astrocytomas (approximately 80 percent) in children are low grade. | Affects of Anaplastic Astrocytoma. Anaplastic astrocytomas affect males slightly more often than females. The exact incidence of these tumors is unknown. Anaplastic astrocytoma and glioblastoma multiforme are estimated to affect 5-8 people per 100,000 in the general population. Anaplastic astrocytomas are more common in adults than children. In adults, anaplastic astrocytomas usually develop between 30 and 50 years of age. Astrocytomas and a related tumor (oligodendroglioma) are the most common primary brain tumors in adults.In children, anaplastic astrocytomas usually develop between 5 and 9 years of age. Malignant astrocytomas (i.e., anaplastic astrocytoma and glioblastoma multiforme) account for approximately 10 percent of childhood central nervous stem tumors. Astrocytomas as a whole account for more than half of all primary childhood tumors of the central nervous system. Most astrocytomas (approximately 80 percent) in children are low grade. | 75 | Anaplastic Astrocytoma |
nord_75_4 | Related disorders of Anaplastic Astrocytoma | Symptoms of the following disorders can be similar to those of anaplastic astrocytoma. Comparisons may be useful for a differential diagnosis.Other brain tumors must be distinguished from anaplastic astrocytomas. Such tumors include metastatic tumors, lymphomas, hemangioblastoma,s craniopharyngiomas, teratomas, ependymomas, and medulloblastomas. Additional conditions that may resemble an anaplastic astrocytoma include inflammation of the membranes (meninges) that surround the brain and spinal cord (meningitis) and pseudotumor cerebri (benign intracranial hypertension). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Anaplastic Astrocytoma. Symptoms of the following disorders can be similar to those of anaplastic astrocytoma. Comparisons may be useful for a differential diagnosis.Other brain tumors must be distinguished from anaplastic astrocytomas. Such tumors include metastatic tumors, lymphomas, hemangioblastoma,s craniopharyngiomas, teratomas, ependymomas, and medulloblastomas. Additional conditions that may resemble an anaplastic astrocytoma include inflammation of the membranes (meninges) that surround the brain and spinal cord (meningitis) and pseudotumor cerebri (benign intracranial hypertension). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 75 | Anaplastic Astrocytoma |
nord_75_5 | Diagnosis of Anaplastic Astrocytoma | A diagnosis of anaplastic astrocytoma is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of imaging techniques including computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Such imaging techniques may also be used to may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures.Surgical removal and microscopic evaluation (biopsy) of tissue from a tumor may confirm a diagnosis. | Diagnosis of Anaplastic Astrocytoma. A diagnosis of anaplastic astrocytoma is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of imaging techniques including computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Such imaging techniques may also be used to may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures.Surgical removal and microscopic evaluation (biopsy) of tissue from a tumor may confirm a diagnosis. | 75 | Anaplastic Astrocytoma |
nord_75_6 | Therapies of Anaplastic Astrocytoma | TreatmentThe therapeutic management of individuals with an anaplastic astrocytoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, neurologists, oncology nurses, and other health care specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites (which rarely occurs with astrocytomas); an individual's age and general health; and/or other elements. 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 the case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.The three main forms of treatment for anaplastic astrocytoma are surgery, radiation and chemotherapy. These treatments may be used alone or in combination with one another. The initial treatment in most cases is surgical excision and removal of as much as the tumor as possible (resection). Sometimes, only a portion of the tumor can be safely removed because malignant cells may have spread into surrounding brain tissue. Because surgery often cannot completely remove a tumor, radiation therapy and chemotherapy are usually used following surgery to continue treatment.Postoperative radiation to help treat known or possible residual disease is frequently used in anaplastic astrocytomas. If initial surgery is not an option due to the specific location and/or progression of the malignancy, therapy may include radiation alone. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. However, some healthy cells (e.g., hair follicles, bone marrow, etc.) may also be damaged, leading to certain side effects. Thus, during such therapy, the radiation is passed through diseased tissue in carefully calculated dosages to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages their genetic material, preventing or slowing their growth and replication.Therapy with certain anticancer drugs (chemotherapy) may also be used to treat individuals with anaplastic astrocytoma. Only one chemotherapeutic agent has been approved for adults with anaplastic astrocytoma. No agents are approved for use in children. Most chemotherapeutic agents have demonstrated only limited effectiveness for treating individuals with anaplastic astrocytoma.The Food and Drug Administration (FDA) has approved temozolomide (Temodar) for the treatment of adults with anaplastic astrocytoma that has not responded to other forms of therapy (refractory anaplastic astrocytoma). Temodar is manufactured by the Schering-Plough Corporation. | Therapies of Anaplastic Astrocytoma. TreatmentThe therapeutic management of individuals with an anaplastic astrocytoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, neurologists, oncology nurses, and other health care specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites (which rarely occurs with astrocytomas); an individual's age and general health; and/or other elements. 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 the case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.The three main forms of treatment for anaplastic astrocytoma are surgery, radiation and chemotherapy. These treatments may be used alone or in combination with one another. The initial treatment in most cases is surgical excision and removal of as much as the tumor as possible (resection). Sometimes, only a portion of the tumor can be safely removed because malignant cells may have spread into surrounding brain tissue. Because surgery often cannot completely remove a tumor, radiation therapy and chemotherapy are usually used following surgery to continue treatment.Postoperative radiation to help treat known or possible residual disease is frequently used in anaplastic astrocytomas. If initial surgery is not an option due to the specific location and/or progression of the malignancy, therapy may include radiation alone. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. However, some healthy cells (e.g., hair follicles, bone marrow, etc.) may also be damaged, leading to certain side effects. Thus, during such therapy, the radiation is passed through diseased tissue in carefully calculated dosages to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages their genetic material, preventing or slowing their growth and replication.Therapy with certain anticancer drugs (chemotherapy) may also be used to treat individuals with anaplastic astrocytoma. Only one chemotherapeutic agent has been approved for adults with anaplastic astrocytoma. No agents are approved for use in children. Most chemotherapeutic agents have demonstrated only limited effectiveness for treating individuals with anaplastic astrocytoma.The Food and Drug Administration (FDA) has approved temozolomide (Temodar) for the treatment of adults with anaplastic astrocytoma that has not responded to other forms of therapy (refractory anaplastic astrocytoma). Temodar is manufactured by the Schering-Plough Corporation. | 75 | Anaplastic Astrocytoma |
nord_76_0 | Overview of Andersen Disease (GSD IV) | Andersen disease belongs to a group of rare genetic disorders of glycogen metabolism, known as glycogen storage diseases. Glycogen is a complex carbohydrate that is converted into the simple sugar glucose for the body's use as energy. Glycogen storage diseases are characterized by deficiencies of certain enzymes involved in the metabolism of glycogen, leading to an accumulation of abnormal forms or amounts of glycogen in various parts of the body, particularly the liver and muscle.Andersen disease is also known as glycogen storage disease (GSD) type IV. It is caused by deficient activity of the glycogen-branching enzyme, resulting in accumulation of abnormal glycogen in the liver, muscle, and/or other tissues. In most affected individuals, symptoms and findings become evident in the first months of life. Such features typically include failure to grow and gain weight at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly). In such cases, the disease course is typically characterized by progressive liver (hepatic) scarring (cirrhosis) and liver failure, leading to potentially life-threatening complications. In rare cases, however, progressive liver disease may not develop. In addition, several neuromuscular variants of Andersen disease have been described that may be evident at birth, in late childhood, or adulthood. The disease is inherited as an autosomal recessive trait.Andersen disease is named for the investigator (DH Andersen) who initially described the disease in 1956. | Overview of Andersen Disease (GSD IV). Andersen disease belongs to a group of rare genetic disorders of glycogen metabolism, known as glycogen storage diseases. Glycogen is a complex carbohydrate that is converted into the simple sugar glucose for the body's use as energy. Glycogen storage diseases are characterized by deficiencies of certain enzymes involved in the metabolism of glycogen, leading to an accumulation of abnormal forms or amounts of glycogen in various parts of the body, particularly the liver and muscle.Andersen disease is also known as glycogen storage disease (GSD) type IV. It is caused by deficient activity of the glycogen-branching enzyme, resulting in accumulation of abnormal glycogen in the liver, muscle, and/or other tissues. In most affected individuals, symptoms and findings become evident in the first months of life. Such features typically include failure to grow and gain weight at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly). In such cases, the disease course is typically characterized by progressive liver (hepatic) scarring (cirrhosis) and liver failure, leading to potentially life-threatening complications. In rare cases, however, progressive liver disease may not develop. In addition, several neuromuscular variants of Andersen disease have been described that may be evident at birth, in late childhood, or adulthood. The disease is inherited as an autosomal recessive trait.Andersen disease is named for the investigator (DH Andersen) who initially described the disease in 1956. | 76 | Andersen Disease (GSD IV) |
nord_76_1 | Symptoms of Andersen Disease (GSD IV) | Andersen disease is a multisystem disorder that may affect the liver, voluntary (skeletal) muscles, the heart, the nervous system, and other bodily tissues. Disease nature and course may vary in several aspects, including age at onset, associated symptoms and signs, degree of abnormal glycogen accumulation in various tissues, and specific organs affected. However, the most common, classic form of the disease is typically characterized by progressive internal scarring (fibrosis) and destruction of liver tissue (cirrhosis), leaving areas of nonfunctioning scar tissue and gradually impaired liver function. In such cases, the disease typically becomes evident during infancy or up to about 18 months of age. Initial symptoms and signs commonly include failure to grow and gain weight at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly). The cirrhosis typically progresses to cause high blood pressure in veins from the spleen and intestines to the liver (portal hypertension); abnormal fluid accumulation in the abdomen (ascites); enlargement of veins in the wall of the esophagus (esophageal varices), which may rupture, resulting in coughing up or vomiting of blood; and liver failure. In some cases, initial symptoms and findings associated with cirrhosis may include yellowish discoloration of the skin, mucous membranes, and whites of the eyes (jaundice); mental confusion; and/or other abnormalities. Rarely, liver cirrhosis associated with Andersen disease may also lead to abnormally reduced blood glucose levels (hypoglycemia). In most individuals with classic Andersen disease, progressive liver disease may lead to liver transplantation or potentially life-threatening complications by approximately age five years. However, some rare cases have also been reported in which affected individuals have nonprogressive liver disease. In some of these cases, mildly affected individuals may not have apparent symptoms (asymptomatic). Several neuromuscular variants of Andersen disease have also been described in the medical literature. Most commonly, there may be primary or isolated muscle involvement beginning in late childhood, with disease of skeletal and/or heart muscle (myopathy and/or cardiomyopathy). Accumulation of abnormal glycogen in skeletal muscle may lead to muscle weakness and fatigue, exercise intolerance, muscle wasting (atrophy), and/or other symptoms and findings. In those with cardiomyopathy, weakening of heart muscle may lead to stretching and enlargement (dilation) of the heart's lower chambers (ventricles). Dilated cardiomyopathy may gradually lead to weakening of the heart's pumping action, causing an impaired ability to circulate enough blood to meet the body's requirements for oxygen (heart failure). Associated symptoms and findings may include fatigue; irritability; feeding difficulties; lack of appetite; failure to thrive; shortness of breath with exertion and eventually at rest; an abnormal accumulation of fluid in body tissues (edema); abnormalities of heart rhythm (arrhythmias); and potentially life-threatening complications in some cases.A neuromuscular variant has also been reported that is evident at birth. This form may be characterized by generalized edema (hydrops), severely diminished skeletal muscle tone (hypotonia), muscle weakness and atrophy, bending or extension of multiple joints in various fixed postures (contractures), and neurologic involvement, leading to potentially life-threatening complications early in life. In addition, a rare neuromuscular variant has also been described in adults. This form of the disease, so-called adult polyglucosan body disease, may be characterized by dysfunction of the central and peripheral nervous systems. The central nervous system (CNS) refers to the brain and spinal cord. The peripheral nerves extend from the CNS to muscles, glands, skin, sensory organs, and internal organs. Peripheral nerves include motor nerves; sensory nerves; and nerves of the autonomic nervous system, which are involved in involuntary functions, including regulating blood pressure, temperature, and heart rate. In individuals with adult polyglucosan body disease, associated symptoms and findings may include sensory loss in the legs; progressive muscle weakness of the arms and legs; walking (gait) disturbances; urination difficulties; mild cognitive impairment or dementia; and/or other abnormalities. | Symptoms of Andersen Disease (GSD IV). Andersen disease is a multisystem disorder that may affect the liver, voluntary (skeletal) muscles, the heart, the nervous system, and other bodily tissues. Disease nature and course may vary in several aspects, including age at onset, associated symptoms and signs, degree of abnormal glycogen accumulation in various tissues, and specific organs affected. However, the most common, classic form of the disease is typically characterized by progressive internal scarring (fibrosis) and destruction of liver tissue (cirrhosis), leaving areas of nonfunctioning scar tissue and gradually impaired liver function. In such cases, the disease typically becomes evident during infancy or up to about 18 months of age. Initial symptoms and signs commonly include failure to grow and gain weight at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly). The cirrhosis typically progresses to cause high blood pressure in veins from the spleen and intestines to the liver (portal hypertension); abnormal fluid accumulation in the abdomen (ascites); enlargement of veins in the wall of the esophagus (esophageal varices), which may rupture, resulting in coughing up or vomiting of blood; and liver failure. In some cases, initial symptoms and findings associated with cirrhosis may include yellowish discoloration of the skin, mucous membranes, and whites of the eyes (jaundice); mental confusion; and/or other abnormalities. Rarely, liver cirrhosis associated with Andersen disease may also lead to abnormally reduced blood glucose levels (hypoglycemia). In most individuals with classic Andersen disease, progressive liver disease may lead to liver transplantation or potentially life-threatening complications by approximately age five years. However, some rare cases have also been reported in which affected individuals have nonprogressive liver disease. In some of these cases, mildly affected individuals may not have apparent symptoms (asymptomatic). Several neuromuscular variants of Andersen disease have also been described in the medical literature. Most commonly, there may be primary or isolated muscle involvement beginning in late childhood, with disease of skeletal and/or heart muscle (myopathy and/or cardiomyopathy). Accumulation of abnormal glycogen in skeletal muscle may lead to muscle weakness and fatigue, exercise intolerance, muscle wasting (atrophy), and/or other symptoms and findings. In those with cardiomyopathy, weakening of heart muscle may lead to stretching and enlargement (dilation) of the heart's lower chambers (ventricles). Dilated cardiomyopathy may gradually lead to weakening of the heart's pumping action, causing an impaired ability to circulate enough blood to meet the body's requirements for oxygen (heart failure). Associated symptoms and findings may include fatigue; irritability; feeding difficulties; lack of appetite; failure to thrive; shortness of breath with exertion and eventually at rest; an abnormal accumulation of fluid in body tissues (edema); abnormalities of heart rhythm (arrhythmias); and potentially life-threatening complications in some cases.A neuromuscular variant has also been reported that is evident at birth. This form may be characterized by generalized edema (hydrops), severely diminished skeletal muscle tone (hypotonia), muscle weakness and atrophy, bending or extension of multiple joints in various fixed postures (contractures), and neurologic involvement, leading to potentially life-threatening complications early in life. In addition, a rare neuromuscular variant has also been described in adults. This form of the disease, so-called adult polyglucosan body disease, may be characterized by dysfunction of the central and peripheral nervous systems. The central nervous system (CNS) refers to the brain and spinal cord. The peripheral nerves extend from the CNS to muscles, glands, skin, sensory organs, and internal organs. Peripheral nerves include motor nerves; sensory nerves; and nerves of the autonomic nervous system, which are involved in involuntary functions, including regulating blood pressure, temperature, and heart rate. In individuals with adult polyglucosan body disease, associated symptoms and findings may include sensory loss in the legs; progressive muscle weakness of the arms and legs; walking (gait) disturbances; urination difficulties; mild cognitive impairment or dementia; and/or other abnormalities. | 76 | Andersen Disease (GSD IV) |
nord_76_2 | Causes of Andersen Disease (GSD IV) | As noted above, Andersen disease is a disorder of glycogen metabolism. Metabolism refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones and processes in which complex substances are built up from simpler ones. Metabolic disorders result from abnormal functioning of a specific protein or enzyme that accelerates particular chemical activities in the body. Glycogen is the major carbohydrate stored in cells of the body. It is a complex carbohydrate (polysaccharide) made up of several sugar molecules that are linked together, forming a long chain. Glycogen, which is stored primarily in the liver and muscles, is converted into the simple sugar (monosaccharide) glucose and released into the bloodstream as needed. When blood sugar levels are increased, the excess is converted into glycogen for storage. Glucose is the body's primary source of energy for cell metabolism. Andersen disease is characterized by deficient activity of the glycogen-branching enzyme or GBE (which normally serves to increase the number of branch points during the formation of glycogen). In most cases, deficient GBE activity leads to a generalized accumulation of structurally abnormal glycogen (i.e., with long, unbranched outer chains) in various body tissues. Such tissue deposition has been demonstrated within the liver, muscle, nerve cells, heart, intestines, skin, etc. Andersen disease is sometimes called amylopectinosis since the abnormal glycogen is similar in structure to another complex carbohydrate known as amylopectin.Various specific mutations of the GBE gene have been identified in people with Andersen disease, including individuals with the classic hepatic form, those with nonprogressive liver disease, and newborns with the severe neuromuscular form. Further research is needed to determine whether certain mutations may be associated with particular variants of the disease.Andersen disease is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, 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 receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. 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. | Causes of Andersen Disease (GSD IV). As noted above, Andersen disease is a disorder of glycogen metabolism. Metabolism refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones and processes in which complex substances are built up from simpler ones. Metabolic disorders result from abnormal functioning of a specific protein or enzyme that accelerates particular chemical activities in the body. Glycogen is the major carbohydrate stored in cells of the body. It is a complex carbohydrate (polysaccharide) made up of several sugar molecules that are linked together, forming a long chain. Glycogen, which is stored primarily in the liver and muscles, is converted into the simple sugar (monosaccharide) glucose and released into the bloodstream as needed. When blood sugar levels are increased, the excess is converted into glycogen for storage. Glucose is the body's primary source of energy for cell metabolism. Andersen disease is characterized by deficient activity of the glycogen-branching enzyme or GBE (which normally serves to increase the number of branch points during the formation of glycogen). In most cases, deficient GBE activity leads to a generalized accumulation of structurally abnormal glycogen (i.e., with long, unbranched outer chains) in various body tissues. Such tissue deposition has been demonstrated within the liver, muscle, nerve cells, heart, intestines, skin, etc. Andersen disease is sometimes called amylopectinosis since the abnormal glycogen is similar in structure to another complex carbohydrate known as amylopectin.Various specific mutations of the GBE gene have been identified in people with Andersen disease, including individuals with the classic hepatic form, those with nonprogressive liver disease, and newborns with the severe neuromuscular form. Further research is needed to determine whether certain mutations may be associated with particular variants of the disease.Andersen disease is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, 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 receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. 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. | 76 | Andersen Disease (GSD IV) |
nord_76_3 | Affects of Andersen Disease (GSD IV) | As noted above, the classic hepatic form of Andersen disease typically becomes apparent during the first months of life. However, other forms of the disease have also been described that may be evident at birth, during late childhood, or in adulthood. Males and females appear to be affected in relatively equal numbers.The frequency of all glycogen storage diseases is estimated to be one in approximately 20,000 to 25,000 live births. However, some investigators suggest that the true frequency may be higher, since some individuals with certain forms of glycogen storage disease may have minimal symptoms that remain undiagnosed. | Affects of Andersen Disease (GSD IV). As noted above, the classic hepatic form of Andersen disease typically becomes apparent during the first months of life. However, other forms of the disease have also been described that may be evident at birth, during late childhood, or in adulthood. Males and females appear to be affected in relatively equal numbers.The frequency of all glycogen storage diseases is estimated to be one in approximately 20,000 to 25,000 live births. However, some investigators suggest that the true frequency may be higher, since some individuals with certain forms of glycogen storage disease may have minimal symptoms that remain undiagnosed. | 76 | Andersen Disease (GSD IV) |
nord_76_4 | Related disorders of Andersen Disease (GSD IV) | Symptoms of the following disorders may be similar to those of Andersen disease. Comparisons may be useful for a differential diagnosis: There are a number of other diseases and conditions that may be characterized by certain symptoms and signs similar to those potentially associated with Andersen disease. These include additional disorders of glycogen metabolism (i.e., glycogen storage diseases). As noted above, these diseases are due to deficiency of one or more enzymes involved in the formation or breakdown of glycogen, resulting in the accumulation of abnormal amounts or forms of glycogen within certain body tissues, particularly the liver, skeletal muscle, and/or heart muscle. Most of these diseases are inherited as an autosomal recessive trait. (For further information, please choose the exact disease name in question or “glycogen storage disease” as your search term in the Rare Disease Database.) | Related disorders of Andersen Disease (GSD IV). Symptoms of the following disorders may be similar to those of Andersen disease. Comparisons may be useful for a differential diagnosis: There are a number of other diseases and conditions that may be characterized by certain symptoms and signs similar to those potentially associated with Andersen disease. These include additional disorders of glycogen metabolism (i.e., glycogen storage diseases). As noted above, these diseases are due to deficiency of one or more enzymes involved in the formation or breakdown of glycogen, resulting in the accumulation of abnormal amounts or forms of glycogen within certain body tissues, particularly the liver, skeletal muscle, and/or heart muscle. Most of these diseases are inherited as an autosomal recessive trait. (For further information, please choose the exact disease name in question or “glycogen storage disease” as your search term in the Rare Disease Database.) | 76 | Andersen Disease (GSD IV) |
nord_76_5 | Diagnosis of Andersen Disease (GSD IV) | Andersen disease is usually diagnosed or confirmed after birth (postnatally) during infancy or childhood (or, in some cases, adulthood), based upon a thorough clinical evaluation; identification of characteristic physical findings; a complete patient and family history; and the results of various specialized tests. Removal (biopsy) and microscopic examination of small samples of certain tissues (e.g., liver, skeletal muscle, heart, skin, peripheral nerve) may demonstrate abnormal deposition of amylopectin-like materials. However, testing to confirm a diagnosis of Andersen disease requires detection of deficient GBE activity (indirect enzyme assay), such as in liver tissue, muscle, certain skin cells (cultured fibroblasts), white blood cells (leukocytes), red blood cells (erythrocytes), nerve cells, or other tissues. Reports indicate that, for individuals with adult polyglucosan body disease, peripheral nerve biopsy or evaluation of leukocytes is required for diagnosis, since deficient GBE activity is limited to such tissues. In addition, partial GBE deficiency may be detected (e.g., in erythrocytes, leukocytes, fibroblasts) in individuals who carry one copy of a mutated gene for Andersen disease (heterozygous carriers).Diagnostic evaluation typically includes various studies to help detect and characterize certain abnormalities that may be associated with the disorder. Such testing may include various laboratory studies (e.g., complete blood count; liver function tests; blood glucose studies; etc.); specialized imaging techniques (e.g., abdominal ultrasound, CT scanning, and/or MRI); testing that records electrical activity in skeletal muscle at rest and during muscle contraction (electromyography [EMG]); studies to help assess cardiac structure and function, such as ultrasound studies of the heart (echocardiography); and/or other tests.In some cases, a diagnosis of Andersen disease may be suggested before birth (prenatally) by specialized tests. These include studies that may detect decreased GBE activity in certain fetal cells obtained via amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. In addition, if available, DNA mutation analysis may be used in selected cases. | Diagnosis of Andersen Disease (GSD IV). Andersen disease is usually diagnosed or confirmed after birth (postnatally) during infancy or childhood (or, in some cases, adulthood), based upon a thorough clinical evaluation; identification of characteristic physical findings; a complete patient and family history; and the results of various specialized tests. Removal (biopsy) and microscopic examination of small samples of certain tissues (e.g., liver, skeletal muscle, heart, skin, peripheral nerve) may demonstrate abnormal deposition of amylopectin-like materials. However, testing to confirm a diagnosis of Andersen disease requires detection of deficient GBE activity (indirect enzyme assay), such as in liver tissue, muscle, certain skin cells (cultured fibroblasts), white blood cells (leukocytes), red blood cells (erythrocytes), nerve cells, or other tissues. Reports indicate that, for individuals with adult polyglucosan body disease, peripheral nerve biopsy or evaluation of leukocytes is required for diagnosis, since deficient GBE activity is limited to such tissues. In addition, partial GBE deficiency may be detected (e.g., in erythrocytes, leukocytes, fibroblasts) in individuals who carry one copy of a mutated gene for Andersen disease (heterozygous carriers).Diagnostic evaluation typically includes various studies to help detect and characterize certain abnormalities that may be associated with the disorder. Such testing may include various laboratory studies (e.g., complete blood count; liver function tests; blood glucose studies; etc.); specialized imaging techniques (e.g., abdominal ultrasound, CT scanning, and/or MRI); testing that records electrical activity in skeletal muscle at rest and during muscle contraction (electromyography [EMG]); studies to help assess cardiac structure and function, such as ultrasound studies of the heart (echocardiography); and/or other tests.In some cases, a diagnosis of Andersen disease may be suggested before birth (prenatally) by specialized tests. These include studies that may detect decreased GBE activity in certain fetal cells obtained via amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. In addition, if available, DNA mutation analysis may be used in selected cases. | 76 | Andersen Disease (GSD IV) |
nord_76_6 | Therapies of Andersen Disease (GSD IV) | TreatmentThe treatment of Andersen disease is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians or internists; physicians who diagnose and treat disorders of the digestive tract; neurologists; cardiologists; dietitians; and/or other health care professionals.Specific therapies are symptomatic and supportive and may include long-term management of cirrhosis and impaired liver function; neuromuscular disease; and/or heart dysfunction. Treatment may commonly require dietary measures to maintain normal levels of glucose in the blood (normoglycemia) and provide sufficient nutritional intake in order to improve liver function and muscular strength. For cases in which there is cardiomyopathy, recommended disease management may include the use of certain medications, such as to treat heart failure and improve cardiac output; surgical intervention; and/or other measures.In individuals with progressive liver failure, liver transplantation has been conducted and may be effective in some cases. According to reports in the medical literature, following transplantation, some patients may develop progressive accumulation of abnormal glycogen in other organs, such as the heart, leading to potentially life-threatening complications. However, reports indicate that most patients have not had neuromuscular or heart complications (i.e., during follow-up periods of up to 13 years); in addition, in some of these patients, accumulations of glycogen in the heart and skeletal muscle have appeared to diminish following transplantation. However, experts advise that the long-term effectiveness (efficacy) of liver transplantation and its effect on other organ systems remains uncertain in those with Andersen disease. Thus, further investigation is needed to determine the long-term safety and efficacy of liver transplantation and its effect on disease progression in classic Andersen disease.Genetic counseling will be of benefit for affected individuals and family members. Other treatment for this disorder is symptomatic and supportive. | Therapies of Andersen Disease (GSD IV). TreatmentThe treatment of Andersen disease is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians or internists; physicians who diagnose and treat disorders of the digestive tract; neurologists; cardiologists; dietitians; and/or other health care professionals.Specific therapies are symptomatic and supportive and may include long-term management of cirrhosis and impaired liver function; neuromuscular disease; and/or heart dysfunction. Treatment may commonly require dietary measures to maintain normal levels of glucose in the blood (normoglycemia) and provide sufficient nutritional intake in order to improve liver function and muscular strength. For cases in which there is cardiomyopathy, recommended disease management may include the use of certain medications, such as to treat heart failure and improve cardiac output; surgical intervention; and/or other measures.In individuals with progressive liver failure, liver transplantation has been conducted and may be effective in some cases. According to reports in the medical literature, following transplantation, some patients may develop progressive accumulation of abnormal glycogen in other organs, such as the heart, leading to potentially life-threatening complications. However, reports indicate that most patients have not had neuromuscular or heart complications (i.e., during follow-up periods of up to 13 years); in addition, in some of these patients, accumulations of glycogen in the heart and skeletal muscle have appeared to diminish following transplantation. However, experts advise that the long-term effectiveness (efficacy) of liver transplantation and its effect on other organ systems remains uncertain in those with Andersen disease. Thus, further investigation is needed to determine the long-term safety and efficacy of liver transplantation and its effect on disease progression in classic Andersen disease.Genetic counseling will be of benefit for affected individuals and family members. Other treatment for this disorder is symptomatic and supportive. | 76 | Andersen Disease (GSD IV) |
nord_77_0 | Overview of Andersen-Tawil Syndrome | SummaryAndersen-Tawil syndrome is a rare genetic disorder characterized by episodes of muscle weakness and paralysis (periodic paralysis); abnormalities affecting the electrical system of the heart that can cause abnormal heart rhythms (arrhythmias); and a variety of distinctive facial and skeletal features. The specific symptoms and severity can vary greatly from one person to another, even among members of the same family. Some individuals will not develop all of the characteristic findings. Distinctive facial features may be so mild as to go unnoticed. In some cases, Andersen-Tawil syndrome is caused by mutations in the KCNJ2 gene; in other cases, the associated gene is unknown. The KCNJ2 gene mutation can occur randomly for unknown reasons (sporadically) or be inherited in an autosomal dominant manner.IntroductionAndersen-Tawil syndrome is sometimes referred to as long QT syndrome 7 because some individuals in early reports of the disorder had a prolonged QT interval, which is measured on an electrocardiogram and indicates that the heart muscle is taking longer than usual to recharge between beats. However, subsequent clinical reports have shown the QT interval is not prolonged or only mildly prolonged in most cases. Instead, the Q-U interval is markedly prolonged. In addition, unlike most forms of long QT syndrome, Andersen-Tawil syndrome is associated with symptoms in addition to disturbances of the electrical system of the heart. Although still sub-classified as a form of long QT syndrome, the disorder is recognized as separate from traditional long QT syndromes.Andersen-Tawil syndrome can also be classified as a form of periodic paralysis, a group of rare neuromuscular disorders characterized by episodes of weakness or paralysis. The terms Andersen-Tawil syndrome type 1 or type 2 are also used in the medical literature. Type 1 refers to cases caused by a known KCNJ2 gene mutation; type 2 refers to cases without an identified KCNJ2 mutation. | Overview of Andersen-Tawil Syndrome. SummaryAndersen-Tawil syndrome is a rare genetic disorder characterized by episodes of muscle weakness and paralysis (periodic paralysis); abnormalities affecting the electrical system of the heart that can cause abnormal heart rhythms (arrhythmias); and a variety of distinctive facial and skeletal features. The specific symptoms and severity can vary greatly from one person to another, even among members of the same family. Some individuals will not develop all of the characteristic findings. Distinctive facial features may be so mild as to go unnoticed. In some cases, Andersen-Tawil syndrome is caused by mutations in the KCNJ2 gene; in other cases, the associated gene is unknown. The KCNJ2 gene mutation can occur randomly for unknown reasons (sporadically) or be inherited in an autosomal dominant manner.IntroductionAndersen-Tawil syndrome is sometimes referred to as long QT syndrome 7 because some individuals in early reports of the disorder had a prolonged QT interval, which is measured on an electrocardiogram and indicates that the heart muscle is taking longer than usual to recharge between beats. However, subsequent clinical reports have shown the QT interval is not prolonged or only mildly prolonged in most cases. Instead, the Q-U interval is markedly prolonged. In addition, unlike most forms of long QT syndrome, Andersen-Tawil syndrome is associated with symptoms in addition to disturbances of the electrical system of the heart. Although still sub-classified as a form of long QT syndrome, the disorder is recognized as separate from traditional long QT syndromes.Andersen-Tawil syndrome can also be classified as a form of periodic paralysis, a group of rare neuromuscular disorders characterized by episodes of weakness or paralysis. The terms Andersen-Tawil syndrome type 1 or type 2 are also used in the medical literature. Type 1 refers to cases caused by a known KCNJ2 gene mutation; type 2 refers to cases without an identified KCNJ2 mutation. | 77 | Andersen-Tawil Syndrome |
nord_77_1 | Symptoms of Andersen-Tawil Syndrome | Andersen-Tawil syndrome is defined by three main features (i.e. a clinical triad), specifically periodic paralysis, arrhythmias and heart abnormalities, and distinctive physical features. However, the disorder is highly variable and not all affected individuals will develop all three of these characteristic symptoms. Andersen-Tawil syndrome can vary greatly in expression and severity from one person to another, even among members of the same family.Although researchers have established a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Affected individuals may experience temporary episodes of flaccid, muscle weakness or paralysis, known as periodic paralysis. The legs are most often affected and the severity of muscle weakness can range from mild weakness to an inability to walk unassisted. The arms, hands, legs and feet are also commonly affected. The frequency and duration of episodes varies from one person to another and from one episode to the next for the same person. Some episodes may last only minutes to hours; others can go on for days. Episodes can occur without warning (spontaneously), but can also occur following prolonged exercise, prolonged rest (e.g. upon awaking in the morning), rest after exercise, going too long without eating, eating a large meal, or emotional stress. Episodes can range in frequency from once per day to once per year. In some cases, a mild, but permanent weakness, present even between episodes, can develop with age and progress slowly over time.In most cases, periodic paralysis may be associated with low levels of potassium in the blood (hypokalemia), a common finding with other forms of periodic paralysis. However, some individuals who experience periodic paralysis have had normal potassium levels or even elevated levels (hyperkalemia). Low potassium levels can also impact the function of heart muscle cells.Affected individuals may experience disturbances of the normal rhythm of the heartbeat (arrhythmias), which can include abnormally fast heartbeats that originate in the lower chamber of the heart (ventricular tachycardia). Generally, this may not cause any symptoms (asymptomatic) or may cause shortness of breath or palpitations. In some cases, these arrhythmias may cause episodes of fainting or loss of consciousness (syncope). In severe cases, the possibility of cardiac arrest and sudden death exists. Although sudden death due to the cardiac abnormalities has occurred in Andersen-Tawil syndrome, it is extremely rare.Some affected individuals also have characteristic physical features including distinctive facial features, which are often mild in expression. Such features include a broad forehead, low-set ears, eyes that are spaced apart wider than usual (hypertelorism), and a small jaw (micrognathia). Additional facial features include a round (bulbous) nose, a thin upper lip, a triangular-shaped face, highly-arched roof of the mouth (palate), a cleft palate, and underdevelopment of the cheek bones (malar hypoplasia). Common physical features include webbing (syndactyly) of the second and/or third toes, pinkies that are fixed in a bent or crooked position (clinodactyly), and disproportionately small fingers and toes (brachydactyly). Additional findings include small hands and feet, loose joints, and abnormal sideways curvature of the spine (scoliosis). Dental anomalies have also been reported including delayed loss of primary or ‘baby’ teeth (persistent primary dentition), multiple missing teeth (oligodontia), and teeth that are abnormally crowded together.As affected children grow into adulthood, short stature may become evident. Short stature refers to an individual whose height is much shorter than would otherwise be expected based upon age and gender.Some individuals with Andersen-Tawil syndrome have experienced neuropsychiatric abnormalities including mild learning disabilities, depression, and deficits in executive functioning and abstract reasoning. Some infants experience seizures without fever (afebrile seizures). | Symptoms of Andersen-Tawil Syndrome. Andersen-Tawil syndrome is defined by three main features (i.e. a clinical triad), specifically periodic paralysis, arrhythmias and heart abnormalities, and distinctive physical features. However, the disorder is highly variable and not all affected individuals will develop all three of these characteristic symptoms. Andersen-Tawil syndrome can vary greatly in expression and severity from one person to another, even among members of the same family.Although researchers have established a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Affected individuals may experience temporary episodes of flaccid, muscle weakness or paralysis, known as periodic paralysis. The legs are most often affected and the severity of muscle weakness can range from mild weakness to an inability to walk unassisted. The arms, hands, legs and feet are also commonly affected. The frequency and duration of episodes varies from one person to another and from one episode to the next for the same person. Some episodes may last only minutes to hours; others can go on for days. Episodes can occur without warning (spontaneously), but can also occur following prolonged exercise, prolonged rest (e.g. upon awaking in the morning), rest after exercise, going too long without eating, eating a large meal, or emotional stress. Episodes can range in frequency from once per day to once per year. In some cases, a mild, but permanent weakness, present even between episodes, can develop with age and progress slowly over time.In most cases, periodic paralysis may be associated with low levels of potassium in the blood (hypokalemia), a common finding with other forms of periodic paralysis. However, some individuals who experience periodic paralysis have had normal potassium levels or even elevated levels (hyperkalemia). Low potassium levels can also impact the function of heart muscle cells.Affected individuals may experience disturbances of the normal rhythm of the heartbeat (arrhythmias), which can include abnormally fast heartbeats that originate in the lower chamber of the heart (ventricular tachycardia). Generally, this may not cause any symptoms (asymptomatic) or may cause shortness of breath or palpitations. In some cases, these arrhythmias may cause episodes of fainting or loss of consciousness (syncope). In severe cases, the possibility of cardiac arrest and sudden death exists. Although sudden death due to the cardiac abnormalities has occurred in Andersen-Tawil syndrome, it is extremely rare.Some affected individuals also have characteristic physical features including distinctive facial features, which are often mild in expression. Such features include a broad forehead, low-set ears, eyes that are spaced apart wider than usual (hypertelorism), and a small jaw (micrognathia). Additional facial features include a round (bulbous) nose, a thin upper lip, a triangular-shaped face, highly-arched roof of the mouth (palate), a cleft palate, and underdevelopment of the cheek bones (malar hypoplasia). Common physical features include webbing (syndactyly) of the second and/or third toes, pinkies that are fixed in a bent or crooked position (clinodactyly), and disproportionately small fingers and toes (brachydactyly). Additional findings include small hands and feet, loose joints, and abnormal sideways curvature of the spine (scoliosis). Dental anomalies have also been reported including delayed loss of primary or ‘baby’ teeth (persistent primary dentition), multiple missing teeth (oligodontia), and teeth that are abnormally crowded together.As affected children grow into adulthood, short stature may become evident. Short stature refers to an individual whose height is much shorter than would otherwise be expected based upon age and gender.Some individuals with Andersen-Tawil syndrome have experienced neuropsychiatric abnormalities including mild learning disabilities, depression, and deficits in executive functioning and abstract reasoning. Some infants experience seizures without fever (afebrile seizures). | 77 | Andersen-Tawil Syndrome |
nord_77_2 | Causes of Andersen-Tawil Syndrome | In approximately 60% of cases, Andersen-Tawil syndrome is caused by a mutation in the KCNJ2 gene. In the other 40% of cases, the underlying genetic mutation is unknown, suggesting that additional as-yet-unidentified genes also cause the disorder.Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.In approximately 50% of cases, the KCNJ2 gene mutation occurs sporadically, which means that in those specific cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. When the disorder runs in families, the mutations are inherited in an autosomal dominant manner.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The KCNJ2 gene produces (encodes) a protein essential for the proper development and function of certain ion channels. These channels are pores in cell membranes that regulate the movement of electrically-charged particles called ions (e.g. potassium and sodium ions) into muscle cells, including heart muscle and limb muscle cells and tissue. These ions carry electrical impulses necessary for the normal function of the cells involved. Mutations in the KCNJ2 gene results in abnormal functioning of the ion channels and, in turn, affect the proper function and development of skeletal muscle and the heart’s electrical system. The exact manner this mutation affects bone development and cause the distinctive facial and other skeletal features associated with Andersen-Tawil syndrome is not known. | Causes of Andersen-Tawil Syndrome. In approximately 60% of cases, Andersen-Tawil syndrome is caused by a mutation in the KCNJ2 gene. In the other 40% of cases, the underlying genetic mutation is unknown, suggesting that additional as-yet-unidentified genes also cause the disorder.Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.In approximately 50% of cases, the KCNJ2 gene mutation occurs sporadically, which means that in those specific cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. When the disorder runs in families, the mutations are inherited in an autosomal dominant manner.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The KCNJ2 gene produces (encodes) a protein essential for the proper development and function of certain ion channels. These channels are pores in cell membranes that regulate the movement of electrically-charged particles called ions (e.g. potassium and sodium ions) into muscle cells, including heart muscle and limb muscle cells and tissue. These ions carry electrical impulses necessary for the normal function of the cells involved. Mutations in the KCNJ2 gene results in abnormal functioning of the ion channels and, in turn, affect the proper function and development of skeletal muscle and the heart’s electrical system. The exact manner this mutation affects bone development and cause the distinctive facial and other skeletal features associated with Andersen-Tawil syndrome is not known. | 77 | Andersen-Tawil Syndrome |
nord_77_3 | Affects of Andersen-Tawil Syndrome | Andersen-Tawil syndrome affects males and females in equal numbers. The exact incidence or prevalence of the disorder is unknown. More than 100 cases have been reported in the medical literature. Because many cases go undiagnosed or misdiagnosed, determining the true frequency of Andersen-Tawil syndrome in the general population is difficult. | Affects of Andersen-Tawil Syndrome. Andersen-Tawil syndrome affects males and females in equal numbers. The exact incidence or prevalence of the disorder is unknown. More than 100 cases have been reported in the medical literature. Because many cases go undiagnosed or misdiagnosed, determining the true frequency of Andersen-Tawil syndrome in the general population is difficult. | 77 | Andersen-Tawil Syndrome |
nord_77_4 | Related disorders of Andersen-Tawil Syndrome | Symptoms of the following disorders can be similar to those of Andersen-Tawil syndrome. Comparisons may be useful for a differential diagnosis.Andersen-Tawil syndrome needs to be distinguished from other forms of periodic paralysis including hypokalemic periodic paralysis, hyperkalemic period paralysis, and thyrotoxic periodic paralysis. Other conditions that cause a prolonged QT interval or syncope should be ruled out as well including vasovagal syncope, orthostatic hypotension, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and catecholamingergic polymorphic ventricular tachycardia (CPVT). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Andersen-Tawil Syndrome. Symptoms of the following disorders can be similar to those of Andersen-Tawil syndrome. Comparisons may be useful for a differential diagnosis.Andersen-Tawil syndrome needs to be distinguished from other forms of periodic paralysis including hypokalemic periodic paralysis, hyperkalemic period paralysis, and thyrotoxic periodic paralysis. Other conditions that cause a prolonged QT interval or syncope should be ruled out as well including vasovagal syncope, orthostatic hypotension, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and catecholamingergic polymorphic ventricular tachycardia (CPVT). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 77 | Andersen-Tawil Syndrome |
nord_77_5 | Diagnosis of Andersen-Tawil Syndrome | A diagnosis of Andersen-Tawil syndrome is based upon identification of characteristic symptoms (e.g. periodic paralysis, symptomatic arrhythmias, and/or distinctive facial and skeletal features), a detailed family and patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and WorkupBecause potassium levels may be reduced during an episode of periodic paralysis, a blood test to determine the serum potassium levels during an episode can be helpful in diagnosing the disorder in some cases.Long exercise nerve conduction studies have been used to help diagnose individuals with Andersen-Tawil syndrome. During this test, an affected individual will perform voluntary muscle contractions of a small muscle on the ulnar side of the palm of the hand for approximately 2-5 minutes. This test allows physician to evaluate muscle function and specific results can be indicative of periodic paralysis.An electrocardiogram or EKG records the heart’s electrical impulses and may reveal abnormal electrical patterns or activity commonly associated with Andersen-Tawil syndrome including prominent U waves, prolonged QU intervals, prolonged QT intervals, premature ventricular contractions, or polymorphic ventricular tachycardia.Some individuals may undergo 24-Holter monitoring, during which an affected individual wears a small device for 24 hours. Through electrodes attached to the chest, this device continuously records the rhythm of the heart in order to detect the presence, frequency and duration of ventricular tachycardia and other symptoms.Molecular genetic testing can confirm a diagnosis of Andersen-Tawil syndrome in some cases. Molecular genetic testing can detect mutations in the KCNJ2 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Andersen-Tawil Syndrome. A diagnosis of Andersen-Tawil syndrome is based upon identification of characteristic symptoms (e.g. periodic paralysis, symptomatic arrhythmias, and/or distinctive facial and skeletal features), a detailed family and patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and WorkupBecause potassium levels may be reduced during an episode of periodic paralysis, a blood test to determine the serum potassium levels during an episode can be helpful in diagnosing the disorder in some cases.Long exercise nerve conduction studies have been used to help diagnose individuals with Andersen-Tawil syndrome. During this test, an affected individual will perform voluntary muscle contractions of a small muscle on the ulnar side of the palm of the hand for approximately 2-5 minutes. This test allows physician to evaluate muscle function and specific results can be indicative of periodic paralysis.An electrocardiogram or EKG records the heart’s electrical impulses and may reveal abnormal electrical patterns or activity commonly associated with Andersen-Tawil syndrome including prominent U waves, prolonged QU intervals, prolonged QT intervals, premature ventricular contractions, or polymorphic ventricular tachycardia.Some individuals may undergo 24-Holter monitoring, during which an affected individual wears a small device for 24 hours. Through electrodes attached to the chest, this device continuously records the rhythm of the heart in order to detect the presence, frequency and duration of ventricular tachycardia and other symptoms.Molecular genetic testing can confirm a diagnosis of Andersen-Tawil syndrome in some cases. Molecular genetic testing can detect mutations in the KCNJ2 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. | 77 | Andersen-Tawil Syndrome |
nord_77_6 | Therapies of Andersen-Tawil Syndrome | TreatmentThe treatment of Andersen-Tawil syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists experienced in the treatment of periodic paralysis, cardiologists experienced in the treatment of long QT syndrome, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disorder, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Andersen-Tawil syndrome.Affected individuals are encouraged to avoid potential triggers of periodic paralysis (e.g. rest following exercise or prolonged exercise). Avoidance of drugs that can prolong the QT interval is also recommended.When periodic paralysis is associated with low potassium levels, treatment with oral supplemental potassium can be beneficial. In individuals prone to low potassium levels, daily potassium supplementation can be considered. Potassium supplementation may also shorten the QT interval, which can be of benefit for individuals who also experience a long QT interval.A periodic paralysis episode that occurs when potassium levels are high usually resolve on their own within 60 minutes. However, eating carbohydrates or continuing mild exercise can shorten the duration of the episode.Specific drugs known as carbonic anhydrase inhibitors, such as acetazolamide and dichlorpenamide, are used to treat periodic paralysis in individuals with Andersen-Tawil syndrome. Clinical trials in other forms of periodic paralysis showed that dichlorphenamide reduces the frequency and severity of attacks of periodic paralysis and is now an FDA approved for the treatment of periodic paralysis.Despite a high frequency of ventricular arrhythmias in some individuals with Andersen-Tawil syndrome, they rarely degenerate into life-threatening arrhythmias. Many arrhythmias do not cause symptoms and go away on their own without problems (self-terminate). Various different drugs have been used, but no standard, effective therapy has been established. Beta-adrenergic blocking drugs (beta blockers), drugs that suppress abnormal heart rhythms (anti-arrhythmics) such as flecainide or amiodarone, or calcium-channel blocking drugs such as verapamil have all shown some effect. Beta blockers are commonly used to treat abnormal heart rhythms. These drugs, which include propranolol, atenolol, metroprolol, and nadolol, reduce the workload of the heart by decreasing the electrical stimulation of the heart, thereby slowing the heartbeat and preventing symptoms. Beta blockers have been used in conjunction with flecainide. Some anti-arrhythmic drugs can worsen neuromuscular symptoms and should be used with caution in individuals with Andersen-Tawil syndrome.Treatment with an implantable automatic cardioverter-defibrillator or ICD is necessary in rare cases. ICDs are considered for individuals in whom cardiac arrhythmias are severe and symptomatic. These small devices are implanted under the skin of the chest. The device detects the abnormal heartbeat automatically and selectively delivers an electrical impulse to restore the proper heartbeat. Opting for an ICD is a lifelong therapy that carries significant implications including the potential for complications, especially in younger individuals, and should be undertaken only after consultation with appropriate medical personnel and a careful risk vs. benefit evaluation.Genetic counseling is recommended for affected individuals and their families. | Therapies of Andersen-Tawil Syndrome. TreatmentThe treatment of Andersen-Tawil syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists experienced in the treatment of periodic paralysis, cardiologists experienced in the treatment of long QT syndrome, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disorder, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Andersen-Tawil syndrome.Affected individuals are encouraged to avoid potential triggers of periodic paralysis (e.g. rest following exercise or prolonged exercise). Avoidance of drugs that can prolong the QT interval is also recommended.When periodic paralysis is associated with low potassium levels, treatment with oral supplemental potassium can be beneficial. In individuals prone to low potassium levels, daily potassium supplementation can be considered. Potassium supplementation may also shorten the QT interval, which can be of benefit for individuals who also experience a long QT interval.A periodic paralysis episode that occurs when potassium levels are high usually resolve on their own within 60 minutes. However, eating carbohydrates or continuing mild exercise can shorten the duration of the episode.Specific drugs known as carbonic anhydrase inhibitors, such as acetazolamide and dichlorpenamide, are used to treat periodic paralysis in individuals with Andersen-Tawil syndrome. Clinical trials in other forms of periodic paralysis showed that dichlorphenamide reduces the frequency and severity of attacks of periodic paralysis and is now an FDA approved for the treatment of periodic paralysis.Despite a high frequency of ventricular arrhythmias in some individuals with Andersen-Tawil syndrome, they rarely degenerate into life-threatening arrhythmias. Many arrhythmias do not cause symptoms and go away on their own without problems (self-terminate). Various different drugs have been used, but no standard, effective therapy has been established. Beta-adrenergic blocking drugs (beta blockers), drugs that suppress abnormal heart rhythms (anti-arrhythmics) such as flecainide or amiodarone, or calcium-channel blocking drugs such as verapamil have all shown some effect. Beta blockers are commonly used to treat abnormal heart rhythms. These drugs, which include propranolol, atenolol, metroprolol, and nadolol, reduce the workload of the heart by decreasing the electrical stimulation of the heart, thereby slowing the heartbeat and preventing symptoms. Beta blockers have been used in conjunction with flecainide. Some anti-arrhythmic drugs can worsen neuromuscular symptoms and should be used with caution in individuals with Andersen-Tawil syndrome.Treatment with an implantable automatic cardioverter-defibrillator or ICD is necessary in rare cases. ICDs are considered for individuals in whom cardiac arrhythmias are severe and symptomatic. These small devices are implanted under the skin of the chest. The device detects the abnormal heartbeat automatically and selectively delivers an electrical impulse to restore the proper heartbeat. Opting for an ICD is a lifelong therapy that carries significant implications including the potential for complications, especially in younger individuals, and should be undertaken only after consultation with appropriate medical personnel and a careful risk vs. benefit evaluation.Genetic counseling is recommended for affected individuals and their families. | 77 | Andersen-Tawil Syndrome |
nord_78_0 | Overview of Anemia of Chronic Disease | Anemia of chronic disease, also called the anemia of inflammation, is a condition that can be associated with many different underlying disorders including chronic illnesses such as cancer, certain infections and autoimmune and inflammatory diseases such as rheumatoid arthritis or lupus. Anemia is defined by low levels of circulating red blood cells or hemoglobin, the part of red blood cells that carries oxygen. Anemia of chronic disease is usually a mild or moderate condition. In mild cases, anemia may not be associated with any symptoms or may cause fatigue, paleness of the skin (pallor) and lightheadedness. The underlying mechanisms that cause anemia of chronic disease are complex and not fully understood. | Overview of Anemia of Chronic Disease. Anemia of chronic disease, also called the anemia of inflammation, is a condition that can be associated with many different underlying disorders including chronic illnesses such as cancer, certain infections and autoimmune and inflammatory diseases such as rheumatoid arthritis or lupus. Anemia is defined by low levels of circulating red blood cells or hemoglobin, the part of red blood cells that carries oxygen. Anemia of chronic disease is usually a mild or moderate condition. In mild cases, anemia may not be associated with any symptoms or may cause fatigue, paleness of the skin (pallor) and lightheadedness. The underlying mechanisms that cause anemia of chronic disease are complex and not fully understood. | 78 | Anemia of Chronic Disease |
nord_78_1 | Symptoms of Anemia of Chronic Disease | Anemia of chronic disease varies in severity from one person to another. In most people, anemia is usually mild or moderate. Affected individuals may develop a variety of symptoms such as fatigue, paleness of the skin (pallor), lightheadedness, shortness of breath, a fast heartbeat, irritability, chest pain and additional findings. These symptoms may occur in any individual who has a comparable degree of anemia. In most cases, the symptoms associated with the underlying disease usually take precedent over the mild or moderate anemia symptoms. In rare cases, anemia of chronic disease can be severe and cause more serious complications. | Symptoms of Anemia of Chronic Disease. Anemia of chronic disease varies in severity from one person to another. In most people, anemia is usually mild or moderate. Affected individuals may develop a variety of symptoms such as fatigue, paleness of the skin (pallor), lightheadedness, shortness of breath, a fast heartbeat, irritability, chest pain and additional findings. These symptoms may occur in any individual who has a comparable degree of anemia. In most cases, the symptoms associated with the underlying disease usually take precedent over the mild or moderate anemia symptoms. In rare cases, anemia of chronic disease can be severe and cause more serious complications. | 78 | Anemia of Chronic Disease |
nord_78_2 | Causes of Anemia of Chronic Disease | The exact cause of anemia of chronic disease may vary. Usually, several processes occur at the same time. Anemia can be caused by a slight shortening of normal red blood cell survival. In addition, the production of red blood cells (erythropoiesis) or of erythropoietin (a hormone that stimulates red blood cell production) may be impaired. Red blood cells carry oxygen to the body. The exact cause of anemia of chronic disease may depend upon the underlying condition. For example, cancer cells or inflammatory diseases like rheumatoid arthritis can cause the secretion of certain substances (cytokines) that may suppress production of erythropoietin or limit the ability of immature red blood cell progenitors to respond to erythropoietin. These cytokines may also have effects on iron metabolism, as discussed below. In some cases, cancer cells or disease-causing microorganisms may infiltrate the bone marrow, the soft spongy material found in long bones where blood cells are formed.Researchers have also learned that individuals with anemia of chronic disease have an imbalance in the distribution of iron in the body and as a result cannot effectively use iron to create new blood cells despite having sufficient or elevated levels of iron stored in the tissues. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found in many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low functional iron levels) or damage to affected organs (due to abnormally high iron levels in certain tissues).Iron is needed to produce hemoglobin, a protein contained in red blood cells that carries oxygen. A key finding in anemia of chronic disease is increased uptake and retention of iron within certain cells that store and release iron, which leads to reduced amounts of functional iron that is available to produce hemoglobin. The lack of functional iron hinders the development of hemoglobin, which, in turn, reduces the amount of oxygen delivered throughout the body (anemia).Researchers believe that the immune system, which remains constantly active in individuals with chronic diseases, produces substances that influence the development, storage and transport of iron within the body. Cells in the immune system produce cytokines, specialized proteins that stimulate or inhibit the function of other immune system cells.Hepcidin, a hormone produced in the liver that helps regulate the metabolism and transport of iron within the body, plays a significant role in the development of anemia of chronic disease. Researchers believe a specific cytokine known as interleukin-6 (IL-6) stimulates the production of hepcidin in most cases, although hepcidin can also be produced in response to inflammation by pathways that do not involve IL-6. Excess hepcidin causes too much iron to be trapped within storage cells, lowering the amount of iron available to produce hemoglobin, thereby resulting in anemia. Most researchers think that hepcidin is a key factor influencing the development of anemia of chronic disease. | Causes of Anemia of Chronic Disease. The exact cause of anemia of chronic disease may vary. Usually, several processes occur at the same time. Anemia can be caused by a slight shortening of normal red blood cell survival. In addition, the production of red blood cells (erythropoiesis) or of erythropoietin (a hormone that stimulates red blood cell production) may be impaired. Red blood cells carry oxygen to the body. The exact cause of anemia of chronic disease may depend upon the underlying condition. For example, cancer cells or inflammatory diseases like rheumatoid arthritis can cause the secretion of certain substances (cytokines) that may suppress production of erythropoietin or limit the ability of immature red blood cell progenitors to respond to erythropoietin. These cytokines may also have effects on iron metabolism, as discussed below. In some cases, cancer cells or disease-causing microorganisms may infiltrate the bone marrow, the soft spongy material found in long bones where blood cells are formed.Researchers have also learned that individuals with anemia of chronic disease have an imbalance in the distribution of iron in the body and as a result cannot effectively use iron to create new blood cells despite having sufficient or elevated levels of iron stored in the tissues. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found in many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low functional iron levels) or damage to affected organs (due to abnormally high iron levels in certain tissues).Iron is needed to produce hemoglobin, a protein contained in red blood cells that carries oxygen. A key finding in anemia of chronic disease is increased uptake and retention of iron within certain cells that store and release iron, which leads to reduced amounts of functional iron that is available to produce hemoglobin. The lack of functional iron hinders the development of hemoglobin, which, in turn, reduces the amount of oxygen delivered throughout the body (anemia).Researchers believe that the immune system, which remains constantly active in individuals with chronic diseases, produces substances that influence the development, storage and transport of iron within the body. Cells in the immune system produce cytokines, specialized proteins that stimulate or inhibit the function of other immune system cells.Hepcidin, a hormone produced in the liver that helps regulate the metabolism and transport of iron within the body, plays a significant role in the development of anemia of chronic disease. Researchers believe a specific cytokine known as interleukin-6 (IL-6) stimulates the production of hepcidin in most cases, although hepcidin can also be produced in response to inflammation by pathways that do not involve IL-6. Excess hepcidin causes too much iron to be trapped within storage cells, lowering the amount of iron available to produce hemoglobin, thereby resulting in anemia. Most researchers think that hepcidin is a key factor influencing the development of anemia of chronic disease. | 78 | Anemia of Chronic Disease |
nord_78_3 | Affects of Anemia of Chronic Disease | Anemia of chronic disease affects males and females in equal proportion. Individuals of any age who have a chronic, inflammatory condition can potentially develop the condition. The exact incidence of anemia of chronic disease is unknown and some researchers believe that it is underreported or often goes unrecognized. Anemia of chronic disease is believed to be the second most common cause of anemia in the United States after iron-deficiency anemia. | Affects of Anemia of Chronic Disease. Anemia of chronic disease affects males and females in equal proportion. Individuals of any age who have a chronic, inflammatory condition can potentially develop the condition. The exact incidence of anemia of chronic disease is unknown and some researchers believe that it is underreported or often goes unrecognized. Anemia of chronic disease is believed to be the second most common cause of anemia in the United States after iron-deficiency anemia. | 78 | Anemia of Chronic Disease |
nord_78_4 | Related disorders of Anemia of Chronic Disease | Iron deficiency anemia is a common condition in which individuals have insufficient levels of iron in the body and cannot produce enough red blood cells to carry oxygen through the body. Iron deficiency anemia can cause a variety of symptoms including fatigue, weakness, pale skin, shortness of breath, headaches and lightheadedness. Additional symptoms that can occur in individuals with iron deficiency anemia include cold hands or feet, irritability, irregular heartbeats and an increased susceptibility to developing infections. Iron deficiency anemia is caused by insufficient levels of iron in the body, which can occur due to blood loss, a diet that supplies little iron, or an inability to absorb enough iron in the gastrointestinal tract. Anemia of chronic disease and iron deficiency anemia may be confused because both are associated with decreased circulating iron.The anemia seen in chronic kidney disease is usually caused by erythropoietin deficiency because of damage to kidney cells. However, some patients with kidney disease also have inflammation or infections, and the anemia of chronic disease may be part of their anemia. | Related disorders of Anemia of Chronic Disease. Iron deficiency anemia is a common condition in which individuals have insufficient levels of iron in the body and cannot produce enough red blood cells to carry oxygen through the body. Iron deficiency anemia can cause a variety of symptoms including fatigue, weakness, pale skin, shortness of breath, headaches and lightheadedness. Additional symptoms that can occur in individuals with iron deficiency anemia include cold hands or feet, irritability, irregular heartbeats and an increased susceptibility to developing infections. Iron deficiency anemia is caused by insufficient levels of iron in the body, which can occur due to blood loss, a diet that supplies little iron, or an inability to absorb enough iron in the gastrointestinal tract. Anemia of chronic disease and iron deficiency anemia may be confused because both are associated with decreased circulating iron.The anemia seen in chronic kidney disease is usually caused by erythropoietin deficiency because of damage to kidney cells. However, some patients with kidney disease also have inflammation or infections, and the anemia of chronic disease may be part of their anemia. | 78 | Anemia of Chronic Disease |
nord_78_5 | Diagnosis of Anemia of Chronic Disease | A diagnosis of anemia of chronic disease is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Such tests can measure the levels of certain substances in the body including hemoglobin levels, levels of iron in the serum, total iron binding capacity, overall red blood cell count, or normal or increased levels of ferritin in the blood. Ferritin is a protein that binds to iron and is used as an indicator of the body’s iron stores in the blood plasma. Another test that may be performed measures transferrin saturation. Transferrin is a protein that is involved in the transport of iron from the intestines into the bloodstream. Methods to allow the reliable measurement of hepcidin in plasma have been developed but are not available or approved for use in the diagnosis of anemia of chronic disease at present. | Diagnosis of Anemia of Chronic Disease. A diagnosis of anemia of chronic disease is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Such tests can measure the levels of certain substances in the body including hemoglobin levels, levels of iron in the serum, total iron binding capacity, overall red blood cell count, or normal or increased levels of ferritin in the blood. Ferritin is a protein that binds to iron and is used as an indicator of the body’s iron stores in the blood plasma. Another test that may be performed measures transferrin saturation. Transferrin is a protein that is involved in the transport of iron from the intestines into the bloodstream. Methods to allow the reliable measurement of hepcidin in plasma have been developed but are not available or approved for use in the diagnosis of anemia of chronic disease at present. | 78 | Anemia of Chronic Disease |
nord_78_6 | Therapies of Anemia of Chronic Disease | Treatment
The treatment of anemia of chronic disease is geared toward the underlying disease. If the treatment of the underlying disease is successful, anemia usually improves or resolves completely without direct treatment of its own.Efforts to treat the anemia by correcting the iron imbalance in the body with therapies such as oral iron supplements or vitamins have generally proven ineffective. In some circumstances where transferrin saturation is very low, intravenous iron may partially correct anemia of chronic disease. On the other hand, increased iron stores may increase susceptibility to infections by iron-dependent organisms. More research is necessary to understand the complex mechanisms that ultimately result in anemia of chronic disease and what role, if any, that traditional therapies for anemia and iron imbalance have in the treatment of affected individuals. | Therapies of Anemia of Chronic Disease. Treatment
The treatment of anemia of chronic disease is geared toward the underlying disease. If the treatment of the underlying disease is successful, anemia usually improves or resolves completely without direct treatment of its own.Efforts to treat the anemia by correcting the iron imbalance in the body with therapies such as oral iron supplements or vitamins have generally proven ineffective. In some circumstances where transferrin saturation is very low, intravenous iron may partially correct anemia of chronic disease. On the other hand, increased iron stores may increase susceptibility to infections by iron-dependent organisms. More research is necessary to understand the complex mechanisms that ultimately result in anemia of chronic disease and what role, if any, that traditional therapies for anemia and iron imbalance have in the treatment of affected individuals. | 78 | Anemia of Chronic Disease |
nord_79_0 | Overview of Anemia, Hemolytic, Acquired Autoimmune | The autoimmune hemolytic anemias are rare disorders characterized by the premature destruction (hemolysis) of red blood cells at a rate faster than they can be replaced. Acquired hemolytic anemias are non-genetic in origin. Idiopathic acquired autoimmune diseases occur when the body's natural defenses against invading organisms (e.g., lymphocytes, antibodies) destroy its own healthy tissues for no known reason. Normally, the red blood cells (erythrocytes) have a life span of approximately 120 days before being removed by the spleen. The severity of this type of anemia is determined by the life span of the red blood cell and by the rate at which these cells are replaced by the bone marrow.Clinicians are able to determine quite accurately (Coombs test) whether or not red blood cells are carrying with them chemicals that are being incorrectly recognized as an “enemy” and therefore subject to autoimmune destruction.Acquired autoimmune hemolytic anemia is a disorder that occurs in individuals who previously had a normal red blood cell system. The disorder may occur as the result of, or in conjunction with, some other medical condition, in which case it is “secondary” to another disorder. Less commonly, it occurs alone without a precipitating factor.Acquired autoimmune hemolytic anemia occurs in different forms, including warm antibody hemolytic anemia and cold antibody hemolytic anemia.In warm antibody hemolytic anemia, the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at temperatures above normal body temperature. In contrast, in the cases of cold antibody hemolytic anemia, the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at temperatures below normal body temperature. (For more information on this disorder, choose “Warm Antibody Hemolytic Anemia” and/or Cold Antibody Hemolytic Anemia as your search term in the Rare Disease Database.) | Overview of Anemia, Hemolytic, Acquired Autoimmune. The autoimmune hemolytic anemias are rare disorders characterized by the premature destruction (hemolysis) of red blood cells at a rate faster than they can be replaced. Acquired hemolytic anemias are non-genetic in origin. Idiopathic acquired autoimmune diseases occur when the body's natural defenses against invading organisms (e.g., lymphocytes, antibodies) destroy its own healthy tissues for no known reason. Normally, the red blood cells (erythrocytes) have a life span of approximately 120 days before being removed by the spleen. The severity of this type of anemia is determined by the life span of the red blood cell and by the rate at which these cells are replaced by the bone marrow.Clinicians are able to determine quite accurately (Coombs test) whether or not red blood cells are carrying with them chemicals that are being incorrectly recognized as an “enemy” and therefore subject to autoimmune destruction.Acquired autoimmune hemolytic anemia is a disorder that occurs in individuals who previously had a normal red blood cell system. The disorder may occur as the result of, or in conjunction with, some other medical condition, in which case it is “secondary” to another disorder. Less commonly, it occurs alone without a precipitating factor.Acquired autoimmune hemolytic anemia occurs in different forms, including warm antibody hemolytic anemia and cold antibody hemolytic anemia.In warm antibody hemolytic anemia, the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at temperatures above normal body temperature. In contrast, in the cases of cold antibody hemolytic anemia, the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at temperatures below normal body temperature. (For more information on this disorder, choose “Warm Antibody Hemolytic Anemia” and/or Cold Antibody Hemolytic Anemia as your search term in the Rare Disease Database.) | 79 | Anemia, Hemolytic, Acquired Autoimmune |
nord_79_1 | Symptoms of Anemia, Hemolytic, Acquired Autoimmune | Generally symptoms of acquired autoimmune hemolytic anemia resemble those of other anemias and may include fatigue, pale color, rapid heartbeat, shortness of breath, dark urine, chills, and backache. In severe cases, yellow skin color (jaundice) may be present and the spleen may be enlarged.If the autoimmune hemolytic anemia is secondary to another cause, the symptoms of the other cause may be most apparent. | Symptoms of Anemia, Hemolytic, Acquired Autoimmune. Generally symptoms of acquired autoimmune hemolytic anemia resemble those of other anemias and may include fatigue, pale color, rapid heartbeat, shortness of breath, dark urine, chills, and backache. In severe cases, yellow skin color (jaundice) may be present and the spleen may be enlarged.If the autoimmune hemolytic anemia is secondary to another cause, the symptoms of the other cause may be most apparent. | 79 | Anemia, Hemolytic, Acquired Autoimmune |
nord_79_2 | Causes of Anemia, Hemolytic, Acquired Autoimmune | Hemolytic anemia may be caused by any one or more of several kinds of disorders. For example, contributing factors may include:An autoimmune response in which the patient's own immune system destroys the patient's red blood cells. The disorder is more common among people who already have an autoimmune disorder such as lupus.The taking of certain types of medication by certain people. Among such medications are penicillin, quinine, methyldopa, and sulfonamides.Inherited enzyme deficiencies inside red blood cells that may cause the cells to become fragile and subject to destruction. Most commonly, low levels of the enzymes pyruvate kinase or glucose-6-phosphate dehydrogenase are the culprits.Hemoglobin disorders such as sickle cell anemia or one of the thalassemias (blood disorders that affect the cells ability to produce hemoglobin).Abnormalities of the cell membrane that cause the red blood cells to take on a shape other than the normal disc-shape. Such red blood cells may show up as spheres or ellipses or cup-like.Some unusual situations may lead to the destruction of red blood cells. For example, as the cells pass through oxygenating machines during open-heart surgery, they may undergo changes that lead to hemolytic anemia. | Causes of Anemia, Hemolytic, Acquired Autoimmune. Hemolytic anemia may be caused by any one or more of several kinds of disorders. For example, contributing factors may include:An autoimmune response in which the patient's own immune system destroys the patient's red blood cells. The disorder is more common among people who already have an autoimmune disorder such as lupus.The taking of certain types of medication by certain people. Among such medications are penicillin, quinine, methyldopa, and sulfonamides.Inherited enzyme deficiencies inside red blood cells that may cause the cells to become fragile and subject to destruction. Most commonly, low levels of the enzymes pyruvate kinase or glucose-6-phosphate dehydrogenase are the culprits.Hemoglobin disorders such as sickle cell anemia or one of the thalassemias (blood disorders that affect the cells ability to produce hemoglobin).Abnormalities of the cell membrane that cause the red blood cells to take on a shape other than the normal disc-shape. Such red blood cells may show up as spheres or ellipses or cup-like.Some unusual situations may lead to the destruction of red blood cells. For example, as the cells pass through oxygenating machines during open-heart surgery, they may undergo changes that lead to hemolytic anemia. | 79 | Anemia, Hemolytic, Acquired Autoimmune |
nord_79_3 | Affects of Anemia, Hemolytic, Acquired Autoimmune | When acquired autoimmune hemolytic anemia occurs from unknown causes, it affects twice as many women as men, specifically women under 50 years old. Cold antibody hemolytic anemia most commonly affects elderly persons, and warm antibody hemolytic anemia can affect anyone at any age. | Affects of Anemia, Hemolytic, Acquired Autoimmune. When acquired autoimmune hemolytic anemia occurs from unknown causes, it affects twice as many women as men, specifically women under 50 years old. Cold antibody hemolytic anemia most commonly affects elderly persons, and warm antibody hemolytic anemia can affect anyone at any age. | 79 | Anemia, Hemolytic, Acquired Autoimmune |
nord_79_4 | Related disorders of Anemia, Hemolytic, Acquired Autoimmune | Symptoms of the following disorder can be similar to those of Acquired Autoimmune Hemolytic Anemia. Comparison may be useful for a differential diagnosis:Paroxysmal Nocturnal Hemoglobinuria is a disorder characterized by a decrease of red blood cells (anemia) caused by a defect in the membrane of the red blood cells. The major symptom is the presence of blood in the urine (hemoglobinuria) which occurs chiefly at night due to the breakdown of red blood cells. Other symptoms may include paleness, severe abdominal or back pain, yellowing of the skin (jaundice) and enlargement of the spleen and liver. (For more information on this disorder, choose “Paroxysmal Nocturnal Hemoglobinuria” as your search term in the Rare Disease Database.)The following disorders may precede the development of Acquired Autoimmune Hemolytic Anemia. They can be useful in identifying an underlying cause of some forms of this disorder:Chronic Lymphatic Leukemia is a disorder characterized by an excessive amount of white blood cells in the bone marrow, spleen, liver and blood. As the disease progresses, the leukemic cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. Symptoms of Chronic Lymphatic Leukemia may include fatigue, weakness, itchiness, night sweats, abdominal discomfort or weight loss. An enlarged spleen is usually discovered upon physical examination. People with this type of leukemia can get Acquired Autoimmune Hemolytic Anemia. (For more information on this disorder, choose “Chronic Myelogenous Leukemia” as your search term in the Rare Disease Database.)Lymphoma is a malignant growth which most commonly occurs in the lymph nodes, spleen and other areas involved in the body's immune system (lymphoreticular system). The major types are Hodgkin's Disease and Non- Hodgkin's Lymphoma. People with Lymphoma can get Acquired Autoimmune Hemolytic Anemia . (For more information on this disorder, choose “Hodgkin” or “Lymphoma” as your search term in the Rare Disease Database.)Lupus Erythematosus is an inflammatory connective tissue disease that can affect many parts of the body including the joints, skin and internal organs. Lupus is an autoimmune disease most often striking young women between the ages of 15 and 35 years. The symptom for which Lupus was originally named, a butterfly-shaped red rash across the bridge of the nose and cheeks, is found in only five percent of newly diagnosed patients. Far more common are arthritic symptoms such as painfully inflamed joints. People with Lupus can get Acquired Autoimmune Hemolytic Anemia. (For more information on this disorder, choose “Lupus” as your search term in the Rare Disease Database.) | Related disorders of Anemia, Hemolytic, Acquired Autoimmune. Symptoms of the following disorder can be similar to those of Acquired Autoimmune Hemolytic Anemia. Comparison may be useful for a differential diagnosis:Paroxysmal Nocturnal Hemoglobinuria is a disorder characterized by a decrease of red blood cells (anemia) caused by a defect in the membrane of the red blood cells. The major symptom is the presence of blood in the urine (hemoglobinuria) which occurs chiefly at night due to the breakdown of red blood cells. Other symptoms may include paleness, severe abdominal or back pain, yellowing of the skin (jaundice) and enlargement of the spleen and liver. (For more information on this disorder, choose “Paroxysmal Nocturnal Hemoglobinuria” as your search term in the Rare Disease Database.)The following disorders may precede the development of Acquired Autoimmune Hemolytic Anemia. They can be useful in identifying an underlying cause of some forms of this disorder:Chronic Lymphatic Leukemia is a disorder characterized by an excessive amount of white blood cells in the bone marrow, spleen, liver and blood. As the disease progresses, the leukemic cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. Symptoms of Chronic Lymphatic Leukemia may include fatigue, weakness, itchiness, night sweats, abdominal discomfort or weight loss. An enlarged spleen is usually discovered upon physical examination. People with this type of leukemia can get Acquired Autoimmune Hemolytic Anemia. (For more information on this disorder, choose “Chronic Myelogenous Leukemia” as your search term in the Rare Disease Database.)Lymphoma is a malignant growth which most commonly occurs in the lymph nodes, spleen and other areas involved in the body's immune system (lymphoreticular system). The major types are Hodgkin's Disease and Non- Hodgkin's Lymphoma. People with Lymphoma can get Acquired Autoimmune Hemolytic Anemia . (For more information on this disorder, choose “Hodgkin” or “Lymphoma” as your search term in the Rare Disease Database.)Lupus Erythematosus is an inflammatory connective tissue disease that can affect many parts of the body including the joints, skin and internal organs. Lupus is an autoimmune disease most often striking young women between the ages of 15 and 35 years. The symptom for which Lupus was originally named, a butterfly-shaped red rash across the bridge of the nose and cheeks, is found in only five percent of newly diagnosed patients. Far more common are arthritic symptoms such as painfully inflamed joints. People with Lupus can get Acquired Autoimmune Hemolytic Anemia. (For more information on this disorder, choose “Lupus” as your search term in the Rare Disease Database.) | 79 | Anemia, Hemolytic, Acquired Autoimmune |
nord_79_5 | Diagnosis of Anemia, Hemolytic, Acquired Autoimmune | Upon suspicion of hemolytic anemia, blood will be tested to determine the proportion of immature red blood cells to mature ones. If the ratio is high, hemolytic anemia is likely. Another blood test (Coombs test) is used to determine whether the amount of certain antibodies is higher than normal. If so, the diagnosis may be autoimmune hemolytic anemia. | Diagnosis of Anemia, Hemolytic, Acquired Autoimmune. Upon suspicion of hemolytic anemia, blood will be tested to determine the proportion of immature red blood cells to mature ones. If the ratio is high, hemolytic anemia is likely. Another blood test (Coombs test) is used to determine whether the amount of certain antibodies is higher than normal. If so, the diagnosis may be autoimmune hemolytic anemia. | 79 | Anemia, Hemolytic, Acquired Autoimmune |
nord_79_6 | Therapies of Anemia, Hemolytic, Acquired Autoimmune | TreatmentWhen acquired autoimmune hemolytic anemia is secondary to other diseases, diagnosis and treatment of the underlying disorder usually brings marked improvement of the anemia. Mild cases may require no treatment. Individuals with more severe cases of warm antibody hemolytic anemia may be treated with oral steroids or intravenous hydrocortisone followed by divided daily oral doses of prednisone. Improvement usually occurs within five to ten days after treatment.If the response to the steroid therapy is unsatisfactory, other therapeutic approaches must be considered.In some resistant cases, total removal of the spleen may be required. Immunosuppressive drugs such as oral azathioprine or cyclophosphamide may be administered. Blood transfusions may be required in the most severe cases. | Therapies of Anemia, Hemolytic, Acquired Autoimmune. TreatmentWhen acquired autoimmune hemolytic anemia is secondary to other diseases, diagnosis and treatment of the underlying disorder usually brings marked improvement of the anemia. Mild cases may require no treatment. Individuals with more severe cases of warm antibody hemolytic anemia may be treated with oral steroids or intravenous hydrocortisone followed by divided daily oral doses of prednisone. Improvement usually occurs within five to ten days after treatment.If the response to the steroid therapy is unsatisfactory, other therapeutic approaches must be considered.In some resistant cases, total removal of the spleen may be required. Immunosuppressive drugs such as oral azathioprine or cyclophosphamide may be administered. Blood transfusions may be required in the most severe cases. | 79 | Anemia, Hemolytic, Acquired Autoimmune |
nord_80_0 | Overview of Anemia, Pernicious | *This condition is no longer considered rarePernicious anemia is a rare blood disorder characterized by the inability of the body to properly utilize vitamin B12, which is essential for the development of red blood cells. Most cases result from the lack of the gastric protein known as intrinsic factor, without which vitamin B12 cannot be absorbed.The symptoms of pernicious anemia may include weakness, fatigue, an upset stomach, an abnormally rapid heartbeat (tachycardia), and/or chest pains. Recurring episodes of anemia (megaloblastic) and an abnormal yellow coloration of the skin (jaundice) are also common. Pernicious anemia is thought to be an autoimmune disorder, and certain people may have a genetic predisposition to this disorder.There is a rare congenital form of pernicious anemia in which babies are born lacking the ability to produce effective intrinsic factor. There is also a juvenile form of the disease, but pernicious anemia typically does not appear before the age of 30. The onset of the disease is slow and may span decades. When the disease goes undiagnosed and untreated for a long period of time, it may lead to neurological complications. Nerve cells and blood cells need vitamin B12 to function properly. | Overview of Anemia, Pernicious. *This condition is no longer considered rarePernicious anemia is a rare blood disorder characterized by the inability of the body to properly utilize vitamin B12, which is essential for the development of red blood cells. Most cases result from the lack of the gastric protein known as intrinsic factor, without which vitamin B12 cannot be absorbed.The symptoms of pernicious anemia may include weakness, fatigue, an upset stomach, an abnormally rapid heartbeat (tachycardia), and/or chest pains. Recurring episodes of anemia (megaloblastic) and an abnormal yellow coloration of the skin (jaundice) are also common. Pernicious anemia is thought to be an autoimmune disorder, and certain people may have a genetic predisposition to this disorder.There is a rare congenital form of pernicious anemia in which babies are born lacking the ability to produce effective intrinsic factor. There is also a juvenile form of the disease, but pernicious anemia typically does not appear before the age of 30. The onset of the disease is slow and may span decades. When the disease goes undiagnosed and untreated for a long period of time, it may lead to neurological complications. Nerve cells and blood cells need vitamin B12 to function properly. | 80 | Anemia, Pernicious |
nord_80_1 | Symptoms of Anemia, Pernicious | Symptoms of pernicious anemia may include fatigue, shortness of breath, rapid heart rate, jaundice or pallor, tingling and numbness of hands and feet, loss of appetite, diarrhea, unsteadiness when walking, bleeding gums, impaired sense of smell, and confusion. The symptoms of juvenile pernicious anemia are usually obvious between the ages of 4 and 28 months. Most affected infants develop a form of anemia known as megaloblastic anemia. Large, immature red blood cells are found in the blood (megaloblasts), impairing the ability of the blood to deliver oxygen to the tissues of the body. Other types of blood cells (e.g., platelets and white blood cells) may also be deficient (pancytopenia). Symptoms may include vomiting, diarrhea, fatigue, headache, inability to sleep (insomnia), lack of appetite, failure to thrive, a yellow coloration of the skin (jaundice), irritability, and/or a pale complexion. Mental retardation is also common in infants with juvenile pernicious anemia. Affected infants may experience repeated episodes of extreme anemia and jaundice. Some children with the juvenile form of the disease have blood protein present in their urine (persistent proteinuria) and some may have urinary tract malformations.Individuals with congenital pernicious anemia present with symptoms very similar to the juvenile form. These however progress comparatively slowly; so slowly that the signs of neurological deficits may precede those associated with the decline in blood capacity. The symptoms may include generalized weakness and fatigue, difficulty breathing (dyspnea), an abnormally rapid heartbeat (tachycardia), and/or chest pains (angina). Affected individuals may also have gastrointestinal problems, such as a profound lack of appetite (anorexia), abdominal pain, indigestion, belching, and/or constipation and diarrhea. Weight loss is also common. Some people with Pernicious Anemia may have an abnormally enlarged liver (hepatomegaly) or spleen (splenomegaly). Other problems involving urinary function may also develop.Because nerve cells need vitamin B12 to function properly, some people with pernicious anemia will display neurological symptoms. Nerves other than those of the brain and spinal cord (peripheral nervous system) are frequently affected. Occasionally, the spinal cord may also be involved. Neurological symptoms may include numbness, tingling, loss of sensation in the arms and/or legs (acroparesthesias). Other neurological symptoms may include impaired ability to coordinate movement (ataxia), a positive Babinski sign (outward motion of the big toe caused by stroking the sole of the foot), and/or exaggerated reflexes (hyperreflexia). Some people with pernicious anemia may also become extremely irritable or depressed and, in some rare cases, even experience paranoia (megaloblastic madness). | Symptoms of Anemia, Pernicious. Symptoms of pernicious anemia may include fatigue, shortness of breath, rapid heart rate, jaundice or pallor, tingling and numbness of hands and feet, loss of appetite, diarrhea, unsteadiness when walking, bleeding gums, impaired sense of smell, and confusion. The symptoms of juvenile pernicious anemia are usually obvious between the ages of 4 and 28 months. Most affected infants develop a form of anemia known as megaloblastic anemia. Large, immature red blood cells are found in the blood (megaloblasts), impairing the ability of the blood to deliver oxygen to the tissues of the body. Other types of blood cells (e.g., platelets and white blood cells) may also be deficient (pancytopenia). Symptoms may include vomiting, diarrhea, fatigue, headache, inability to sleep (insomnia), lack of appetite, failure to thrive, a yellow coloration of the skin (jaundice), irritability, and/or a pale complexion. Mental retardation is also common in infants with juvenile pernicious anemia. Affected infants may experience repeated episodes of extreme anemia and jaundice. Some children with the juvenile form of the disease have blood protein present in their urine (persistent proteinuria) and some may have urinary tract malformations.Individuals with congenital pernicious anemia present with symptoms very similar to the juvenile form. These however progress comparatively slowly; so slowly that the signs of neurological deficits may precede those associated with the decline in blood capacity. The symptoms may include generalized weakness and fatigue, difficulty breathing (dyspnea), an abnormally rapid heartbeat (tachycardia), and/or chest pains (angina). Affected individuals may also have gastrointestinal problems, such as a profound lack of appetite (anorexia), abdominal pain, indigestion, belching, and/or constipation and diarrhea. Weight loss is also common. Some people with Pernicious Anemia may have an abnormally enlarged liver (hepatomegaly) or spleen (splenomegaly). Other problems involving urinary function may also develop.Because nerve cells need vitamin B12 to function properly, some people with pernicious anemia will display neurological symptoms. Nerves other than those of the brain and spinal cord (peripheral nervous system) are frequently affected. Occasionally, the spinal cord may also be involved. Neurological symptoms may include numbness, tingling, loss of sensation in the arms and/or legs (acroparesthesias). Other neurological symptoms may include impaired ability to coordinate movement (ataxia), a positive Babinski sign (outward motion of the big toe caused by stroking the sole of the foot), and/or exaggerated reflexes (hyperreflexia). Some people with pernicious anemia may also become extremely irritable or depressed and, in some rare cases, even experience paranoia (megaloblastic madness). | 80 | Anemia, Pernicious |
nord_80_2 | Causes of Anemia, Pernicious | Pernicious anemia is thought to be an autoimmune disease. Autoimmune disorders are caused when the body's natural defenses (e.g., antibodies) against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Pernicious anemia is sometimes seen in association with certain autoimmune endocrine diseases, such as type 1 diabetes, hypoparathyroidism, Addison's disease, and Graves' disease.However, since the disorder also tends to occur with greater frequency in certain families than in others, it is also believed that there may be a genetic component to pernicious anemia. In general, risk factors for pernicious anemia include a family history of the disease, being of Northern European or Scandinavian descent, and a history of autoimmune endocrine disorders.The congenital and juvenile forms are thought to be inherited as autosomal recessive traits. The gene responsible for anemia due to intrinsic factor deficiency has been tracked to a location on chromosome 11 (11q13). The gene responsible for anemia due to the intestinal malabsorption of vitamin B12 has been tracked to sites on chromosome 14 (14q32) and 10 (10p12.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 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 11q13” refers to band 13 on the long arm of chromosome 11. Similarly gene map loci 14q32 and 10p12.1 refer to a site at band 32 on the long arm of chromosome 14, and at band 12.1 on the short arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Anemia, Pernicious. Pernicious anemia is thought to be an autoimmune disease. Autoimmune disorders are caused when the body's natural defenses (e.g., antibodies) against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Pernicious anemia is sometimes seen in association with certain autoimmune endocrine diseases, such as type 1 diabetes, hypoparathyroidism, Addison's disease, and Graves' disease.However, since the disorder also tends to occur with greater frequency in certain families than in others, it is also believed that there may be a genetic component to pernicious anemia. In general, risk factors for pernicious anemia include a family history of the disease, being of Northern European or Scandinavian descent, and a history of autoimmune endocrine disorders.The congenital and juvenile forms are thought to be inherited as autosomal recessive traits. The gene responsible for anemia due to intrinsic factor deficiency has been tracked to a location on chromosome 11 (11q13). The gene responsible for anemia due to the intestinal malabsorption of vitamin B12 has been tracked to sites on chromosome 14 (14q32) and 10 (10p12.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 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 11q13” refers to band 13 on the long arm of chromosome 11. Similarly gene map loci 14q32 and 10p12.1 refer to a site at band 32 on the long arm of chromosome 14, and at band 12.1 on the short arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 80 | Anemia, Pernicious |
nord_80_3 | Affects of Anemia, Pernicious | Slightly more women than men are affected by pernicious anemia. The adult form is the most common, and diagnosis typically takes place at around 60 years of age. Pernicious anemia is more common among people from northern Europe, Scandinavia, and North America than among those from other parts of the world. It is believed that a significant number of cases go undiagnosed. This disorder occurs much more frequently among people who have diseases such as multiple myeloma and various other immunoglobulin deficiencies than in the general population. | Affects of Anemia, Pernicious. Slightly more women than men are affected by pernicious anemia. The adult form is the most common, and diagnosis typically takes place at around 60 years of age. Pernicious anemia is more common among people from northern Europe, Scandinavia, and North America than among those from other parts of the world. It is believed that a significant number of cases go undiagnosed. This disorder occurs much more frequently among people who have diseases such as multiple myeloma and various other immunoglobulin deficiencies than in the general population. | 80 | Anemia, Pernicious |
nord_80_4 | Related disorders of Anemia, Pernicious | Acquired aplastic anemiaAcquired aplastic anemia is a rare disorder caused by profound, almost complete bone marrow failure. Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells eventually results in low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, chronic infections, dizziness, weakness, headaches, and episodes of excessive bleeding. Although some cases of acquired aplastic anemia occur secondary to other disorders, researchers now believe that most cases result from a disorder of the patient's immune system, in which the immune system mistakenly targets the bone marrow. (For more information, choose “Anemia, acquired aplastic” as your search term in the Rare Disease Database.)Megaloblastic anemiaMegaloblastic anemia is a rare blood disorder characterized by the presence of abnormal white blood cells, low white blood cell counts, and abnormally low levels of circulating platelets. The initial symptoms may include diarrhea, vomiting, a profound loss of appetite (anorexia), and weight loss. Other symptoms may include an abnormally enlarged liver and/or spleen, weakness, heart palpitations, breathing problems, and/or irritability. (For more information, choose “Anemia, Megaloblastic” as your search term in the Rare Disease Database.)Myelodysplastic syndromesThe myelodysplastic syndromes are a group of diseases that affect bone marrow. Healthy bone marrow produces immature blood cells that then develop into red blood cells, white blood cells, and platelets. When MDS affects the normal development process, precursor cells (“blasts”) fail to respond to normal control signals, resulting in a disproportionate number of these primitive cells remaining in the bone marrow. Meanwhile, levels of the circulating mature blood cells fall. The mature blood cells, in addition to being fewer in number, may not function properly due to distortions in their shape.Vitamin B12 deficiencyVitamin B12 deficiency is characterized by abnormally low levels of circulating B12 due to a poor diet or inadequate absorption of this vitamin by the stomach. Unlike pernicious anemia, people with Vitamin B12 deficiency typically have normal levels of intrinsic factor. Most people with the disorder have abnormally low red blood cell counts (anemia). Symptoms may include an abnormally enlarged spleen or liver, lack of appetite, intermittent constipation and diarrhea, and/or abdominal pain. This deficiency is very rare due to storage of fitamin B12 in the liver that lasts for 3 to 5 years. When insufficient B12 is in the diet, the liver releases B12 to compensate for the loss. (For more information, choose “Vitamin B12 deficiency” as your search term in the Rare Disease Database.) | Related disorders of Anemia, Pernicious. Acquired aplastic anemiaAcquired aplastic anemia is a rare disorder caused by profound, almost complete bone marrow failure. Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells eventually results in low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, chronic infections, dizziness, weakness, headaches, and episodes of excessive bleeding. Although some cases of acquired aplastic anemia occur secondary to other disorders, researchers now believe that most cases result from a disorder of the patient's immune system, in which the immune system mistakenly targets the bone marrow. (For more information, choose “Anemia, acquired aplastic” as your search term in the Rare Disease Database.)Megaloblastic anemiaMegaloblastic anemia is a rare blood disorder characterized by the presence of abnormal white blood cells, low white blood cell counts, and abnormally low levels of circulating platelets. The initial symptoms may include diarrhea, vomiting, a profound loss of appetite (anorexia), and weight loss. Other symptoms may include an abnormally enlarged liver and/or spleen, weakness, heart palpitations, breathing problems, and/or irritability. (For more information, choose “Anemia, Megaloblastic” as your search term in the Rare Disease Database.)Myelodysplastic syndromesThe myelodysplastic syndromes are a group of diseases that affect bone marrow. Healthy bone marrow produces immature blood cells that then develop into red blood cells, white blood cells, and platelets. When MDS affects the normal development process, precursor cells (“blasts”) fail to respond to normal control signals, resulting in a disproportionate number of these primitive cells remaining in the bone marrow. Meanwhile, levels of the circulating mature blood cells fall. The mature blood cells, in addition to being fewer in number, may not function properly due to distortions in their shape.Vitamin B12 deficiencyVitamin B12 deficiency is characterized by abnormally low levels of circulating B12 due to a poor diet or inadequate absorption of this vitamin by the stomach. Unlike pernicious anemia, people with Vitamin B12 deficiency typically have normal levels of intrinsic factor. Most people with the disorder have abnormally low red blood cell counts (anemia). Symptoms may include an abnormally enlarged spleen or liver, lack of appetite, intermittent constipation and diarrhea, and/or abdominal pain. This deficiency is very rare due to storage of fitamin B12 in the liver that lasts for 3 to 5 years. When insufficient B12 is in the diet, the liver releases B12 to compensate for the loss. (For more information, choose “Vitamin B12 deficiency” as your search term in the Rare Disease Database.) | 80 | Anemia, Pernicious |
nord_80_5 | Diagnosis of Anemia, Pernicious | The diagnosis of pernicious anemia may be confirmed by a thorough clinical evaluation, including a detailed patient history and specialized laboratory tests. During a Schilling test, the intestines' ability to absorb vitamin B12 is measured. The vitamin is labeled with radioactive cobalt and is ingested by mouth. X-ray studies can then determine if the body is properly absorbing this vitamin. | Diagnosis of Anemia, Pernicious. The diagnosis of pernicious anemia may be confirmed by a thorough clinical evaluation, including a detailed patient history and specialized laboratory tests. During a Schilling test, the intestines' ability to absorb vitamin B12 is measured. The vitamin is labeled with radioactive cobalt and is ingested by mouth. X-ray studies can then determine if the body is properly absorbing this vitamin. | 80 | Anemia, Pernicious |
nord_80_6 | Therapies of Anemia, Pernicious | TreatmentIf pernicious anemia is ignored, undiagnosed, or left untreated, life-threatening complications can occur. Pernicious anemia is treated by injection of vitamin B12 (hydroxocobalamin or cyanocobalamin) into the muscle. A physician must closely monitor the amount of vitamin that is given and adjust the dosage when necessary. People with pernicious anemia must continue to receive maintenance doses of vitamin B12 throughout life.Genetic counseling may be of benefit for people with pernicious anemia and their families. | Therapies of Anemia, Pernicious. TreatmentIf pernicious anemia is ignored, undiagnosed, or left untreated, life-threatening complications can occur. Pernicious anemia is treated by injection of vitamin B12 (hydroxocobalamin or cyanocobalamin) into the muscle. A physician must closely monitor the amount of vitamin that is given and adjust the dosage when necessary. People with pernicious anemia must continue to receive maintenance doses of vitamin B12 throughout life.Genetic counseling may be of benefit for people with pernicious anemia and their families. | 80 | Anemia, Pernicious |
nord_81_0 | Overview of Anencephaly | Anencephaly is a term that refers to the incomplete development of the brain, skull, and scalp and is part of a group of birth defects called neural tube defects (NTD). The structure which will become the neural tube is supposed to fold and to close together (to form a tube) during the third and fourth weeks of pregnancy. From this neural tube, the brain and spinal cord of the embryo develop. Neural tube defects happen when the neural tube does not close as expected. Anencephaly occurs when the end of the neural tube that would have developed into the brain does not close properly, resulting in the failure of the development of major portions of brain, skull and scalp. Other neural tube defects, such as spina bifida, form when the neural tube does not close properly in a different part of the neural tube.Infants with anencephaly are born without the front part of the brain, (forebrain) and the thinking and coordinating part of the brain (cerebral hemispheres and cerebellum). Most of the time the remaining brain tissue may be exposed, without skull or scalp to cover and protect it. Although reflex actions such as breathing and responses to touch or sound may occur, gaining consciousness is not possible. Usually infants with anencephaly do not survive more than a few days or weeks.Meroanencephaly and holoanencephaly are terms refer to the extent of the cranial defect, however, they typically are not used in clinical descriptions and are not predictive of severity of the condition. The term acrania has been used interchangeably with anencephaly in some parts of the world but that practice is discouraged as it confuses two very different conditions. | Overview of Anencephaly. Anencephaly is a term that refers to the incomplete development of the brain, skull, and scalp and is part of a group of birth defects called neural tube defects (NTD). The structure which will become the neural tube is supposed to fold and to close together (to form a tube) during the third and fourth weeks of pregnancy. From this neural tube, the brain and spinal cord of the embryo develop. Neural tube defects happen when the neural tube does not close as expected. Anencephaly occurs when the end of the neural tube that would have developed into the brain does not close properly, resulting in the failure of the development of major portions of brain, skull and scalp. Other neural tube defects, such as spina bifida, form when the neural tube does not close properly in a different part of the neural tube.Infants with anencephaly are born without the front part of the brain, (forebrain) and the thinking and coordinating part of the brain (cerebral hemispheres and cerebellum). Most of the time the remaining brain tissue may be exposed, without skull or scalp to cover and protect it. Although reflex actions such as breathing and responses to touch or sound may occur, gaining consciousness is not possible. Usually infants with anencephaly do not survive more than a few days or weeks.Meroanencephaly and holoanencephaly are terms refer to the extent of the cranial defect, however, they typically are not used in clinical descriptions and are not predictive of severity of the condition. The term acrania has been used interchangeably with anencephaly in some parts of the world but that practice is discouraged as it confuses two very different conditions. | 81 | Anencephaly |
nord_81_1 | Symptoms of Anencephaly | Pregnancies affected by anencephaly show high levels of a specific fetal protein (called alpha fetoprotein) in tests done on the mother's blood or on amniotic fluid. The presence of excess fluid in the amniotic sac that contains the fetus (polyhydramnios) may be noted during an ultrasound. Anencephaly may also be seen before birth using any one of several imaging techniques. The condition is characterized by the absence of the skull and parts of the brain (cerebral hemispheres and cerebellum). Abnormalities of facial features secondary to the absent skull are common and vary depending on the development of each fetus. Anencephaly usually (~80%) occurs without other birth defects. | Symptoms of Anencephaly. Pregnancies affected by anencephaly show high levels of a specific fetal protein (called alpha fetoprotein) in tests done on the mother's blood or on amniotic fluid. The presence of excess fluid in the amniotic sac that contains the fetus (polyhydramnios) may be noted during an ultrasound. Anencephaly may also be seen before birth using any one of several imaging techniques. The condition is characterized by the absence of the skull and parts of the brain (cerebral hemispheres and cerebellum). Abnormalities of facial features secondary to the absent skull are common and vary depending on the development of each fetus. Anencephaly usually (~80%) occurs without other birth defects. | 81 | Anencephaly |
nord_81_2 | Causes of Anencephaly | Not all of the causes of anencephaly are understood. Anencephaly can be a multifactorial condition meaning that multiple genes are involved interacting with environmental agents and chance events to cause the condition. Anencephaly can also be a feature of some chromosomal disorders such as trisomy 18 which are usually sporadic and not familial (inherited). Most times anencephaly occurs in a pregnancy where there is no family history of neutral tube defects. However, research has shown that once a woman has had one pregnancy that resulted in a fetus with a neural tube defect, any additional pregnancies have an increased risk that a similar defect will occur again (recurrence risk). This recurrence risk is estimated to be 3-4% compared to the background risk of much less than 1%. Researchers also expect that if a subsequent fetus has a neural tube defect, the defect, whether anencephaly or spina bifida, tends to be in a location similar to the prior pregnancy. While not all the causes of anencephaly are known, many epidemiologic studies have demonstrated that folic acid supplementation prior to conception and during the first trimester can reduce the birth prevalence of spina bifida and anencephaly by at least 50%. | Causes of Anencephaly. Not all of the causes of anencephaly are understood. Anencephaly can be a multifactorial condition meaning that multiple genes are involved interacting with environmental agents and chance events to cause the condition. Anencephaly can also be a feature of some chromosomal disorders such as trisomy 18 which are usually sporadic and not familial (inherited). Most times anencephaly occurs in a pregnancy where there is no family history of neutral tube defects. However, research has shown that once a woman has had one pregnancy that resulted in a fetus with a neural tube defect, any additional pregnancies have an increased risk that a similar defect will occur again (recurrence risk). This recurrence risk is estimated to be 3-4% compared to the background risk of much less than 1%. Researchers also expect that if a subsequent fetus has a neural tube defect, the defect, whether anencephaly or spina bifida, tends to be in a location similar to the prior pregnancy. While not all the causes of anencephaly are known, many epidemiologic studies have demonstrated that folic acid supplementation prior to conception and during the first trimester can reduce the birth prevalence of spina bifida and anencephaly by at least 50%. | 81 | Anencephaly |
nord_81_3 | Affects of Anencephaly | Many fetuses with anencephaly are stillborn or are spontaneously aborted, but more females are born with anencephaly than males.Beginning in January 1998, the US Food and Drug Administration mandated that folic acid be added to all enriched cereal grain products. After this mandate, anencephaly affects about 1 in per 5,000 to 10,000 births in the U.S. Internationally, the number of births affected varies and is greatly influenced by the use of folic acid supplementation or food fortification, prenatal diagnosis, and pregnancy termination. | Affects of Anencephaly. Many fetuses with anencephaly are stillborn or are spontaneously aborted, but more females are born with anencephaly than males.Beginning in January 1998, the US Food and Drug Administration mandated that folic acid be added to all enriched cereal grain products. After this mandate, anencephaly affects about 1 in per 5,000 to 10,000 births in the U.S. Internationally, the number of births affected varies and is greatly influenced by the use of folic acid supplementation or food fortification, prenatal diagnosis, and pregnancy termination. | 81 | Anencephaly |
nord_81_4 | Related disorders of Anencephaly | The following birth defects can be similar to those of anencephaly. Comparing these terms may help you understand the difference between the diagnoses. Spina bifida is a term meaning open spine and this defect can be mild to very severe. In spina bifida, the structure which will become the spinal cord fails to form the neural tube. When the tube does not close properly, the bony spine (vertebrae) does not form correctly and leaves parts of the spinal column open. The covering membrane of the neural tissue (meninges) bulges out as a sac that may or may not contain spinal nerve tissue (meningomyelocele or meningocele, respectively). Children with spina bifida usually have surgery to close the defect; however, difficulties with walking and bowel and bladder control remain. Although intellectual ability in children with spinal bifida is not usually severely affected, specific learning disabilities are common. (For more information, choose “spina bifida” as your search term in the Rare Disease Database.)Acrania refers to a condition in which the skull is not developed; the brain and scalp may be present but usually are incompletely formed. The term acrania has been used interchangeably with anencephaly in some parts of the world but that practice is discouraged as it confuses two very different conditions.Rarely, a layer of the amniotic sac separates to form a ribbon-like strip called an amniotic band. Amniotic bands can prevent proper growth of any part of a developing fetus, a condition known as amniotic band disruption sequence. When the development of the brain, skull and/or scalp is interrupted by an amniotic band, the defect may resemble anencephaly; however, this condition is not a neural tube defect and rarely recurs in a subsequent pregnancy. (For more information, choose “amniotic band” as your search term in the Rare Disease Database.) | Related disorders of Anencephaly. The following birth defects can be similar to those of anencephaly. Comparing these terms may help you understand the difference between the diagnoses. Spina bifida is a term meaning open spine and this defect can be mild to very severe. In spina bifida, the structure which will become the spinal cord fails to form the neural tube. When the tube does not close properly, the bony spine (vertebrae) does not form correctly and leaves parts of the spinal column open. The covering membrane of the neural tissue (meninges) bulges out as a sac that may or may not contain spinal nerve tissue (meningomyelocele or meningocele, respectively). Children with spina bifida usually have surgery to close the defect; however, difficulties with walking and bowel and bladder control remain. Although intellectual ability in children with spinal bifida is not usually severely affected, specific learning disabilities are common. (For more information, choose “spina bifida” as your search term in the Rare Disease Database.)Acrania refers to a condition in which the skull is not developed; the brain and scalp may be present but usually are incompletely formed. The term acrania has been used interchangeably with anencephaly in some parts of the world but that practice is discouraged as it confuses two very different conditions.Rarely, a layer of the amniotic sac separates to form a ribbon-like strip called an amniotic band. Amniotic bands can prevent proper growth of any part of a developing fetus, a condition known as amniotic band disruption sequence. When the development of the brain, skull and/or scalp is interrupted by an amniotic band, the defect may resemble anencephaly; however, this condition is not a neural tube defect and rarely recurs in a subsequent pregnancy. (For more information, choose “amniotic band” as your search term in the Rare Disease Database.) | 81 | Anencephaly |
nord_81_5 | Diagnosis of Anencephaly | Diagnosis of Anencephaly. | 81 | Anencephaly |
|
nord_81_6 | Therapies of Anencephaly | PreventionThe U.S. Public Health Service advises women of childbearing age to take 0.4 mg of folic acid daily, either through supplements or fortified foods, even if those women do not think they are likely to become pregnant. This is recommended because the neural tube forms early, often before women realize they are pregnant.Women are urged not to take more than 1.0 mg of folic acid daily unless advised by a physician because high doses of folic acid may mask the diagnosis of severe B12 deficiency (pernicious anemia).Women who have had a previous pregnancy affected by a neural tube defect are advised to consume 4 mg of folic acid beginning 30 days before conception through the first trimester under the care of their physician.PalliativeInfants with anencephaly usually do not survive more than a few days or weeks. The role of healthcare providers is to provide a supportive environment that will enable the family to accept the diagnosis and make preparations for their loss. | Therapies of Anencephaly. PreventionThe U.S. Public Health Service advises women of childbearing age to take 0.4 mg of folic acid daily, either through supplements or fortified foods, even if those women do not think they are likely to become pregnant. This is recommended because the neural tube forms early, often before women realize they are pregnant.Women are urged not to take more than 1.0 mg of folic acid daily unless advised by a physician because high doses of folic acid may mask the diagnosis of severe B12 deficiency (pernicious anemia).Women who have had a previous pregnancy affected by a neural tube defect are advised to consume 4 mg of folic acid beginning 30 days before conception through the first trimester under the care of their physician.PalliativeInfants with anencephaly usually do not survive more than a few days or weeks. The role of healthcare providers is to provide a supportive environment that will enable the family to accept the diagnosis and make preparations for their loss. | 81 | Anencephaly |
nord_82_0 | Overview of Angelman Syndrome | SummaryAngelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delay and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional symptoms may occur including seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene.IntroductionAngelman syndrome was first described in the medical literature in 1965 by Dr. Harry Angelman, an English physician. The characteristic findings of Angelman syndrome are not usually apparent at birth and diagnosis of the disorder is usually made between 1 and 4 years of age. | Overview of Angelman Syndrome. SummaryAngelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delay and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional symptoms may occur including seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene.IntroductionAngelman syndrome was first described in the medical literature in 1965 by Dr. Harry Angelman, an English physician. The characteristic findings of Angelman syndrome are not usually apparent at birth and diagnosis of the disorder is usually made between 1 and 4 years of age. | 82 | Angelman Syndrome |
nord_82_1 | Symptoms of Angelman Syndrome | Angelman syndrome is associated with a broad spectrum of possible symptoms. The specific symptoms of Angelman syndrome vary from person to person. Individuals with Angelman syndrome will not have all of the symptoms discussed below. For example, some individuals with Angelman syndrome may have seizures, others may not. Most may be unable to speak while in a few there is some limited speech.Children with Angelman syndrome experience delays in reaching developmental milestones (developmental delays) and have severe learning disabilities. Children with Angelman syndrome also have significant communication difficulties. Most children do not develop the ability to speak more than a few words. Children usually can understand simple commands. Older children and adults may be able to communicate through gesturing and or using communication boards.An early finding in most children with Angelman syndrome is a movement or balance abnormality that includes jerky movements due to an inability to coordinate voluntary movements (ataxia). Children with Angelman syndrome may hold their arms up with the wrists and elbows bent and may flap their hands repeatedly when walking or excited. Diminished muscle tone (hypotonia) of the trunk, increased muscle tone (hypertonia) of the arms and legs, and abnormally exaggerated or brisk reflex responses (hyperreflexia) may also occur. Some children with Angelman syndrome experience subtle tremors of the arms and legs. These movement disorders may be apparent early during infancy (approximately 6-12 months of age). Motor milestones (e.g., walking) are usually delayed. In mild cases, children may begin to walk at 2-3 years of age. In more severe cases, walking may be noticeably slow, stiff and jerky. Some children may not be able to walk until they are 5-10 years of age. In approximately 10 percent of cases, children with Angelman syndrome do not walk unaided.Infants and children with Angelman syndrome have a distinct behavioral pattern marked by a happy demeanor with frequent and often inappropriate episodes of unprovoked, prolonged laughter and smiling. Children with Angelman syndrome may be easily excited, hypermotoric and hyperactive. They are active explorers and often may appear to be constantly in motion.Individuals with Angelman syndrome may have microcephaly in which the circumference of the head is smaller than would normally be expected for a child’s age and weight. In many cases, epileptic seizures may also occur. Seizures usually begin between one and five years of age and often improve by adolescence.Some findings associated with Angelman syndrome occur less often than the above-mentioned symptoms. In some cases, individuals with Angelman syndrome may have distinctive facial features including a prominent chin, deep-set eyes, an abnormally wide mouth (marcostomia) with a protruding tongue, widely-spaced teeth and an abnormally flat back of the head (brachycephaly).Feeding problems may occur during infancy often as a result of poor sucking ability. Infants with Angelman syndrome may also have swallowing difficulties. Feeding problems associated with Angelman syndrome are usually not severe. Children or adults with Angelman syndrome may experience constipation or gastroesophageal reflux disorder (GERD), a condition characterized by backflow (reflux) of the contents of stomach or small intestines into the tube that connects the mouth to the stomach (esophagus).Additional findings include excessive drooling, crossed eyes (strabismus), lack of normal color of the (hypopigmentation) of the skin, eyes and hair due to lack of certain melanin pigments. This lack of pigment in the eye may cause sensitivity to light (photophobia), rapid, involuntary eye movements (nystagmus) and decreased clarity of vision (visual acuity). Sleep disturbances such as a decreased need for sleep and disrupted or abnormal sleep/wake cycles (e.g., awaking at night or rising earlier than normal) are frequent findings in children with Angelman syndrome. Children with Angelman syndrome may also have a fascination with water, love music, and be attracted to shiny objects. Some children may have an increased sensitivity to heat. As children with Angelman syndrome age, progressive side-to-side curvature of the spine (scoliosis) may become apparent. Puberty is usually unaffected in children with Angelman syndrome and fertility is possible.Adults with Angelman syndrome may have more pronounced facial features such as a more prominent lower jaw (mandibular prognathism). Some individuals may develop abnormal protrusion of the cornea (keratoconus). Mobility may decrease as some individuals grow older and stiffening of the joints (contractures) may also develop. Some older children and adults may be prone to obesity. | Symptoms of Angelman Syndrome. Angelman syndrome is associated with a broad spectrum of possible symptoms. The specific symptoms of Angelman syndrome vary from person to person. Individuals with Angelman syndrome will not have all of the symptoms discussed below. For example, some individuals with Angelman syndrome may have seizures, others may not. Most may be unable to speak while in a few there is some limited speech.Children with Angelman syndrome experience delays in reaching developmental milestones (developmental delays) and have severe learning disabilities. Children with Angelman syndrome also have significant communication difficulties. Most children do not develop the ability to speak more than a few words. Children usually can understand simple commands. Older children and adults may be able to communicate through gesturing and or using communication boards.An early finding in most children with Angelman syndrome is a movement or balance abnormality that includes jerky movements due to an inability to coordinate voluntary movements (ataxia). Children with Angelman syndrome may hold their arms up with the wrists and elbows bent and may flap their hands repeatedly when walking or excited. Diminished muscle tone (hypotonia) of the trunk, increased muscle tone (hypertonia) of the arms and legs, and abnormally exaggerated or brisk reflex responses (hyperreflexia) may also occur. Some children with Angelman syndrome experience subtle tremors of the arms and legs. These movement disorders may be apparent early during infancy (approximately 6-12 months of age). Motor milestones (e.g., walking) are usually delayed. In mild cases, children may begin to walk at 2-3 years of age. In more severe cases, walking may be noticeably slow, stiff and jerky. Some children may not be able to walk until they are 5-10 years of age. In approximately 10 percent of cases, children with Angelman syndrome do not walk unaided.Infants and children with Angelman syndrome have a distinct behavioral pattern marked by a happy demeanor with frequent and often inappropriate episodes of unprovoked, prolonged laughter and smiling. Children with Angelman syndrome may be easily excited, hypermotoric and hyperactive. They are active explorers and often may appear to be constantly in motion.Individuals with Angelman syndrome may have microcephaly in which the circumference of the head is smaller than would normally be expected for a child’s age and weight. In many cases, epileptic seizures may also occur. Seizures usually begin between one and five years of age and often improve by adolescence.Some findings associated with Angelman syndrome occur less often than the above-mentioned symptoms. In some cases, individuals with Angelman syndrome may have distinctive facial features including a prominent chin, deep-set eyes, an abnormally wide mouth (marcostomia) with a protruding tongue, widely-spaced teeth and an abnormally flat back of the head (brachycephaly).Feeding problems may occur during infancy often as a result of poor sucking ability. Infants with Angelman syndrome may also have swallowing difficulties. Feeding problems associated with Angelman syndrome are usually not severe. Children or adults with Angelman syndrome may experience constipation or gastroesophageal reflux disorder (GERD), a condition characterized by backflow (reflux) of the contents of stomach or small intestines into the tube that connects the mouth to the stomach (esophagus).Additional findings include excessive drooling, crossed eyes (strabismus), lack of normal color of the (hypopigmentation) of the skin, eyes and hair due to lack of certain melanin pigments. This lack of pigment in the eye may cause sensitivity to light (photophobia), rapid, involuntary eye movements (nystagmus) and decreased clarity of vision (visual acuity). Sleep disturbances such as a decreased need for sleep and disrupted or abnormal sleep/wake cycles (e.g., awaking at night or rising earlier than normal) are frequent findings in children with Angelman syndrome. Children with Angelman syndrome may also have a fascination with water, love music, and be attracted to shiny objects. Some children may have an increased sensitivity to heat. As children with Angelman syndrome age, progressive side-to-side curvature of the spine (scoliosis) may become apparent. Puberty is usually unaffected in children with Angelman syndrome and fertility is possible.Adults with Angelman syndrome may have more pronounced facial features such as a more prominent lower jaw (mandibular prognathism). Some individuals may develop abnormal protrusion of the cornea (keratoconus). Mobility may decrease as some individuals grow older and stiffening of the joints (contractures) may also develop. Some older children and adults may be prone to obesity. | 82 | Angelman Syndrome |
nord_82_2 | Causes of Angelman Syndrome | Deficiency of the E3 ubiquitin protein ligase (UBE3A) gene expression causes Angelman syndrome. The gene is located in chromosome region 15 (15q11-q13).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 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 15q11-q13” refers to bands 11-13 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The abnormalities of UBE3A that can cause Angelman syndrome involve absence of the gene, changes in the structure of the gene, or changes in the function or expression of the gene. Genetic mechanisms that can disrupt UBE3A include chromosome deletion, imprinting error, paternal uniparental disomy and UBE3A mutation (see below). In approximately 10 percent of cases, no cause can be identified. In most cases of Angelman syndrome, these genetic changes appear to occur randomly (sporadically) but in about 3-5% they can be inherited.In approximately 70-75 percent of cases there is a microdeletion of region 15q11-13 of the maternally-derived chromosome 15 that includes deletion of the UBE3A gene. This deletion usually occurs sporadically (de novo) and is not inherited. The risk of recurrence for the deletion in a family is estimated to be 1-2 percent or less.In about 1 percent of cases, a deletion of this chromosomal region may occur due to a complex chromosomal rearrangement, in which a segment of chromosome 15 breaks off and moves to another chromosomal location. Those with this type of mechanism for the deletion are at a greater risk for recurrence.A unique genetic phenomenon associated with Angelman syndrome is “imprinting.” Everyone has two copies of every gene (except for genes on the Y chromosome): one received from the father and the other from the mother. In most cases both genes are turned on and are thus active. However, in some cases, one gene is preferentially silenced or turned off depending upon which parent that gene came from. This process of “parent-of-origin” inactivation is an example of “genomic imprinting”. Genomic imprinting is controlled by molecular switches, and some of these switches act through a process called DNA methylation. Proper genetic imprinting is necessary for normal development. Imprinted genes tend to be found clustered or grouped together. Several imprinted genes are found in region 15q11-13 of chromosome 15. This region also contains an area known as the Imprinting Center, and this area regulates the imprinted genes in this region.Some individuals with Angelman syndrome (approximately 3-5 percent) have a defect in genetic imprinting caused by errors in DNA methylation (see above for imprinting definition). In approximately 20 percent of cases (of the 3-5%) this is caused by a deletion of DNA within the Imprinting Center; the remaining 80 percent of cases are caused by as yet unknown or unidentified defects in genetic imprinting. There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to imprinting defects that have DNA deletions.Approximately 2-5 percent of Angelman syndrome cases are caused by uniparental disomy, an abnormality in which a person receives both copies of a chromosome from one parent instead of receiving one from each parent. In Angelman syndrome, both copies of chromosome 15 can be received from the father (paternal uniparental disomy). As a result, there are only paternally-expressed genes in this region and UBE3A is thus not expressed at all in the brain since it is normally only expressed on the maternal-derived chromosome. The risk of recurrence of uniparental disomy is less than 1 percent.Abnormal changes (mutations) within UBE3A have been detected in 10-20 percent of individuals with Angelman syndrome. Loss of function of this gene causes all the cardinal clinical features of Angelman syndrome. UBE3A contains instructions for creating (encoding) the ubiquitin ligase protein. This protein marks other proteins so that the body is able to degrade targeted proteins, a process known as ubiquitination. There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to a mutation of the UBE3A gene.Some individuals with the symptoms of Angelman syndrome have no identifiable abnormality of chromosome 15. Some individuals in this group may have a disorder different from Angelman syndrome, but others may have an undetected mutation of the UBE3A gene or a mutation in another, yet-to-be-identified gene that can also cause or mimic Angelman syndrome. | Causes of Angelman Syndrome. Deficiency of the E3 ubiquitin protein ligase (UBE3A) gene expression causes Angelman syndrome. The gene is located in chromosome region 15 (15q11-q13).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 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 15q11-q13” refers to bands 11-13 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The abnormalities of UBE3A that can cause Angelman syndrome involve absence of the gene, changes in the structure of the gene, or changes in the function or expression of the gene. Genetic mechanisms that can disrupt UBE3A include chromosome deletion, imprinting error, paternal uniparental disomy and UBE3A mutation (see below). In approximately 10 percent of cases, no cause can be identified. In most cases of Angelman syndrome, these genetic changes appear to occur randomly (sporadically) but in about 3-5% they can be inherited.In approximately 70-75 percent of cases there is a microdeletion of region 15q11-13 of the maternally-derived chromosome 15 that includes deletion of the UBE3A gene. This deletion usually occurs sporadically (de novo) and is not inherited. The risk of recurrence for the deletion in a family is estimated to be 1-2 percent or less.In about 1 percent of cases, a deletion of this chromosomal region may occur due to a complex chromosomal rearrangement, in which a segment of chromosome 15 breaks off and moves to another chromosomal location. Those with this type of mechanism for the deletion are at a greater risk for recurrence.A unique genetic phenomenon associated with Angelman syndrome is “imprinting.” Everyone has two copies of every gene (except for genes on the Y chromosome): one received from the father and the other from the mother. In most cases both genes are turned on and are thus active. However, in some cases, one gene is preferentially silenced or turned off depending upon which parent that gene came from. This process of “parent-of-origin” inactivation is an example of “genomic imprinting”. Genomic imprinting is controlled by molecular switches, and some of these switches act through a process called DNA methylation. Proper genetic imprinting is necessary for normal development. Imprinted genes tend to be found clustered or grouped together. Several imprinted genes are found in region 15q11-13 of chromosome 15. This region also contains an area known as the Imprinting Center, and this area regulates the imprinted genes in this region.Some individuals with Angelman syndrome (approximately 3-5 percent) have a defect in genetic imprinting caused by errors in DNA methylation (see above for imprinting definition). In approximately 20 percent of cases (of the 3-5%) this is caused by a deletion of DNA within the Imprinting Center; the remaining 80 percent of cases are caused by as yet unknown or unidentified defects in genetic imprinting. There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to imprinting defects that have DNA deletions.Approximately 2-5 percent of Angelman syndrome cases are caused by uniparental disomy, an abnormality in which a person receives both copies of a chromosome from one parent instead of receiving one from each parent. In Angelman syndrome, both copies of chromosome 15 can be received from the father (paternal uniparental disomy). As a result, there are only paternally-expressed genes in this region and UBE3A is thus not expressed at all in the brain since it is normally only expressed on the maternal-derived chromosome. The risk of recurrence of uniparental disomy is less than 1 percent.Abnormal changes (mutations) within UBE3A have been detected in 10-20 percent of individuals with Angelman syndrome. Loss of function of this gene causes all the cardinal clinical features of Angelman syndrome. UBE3A contains instructions for creating (encoding) the ubiquitin ligase protein. This protein marks other proteins so that the body is able to degrade targeted proteins, a process known as ubiquitination. There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to a mutation of the UBE3A gene.Some individuals with the symptoms of Angelman syndrome have no identifiable abnormality of chromosome 15. Some individuals in this group may have a disorder different from Angelman syndrome, but others may have an undetected mutation of the UBE3A gene or a mutation in another, yet-to-be-identified gene that can also cause or mimic Angelman syndrome. | 82 | Angelman Syndrome |
nord_82_3 | Affects of Angelman Syndrome | Angelman syndrome affects males and females in equal numbers. The prevalence of Angelman syndrome is estimated to be approximately 1 in 12,000-20,000 people in the general population. However, many cases may go undiagnosed making it difficult to determine the disorder’s prevalence in the general population. | Affects of Angelman Syndrome. Angelman syndrome affects males and females in equal numbers. The prevalence of Angelman syndrome is estimated to be approximately 1 in 12,000-20,000 people in the general population. However, many cases may go undiagnosed making it difficult to determine the disorder’s prevalence in the general population. | 82 | Angelman Syndrome |
nord_82_4 | Related disorders of Angelman Syndrome | Symptoms of the following disorders can be similar to those of Angelman syndrome. Comparisons may be useful for a differential diagnosis.Infants with Angelman syndrome commonly present with nonspecific psychomotor delay and/or seizures and so the differential diagnosis is often broad and nonspecific, encompassing such entities as cerebral palsy, static encephalopathy or mitochondrial encephalomyopathy. Tremulousness and jerky limb movements seen in most infants with Angelman syndrome may help distinguish Angelman syndrome from these conditions.Mowat-Wilson syndrome can present with findings that suggest Angelman syndrome, including happy affect, prominent mandible, diminished speech, microcephaly, and constipation. Mowat-Wilson syndrome typically results from heterozygous mutations in the ZEB2 gene. (For more information on this disorder, choose “Mowat-Wilson” as your search term in the Rare Disease Database.)Christianson syndrome, an X-linked disorder can mimic Angelman syndrome and involves mutations in the SLC9A6 gene. The clinical features include apparently happy disposition, severe cognitive delays, ataxia, microcephaly and a seizure disorder. Some may have cerebellar and brain stem atrophy. Individuals with SLC9A6 disorder may have thinner body appearance and may lose ambulation beyond 10 years of age.Adenylosuccinate lyase deficiency results in accumulation of succinylpurines leading to psychomotor retardation, autistic features, hypotonia, and seizures. Motor apraxia, severe speech deficits, excessive laughter, a very happy disposition, hyperactivity, a short attention span, mouthing of objects, tantrums and stereotyped movements have been reported.The characteristic features of Pitt-Hopkins syndrome are intellectual disability, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea. It may have overlapping features with Angelman syndrome such as microcephaly, seizures, ataxic gait and happy personality. Diurnal hyperventilation is a salient feature in some and occurs after three years of age. Mutation and deletion screening for the TCF4 gene is available. (For more information on this disorder, choose “Pitt-Hopkins” as your search term in the Rare Disease Database.)Infant girls with Angelman syndrome having seizures and severe speech impairment can resemble Rett syndrome, but children with Angelman syndrome do not have a regressive course and do not lose purposeful use of their hands, as do girls with Rett syndrome. Older girls with undiagnosed Rett syndrome may also have features that resemble Angelman syndrome, leading to the erroneous clinical diagnosis of Angelman syndrome. Testing for mutations of MECP2 is widely available. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.)Sometimes infants with Angelman syndrome who present with feeding difficulties and muscle hypotonia are misdiagnosed as having Prader-Willi syndrome because the 15q11.2-q13 deletion, detected by CGH or FISH, was not proven by DNA methylation analysis to be of maternal origin. (For more information on this disorder, choose “Prader-Willi” as your search term in the Rare Disease Database.)Other chromosome disorders can also mimic some of the features of Angelman syndrome, especially the 22q13.3 deletion (Phelan-McDermid syndrome). This condition may present with nondysmorphic facial features, absent or minimal speech, and moderate to severe developmental delay, sometimes with behavioral features in the autism spectrum. (For more information on this disorder, choose “Phelan-McDermid” as your search term in the Rare Disease Database.)Microdeletions of the 2q23.1 region may result in severe speech delay, seizures, behavioral disorders and microcephaly. Some individuals present with an Angelman syndrome-like phenotype. Other microdeletion disorders, especially newer ones detected by comparative genomic hybridization (chromosomal microarray analysis) may be associated with some features of Angelman syndrome.As chromosome microarray analysis and whole exome sequencing become more frequent in the testing of individuals who have nonspecific intellectual disability, additional conditions have been identified that mimic Angelman syndrome, and surely these conditions will increase over time. Some of these conditions include: KANSL1 haploinsufficiency syndrome (Koolen–de Vries syndrome); Kleefstra syndrome and variants; HERC2 deficiency syndrome; male MECP2 duplications; MEF2C syndrome and WAC-related intellectual disability. | Related disorders of Angelman Syndrome. Symptoms of the following disorders can be similar to those of Angelman syndrome. Comparisons may be useful for a differential diagnosis.Infants with Angelman syndrome commonly present with nonspecific psychomotor delay and/or seizures and so the differential diagnosis is often broad and nonspecific, encompassing such entities as cerebral palsy, static encephalopathy or mitochondrial encephalomyopathy. Tremulousness and jerky limb movements seen in most infants with Angelman syndrome may help distinguish Angelman syndrome from these conditions.Mowat-Wilson syndrome can present with findings that suggest Angelman syndrome, including happy affect, prominent mandible, diminished speech, microcephaly, and constipation. Mowat-Wilson syndrome typically results from heterozygous mutations in the ZEB2 gene. (For more information on this disorder, choose “Mowat-Wilson” as your search term in the Rare Disease Database.)Christianson syndrome, an X-linked disorder can mimic Angelman syndrome and involves mutations in the SLC9A6 gene. The clinical features include apparently happy disposition, severe cognitive delays, ataxia, microcephaly and a seizure disorder. Some may have cerebellar and brain stem atrophy. Individuals with SLC9A6 disorder may have thinner body appearance and may lose ambulation beyond 10 years of age.Adenylosuccinate lyase deficiency results in accumulation of succinylpurines leading to psychomotor retardation, autistic features, hypotonia, and seizures. Motor apraxia, severe speech deficits, excessive laughter, a very happy disposition, hyperactivity, a short attention span, mouthing of objects, tantrums and stereotyped movements have been reported.The characteristic features of Pitt-Hopkins syndrome are intellectual disability, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea. It may have overlapping features with Angelman syndrome such as microcephaly, seizures, ataxic gait and happy personality. Diurnal hyperventilation is a salient feature in some and occurs after three years of age. Mutation and deletion screening for the TCF4 gene is available. (For more information on this disorder, choose “Pitt-Hopkins” as your search term in the Rare Disease Database.)Infant girls with Angelman syndrome having seizures and severe speech impairment can resemble Rett syndrome, but children with Angelman syndrome do not have a regressive course and do not lose purposeful use of their hands, as do girls with Rett syndrome. Older girls with undiagnosed Rett syndrome may also have features that resemble Angelman syndrome, leading to the erroneous clinical diagnosis of Angelman syndrome. Testing for mutations of MECP2 is widely available. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.)Sometimes infants with Angelman syndrome who present with feeding difficulties and muscle hypotonia are misdiagnosed as having Prader-Willi syndrome because the 15q11.2-q13 deletion, detected by CGH or FISH, was not proven by DNA methylation analysis to be of maternal origin. (For more information on this disorder, choose “Prader-Willi” as your search term in the Rare Disease Database.)Other chromosome disorders can also mimic some of the features of Angelman syndrome, especially the 22q13.3 deletion (Phelan-McDermid syndrome). This condition may present with nondysmorphic facial features, absent or minimal speech, and moderate to severe developmental delay, sometimes with behavioral features in the autism spectrum. (For more information on this disorder, choose “Phelan-McDermid” as your search term in the Rare Disease Database.)Microdeletions of the 2q23.1 region may result in severe speech delay, seizures, behavioral disorders and microcephaly. Some individuals present with an Angelman syndrome-like phenotype. Other microdeletion disorders, especially newer ones detected by comparative genomic hybridization (chromosomal microarray analysis) may be associated with some features of Angelman syndrome.As chromosome microarray analysis and whole exome sequencing become more frequent in the testing of individuals who have nonspecific intellectual disability, additional conditions have been identified that mimic Angelman syndrome, and surely these conditions will increase over time. Some of these conditions include: KANSL1 haploinsufficiency syndrome (Koolen–de Vries syndrome); Kleefstra syndrome and variants; HERC2 deficiency syndrome; male MECP2 duplications; MEF2C syndrome and WAC-related intellectual disability. | 82 | Angelman Syndrome |
nord_82_5 | Diagnosis of Angelman Syndrome | A diagnosis of Angelman syndrome may be made based upon a detailed patient history, a thorough clinical evaluation and identification of characteristic findings. About 80% of cases can be confirmed through a variety of specialized blood tests such as DNA methylation (detects, but does not discriminate between chromosome deletion, imprinting center defect and paternal uniparental disomy). Fluorescent in situ hybridization (FISH) or, most commonly, microarray chromosome analysis can detect the characteristic deletion (seen in 70% of cases) of chromosome 15q11-q13 in cells of the body. Mutation analysis of the Angelman gene, UBE3A, can detect about 10% of individuals with Angelman syndrome who have negative DNA methylation studies. Mutation analysis of UBE3A can be either ordered specifically as a single test but, more often now, UBE3A mutations are identified by use of a whole exome sequencing panel that includes a group of many genes known to cause intellectual deficiency or when one performs a complete whole exome sequencing test (e.g., a screening test on approximately 20,000 genes). | Diagnosis of Angelman Syndrome. A diagnosis of Angelman syndrome may be made based upon a detailed patient history, a thorough clinical evaluation and identification of characteristic findings. About 80% of cases can be confirmed through a variety of specialized blood tests such as DNA methylation (detects, but does not discriminate between chromosome deletion, imprinting center defect and paternal uniparental disomy). Fluorescent in situ hybridization (FISH) or, most commonly, microarray chromosome analysis can detect the characteristic deletion (seen in 70% of cases) of chromosome 15q11-q13 in cells of the body. Mutation analysis of the Angelman gene, UBE3A, can detect about 10% of individuals with Angelman syndrome who have negative DNA methylation studies. Mutation analysis of UBE3A can be either ordered specifically as a single test but, more often now, UBE3A mutations are identified by use of a whole exome sequencing panel that includes a group of many genes known to cause intellectual deficiency or when one performs a complete whole exome sequencing test (e.g., a screening test on approximately 20,000 genes). | 82 | Angelman Syndrome |
nord_82_6 | Therapies of Angelman Syndrome | Treatment
At this time, therapies for Angelman syndrome are symptomatic and supportive. Several clinical trials on Angelman syndrome are ongoing (see below) but there is no genetic therapy or curative medication available. Advances in neuroscience and in gene therapy techniques however hold great potential for providing meaningful treatment and/or cure of the syndrome. The general physical health of those with Angelman syndrome is good and usual pediatric care, including customary childhood immunizations, can be provided.Anti-seizure medications (anticonvulsants) are helpful to those experiencing seizures. Usually seizures can be adequately controlled with a single medication but in some cases seizure control may be difficult and multiple medications are needed. No one anticonvulsant drug has been proven to be most effective in all cases. Sleep disorders are common and may require behavioral therapy and adherence to strict bedtime routines. At time, sedating medications can be helpful.Feeding difficulties may be treated by modified breast feeding methods and by means such as special nipples to assist infants with a poor ability to suck. Gastroesophageal reflux may be treated by upright positioning and drugs that aid the movement of food through the digestive system (motility drugs). Surgical tightening of the valve that connects the esophagus to the stomach (esophageal sphincter) may be required in some cases. Laxatives may be used to treat constipation.Ankle braces/supports and physical therapy can help in achievement of walking. Scoliosis can develop in about 10% and may require braces or surgical correction. In some cases, strabismus may require surgical correction.Early intervention is important to ensure that children with Angelman syndrome reach their potential. Special services that may be beneficial to children with Angelman syndrome may include special social support and other medical, social, and/or vocational services. Most children with Angelman syndrome benefit from physical, speech and occupational therapy. Behavioral modification therapy may be used to discourage unwanted behaviors. Use of special communication devices such as computer picture-based systems, voice emitting devices and other modern uses of technology all help Angelman syndrome individuals provide for improved learning and social communication.Genetic counseling is recommended for the families of those with Angelman syndrome. | Therapies of Angelman Syndrome. Treatment
At this time, therapies for Angelman syndrome are symptomatic and supportive. Several clinical trials on Angelman syndrome are ongoing (see below) but there is no genetic therapy or curative medication available. Advances in neuroscience and in gene therapy techniques however hold great potential for providing meaningful treatment and/or cure of the syndrome. The general physical health of those with Angelman syndrome is good and usual pediatric care, including customary childhood immunizations, can be provided.Anti-seizure medications (anticonvulsants) are helpful to those experiencing seizures. Usually seizures can be adequately controlled with a single medication but in some cases seizure control may be difficult and multiple medications are needed. No one anticonvulsant drug has been proven to be most effective in all cases. Sleep disorders are common and may require behavioral therapy and adherence to strict bedtime routines. At time, sedating medications can be helpful.Feeding difficulties may be treated by modified breast feeding methods and by means such as special nipples to assist infants with a poor ability to suck. Gastroesophageal reflux may be treated by upright positioning and drugs that aid the movement of food through the digestive system (motility drugs). Surgical tightening of the valve that connects the esophagus to the stomach (esophageal sphincter) may be required in some cases. Laxatives may be used to treat constipation.Ankle braces/supports and physical therapy can help in achievement of walking. Scoliosis can develop in about 10% and may require braces or surgical correction. In some cases, strabismus may require surgical correction.Early intervention is important to ensure that children with Angelman syndrome reach their potential. Special services that may be beneficial to children with Angelman syndrome may include special social support and other medical, social, and/or vocational services. Most children with Angelman syndrome benefit from physical, speech and occupational therapy. Behavioral modification therapy may be used to discourage unwanted behaviors. Use of special communication devices such as computer picture-based systems, voice emitting devices and other modern uses of technology all help Angelman syndrome individuals provide for improved learning and social communication.Genetic counseling is recommended for the families of those with Angelman syndrome. | 82 | Angelman Syndrome |
nord_83_0 | Overview of Angioimmunoblastic T-Cell Lymphoma | Angioimmunoblastic T-cell lymphoma (AITL) is a rare form of non-Hodgkin lymphoma, which is a group of related malignancies (cancers) that affect the lymphatic system (lymphomas). Lymphomas are cancer of white blood cells (lymphocytes) and can be divided depending on the type of cells, B-lymphocytes (B-cells) or T-lymphocytes (T-cells), AITL is a T-cell lymphoma. The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream.Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including, but not limited to, the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body. There are two main types of lymphocytes: B-lymphocytes (B-cells), which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes (T-cells), which may directly destroy microorganisms or assist in the activities of other lymphocytes.AITL is characterized by the transformation of a T-cell into a malignant cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant T-cells may lead to enlargement of a specific lymph node region or regions; involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs. A key and differentiating aspect of AITL is dysfunction of the immune system, which can lead to a variety of symptoms. Affected individuals may develop a rash, persistent fever, unintended weight loss, tissue swelling due to the accumulation of fluid (edema) and additional symptoms. The exact, underlying cause of AITL is not fully understood. | Overview of Angioimmunoblastic T-Cell Lymphoma. Angioimmunoblastic T-cell lymphoma (AITL) is a rare form of non-Hodgkin lymphoma, which is a group of related malignancies (cancers) that affect the lymphatic system (lymphomas). Lymphomas are cancer of white blood cells (lymphocytes) and can be divided depending on the type of cells, B-lymphocytes (B-cells) or T-lymphocytes (T-cells), AITL is a T-cell lymphoma. The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream.Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including, but not limited to, the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body. There are two main types of lymphocytes: B-lymphocytes (B-cells), which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes (T-cells), which may directly destroy microorganisms or assist in the activities of other lymphocytes.AITL is characterized by the transformation of a T-cell into a malignant cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant T-cells may lead to enlargement of a specific lymph node region or regions; involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs. A key and differentiating aspect of AITL is dysfunction of the immune system, which can lead to a variety of symptoms. Affected individuals may develop a rash, persistent fever, unintended weight loss, tissue swelling due to the accumulation of fluid (edema) and additional symptoms. The exact, underlying cause of AITL is not fully understood. | 83 | Angioimmunoblastic T-Cell Lymphoma |
nord_83_1 | Symptoms of Angioimmunoblastic T-Cell Lymphoma | The specific symptoms and physical findings may vary from one person to another, depending upon the extent and region(s) of involvement and other factors. The progression is often aggressive, but spontaneous remission has occurred in some people. All organ systems can potentially be affected. Researchers believe that many of the symptoms associated with AITL result from dysfunction of the immune system rather than from complications relating to tumor growth or spread. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific situation, associated symptoms and overall prognosis.The initial symptoms are often vague and tend to come and go. Some affected individuals develop certain generalized (systemic) symptoms known as “B symptoms”. These symptoms are common in many different types of disorders. Such symptoms include persistent or repeated fever, unexplained weight loss (i.e., loss of at least 10 percent of normal body weight), and/or sweating, particularly at night (known as “night sweats”). Another common finding associated with AITL is the mild-to-moderate enlargement of various lymph nodes in the body (generalized lymphadenopathy). Lymph nodes in the neck, armpit and groin are most often affected. Another symptom sometimes associated with AITL is the development of a distinctive skin rash that may or may not be itchy (pruritic). Itchiness can be a significant problem in some people. Affected individuals may have a history of chronic skin rashes. Generally, the skin rash resembles the rash associated with measles (morbilliform) and may be reddened (erythematous) with small spots or bumps (maculopapular). Individuals may also experience fatigue, a general feeling of poor health (malaise), fluid accumulation around the lungs (pleural effusion) and ascites, which is the excess fluid accumulation between the space lining the abdomen and the abdominal organs (peritoneal cavity). Abnormal enlargement of the liver (hepatomegaly) and/or the spleen (splenomegaly) may also occur. Individuals with AITL may also develop symptoms directly associated with immune dysfunction including autoimmune hemolytic anemia, low levels of specialized red blood cells called platelets that assist in clotting (thrombocytopenia), inflammation of multiple joints (polyarthritis), vasculitis and autoimmune thyroid disease. Autoimmune hemolytic anemia is caused by the premature destruction of red blood cells and may result in fatigue, pale skin color, dark urine, shortness of breath and a rapid heartbeat. A common symptom of thrombocytopenia is bleeding into the skin resulting in bruising (purpura), or bleeding from the mucous membrane. Vasculitis is a general term for inflammation of the blood vessels. The symptoms of vasculitis vary based upon the specific blood vessels and organ systems involved. Autoimmune thyroid disease occurs when the immune system attacks and damages the thyroid.Affected individuals may also be prone to developing certain infections because of disease-related suppression of the immune system. Such infections can potentially cause severe, life-threatening complications.Less often, individuals with AITL may develop neurological and gastrointestinal abnormalities. Neurological abnormalities may include confusion, a lack of interest in normal activities and social interaction (apathy), ringing in the ears (tinnitus), inflammation of the peripheral nerves (polyneuritis), swelling of the optic disc (papilledema) and hearing or visual impairment. Gastrointestinal abnormalities may include mucosal ulcers, diarrhea, GI bleeding, the development of multiple polyps in the GI tract (lymphomatous polyposis) and inflammation, hardening and destruction of the bile ducts (sclerosing cholangitis). | Symptoms of Angioimmunoblastic T-Cell Lymphoma. The specific symptoms and physical findings may vary from one person to another, depending upon the extent and region(s) of involvement and other factors. The progression is often aggressive, but spontaneous remission has occurred in some people. All organ systems can potentially be affected. Researchers believe that many of the symptoms associated with AITL result from dysfunction of the immune system rather than from complications relating to tumor growth or spread. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific situation, associated symptoms and overall prognosis.The initial symptoms are often vague and tend to come and go. Some affected individuals develop certain generalized (systemic) symptoms known as “B symptoms”. These symptoms are common in many different types of disorders. Such symptoms include persistent or repeated fever, unexplained weight loss (i.e., loss of at least 10 percent of normal body weight), and/or sweating, particularly at night (known as “night sweats”). Another common finding associated with AITL is the mild-to-moderate enlargement of various lymph nodes in the body (generalized lymphadenopathy). Lymph nodes in the neck, armpit and groin are most often affected. Another symptom sometimes associated with AITL is the development of a distinctive skin rash that may or may not be itchy (pruritic). Itchiness can be a significant problem in some people. Affected individuals may have a history of chronic skin rashes. Generally, the skin rash resembles the rash associated with measles (morbilliform) and may be reddened (erythematous) with small spots or bumps (maculopapular). Individuals may also experience fatigue, a general feeling of poor health (malaise), fluid accumulation around the lungs (pleural effusion) and ascites, which is the excess fluid accumulation between the space lining the abdomen and the abdominal organs (peritoneal cavity). Abnormal enlargement of the liver (hepatomegaly) and/or the spleen (splenomegaly) may also occur. Individuals with AITL may also develop symptoms directly associated with immune dysfunction including autoimmune hemolytic anemia, low levels of specialized red blood cells called platelets that assist in clotting (thrombocytopenia), inflammation of multiple joints (polyarthritis), vasculitis and autoimmune thyroid disease. Autoimmune hemolytic anemia is caused by the premature destruction of red blood cells and may result in fatigue, pale skin color, dark urine, shortness of breath and a rapid heartbeat. A common symptom of thrombocytopenia is bleeding into the skin resulting in bruising (purpura), or bleeding from the mucous membrane. Vasculitis is a general term for inflammation of the blood vessels. The symptoms of vasculitis vary based upon the specific blood vessels and organ systems involved. Autoimmune thyroid disease occurs when the immune system attacks and damages the thyroid.Affected individuals may also be prone to developing certain infections because of disease-related suppression of the immune system. Such infections can potentially cause severe, life-threatening complications.Less often, individuals with AITL may develop neurological and gastrointestinal abnormalities. Neurological abnormalities may include confusion, a lack of interest in normal activities and social interaction (apathy), ringing in the ears (tinnitus), inflammation of the peripheral nerves (polyneuritis), swelling of the optic disc (papilledema) and hearing or visual impairment. Gastrointestinal abnormalities may include mucosal ulcers, diarrhea, GI bleeding, the development of multiple polyps in the GI tract (lymphomatous polyposis) and inflammation, hardening and destruction of the bile ducts (sclerosing cholangitis). | 83 | Angioimmunoblastic T-Cell Lymphoma |
nord_83_2 | Causes of Angioimmunoblastic T-Cell Lymphoma | The exact, underlying cause of AITL is unknown. It is believed that a dysfunctional immune system response to an unknown antigen ultimately leads to the development of the disorder. An antigen is any substance that causes the immune system to produce antibodies. The process through which a dysfunctional or abnormal immune system response ultimately progresses to lymphoma is not fully understood. No specific risk factors have been confirmed to be associated with AITL. Many people have developed the disorder following the administration of certain drugs such as antibiotics, after a viral infection, or after an allergic reaction. Suspected risk factors include several viruses including the Epstein-Barr virus, cytomegalovirus, hepatitis C virus, human herpes viruses 6 and 8, and the human immunodeficiency virus. Certain infectious agents including tuberculosis and Cryptococcus have also been linked to AITL. It is not known what role, if any, that these potential risk factors play in the development of the disorder. The Epstein-Barr virus, in particular, has been found in more than 90 percent of individuals with AITL. However, the virus is found in B-cells and not the cancerous T-cells. Consequently, some researchers have suggested that the virus most likely does not play a primary role in the development of the disorder. However, EBV positive B cells are found very early in the disease process and other researchers suggest that the virus may play a more significant role in the development of AITL than previously thought. Researchers have also discovered that some people may have a genetic predisposition to developing AITL. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. Researchers have shown that many people have specific altered genes including the DNMT3A, TET2, IDH2, and RhoA genes. The exact role these gene changes play in the development of AITL is not fully understood. Another substance that may play a role in the development of AITL is vascular endothelial growth factor A (VEGF-A). This substance is critical in tumor angiogenesis, which is the process by which tumors create a network of blood vessels in order to receive nutrients and oxygen and remove waste. Researchers believe that therapies targeted at VEGF-A can disrupt tumor angiogenesis and prevent tumors from growing. More research is necessary to determine the exact underlying mechanisms that ultimately cause AITL. | Causes of Angioimmunoblastic T-Cell Lymphoma. The exact, underlying cause of AITL is unknown. It is believed that a dysfunctional immune system response to an unknown antigen ultimately leads to the development of the disorder. An antigen is any substance that causes the immune system to produce antibodies. The process through which a dysfunctional or abnormal immune system response ultimately progresses to lymphoma is not fully understood. No specific risk factors have been confirmed to be associated with AITL. Many people have developed the disorder following the administration of certain drugs such as antibiotics, after a viral infection, or after an allergic reaction. Suspected risk factors include several viruses including the Epstein-Barr virus, cytomegalovirus, hepatitis C virus, human herpes viruses 6 and 8, and the human immunodeficiency virus. Certain infectious agents including tuberculosis and Cryptococcus have also been linked to AITL. It is not known what role, if any, that these potential risk factors play in the development of the disorder. The Epstein-Barr virus, in particular, has been found in more than 90 percent of individuals with AITL. However, the virus is found in B-cells and not the cancerous T-cells. Consequently, some researchers have suggested that the virus most likely does not play a primary role in the development of the disorder. However, EBV positive B cells are found very early in the disease process and other researchers suggest that the virus may play a more significant role in the development of AITL than previously thought. Researchers have also discovered that some people may have a genetic predisposition to developing AITL. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. Researchers have shown that many people have specific altered genes including the DNMT3A, TET2, IDH2, and RhoA genes. The exact role these gene changes play in the development of AITL is not fully understood. Another substance that may play a role in the development of AITL is vascular endothelial growth factor A (VEGF-A). This substance is critical in tumor angiogenesis, which is the process by which tumors create a network of blood vessels in order to receive nutrients and oxygen and remove waste. Researchers believe that therapies targeted at VEGF-A can disrupt tumor angiogenesis and prevent tumors from growing. More research is necessary to determine the exact underlying mechanisms that ultimately cause AITL. | 83 | Angioimmunoblastic T-Cell Lymphoma |
nord_83_3 | Affects of Angioimmunoblastic T-Cell Lymphoma | The incidence of AITL in the general population is unknown. It is estimated to account for 1-2 percent of all people with non-Hodgkin lymphoma. Some reports state the AITL occurs slightly more often in men than women, but others state the ratio is 1:1. Most people develop AITL in their 60s and 70s. The disorder can occur in younger adults and, although rarely, has also been reported in children. The disorder was first reported in the medical literature in 1974 by Frizzera et al. and called angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). AITL is subclassified as a peripheral T-cell lymphoma (PTCL). PTCLs account for approximately 10-15 percent of all occurrences of non-Hodgkin lymphoma. | Affects of Angioimmunoblastic T-Cell Lymphoma. The incidence of AITL in the general population is unknown. It is estimated to account for 1-2 percent of all people with non-Hodgkin lymphoma. Some reports state the AITL occurs slightly more often in men than women, but others state the ratio is 1:1. Most people develop AITL in their 60s and 70s. The disorder can occur in younger adults and, although rarely, has also been reported in children. The disorder was first reported in the medical literature in 1974 by Frizzera et al. and called angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). AITL is subclassified as a peripheral T-cell lymphoma (PTCL). PTCLs account for approximately 10-15 percent of all occurrences of non-Hodgkin lymphoma. | 83 | Angioimmunoblastic T-Cell Lymphoma |
nord_83_4 | Related disorders of Angioimmunoblastic T-Cell Lymphoma | Symptoms of the following disorders can be similar to those of AITL. Comparisons may be useful for a differential diagnosis.As stated earlier, lymphomas are cancer of white blood cells (lymphocytes). There are two major categories called Hodgkin disease (lymphoma) and non-Hodgkin lymphoma (NHL). Hodgkin disease is typically characterized by the presence of a specific type of cancer cell known as a Reed-Sternberg cell that has more than one nucleus. This cell is a mature B-lymphocyte (B-cell) that has become malignant. NHL is broadly categorized into lymphomas that arise from two different types of cells, B-lymphocytes or T-lymphocytes (T-cells). There are many forms of NHL. (For more information on some of these disorders, choose the specific type of lymphoma as your search term in the Rare Disease Database.)PTCL is a group of rare, aggressive lymphomas. PTCLs are a subgroup of non-Hodgkin lymphoma (NHL). PTCLs are T-cell lymphomas that develop from malignant T-lymphocytes. PTCLs are generally classified as rapidly-growing (aggressive) lymphomas. Because of their rarity, PTCLs are poorly understood. However, new techniques to distinguish the various subtypes of PTCL have recently been developed and it is hoped that standards for the best treatment will be established soon as well. | Related disorders of Angioimmunoblastic T-Cell Lymphoma. Symptoms of the following disorders can be similar to those of AITL. Comparisons may be useful for a differential diagnosis.As stated earlier, lymphomas are cancer of white blood cells (lymphocytes). There are two major categories called Hodgkin disease (lymphoma) and non-Hodgkin lymphoma (NHL). Hodgkin disease is typically characterized by the presence of a specific type of cancer cell known as a Reed-Sternberg cell that has more than one nucleus. This cell is a mature B-lymphocyte (B-cell) that has become malignant. NHL is broadly categorized into lymphomas that arise from two different types of cells, B-lymphocytes or T-lymphocytes (T-cells). There are many forms of NHL. (For more information on some of these disorders, choose the specific type of lymphoma as your search term in the Rare Disease Database.)PTCL is a group of rare, aggressive lymphomas. PTCLs are a subgroup of non-Hodgkin lymphoma (NHL). PTCLs are T-cell lymphomas that develop from malignant T-lymphocytes. PTCLs are generally classified as rapidly-growing (aggressive) lymphomas. Because of their rarity, PTCLs are poorly understood. However, new techniques to distinguish the various subtypes of PTCL have recently been developed and it is hoped that standards for the best treatment will be established soon as well. | 83 | Angioimmunoblastic T-Cell Lymphoma |
nord_83_5 | Diagnosis of Angioimmunoblastic T-Cell Lymphoma | A diagnosis of AITL is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a biopsy of an affected lymph node or other affected areas such as the skin or bone marrow.During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling, including in the neck and tonsil region, under the arms, on or near the elbows, and in the groin. They may also examine other regions to help determine whether there is enlargement of certain internal organs, particularly the spleen and liver, and to detect swelling and abnormal fluid accumulation that may be associated with disease of the lymphatic system.Biopsies typically involve the removal and microscopic (i.e., histologic) examination of small samples of tissue cells from a lymph node–or, in some instances, removal of an entire, enlarged lymph node–that is suspected of being cancerous. Biopsy samples are examined by physicians who specialize in analyzing cells and tissues to help obtain accurate diagnosis (pathologists).Additional various diagnostic tests may be recommended to assess the extent of AITL. These tests may include blood tests, specialized imaging tests and bone marrow examination. For example, blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; liver enzyme studies; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies.)Specialized imaging techniques may include magnetic resonance imaging (MRI), computed tomography (CT) scanning, and positron emission tomography (PET scan) may aid in the diagnosis of AITL. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. CT scanning and MRIs may be used to help detect enlargement of certain lymph nodes or the spread of malignancy to certain organs. During a PET scan, three-dimensional images are produced to evaluate how healthy and functional certain tissues and organs are. This exam involves the use of a radioactive drug called a tracer. This drug is inhaled, injected or swallowed by an individual, and will accumulate in areas where there is excess areas of chemical activity, which is an indication of disease. These areas will show up on the PET scan as brighter than the surrounding areas. A procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. During this procedure, a sample of bone marrow is obtained, usually from the hipbone (iliac crest). Skin and tissue over the bone is first numbed with local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. The sample is then examined under a microscope by a pathologist. Because a bone marrow biopsy may be painful, a mild, calming (sedative) medication may be offered before the procedure is conducted.Staging
When an individual is diagnosed with a non-Hodgkin lymphoma (NHL) such as AITL, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging NHL (e.g., blood tests, CT scanning, bone marrow biopsy, PET scan). In addition, in some people, additional biopsies may be obtained to assist in lymphoma staging.The specific stage of NHL may be based upon the number of lymph node regions involved; whether such lymph nodes are located above, below, or on both sides of the diaphragm*; and/or whether the malignancy has infiltrated other lymphatic tissues, such as the spleen or bone marrow, or spread to involve other organs outside the lymphatic system, such as the liver. (*The diaphragm is the dome-shaped muscle that separates the chest from the abdomen and plays an essential role in breathing.)Although various staging systems have been described, a system commonly used for adult NHL is the Ann Arbor staging system, which includes the following stages:Stage I – indicates early, localized disease in which the malignancy is limited to a single lymph node region or in a single organ or region outside the lymph node (extralymphatic organ or site).Stage II – indicates locally advanced disease in which the malignancy involves more than one lymph node region on one side of the diaphragm or is found within one extralymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).Stage III – indicates advanced disease in which the lymphoma involves lymph node regions on both sides of (i.e., above and below) the diaphragm and may involve the spleen. There may also be localized involvement of an extralymphatic organ or site.Stage IV – indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extralymphatic organs or sites with or without associated lymph node involvement.Each stage of NHL may be further divided into categories A or B, based upon whether or not affected individuals have symptoms. More specifically:A indicates that no generalized (systemic) symptoms are present upon diagnosis.B indicates that an affected individual has experienced drenching night sweats, unexplained fever (above 38 degrees Celsius), and/or unexplained weight loss (i.e., loss of at least 10 percent of total body weight in the six months prior to diagnosis). In addition, category E may indicate that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ.Various additional elements may be considered as physicians determine the stage of NHL, potential disease course, and appropriate treatment options. Such factors may include patient age and general health, tumor size, levels of the enzyme lactate dehydrogenase, extranodal site involvement, and other factors. | Diagnosis of Angioimmunoblastic T-Cell Lymphoma. A diagnosis of AITL is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a biopsy of an affected lymph node or other affected areas such as the skin or bone marrow.During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling, including in the neck and tonsil region, under the arms, on or near the elbows, and in the groin. They may also examine other regions to help determine whether there is enlargement of certain internal organs, particularly the spleen and liver, and to detect swelling and abnormal fluid accumulation that may be associated with disease of the lymphatic system.Biopsies typically involve the removal and microscopic (i.e., histologic) examination of small samples of tissue cells from a lymph node–or, in some instances, removal of an entire, enlarged lymph node–that is suspected of being cancerous. Biopsy samples are examined by physicians who specialize in analyzing cells and tissues to help obtain accurate diagnosis (pathologists).Additional various diagnostic tests may be recommended to assess the extent of AITL. These tests may include blood tests, specialized imaging tests and bone marrow examination. For example, blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; liver enzyme studies; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies.)Specialized imaging techniques may include magnetic resonance imaging (MRI), computed tomography (CT) scanning, and positron emission tomography (PET scan) may aid in the diagnosis of AITL. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. CT scanning and MRIs may be used to help detect enlargement of certain lymph nodes or the spread of malignancy to certain organs. During a PET scan, three-dimensional images are produced to evaluate how healthy and functional certain tissues and organs are. This exam involves the use of a radioactive drug called a tracer. This drug is inhaled, injected or swallowed by an individual, and will accumulate in areas where there is excess areas of chemical activity, which is an indication of disease. These areas will show up on the PET scan as brighter than the surrounding areas. A procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. During this procedure, a sample of bone marrow is obtained, usually from the hipbone (iliac crest). Skin and tissue over the bone is first numbed with local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. The sample is then examined under a microscope by a pathologist. Because a bone marrow biopsy may be painful, a mild, calming (sedative) medication may be offered before the procedure is conducted.Staging
When an individual is diagnosed with a non-Hodgkin lymphoma (NHL) such as AITL, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging NHL (e.g., blood tests, CT scanning, bone marrow biopsy, PET scan). In addition, in some people, additional biopsies may be obtained to assist in lymphoma staging.The specific stage of NHL may be based upon the number of lymph node regions involved; whether such lymph nodes are located above, below, or on both sides of the diaphragm*; and/or whether the malignancy has infiltrated other lymphatic tissues, such as the spleen or bone marrow, or spread to involve other organs outside the lymphatic system, such as the liver. (*The diaphragm is the dome-shaped muscle that separates the chest from the abdomen and plays an essential role in breathing.)Although various staging systems have been described, a system commonly used for adult NHL is the Ann Arbor staging system, which includes the following stages:Stage I – indicates early, localized disease in which the malignancy is limited to a single lymph node region or in a single organ or region outside the lymph node (extralymphatic organ or site).Stage II – indicates locally advanced disease in which the malignancy involves more than one lymph node region on one side of the diaphragm or is found within one extralymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).Stage III – indicates advanced disease in which the lymphoma involves lymph node regions on both sides of (i.e., above and below) the diaphragm and may involve the spleen. There may also be localized involvement of an extralymphatic organ or site.Stage IV – indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extralymphatic organs or sites with or without associated lymph node involvement.Each stage of NHL may be further divided into categories A or B, based upon whether or not affected individuals have symptoms. More specifically:A indicates that no generalized (systemic) symptoms are present upon diagnosis.B indicates that an affected individual has experienced drenching night sweats, unexplained fever (above 38 degrees Celsius), and/or unexplained weight loss (i.e., loss of at least 10 percent of total body weight in the six months prior to diagnosis). In addition, category E may indicate that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ.Various additional elements may be considered as physicians determine the stage of NHL, potential disease course, and appropriate treatment options. Such factors may include patient age and general health, tumor size, levels of the enzyme lactate dehydrogenase, extranodal site involvement, and other factors. | 83 | Angioimmunoblastic T-Cell Lymphoma |
nord_83_6 | Therapies of Angioimmunoblastic T-Cell Lymphoma | The diagnosis and therapeutic management of AITL may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage (see “Stages” above); tumor size; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Therapies used to treat individuals with AITL include corticosteroids, watch and wait, single-agent chemotherapy and multiagent chemotherapy.Corticosteroids, such as prednisone, are used to treat the symptoms of AITL that result from dysfunction of the immune system. Prednisone may be used alone or in conjunction with chemotherapy regimens.In select individuals with no aggressive features of AITL, physicians may recommend waiting before implementing treatment until the disease leads to certain symptoms. In such instances, thorough, frequent checkups are required to ensure that appropriate therapies are begun when the disease course accelerates. This approach to disease management is often called “watch and wait”.However, as discussed above, AITL is typically considered an aggressive form of lymphoma. Therefore, physicians may recommend combination therapy with multiple anticancer (chemotherapeutic) drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. For example, recommended treatment may include cyclophosphamide, doxorubicin or hydroxydaunorubicin (Adriamycin or Rubex), vincristine (Oncovin), and prednisone, known as the “CHOP” regimen.The initial response to CHOP is often good, but the overall effectiveness of CHOP and other chemotherapy regimens has largely been inadequate. Although many individuals initially experience a remission, most will eventually experience a relapse.Romidepsin is approved by the Food and Drug Administration for the treatment of individuals with peripheral T-cell lymphoma. The drug is a selective histone deacetylase (HDAC) inhibitor. Initial studies have shown the drug to be effective in individuals with AITL. | Therapies of Angioimmunoblastic T-Cell Lymphoma. The diagnosis and therapeutic management of AITL may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage (see “Stages” above); tumor size; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Therapies used to treat individuals with AITL include corticosteroids, watch and wait, single-agent chemotherapy and multiagent chemotherapy.Corticosteroids, such as prednisone, are used to treat the symptoms of AITL that result from dysfunction of the immune system. Prednisone may be used alone or in conjunction with chemotherapy regimens.In select individuals with no aggressive features of AITL, physicians may recommend waiting before implementing treatment until the disease leads to certain symptoms. In such instances, thorough, frequent checkups are required to ensure that appropriate therapies are begun when the disease course accelerates. This approach to disease management is often called “watch and wait”.However, as discussed above, AITL is typically considered an aggressive form of lymphoma. Therefore, physicians may recommend combination therapy with multiple anticancer (chemotherapeutic) drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. For example, recommended treatment may include cyclophosphamide, doxorubicin or hydroxydaunorubicin (Adriamycin or Rubex), vincristine (Oncovin), and prednisone, known as the “CHOP” regimen.The initial response to CHOP is often good, but the overall effectiveness of CHOP and other chemotherapy regimens has largely been inadequate. Although many individuals initially experience a remission, most will eventually experience a relapse.Romidepsin is approved by the Food and Drug Administration for the treatment of individuals with peripheral T-cell lymphoma. The drug is a selective histone deacetylase (HDAC) inhibitor. Initial studies have shown the drug to be effective in individuals with AITL. | 83 | Angioimmunoblastic T-Cell Lymphoma |
nord_84_0 | Overview of Aniridia | SummaryAniridia is a rare condition characterized by abnormal development of the iris of the eye. The iris is the circular, colored part in the middle of the eyeball. The center of the iris is known as the pupil. The iris can control the size of the pupil, which regulates the amount of light that enters the eye. Aniridia is a condition in which the iris is either partly or completely missing. Various forms of aniridia have been identified. Each form can be determined by what additional symptoms are present. | Overview of Aniridia. SummaryAniridia is a rare condition characterized by abnormal development of the iris of the eye. The iris is the circular, colored part in the middle of the eyeball. The center of the iris is known as the pupil. The iris can control the size of the pupil, which regulates the amount of light that enters the eye. Aniridia is a condition in which the iris is either partly or completely missing. Various forms of aniridia have been identified. Each form can be determined by what additional symptoms are present. | 84 | Aniridia |
nord_84_1 | Symptoms of Aniridia | Aniridia is marked by partial or complete absence of the iris of the eye. Vision is preserved in some patients with mild cases of aniridia. This condition occurs when the iris fails to develop normally before birth in one or both eyes. Typically, aniridia can be seen from birth. Aniridia can occur as a single abnormality or can be one of many symptoms in an underlying condition. Isolated aniridia: Isolated aniridia is the partial or complete absence of the iris from birth. Some people with this type of aniridia may be unaware of any eye problems because pupils appear normal and usually only one eye is mildly affected. In more severe cases, isolated aniridia can cause vision problems later in life. Accompanying symptoms may include clouding of the crystalline lens of the eye (cataracts), gradual loss of vision due to increased pressure inside the eyeball which may be accompanied by varying degrees of pain (glaucoma) or superficial clouding of the cornea (corneal pannus). Rapid involuntary movement of the eyeball (nystagmus) and underdevelopment of the fovea area of the retina (which controls acute vision) may also occur. These accompanying symptoms can make vision cloudy or blurry. Gillespie syndrome: Symptoms of Gillespie syndrome include aniridia, intellectual disability, and ataxia (lack of coordination of muscle movements). (For more information choose “Gillespie” as your search term in the Rare Disease Database.) WAGR syndrome: WAGR stands for Wilms’ tumor (a type of kidney tumor), Aniridia, Genitourinary abnormalities, and Retardation (now called “Intellectual disability”). WAGR syndrome can also be associated with obesity. WAGR syndrome can present with some or all of these symptoms. (For more information choose “Wilms” as your search term in the Rare Disease Database.) | Symptoms of Aniridia. Aniridia is marked by partial or complete absence of the iris of the eye. Vision is preserved in some patients with mild cases of aniridia. This condition occurs when the iris fails to develop normally before birth in one or both eyes. Typically, aniridia can be seen from birth. Aniridia can occur as a single abnormality or can be one of many symptoms in an underlying condition. Isolated aniridia: Isolated aniridia is the partial or complete absence of the iris from birth. Some people with this type of aniridia may be unaware of any eye problems because pupils appear normal and usually only one eye is mildly affected. In more severe cases, isolated aniridia can cause vision problems later in life. Accompanying symptoms may include clouding of the crystalline lens of the eye (cataracts), gradual loss of vision due to increased pressure inside the eyeball which may be accompanied by varying degrees of pain (glaucoma) or superficial clouding of the cornea (corneal pannus). Rapid involuntary movement of the eyeball (nystagmus) and underdevelopment of the fovea area of the retina (which controls acute vision) may also occur. These accompanying symptoms can make vision cloudy or blurry. Gillespie syndrome: Symptoms of Gillespie syndrome include aniridia, intellectual disability, and ataxia (lack of coordination of muscle movements). (For more information choose “Gillespie” as your search term in the Rare Disease Database.) WAGR syndrome: WAGR stands for Wilms’ tumor (a type of kidney tumor), Aniridia, Genitourinary abnormalities, and Retardation (now called “Intellectual disability”). WAGR syndrome can also be associated with obesity. WAGR syndrome can present with some or all of these symptoms. (For more information choose “Wilms” as your search term in the Rare Disease Database.) | 84 | Aniridia |
nord_84_2 | Causes of Aniridia | Most forms of isolated aniridia are caused by harmful changes (mutations) in the PAX6 gene causing it to not work normally. This condition typically follows an autosomal dominant pattern. Most people with aniridia have a parent with aniridia. Some patients appear to have a spontaneous, new genetic variant. Gillespie syndrome is a caused by harmful gene changes in in the ITPR1 gene. Gillespie syndrome follows an autosomal dominant pattern, or it can occur as a new genetic change. WAGR syndrome is mainly caused by missing genetic information along chromosome 11. This missing genetic information sometimes encompasses the PAX6 and WT1 genes. WAGR syndrome gene deletions can occur in a dominant pattern. WAGR syndrome gene deletions can also occur for the first time in the affected individual. We all have two copies of every gene. Dominant genetic disorders 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 new 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. Sometimes a genetic cause for aniridia cannot be identified. | Causes of Aniridia. Most forms of isolated aniridia are caused by harmful changes (mutations) in the PAX6 gene causing it to not work normally. This condition typically follows an autosomal dominant pattern. Most people with aniridia have a parent with aniridia. Some patients appear to have a spontaneous, new genetic variant. Gillespie syndrome is a caused by harmful gene changes in in the ITPR1 gene. Gillespie syndrome follows an autosomal dominant pattern, or it can occur as a new genetic change. WAGR syndrome is mainly caused by missing genetic information along chromosome 11. This missing genetic information sometimes encompasses the PAX6 and WT1 genes. WAGR syndrome gene deletions can occur in a dominant pattern. WAGR syndrome gene deletions can also occur for the first time in the affected individual. We all have two copies of every gene. Dominant genetic disorders 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 new 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. Sometimes a genetic cause for aniridia cannot be identified. | 84 | Aniridia |
nord_84_3 | Affects of Aniridia | All types of aniridia affect males and females in equal numbers. This disorder is thought to occur in approximately 1 in 40,000 to 96,000 live births in the United States. | Affects of Aniridia. All types of aniridia affect males and females in equal numbers. This disorder is thought to occur in approximately 1 in 40,000 to 96,000 live births in the United States. | 84 | Aniridia |
nord_84_4 | Related disorders of Aniridia | Symptoms of the following disorders can be similar to those of aniridia. Comparisons may be useful in helping your doctor find a diagnosis: Irido goniodysgenesis is a genetic eye structure disorder. People with this disorder are born with underdevelopment of the foundation substance (stroma) of the iris. Glaucoma also occurs followed by the iris changing to a lighter color. Glaucoma is a vision disorder marked by gradual loss of vision and increased pressure inside the eyeball. It may be result in varying degrees of pain. Rieger syndrome, also known as Irido gonodysgenesis with somatic anomalies, is characterized by incorrect development of the middle layer of the cornea and iris. There may also be abnormalities in the pupil, which is the opening that regulates the amount of light entering the eyeball. The edges of the cornea are clouded at birth and glaucoma also occurs. Hereditary juvenile glaucoma is a genetic vision disorder which may be present at birth. However, onset of symptoms can occur later in childhood or adolescence. Glaucoma is characterized by diminished clear vision along with increased pressure with possible and variable pain of inside the eyeball. | Related disorders of Aniridia. Symptoms of the following disorders can be similar to those of aniridia. Comparisons may be useful in helping your doctor find a diagnosis: Irido goniodysgenesis is a genetic eye structure disorder. People with this disorder are born with underdevelopment of the foundation substance (stroma) of the iris. Glaucoma also occurs followed by the iris changing to a lighter color. Glaucoma is a vision disorder marked by gradual loss of vision and increased pressure inside the eyeball. It may be result in varying degrees of pain. Rieger syndrome, also known as Irido gonodysgenesis with somatic anomalies, is characterized by incorrect development of the middle layer of the cornea and iris. There may also be abnormalities in the pupil, which is the opening that regulates the amount of light entering the eyeball. The edges of the cornea are clouded at birth and glaucoma also occurs. Hereditary juvenile glaucoma is a genetic vision disorder which may be present at birth. However, onset of symptoms can occur later in childhood or adolescence. Glaucoma is characterized by diminished clear vision along with increased pressure with possible and variable pain of inside the eyeball. | 84 | Aniridia |
nord_84_5 | Diagnosis of Aniridia | Diagnosis of Aniridia. | 84 | Aniridia |
|
nord_84_6 | Therapies of Aniridia | Treatment
Treatment of aniridia is usually directed at improving and preserving vision. Drugs or surgery may be helpful for glaucoma and/or cataracts. Contact lenses may be beneficial in some cases. When a genetic cause cannot be identified, patients should be evaluated for the possibility of the development of Wilms’ tumor. (For more information on this disorder, please choose “Wilms” as your search term in the Rare Disease Database.) In 2018, the FDA approved the first artificial iris, a surgically implanted device to treat adults and children with aniridia. This device may help to reduce light sensitivity and glare and improve the cosmetic appearance of the eye. Genetic counseling is recommended. Other treatment is symptomatic and supportive. | Therapies of Aniridia. Treatment
Treatment of aniridia is usually directed at improving and preserving vision. Drugs or surgery may be helpful for glaucoma and/or cataracts. Contact lenses may be beneficial in some cases. When a genetic cause cannot be identified, patients should be evaluated for the possibility of the development of Wilms’ tumor. (For more information on this disorder, please choose “Wilms” as your search term in the Rare Disease Database.) In 2018, the FDA approved the first artificial iris, a surgically implanted device to treat adults and children with aniridia. This device may help to reduce light sensitivity and glare and improve the cosmetic appearance of the eye. Genetic counseling is recommended. Other treatment is symptomatic and supportive. | 84 | Aniridia |
nord_85_0 | Overview of Aniridia Cerebellar Ataxia Mental Deficiency | Aniridia, cerebellar ataxia, and mental deficiency, also known as Gillespie syndrome, is an extremely rare inherited disorder that is characterized by the absence, in whole (aniridia) or in part (partial aniridia), of the colored portion (iris) of the eye; impaired coordination of voluntary movements due to underdevelopment (hypoplasia) of the brain's cerebellum (cerebellar ataxia); and mental retardation. The condition usually affects both eyes (bilateral) but a few cases have been reported in which only one eye is affected. Some individuals with this syndrome also exhibit a delay in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor retardation). ACAMD is thought to be inherited as an autosomal recessive genetic trait and is extremely rare, with only 20 to 30 cases reported in the medical literature. | Overview of Aniridia Cerebellar Ataxia Mental Deficiency. Aniridia, cerebellar ataxia, and mental deficiency, also known as Gillespie syndrome, is an extremely rare inherited disorder that is characterized by the absence, in whole (aniridia) or in part (partial aniridia), of the colored portion (iris) of the eye; impaired coordination of voluntary movements due to underdevelopment (hypoplasia) of the brain's cerebellum (cerebellar ataxia); and mental retardation. The condition usually affects both eyes (bilateral) but a few cases have been reported in which only one eye is affected. Some individuals with this syndrome also exhibit a delay in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor retardation). ACAMD is thought to be inherited as an autosomal recessive genetic trait and is extremely rare, with only 20 to 30 cases reported in the medical literature. | 85 | Aniridia Cerebellar Ataxia Mental Deficiency |
nord_85_1 | Symptoms of Aniridia Cerebellar Ataxia Mental Deficiency | Aniridia-cerebellar ataxia-mental deficiency, also known as Gillespie syndrome, is an extremely rare inherited disorder that is characterized by malformations of the eye, neuromuscular abnormalities, developmental delays, and/or mental retardation. Some affected individuals may also exhibit additional physical abnormalities. The eye abnormality most frequently associated with this disorder is the partial or complete absence of the colored portion (iris) of the eye, resulting in poor vision. Both eyes are usually affected (bilateral). The inner edge of the iris that normally surrounds the pupil (pupillary margin of iris) may be absent, as may be the circular band of muscle fibers in the iris that reduces the size of the pupil (sphincter pupillae) in response to light. In many cases, people with aniridia may also exhibit repeated, involuntary movements of the eye (nystagmus). In addition, during late childhood or early adolescence, the pressure of the fluid in the eye may become abnormally high (glaucoma) in some individuals with aniridia, potentially leading to progressive loss of vision.Individuals with aniridia-cerebellar ataxia-mental deficiency may also have additional eye abnormalities, such as excessive widening (dilatation) of the pupils (mydriasis) and/or extreme sensitivity to light (photophobia). In addition, they may exhibit droopy eyelids (ptosis); inward deviation of one eye (esotropia), resulting in double vision (diplopia); and/or farsightedness (hypermetropia), causing blurred vision, eye strain, and/or difficulty in viewing close objects.Aniridia-cerebellar ataxia-mental deficiency is also characterized by neuromuscular abnormalities, such as an impaired ability to coordinate voluntary movement due to incomplete development (hypoplasia) of the cerebellum (cerebellar ataxia). The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movement. People with this disorder may walk unsteadily and have difficulty positioning the feet and turning (cerebellar gait); they may also speak slowly and haltingly, with pauses between each syllable (scanning speech). Affected individuals may also exhibit severely diminished muscle tone (hypotonia). The cerebellar ataxia does not seem to worsen over time in individuals with this disorder (non-progressive cerebellar ataxia); in fact, in some cases, the control of certain voluntary movements may improve with age.People with this disorder may also exhibit developmental abnormalities, such as a delay in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation). As a result, they may achieve certain developmental milestones (e.g., crawling, walking, speaking, etc.) later than normally expected. Mild to moderate mental retardation may also be present.In rare cases, individuals with aniridia-cerebellar ataxia-mental deficiency may have additional physical abnormalities. For example, affected individuals have exhibited skeletal malformations, such as fusion of certain bones in the spinal column of the neck (cervical vertebrae), flat feet (pes planus), and/or feet with heels that are abnormally turned inward and soles that are flexed (equinovarus clubfeet). Other features have included heart abnormalities, such as a heart murmur, and/or abnormal narrowing of the opening between the heart's right ventricle and the artery that supplies blood to the lung (pulmonary stenosis). | Symptoms of Aniridia Cerebellar Ataxia Mental Deficiency. Aniridia-cerebellar ataxia-mental deficiency, also known as Gillespie syndrome, is an extremely rare inherited disorder that is characterized by malformations of the eye, neuromuscular abnormalities, developmental delays, and/or mental retardation. Some affected individuals may also exhibit additional physical abnormalities. The eye abnormality most frequently associated with this disorder is the partial or complete absence of the colored portion (iris) of the eye, resulting in poor vision. Both eyes are usually affected (bilateral). The inner edge of the iris that normally surrounds the pupil (pupillary margin of iris) may be absent, as may be the circular band of muscle fibers in the iris that reduces the size of the pupil (sphincter pupillae) in response to light. In many cases, people with aniridia may also exhibit repeated, involuntary movements of the eye (nystagmus). In addition, during late childhood or early adolescence, the pressure of the fluid in the eye may become abnormally high (glaucoma) in some individuals with aniridia, potentially leading to progressive loss of vision.Individuals with aniridia-cerebellar ataxia-mental deficiency may also have additional eye abnormalities, such as excessive widening (dilatation) of the pupils (mydriasis) and/or extreme sensitivity to light (photophobia). In addition, they may exhibit droopy eyelids (ptosis); inward deviation of one eye (esotropia), resulting in double vision (diplopia); and/or farsightedness (hypermetropia), causing blurred vision, eye strain, and/or difficulty in viewing close objects.Aniridia-cerebellar ataxia-mental deficiency is also characterized by neuromuscular abnormalities, such as an impaired ability to coordinate voluntary movement due to incomplete development (hypoplasia) of the cerebellum (cerebellar ataxia). The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movement. People with this disorder may walk unsteadily and have difficulty positioning the feet and turning (cerebellar gait); they may also speak slowly and haltingly, with pauses between each syllable (scanning speech). Affected individuals may also exhibit severely diminished muscle tone (hypotonia). The cerebellar ataxia does not seem to worsen over time in individuals with this disorder (non-progressive cerebellar ataxia); in fact, in some cases, the control of certain voluntary movements may improve with age.People with this disorder may also exhibit developmental abnormalities, such as a delay in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation). As a result, they may achieve certain developmental milestones (e.g., crawling, walking, speaking, etc.) later than normally expected. Mild to moderate mental retardation may also be present.In rare cases, individuals with aniridia-cerebellar ataxia-mental deficiency may have additional physical abnormalities. For example, affected individuals have exhibited skeletal malformations, such as fusion of certain bones in the spinal column of the neck (cervical vertebrae), flat feet (pes planus), and/or feet with heels that are abnormally turned inward and soles that are flexed (equinovarus clubfeet). Other features have included heart abnormalities, such as a heart murmur, and/or abnormal narrowing of the opening between the heart's right ventricle and the artery that supplies blood to the lung (pulmonary stenosis). | 85 | Aniridia Cerebellar Ataxia Mental Deficiency |
nord_85_2 | Causes of Aniridia Cerebellar Ataxia Mental Deficiency | The disorder aniridia, cerebellar ataxia and mental deficiency is thought to be inherited as an autosomal recessive genetic trait, but researchers have not yet been able to establish the mode of inheritance conclusively. The genetics of the disorder are not well understood at this time. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 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.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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. | Causes of Aniridia Cerebellar Ataxia Mental Deficiency. The disorder aniridia, cerebellar ataxia and mental deficiency is thought to be inherited as an autosomal recessive genetic trait, but researchers have not yet been able to establish the mode of inheritance conclusively. The genetics of the disorder are not well understood at this time. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 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.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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. | 85 | Aniridia Cerebellar Ataxia Mental Deficiency |
nord_85_3 | Affects of Aniridia Cerebellar Ataxia Mental Deficiency | Aniridia, cerebellar ataxia and mental deficiency is an extremely rare inherited disorder that appears to affect females more than males, although the sample size is very low. Only about 20 or 30 cases have been reported in the medical literature. One report suggests that people with this syndrome make up about 2% of all patients with aniridia. | Affects of Aniridia Cerebellar Ataxia Mental Deficiency. Aniridia, cerebellar ataxia and mental deficiency is an extremely rare inherited disorder that appears to affect females more than males, although the sample size is very low. Only about 20 or 30 cases have been reported in the medical literature. One report suggests that people with this syndrome make up about 2% of all patients with aniridia. | 85 | Aniridia Cerebellar Ataxia Mental Deficiency |
nord_85_4 | Related disorders of Aniridia Cerebellar Ataxia Mental Deficiency | Marinesco-Sjogren Syndrome is a rare inherited disorder that is characterized by impaired coordination of voluntary movement due to underdevelopment (hypoplasia) of the cerebellum (cerebellar ataxia), clouding of the lens of both eyes (bilateral cataracts), involuntary movements of the eyes (nystagmus), difficulty speaking due to an impaired ability to control the muscles enabling speech (dysarthria), and/or mild mental retardation. Many affected individuals exhibit additional physical abnormalities. Marinesco-Sjogren Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Marinesco-Sjogren” as your search term in the Rare Disease Database.)In Aniridia, Type II, a rare vision disorder that is present at birth (congenital), affected individuals exhibit partial or nearly complete absence (aplasia) of the colored portion (iris) of the eye (aniridia). Vision may range from nearly normal to poor, depending upon the severity of the aniridia. In many cases, affected infants may also exhibit clouding of the lens of the eyes (cataracts) and/or repeated, involuntary eye movements (nystagmus). During late childhood or early adolescence, the pressure of the fluid in the eyes may become abnormally high (glaucoma) in some affected individuals, potentially leading to progressive loss of vision. Aniridia, Type II may occur randomly, for no apparent reason (sporadic); cases where a familial pattern has been identified show that the disorder may be inherited as an autosomal dominant genetic trait. In both sporadic and familial cases of Aniridia, Type II, abnormalities (mutations) of a gene called PAX6, which has been located on the short arm (p) of chromosome 11 (11p13), are believed to play a role in causing the disorder. (At least four types of Aniridia are thought to exist. Aniridia, Type I is marked by incomplete expression of the disorder. In Type III, Aniridia occurs in association with mental retardation. Aniridia, Type IV is associated with Wilms' Tumor, abnormalities of the reproductive and urinary (genitourinary) tracts, and possible mental retardation; this association of symptoms is called “WAGR Syndrome.” (For more information on these disorders, choose “Aniridia,” “Wilms' Tumor,” or “WAGR” as your search terms in the Rare Disease Database.) | Related disorders of Aniridia Cerebellar Ataxia Mental Deficiency. Marinesco-Sjogren Syndrome is a rare inherited disorder that is characterized by impaired coordination of voluntary movement due to underdevelopment (hypoplasia) of the cerebellum (cerebellar ataxia), clouding of the lens of both eyes (bilateral cataracts), involuntary movements of the eyes (nystagmus), difficulty speaking due to an impaired ability to control the muscles enabling speech (dysarthria), and/or mild mental retardation. Many affected individuals exhibit additional physical abnormalities. Marinesco-Sjogren Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Marinesco-Sjogren” as your search term in the Rare Disease Database.)In Aniridia, Type II, a rare vision disorder that is present at birth (congenital), affected individuals exhibit partial or nearly complete absence (aplasia) of the colored portion (iris) of the eye (aniridia). Vision may range from nearly normal to poor, depending upon the severity of the aniridia. In many cases, affected infants may also exhibit clouding of the lens of the eyes (cataracts) and/or repeated, involuntary eye movements (nystagmus). During late childhood or early adolescence, the pressure of the fluid in the eyes may become abnormally high (glaucoma) in some affected individuals, potentially leading to progressive loss of vision. Aniridia, Type II may occur randomly, for no apparent reason (sporadic); cases where a familial pattern has been identified show that the disorder may be inherited as an autosomal dominant genetic trait. In both sporadic and familial cases of Aniridia, Type II, abnormalities (mutations) of a gene called PAX6, which has been located on the short arm (p) of chromosome 11 (11p13), are believed to play a role in causing the disorder. (At least four types of Aniridia are thought to exist. Aniridia, Type I is marked by incomplete expression of the disorder. In Type III, Aniridia occurs in association with mental retardation. Aniridia, Type IV is associated with Wilms' Tumor, abnormalities of the reproductive and urinary (genitourinary) tracts, and possible mental retardation; this association of symptoms is called “WAGR Syndrome.” (For more information on these disorders, choose “Aniridia,” “Wilms' Tumor,” or “WAGR” as your search terms in the Rare Disease Database.) | 85 | Aniridia Cerebellar Ataxia Mental Deficiency |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.