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nord_342_6 | Therapies of Cutis Laxa | TreatmentThe treatment of cutis laxa is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dermatologists, cardiologists, pulmonologists, neurologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.Specific therapies for individuals with cutis laxa can include surgery to repair hernias, skeletal malformations or intestinal diverticula. Some individuals elect for plastic (cosmetic) surgery to improve skin symptoms. Results are typically good, but loose, lax skin often recurs.Medications such as beta-blockers to prevent aortic aneurysms may be prescribed. Regular cardiac and pulmonary follow up is necessary to detect cardiovascular and pulmonary complications potentially associated with certain forms of cutis laxa.Affected individuals should avoid environmental triggers that can worsen cutis laxa or associated symptoms. For example, cigarette smoking can worsen emphysema and sunbathing can damage the skin. | Therapies of Cutis Laxa. TreatmentThe treatment of cutis laxa is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dermatologists, cardiologists, pulmonologists, neurologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.Specific therapies for individuals with cutis laxa can include surgery to repair hernias, skeletal malformations or intestinal diverticula. Some individuals elect for plastic (cosmetic) surgery to improve skin symptoms. Results are typically good, but loose, lax skin often recurs.Medications such as beta-blockers to prevent aortic aneurysms may be prescribed. Regular cardiac and pulmonary follow up is necessary to detect cardiovascular and pulmonary complications potentially associated with certain forms of cutis laxa.Affected individuals should avoid environmental triggers that can worsen cutis laxa or associated symptoms. For example, cigarette smoking can worsen emphysema and sunbathing can damage the skin. | 342 | Cutis Laxa |
nord_343_0 | Overview of Cutis Marmorata Telangiectatica Congenita | Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital (present at birth)disorder characterized by discolored patches of skin caused by widened (dilated) surface blood vessels. As a result, the skin has a purple or blue “marbled” or “fishnet” appearance (cutis marmorata). In some affected individuals, ulcerations or congenital skin defects (aplasia cutis) can be present. The latter association can be part of Adams-Oliver syndrome. Additional associated abnormalities have been reported including pink or dark red, irregularly shaped patches of skin (nevus flammeus); loss of muscle tissue (wasting) on one side of the body (hemiatrophy); elevated fluid pressure within the eye (glaucoma); and/or undergrowth (hypotrophy) of one leg. However, many if not all of those cases represent forms of Klippel-Trenaunay syndrome or related disorders, in particular Cowden's disease. The most common association of true CMTC is with soft tissue (subcutaneous fat and muscle) hypoplasia. The disorder formerly known as macrocephaly-cutis marmoratatelangiectatica congenital (M-CMTC) is a distinct genetic disease and is now called macrocephaly-capillary malformation (M-CM/MCAP) Virtually all cases of CMTC occur randomly for no apparent reason (sporadically). It is thought that CMTC represents a form of genetic mosaicism. | Overview of Cutis Marmorata Telangiectatica Congenita. Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital (present at birth)disorder characterized by discolored patches of skin caused by widened (dilated) surface blood vessels. As a result, the skin has a purple or blue “marbled” or “fishnet” appearance (cutis marmorata). In some affected individuals, ulcerations or congenital skin defects (aplasia cutis) can be present. The latter association can be part of Adams-Oliver syndrome. Additional associated abnormalities have been reported including pink or dark red, irregularly shaped patches of skin (nevus flammeus); loss of muscle tissue (wasting) on one side of the body (hemiatrophy); elevated fluid pressure within the eye (glaucoma); and/or undergrowth (hypotrophy) of one leg. However, many if not all of those cases represent forms of Klippel-Trenaunay syndrome or related disorders, in particular Cowden's disease. The most common association of true CMTC is with soft tissue (subcutaneous fat and muscle) hypoplasia. The disorder formerly known as macrocephaly-cutis marmoratatelangiectatica congenital (M-CMTC) is a distinct genetic disease and is now called macrocephaly-capillary malformation (M-CM/MCAP) Virtually all cases of CMTC occur randomly for no apparent reason (sporadically). It is thought that CMTC represents a form of genetic mosaicism. | 343 | Cutis Marmorata Telangiectatica Congenita |
nord_343_1 | Symptoms of Cutis Marmorata Telangiectatica Congenita | The symptoms of CMTC are present at birth (congenital). Affected infants have discolored patches of skin caused by widened (dilated) surface blood vessels (livedoreticularistelangiectases). The affected areas of skin have a “marbled” or “fishnet” appearance (cutis marmorata). In most cases, skin abnormalities affect the arms and legs (limbs), although the trunk may also be involved. Facial involvement is very rare. The skin symptoms associated with classical CMTC improve with age and usually disappear completely around puberty. Atrophic patches may remain. The soft tissue hypoplasia can likewise remain present, in particular if muscles are affected. This has no consequences for normal functionality. In an affected leg, the greater saphenous vein may be too wide. It is not yet known whether this will lead to venous insufficiency later in life.A plethora of associated abnormalities have been reported. However, careful evaluation of these and more recent cases strongly suggests that the skin abnormalities in these patients are not CMTC but capillary malformations. These can be associated with several syndromic disorders. The ones most commonly mistaken for CMTC variants are Klippel-Trenaunay syndrome, Cowden's disease and M-CM. Rarely, Adams-Oliver and Proteus(-like) syndromes underlie the vascular abnormalities. | Symptoms of Cutis Marmorata Telangiectatica Congenita. The symptoms of CMTC are present at birth (congenital). Affected infants have discolored patches of skin caused by widened (dilated) surface blood vessels (livedoreticularistelangiectases). The affected areas of skin have a “marbled” or “fishnet” appearance (cutis marmorata). In most cases, skin abnormalities affect the arms and legs (limbs), although the trunk may also be involved. Facial involvement is very rare. The skin symptoms associated with classical CMTC improve with age and usually disappear completely around puberty. Atrophic patches may remain. The soft tissue hypoplasia can likewise remain present, in particular if muscles are affected. This has no consequences for normal functionality. In an affected leg, the greater saphenous vein may be too wide. It is not yet known whether this will lead to venous insufficiency later in life.A plethora of associated abnormalities have been reported. However, careful evaluation of these and more recent cases strongly suggests that the skin abnormalities in these patients are not CMTC but capillary malformations. These can be associated with several syndromic disorders. The ones most commonly mistaken for CMTC variants are Klippel-Trenaunay syndrome, Cowden's disease and M-CM. Rarely, Adams-Oliver and Proteus(-like) syndromes underlie the vascular abnormalities. | 343 | Cutis Marmorata Telangiectatica Congenita |
nord_343_2 | Causes of Cutis Marmorata Telangiectatica Congenita | The exact cause of CMTC is not known. Most cases occur randomly, for no apparent reason (spontaneously). Researchers believe that the disease results from genetic mosaicism. One theory suggests that abnormal pericyte recruitment can cause skin capillaries to contract inappropriately. In a few rare cases, it has appeared that CMTC may occasionally run in families (familial cases). | Causes of Cutis Marmorata Telangiectatica Congenita. The exact cause of CMTC is not known. Most cases occur randomly, for no apparent reason (spontaneously). Researchers believe that the disease results from genetic mosaicism. One theory suggests that abnormal pericyte recruitment can cause skin capillaries to contract inappropriately. In a few rare cases, it has appeared that CMTC may occasionally run in families (familial cases). | 343 | Cutis Marmorata Telangiectatica Congenita |
nord_343_3 | Affects of Cutis Marmorata Telangiectatica Congenita | CMTC affects males and females in equal numbers and is present at birth (congenital). Fewer than 300 cases of CMTC have been reported in the medical literature. Since many cases of CMTC are mild and clear up without treatment, the disorder may be under-diagnosed making it difficult to determine the true frequency of CMTC in the general population. | Affects of Cutis Marmorata Telangiectatica Congenita. CMTC affects males and females in equal numbers and is present at birth (congenital). Fewer than 300 cases of CMTC have been reported in the medical literature. Since many cases of CMTC are mild and clear up without treatment, the disorder may be under-diagnosed making it difficult to determine the true frequency of CMTC in the general population. | 343 | Cutis Marmorata Telangiectatica Congenita |
nord_343_4 | Related disorders of Cutis Marmorata Telangiectatica Congenita | Symptoms of the following disorders can be similar to those of CMTC. Comparisons may be useful for a differential diagnosis:Cutis marmorata is a transient skin disorder in which the skin has a bluish red marbling pattern when exposed to cold temperatures. This condition is found most often in infants but may also affect adults. When the skin is warmed the condition disappears. Cutis marmorata is very common in premature infants and usually disappears completely at two months of age. Cutis marmorata may occur in conjunction with other syndromes but is not diagnostic.Klippel-Trenaunay syndrome is a group of congenital raredisorders characterized by varying combinations of cutaneous capillary malformation (port-wine stain), bone and soft tissue hyper/hypotrophy, and malformations of larger vessels. Lymphatic malformations also can be present. The symptoms and findings associated with the disorder vary in range and severity from case to case. (For more information on this disorder, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database.)Adams-Oliver syndrome (AOS) is an extremely 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. Some cases may be very mild while others may be severe. In infants with Adams-Oliver syndrome, scalp defects are 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 fingers and toes with small or absent nails to absent hands and/or lower legs. In some cases, additional abnormalities may also be present.). Adams-Oliver syndrome is caused bymutations in the ARHGAP31, DOCK6, EOGT, or RBPJ gene. An association with CMTC has been reported but may have been a coincidence. Inheritance is autosomal dominant. (For more information on this disorder, choose “Adams-Oliver” as your search term in the Rare Disease Database.) | Related disorders of Cutis Marmorata Telangiectatica Congenita. Symptoms of the following disorders can be similar to those of CMTC. Comparisons may be useful for a differential diagnosis:Cutis marmorata is a transient skin disorder in which the skin has a bluish red marbling pattern when exposed to cold temperatures. This condition is found most often in infants but may also affect adults. When the skin is warmed the condition disappears. Cutis marmorata is very common in premature infants and usually disappears completely at two months of age. Cutis marmorata may occur in conjunction with other syndromes but is not diagnostic.Klippel-Trenaunay syndrome is a group of congenital raredisorders characterized by varying combinations of cutaneous capillary malformation (port-wine stain), bone and soft tissue hyper/hypotrophy, and malformations of larger vessels. Lymphatic malformations also can be present. The symptoms and findings associated with the disorder vary in range and severity from case to case. (For more information on this disorder, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database.)Adams-Oliver syndrome (AOS) is an extremely 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. Some cases may be very mild while others may be severe. In infants with Adams-Oliver syndrome, scalp defects are 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 fingers and toes with small or absent nails to absent hands and/or lower legs. In some cases, additional abnormalities may also be present.). Adams-Oliver syndrome is caused bymutations in the ARHGAP31, DOCK6, EOGT, or RBPJ gene. An association with CMTC has been reported but may have been a coincidence. Inheritance is autosomal dominant. (For more information on this disorder, choose “Adams-Oliver” as your search term in the Rare Disease Database.) | 343 | Cutis Marmorata Telangiectatica Congenita |
nord_343_5 | Diagnosis of Cutis Marmorata Telangiectatica Congenita | The diagnosis of CMTC may be confirmed by a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. | Diagnosis of Cutis Marmorata Telangiectatica Congenita. The diagnosis of CMTC may be confirmed by a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. | 343 | Cutis Marmorata Telangiectatica Congenita |
nord_343_6 | Therapies of Cutis Marmorata Telangiectatica Congenita | TreatmentThe skin abnormalities associated with CMTC often go away without treatment (spontaneous remission) within the first years of life. Other treatment is symptomatic and supportive. CMTC of the legs might be associated with early development of superficial venous insufficiency, which may require treatment.Infants with a diagnosis of CMTC and/or associated abnormalities should be referred to a specialist center. If indicated, they will receive a thorough clinical evaluation to reach a definitive diagnosis. No diagnostic procedures are required if the diagnosis is typical isolated CMTC. | Therapies of Cutis Marmorata Telangiectatica Congenita. TreatmentThe skin abnormalities associated with CMTC often go away without treatment (spontaneous remission) within the first years of life. Other treatment is symptomatic and supportive. CMTC of the legs might be associated with early development of superficial venous insufficiency, which may require treatment.Infants with a diagnosis of CMTC and/or associated abnormalities should be referred to a specialist center. If indicated, they will receive a thorough clinical evaluation to reach a definitive diagnosis. No diagnostic procedures are required if the diagnosis is typical isolated CMTC. | 343 | Cutis Marmorata Telangiectatica Congenita |
nord_344_0 | Overview of Cyclic Neutropenia | Cyclic neutropenia is a rare blood disorder characterized by recurrent episodes of abnormally low levels of certain white blood cells (neutrophils) in the body. Neutrophils are instrumental in fighting off infection by surrounding and destroying bacteria that enter the body. Symptoms associated with cyclic neutropenia may include fever, a general feeling of ill health (malaise), and/or sores (ulcers) of the mucous membranes of the mouth. In most cases, individuals with low levels of neutrophils (neutropenia) are abnormally susceptible to recurrent infections. | Overview of Cyclic Neutropenia. Cyclic neutropenia is a rare blood disorder characterized by recurrent episodes of abnormally low levels of certain white blood cells (neutrophils) in the body. Neutrophils are instrumental in fighting off infection by surrounding and destroying bacteria that enter the body. Symptoms associated with cyclic neutropenia may include fever, a general feeling of ill health (malaise), and/or sores (ulcers) of the mucous membranes of the mouth. In most cases, individuals with low levels of neutrophils (neutropenia) are abnormally susceptible to recurrent infections. | 344 | Cyclic Neutropenia |
nord_344_1 | Symptoms of Cyclic Neutropenia | The primary finding associated with cyclic neutropenia is regularly recurring severe decrease in certain white blood cells (neutrophils). In most cases, episodes of neutropenia recur every 21 days (a cyclic phenomenon), and the severe neutropenia may last for three to six days. The cycling period usually remains constant and consistent among affected individuals. In addition, abnormal levels of red blood cells (anemia), changes in levels of the blood particles that assist in clotting (platelets), presence of immature red blood cells (reticulocytes), and cyclic changes in other white blood cells can occur. An almost constant feature is an increase in blood monocytes at the lowest point in the neutrophil cycle. During episodes of neutropenia, affected individuals may experience fever, a general feeling of ill health (malaise), inflammation and deep ulceration of the mucous membranes of the mouth (aphthae and stomatitis), inflammation of the throat (pharyngitis), inflammation and degeneration of the tissues that surround and support the teeth (periodontal disease), and/or loss of appetite. Periodontal disease may result in loosening of teeth and early tooth loss in young children and adults.Individuals with cyclic neutropenia are abnormally susceptible to bacterial infections that often affect the skin, digestive (gastrointestinal) tract, and respiratory system. Such bacterial infections vary in severity and, in some cases, may result in life-threatening complications. | Symptoms of Cyclic Neutropenia. The primary finding associated with cyclic neutropenia is regularly recurring severe decrease in certain white blood cells (neutrophils). In most cases, episodes of neutropenia recur every 21 days (a cyclic phenomenon), and the severe neutropenia may last for three to six days. The cycling period usually remains constant and consistent among affected individuals. In addition, abnormal levels of red blood cells (anemia), changes in levels of the blood particles that assist in clotting (platelets), presence of immature red blood cells (reticulocytes), and cyclic changes in other white blood cells can occur. An almost constant feature is an increase in blood monocytes at the lowest point in the neutrophil cycle. During episodes of neutropenia, affected individuals may experience fever, a general feeling of ill health (malaise), inflammation and deep ulceration of the mucous membranes of the mouth (aphthae and stomatitis), inflammation of the throat (pharyngitis), inflammation and degeneration of the tissues that surround and support the teeth (periodontal disease), and/or loss of appetite. Periodontal disease may result in loosening of teeth and early tooth loss in young children and adults.Individuals with cyclic neutropenia are abnormally susceptible to bacterial infections that often affect the skin, digestive (gastrointestinal) tract, and respiratory system. Such bacterial infections vary in severity and, in some cases, may result in life-threatening complications. | 344 | Cyclic Neutropenia |
nord_344_2 | Causes of Cyclic Neutropenia | Cyclic neutropenia is usually a hereditary disease, but there are a few reported cases of acquired cyclic neutropenia. There are reports in the medical literature of several multigenerational families (kindreds) with increased incidence of cyclic neutropenia. Based on these genetic studies, we know that it is an autosomal dominant disease and can be passed on from one affected parent. Investigators have determined that sporadic and autosomal dominant cyclic neutropenia are caused by disruption or changes (mutations) of the ELANE gene responsible for production of a neutrophil protein called neutrophil elastase. Mutations in this gene cause production of abnormal neutrophil elastase and this is the fundamental cause of cyclic neutropenia. Neutrophils are produced in the cavities in many bones (bone marrow). Neutropenia, fever and infections occur when the bone marrow fails to produce sufficient numbers of neutrophils. | Causes of Cyclic Neutropenia. Cyclic neutropenia is usually a hereditary disease, but there are a few reported cases of acquired cyclic neutropenia. There are reports in the medical literature of several multigenerational families (kindreds) with increased incidence of cyclic neutropenia. Based on these genetic studies, we know that it is an autosomal dominant disease and can be passed on from one affected parent. Investigators have determined that sporadic and autosomal dominant cyclic neutropenia are caused by disruption or changes (mutations) of the ELANE gene responsible for production of a neutrophil protein called neutrophil elastase. Mutations in this gene cause production of abnormal neutrophil elastase and this is the fundamental cause of cyclic neutropenia. Neutrophils are produced in the cavities in many bones (bone marrow). Neutropenia, fever and infections occur when the bone marrow fails to produce sufficient numbers of neutrophils. | 344 | Cyclic Neutropenia |
nord_344_3 | Affects of Cyclic Neutropenia | Cyclic neutropenia affects males and females in equal numbers. Most cases of cyclic neutropenia are thought to be present at birth (congenital); however, in some cases, the diagnosis may not become obvious until childhood, adolescence, or early adulthood.Cyclic neutropenia is a subdivision of severe chronic neutropenia. Severe chronic neutropenia affects approximately 0.5 to 1 per million people in the United States. (For more information on severe chronic neutropenia, see the Related Disorders section of this report.) | Affects of Cyclic Neutropenia. Cyclic neutropenia affects males and females in equal numbers. Most cases of cyclic neutropenia are thought to be present at birth (congenital); however, in some cases, the diagnosis may not become obvious until childhood, adolescence, or early adulthood.Cyclic neutropenia is a subdivision of severe chronic neutropenia. Severe chronic neutropenia affects approximately 0.5 to 1 per million people in the United States. (For more information on severe chronic neutropenia, see the Related Disorders section of this report.) | 344 | Cyclic Neutropenia |
nord_344_4 | Related disorders of Cyclic Neutropenia | Symptoms of the following disorders may be similar to those of cyclic neutropenia. Comparisons may be useful for a differential diagnosis:There are many different causes of neutropenia. Neutropenia may result from viral infection, due to use of certain drugs, and/or following exposure to certain poisons. In addition, in some cases, the body may produce antibodies against neutrophils (autoimmune neutropenia) causing an abnormal decrease in these white blood cells. Some individuals may develop neutropenia following therapy with certain chemotherapeutic medications for the treatment of cancer. Neutropenia may also occur as a secondary finding due to other primary disorders (e.g., leukemia).Severe chronic neutropenia is a group of disorders characterized by abnormally low levels of certain white blood cells (neutrophils) in the body. The three main classifications of severe chronic neutropenia are congenital, idiopathic, and cyclic. The congenital forms of severe chronic neutropenia are usually present at birth or during early childhood and are often the most severe. Idiopathic neutropenia is a group of disorders that cannot be classified into one of the other categories of neutropenia. The exact cause of these disorders is not known (idiopathic). Congenital forms of severe chronic neutropenia may be inherited in an autosomal dominant or recessive pattern. Unlike severe congenital neutropenia cyclic neutropenia is not associated with a risk of developing acute myeloid leukemia. (For more information on these disorders, choose “severe chronic neutropenia” as your search term in the Rare Disease Database.) | Related disorders of Cyclic Neutropenia. Symptoms of the following disorders may be similar to those of cyclic neutropenia. Comparisons may be useful for a differential diagnosis:There are many different causes of neutropenia. Neutropenia may result from viral infection, due to use of certain drugs, and/or following exposure to certain poisons. In addition, in some cases, the body may produce antibodies against neutrophils (autoimmune neutropenia) causing an abnormal decrease in these white blood cells. Some individuals may develop neutropenia following therapy with certain chemotherapeutic medications for the treatment of cancer. Neutropenia may also occur as a secondary finding due to other primary disorders (e.g., leukemia).Severe chronic neutropenia is a group of disorders characterized by abnormally low levels of certain white blood cells (neutrophils) in the body. The three main classifications of severe chronic neutropenia are congenital, idiopathic, and cyclic. The congenital forms of severe chronic neutropenia are usually present at birth or during early childhood and are often the most severe. Idiopathic neutropenia is a group of disorders that cannot be classified into one of the other categories of neutropenia. The exact cause of these disorders is not known (idiopathic). Congenital forms of severe chronic neutropenia may be inherited in an autosomal dominant or recessive pattern. Unlike severe congenital neutropenia cyclic neutropenia is not associated with a risk of developing acute myeloid leukemia. (For more information on these disorders, choose “severe chronic neutropenia” as your search term in the Rare Disease Database.) | 344 | Cyclic Neutropenia |
nord_344_5 | Diagnosis of Cyclic Neutropenia | A diagnosis of cyclic neutropenia is made based upon a detailed patient history and thorough clinical evaluation. A diagnosis may be confirmed by monitoring an individual’s neutrophil count twice or three times per week for six weeks. Individuals with cyclic neutropenia should be genetically tested for mutations in the ELANE gene. | Diagnosis of Cyclic Neutropenia. A diagnosis of cyclic neutropenia is made based upon a detailed patient history and thorough clinical evaluation. A diagnosis may be confirmed by monitoring an individual’s neutrophil count twice or three times per week for six weeks. Individuals with cyclic neutropenia should be genetically tested for mutations in the ELANE gene. | 344 | Cyclic Neutropenia |
nord_344_6 | Therapies of Cyclic Neutropenia | Treatment
Prompt, appropriate treatment of the infections associated with cyclic neutropenia is important. Such treatment may include antibiotic therapy. Careful oral and dental care is also required. In addition, individuals with cyclic neutropenia should avoid activities that may cause minor injuries.Since 1987 the human grow factor called recombinant human granulocyte-colony stimulating factor [rhG-CSF]) has been used to treat cyclic neutropenia and other forms of severe chronic neutropenia. One form, the orphan drug neupogen (Filgrastim) was approved by the Food and Drug Administration for use in the treatment of cyclic and other types of severe chronic neutropenia. Studies have shown that long-term therapy can elevate the numbers of neutrophils to normal range in most individuals, thereby reducing infections and other associated symptoms. Careful evaluation prior to initiation of such therapy and ongoing observation during therapy are essential to ensure the long-term safety and effectiveness of such treatment in individuals with severe chronic neutropenia. Neupogen is manufactured by Amgen, Inc.Genetic counseling is recommended for individuals with inherited forms of cyclic neutropenia and their families. Other treatment is symptomatic and supportive. | Therapies of Cyclic Neutropenia. Treatment
Prompt, appropriate treatment of the infections associated with cyclic neutropenia is important. Such treatment may include antibiotic therapy. Careful oral and dental care is also required. In addition, individuals with cyclic neutropenia should avoid activities that may cause minor injuries.Since 1987 the human grow factor called recombinant human granulocyte-colony stimulating factor [rhG-CSF]) has been used to treat cyclic neutropenia and other forms of severe chronic neutropenia. One form, the orphan drug neupogen (Filgrastim) was approved by the Food and Drug Administration for use in the treatment of cyclic and other types of severe chronic neutropenia. Studies have shown that long-term therapy can elevate the numbers of neutrophils to normal range in most individuals, thereby reducing infections and other associated symptoms. Careful evaluation prior to initiation of such therapy and ongoing observation during therapy are essential to ensure the long-term safety and effectiveness of such treatment in individuals with severe chronic neutropenia. Neupogen is manufactured by Amgen, Inc.Genetic counseling is recommended for individuals with inherited forms of cyclic neutropenia and their families. Other treatment is symptomatic and supportive. | 344 | Cyclic Neutropenia |
nord_345_0 | Overview of Cyclic Vomiting Syndrome | Cyclic vomiting syndrome (CVS) is an uncommon disorder affecting both children and adults and characterized by recurrent episodes of severe nausea and vomiting. An episode may last for a few hours to several days and is then followed by a period of time during which affected individuals are relatively free of severe nausea and vomiting. Some can experience milder symptoms between attacks. This alternating pattern of disease and disease-free periods distinguishes cyclic vomiting syndrome from other gastrointestinal disorders. For each person who suffers from this condition, the episodes are similar to each other. The associated nausea and vomiting can be severe enough to incapacitate the individual who may be unable to walk or talk and/or be bedridden. Additional symptoms often present during an episode including dizziness, paleness of the skin (pallor), lack of energy (listlessness) and, abdominal pain and headaches. Oftentimes, nausea is the most disturbing symptom, more so than vomiting. Some affected children outgrow these episodes as they get older but for many others, CVS transitions into migraine headache. Cyclic vomiting syndrome may affect children more often than adults. The exact causes of cyclic vomiting syndrome remains unknown in many people, but a cause or risk factors can be determined in many others. | Overview of Cyclic Vomiting Syndrome. Cyclic vomiting syndrome (CVS) is an uncommon disorder affecting both children and adults and characterized by recurrent episodes of severe nausea and vomiting. An episode may last for a few hours to several days and is then followed by a period of time during which affected individuals are relatively free of severe nausea and vomiting. Some can experience milder symptoms between attacks. This alternating pattern of disease and disease-free periods distinguishes cyclic vomiting syndrome from other gastrointestinal disorders. For each person who suffers from this condition, the episodes are similar to each other. The associated nausea and vomiting can be severe enough to incapacitate the individual who may be unable to walk or talk and/or be bedridden. Additional symptoms often present during an episode including dizziness, paleness of the skin (pallor), lack of energy (listlessness) and, abdominal pain and headaches. Oftentimes, nausea is the most disturbing symptom, more so than vomiting. Some affected children outgrow these episodes as they get older but for many others, CVS transitions into migraine headache. Cyclic vomiting syndrome may affect children more often than adults. The exact causes of cyclic vomiting syndrome remains unknown in many people, but a cause or risk factors can be determined in many others. | 345 | Cyclic Vomiting Syndrome |
nord_345_1 | Symptoms of Cyclic Vomiting Syndrome | The hallmark of cyclic vomiting syndrome is recurrent episodes of severe nausea and vomiting. In children, these episodes usually last for several hours to a few days. In adults, episodes tend to occur less frequently, but can last longer, even over a week. These recurrent, characteristic episodes are quite similar within each individual, often beginning at the same time of day, with similar severity, duration and associated symptoms as in previous episodes. Episodes often occur in the early morning hours or upon awakening in the morning. Affected individuals may only experience episodes several times a year or as frequently as several times a month. On occasion, after years of cycling, episodes can “coalesce” together with daily nausea and vomiting between severe attacks such that there is no symptom-free period.The nausea and vomiting that characterize CVS episodes are often quite severe. Nausea can be persistent and intense. Unlike most other gastrointestinal disorders, the vomiting in CVS may not relieve the nausea. Affected children may experience bouts of rapid-fire, projectile vomiting as frequently as four or more times per hour with a peak pace of every 5-15 minutes. After the contents of the stomach are emptied, individuals may continue to dry heave. Symptoms can be so severe that affected individuals are unable to walk or talk and in some cases may appear unconscious or comatose. Episodes may cause affected individuals to withdraw from social interaction. The behavior of drinking water to dilute the bile and induce vomiting and hence reduce nausea is common, and should not be confused with a psychogenic cause. More commonly described in adults but also occurring in children, many take prolonged hot showers or baths to alleviate the nausea.Additional symptoms may occur during an episode including paleness of the skin (pallor), lack of energy (lethargy), fever and drooling. The vomit may be bilious (green or yellow). Repetitive vomiting may cause loss of vital fluids (dehydration). Gastrointestinal symptoms such as severe abdominal pain, diarrhea and retching (gagging) are not uncommon. Affected individuals have a reduced appetite and weight loss may occur. Some individuals may exhibit a variety of migraine-like neurological symptoms including headaches, abnormal sensitivity to light (photophobia), increased sensitivity to sound (phonophobia) and dizziness or vertigo.Many affected individuals can identify a precipitating event or “trigger” that sets off an episode of CVS. Stress is a common trigger, more commonly excitement/positive stress (birthdays, holidays) than negative stress. Additional triggers include infection, certain foods, alcohol, physical exhaustion, lack of sleep, motion sickness and incoming weather fronts. In adolescents and women, menstruation may trigger an episode. Many adults with cyclic vomiting syndrome are prone to anxiety or panic attacks which can trigger episodes. | Symptoms of Cyclic Vomiting Syndrome. The hallmark of cyclic vomiting syndrome is recurrent episodes of severe nausea and vomiting. In children, these episodes usually last for several hours to a few days. In adults, episodes tend to occur less frequently, but can last longer, even over a week. These recurrent, characteristic episodes are quite similar within each individual, often beginning at the same time of day, with similar severity, duration and associated symptoms as in previous episodes. Episodes often occur in the early morning hours or upon awakening in the morning. Affected individuals may only experience episodes several times a year or as frequently as several times a month. On occasion, after years of cycling, episodes can “coalesce” together with daily nausea and vomiting between severe attacks such that there is no symptom-free period.The nausea and vomiting that characterize CVS episodes are often quite severe. Nausea can be persistent and intense. Unlike most other gastrointestinal disorders, the vomiting in CVS may not relieve the nausea. Affected children may experience bouts of rapid-fire, projectile vomiting as frequently as four or more times per hour with a peak pace of every 5-15 minutes. After the contents of the stomach are emptied, individuals may continue to dry heave. Symptoms can be so severe that affected individuals are unable to walk or talk and in some cases may appear unconscious or comatose. Episodes may cause affected individuals to withdraw from social interaction. The behavior of drinking water to dilute the bile and induce vomiting and hence reduce nausea is common, and should not be confused with a psychogenic cause. More commonly described in adults but also occurring in children, many take prolonged hot showers or baths to alleviate the nausea.Additional symptoms may occur during an episode including paleness of the skin (pallor), lack of energy (lethargy), fever and drooling. The vomit may be bilious (green or yellow). Repetitive vomiting may cause loss of vital fluids (dehydration). Gastrointestinal symptoms such as severe abdominal pain, diarrhea and retching (gagging) are not uncommon. Affected individuals have a reduced appetite and weight loss may occur. Some individuals may exhibit a variety of migraine-like neurological symptoms including headaches, abnormal sensitivity to light (photophobia), increased sensitivity to sound (phonophobia) and dizziness or vertigo.Many affected individuals can identify a precipitating event or “trigger” that sets off an episode of CVS. Stress is a common trigger, more commonly excitement/positive stress (birthdays, holidays) than negative stress. Additional triggers include infection, certain foods, alcohol, physical exhaustion, lack of sleep, motion sickness and incoming weather fronts. In adolescents and women, menstruation may trigger an episode. Many adults with cyclic vomiting syndrome are prone to anxiety or panic attacks which can trigger episodes. | 345 | Cyclic Vomiting Syndrome |
nord_345_2 | Causes of Cyclic Vomiting Syndrome | Although nausea and vomiting are the main features of cyclic vomiting syndrome, researchers now believe that the primary system affected is the nervous system, including the brain and peripheral nerves. There are more nerve cells (neurons) in the abdomen than in the head, and symptoms of the disorder develop due to abnormalities in the normal interaction between neurons in the brain and in the gut (thus, brain-gut disorder).Although the specific cause of cyclic vomiting syndrome is unknown in many people, there are likely to be several contributing causes. Researchers have found a strong relationship between CVS and migraines, and some theorize that CVS is a migraine variant. Most children with CVS have a family history of migraines or have migraines themselves (> 80%). CVS has been referred to as “abdominal migraine” and the terms are sometimes used interchangeably. An abdominal migraine is a migraine variant in which there are recurrent episodes of predominating abdominal pain. Vomiting may or may not accompany an abdominal migraine. Channelopathies caused by defects in cellular ion (salt) channels are a common cause for migraine and are recently being reported in abdominal migraine and CVS as well.Additional factors that may be associated with the development of CVS include dysfunction of the autonomic nervous system. The autonomic nervous system is the system that controls or regulates certain involuntary body functions including heart rate, blood pressure, sweating, the production and release of certain hormones and bowel and bladder control. Autonomic “functional” disturbances are common during episodes, including fever, pallor, tachycardia, high blood pressure and urinary retention. Vomiting itself is an autonomic disturbance. Autonomic disturbances can also occur between episodes, such as reflex sympathetic dystrophy (a chronic pain condition), syncope/POTS (fainting) and disorders of gastrointestinal motility. Dysmotility refers to abnormal motion through the gastrointestinal tract, either too fast, too slow or in the wrong direction. During CVS episodes, motion through the gut is very abnormal, and thus there is severe dysmotility. However, many CVS patients have lesser degrees of dysmotility between episodes. Different types of dysmotility that are common in people with CVS include gastroesophageal reflux (GERD), gastroparesis (low stomach motility causing delayed emptying of the stomach) and forms of irritable bowel disease (IBS: diarrhea, constipation, and/or bloating). Nausea is a common component of dysmotility and is especially common among adults. Thus, nausea (and occasionally vomiting) can be present between CVS episodes. However, during CVS episodes the nausea (and possibly vomiting) is far more intense than it is between episodes. Additional conditions that occur more often in those with CVS include anxiety, depression, attention deficit hyperactivity disorder (ADHD), seizures, autistic spectrum disorders and learning disabilities.Some research indicates that the body’s response to stress may be overactive and contribute or trigger episodes of CVS. Affected individuals may have increased release of corticotrophin-releasing factor (CRF) from the hypothalamus. CRF is a stress hormone that stimulates the adrenal cortex, which controls the body’s response to stress. Some research has indicated that CRF may inhibit the stomach pumping.Researchers have also learned that blood and urine testing reveal signs of abnormal energy metabolism in most people with CVS. Changes (mutations) in the genetic material of mitochondrial genes may play a role in the development of CVS. Mitochondria provide most of the power for cells. As muscle and nerve tissue have very high energy requirements, defective mitochondrial energy production may lead to an energy shortage during stress that affects nerve function, especially the autonomic nerves that control the gut. This might lead to disease by reducing the capacity to produce sufficient energy during times of stress such as with fever, illness, hot weather (sweating), excitement and exercise.Because the genetic instructions (blueprints) for mitochondria DNA (mtDNA) are inherited from the mother, an affected mother will pass the same mutation to all of her children. As a result, in some families disease is found primarily on the mother’s side – the siblings, the maternal aunts and uncles and the maternal grandmother – all of whom carry the same mtDNA genetic sequences. Only females will pass a mtDNA mutation on to their children. In half or more of CVS families, those relatives often suffer themselves from dysautonomic or functional-related symptoms, especially chronic pain (including migraine), bowel disorders (GE reflux or constipation), fatigue and anxiety/depression.In other cases, CVS can be caused by abnormal genes for mitochondrial function in the nuclear DNA (not in the mtDNA) and can be inherited from either the mother or the father.The exact manner that all the above mentioned and additional factors fit together in the puzzle to cause CVS is still unclear. Research is ongoing to determine the cause and underlying mechanisms that result in CVS. | Causes of Cyclic Vomiting Syndrome. Although nausea and vomiting are the main features of cyclic vomiting syndrome, researchers now believe that the primary system affected is the nervous system, including the brain and peripheral nerves. There are more nerve cells (neurons) in the abdomen than in the head, and symptoms of the disorder develop due to abnormalities in the normal interaction between neurons in the brain and in the gut (thus, brain-gut disorder).Although the specific cause of cyclic vomiting syndrome is unknown in many people, there are likely to be several contributing causes. Researchers have found a strong relationship between CVS and migraines, and some theorize that CVS is a migraine variant. Most children with CVS have a family history of migraines or have migraines themselves (> 80%). CVS has been referred to as “abdominal migraine” and the terms are sometimes used interchangeably. An abdominal migraine is a migraine variant in which there are recurrent episodes of predominating abdominal pain. Vomiting may or may not accompany an abdominal migraine. Channelopathies caused by defects in cellular ion (salt) channels are a common cause for migraine and are recently being reported in abdominal migraine and CVS as well.Additional factors that may be associated with the development of CVS include dysfunction of the autonomic nervous system. The autonomic nervous system is the system that controls or regulates certain involuntary body functions including heart rate, blood pressure, sweating, the production and release of certain hormones and bowel and bladder control. Autonomic “functional” disturbances are common during episodes, including fever, pallor, tachycardia, high blood pressure and urinary retention. Vomiting itself is an autonomic disturbance. Autonomic disturbances can also occur between episodes, such as reflex sympathetic dystrophy (a chronic pain condition), syncope/POTS (fainting) and disorders of gastrointestinal motility. Dysmotility refers to abnormal motion through the gastrointestinal tract, either too fast, too slow or in the wrong direction. During CVS episodes, motion through the gut is very abnormal, and thus there is severe dysmotility. However, many CVS patients have lesser degrees of dysmotility between episodes. Different types of dysmotility that are common in people with CVS include gastroesophageal reflux (GERD), gastroparesis (low stomach motility causing delayed emptying of the stomach) and forms of irritable bowel disease (IBS: diarrhea, constipation, and/or bloating). Nausea is a common component of dysmotility and is especially common among adults. Thus, nausea (and occasionally vomiting) can be present between CVS episodes. However, during CVS episodes the nausea (and possibly vomiting) is far more intense than it is between episodes. Additional conditions that occur more often in those with CVS include anxiety, depression, attention deficit hyperactivity disorder (ADHD), seizures, autistic spectrum disorders and learning disabilities.Some research indicates that the body’s response to stress may be overactive and contribute or trigger episodes of CVS. Affected individuals may have increased release of corticotrophin-releasing factor (CRF) from the hypothalamus. CRF is a stress hormone that stimulates the adrenal cortex, which controls the body’s response to stress. Some research has indicated that CRF may inhibit the stomach pumping.Researchers have also learned that blood and urine testing reveal signs of abnormal energy metabolism in most people with CVS. Changes (mutations) in the genetic material of mitochondrial genes may play a role in the development of CVS. Mitochondria provide most of the power for cells. As muscle and nerve tissue have very high energy requirements, defective mitochondrial energy production may lead to an energy shortage during stress that affects nerve function, especially the autonomic nerves that control the gut. This might lead to disease by reducing the capacity to produce sufficient energy during times of stress such as with fever, illness, hot weather (sweating), excitement and exercise.Because the genetic instructions (blueprints) for mitochondria DNA (mtDNA) are inherited from the mother, an affected mother will pass the same mutation to all of her children. As a result, in some families disease is found primarily on the mother’s side – the siblings, the maternal aunts and uncles and the maternal grandmother – all of whom carry the same mtDNA genetic sequences. Only females will pass a mtDNA mutation on to their children. In half or more of CVS families, those relatives often suffer themselves from dysautonomic or functional-related symptoms, especially chronic pain (including migraine), bowel disorders (GE reflux or constipation), fatigue and anxiety/depression.In other cases, CVS can be caused by abnormal genes for mitochondrial function in the nuclear DNA (not in the mtDNA) and can be inherited from either the mother or the father.The exact manner that all the above mentioned and additional factors fit together in the puzzle to cause CVS is still unclear. Research is ongoing to determine the cause and underlying mechanisms that result in CVS. | 345 | Cyclic Vomiting Syndrome |
nord_345_3 | Affects of Cyclic Vomiting Syndrome | Cyclic vomiting syndrome affects females somewhat more often than males (55:45). It most commonly occurs in children between the ages of three and seven, although it can begin at any age, from early infancy through to old age (73 is the oldest reported). Because CVS it is sometimes not recognized or misdiagnosed as stomach flu, a correct diagnosis is often delayed for many years. Although CVS is found more often in children, it is being recognized with greater frequency in adults. The incidence of CVS is unknown, although it is not rare. Two studies in Scotland and Australia have suggested that as many as 2% of all Caucasian school-aged children suffer from CVS. However, researchers believe the disorder is underdiagnosed, making it difficult to estimate its true frequency in the general population. | Affects of Cyclic Vomiting Syndrome. Cyclic vomiting syndrome affects females somewhat more often than males (55:45). It most commonly occurs in children between the ages of three and seven, although it can begin at any age, from early infancy through to old age (73 is the oldest reported). Because CVS it is sometimes not recognized or misdiagnosed as stomach flu, a correct diagnosis is often delayed for many years. Although CVS is found more often in children, it is being recognized with greater frequency in adults. The incidence of CVS is unknown, although it is not rare. Two studies in Scotland and Australia have suggested that as many as 2% of all Caucasian school-aged children suffer from CVS. However, researchers believe the disorder is underdiagnosed, making it difficult to estimate its true frequency in the general population. | 345 | Cyclic Vomiting Syndrome |
nord_345_4 | Related disorders of Cyclic Vomiting Syndrome | Symptoms of the following disorders can be similar to those of cyclic vomiting syndrome. Comparisons may be useful for a differential diagnosis.Many different conditions can cause nausea and vomiting including viral gastroenteritis (“stomach flu”), peptic disorders (e.g. gastritis or ulcer), inflammation of the pancreas (pancreatitis) or the appendix (appendicitis), volvulus (due to malrotation of the intestines), certain metabolic disorders (disorders of fatty acid oxidation, organic acids, urea cycle), abnormal accumulation of urine in the kidneys (acute hydronephrosis) usually due to obstruction, endocrine disorders (Addison disease), brain tumors and other masses (Chiari malformation) in the head and disorders affecting the autonomic nervous system such as familial dysautonomia. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) Gastroesophageal reflux disease (GERD) is a very common gut dysmotility disorder characterized by the back flow (reflux) of the contents of the stomach or small intestine (duodenum) into the esophagus. The esophagus is the tube that carries food from the mouth to the stomach. Symptoms of GERD include a sensation of burning rising up to the neck area (heartburn or pyrosis), swallowing difficulties (dysphagia), and chest pain. Not uncommonly, symptoms can be vaguer, such as irritability (in infants), fatigue and malaise (feeling bad). GERD is a common condition in children and adults. When GERD occurs in children or infants (pediatric gastroesophageal reflux), the most common symptoms include irritability, frequent episodes of vomiting or spitting-up and poor sleeping habits. Less common symptoms include swallowing problems, gagging, sore throat, and poor food intake which may cause an infant to fail to grow and gain weight as expected (failure to thrive). | Related disorders of Cyclic Vomiting Syndrome. Symptoms of the following disorders can be similar to those of cyclic vomiting syndrome. Comparisons may be useful for a differential diagnosis.Many different conditions can cause nausea and vomiting including viral gastroenteritis (“stomach flu”), peptic disorders (e.g. gastritis or ulcer), inflammation of the pancreas (pancreatitis) or the appendix (appendicitis), volvulus (due to malrotation of the intestines), certain metabolic disorders (disorders of fatty acid oxidation, organic acids, urea cycle), abnormal accumulation of urine in the kidneys (acute hydronephrosis) usually due to obstruction, endocrine disorders (Addison disease), brain tumors and other masses (Chiari malformation) in the head and disorders affecting the autonomic nervous system such as familial dysautonomia. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) Gastroesophageal reflux disease (GERD) is a very common gut dysmotility disorder characterized by the back flow (reflux) of the contents of the stomach or small intestine (duodenum) into the esophagus. The esophagus is the tube that carries food from the mouth to the stomach. Symptoms of GERD include a sensation of burning rising up to the neck area (heartburn or pyrosis), swallowing difficulties (dysphagia), and chest pain. Not uncommonly, symptoms can be vaguer, such as irritability (in infants), fatigue and malaise (feeling bad). GERD is a common condition in children and adults. When GERD occurs in children or infants (pediatric gastroesophageal reflux), the most common symptoms include irritability, frequent episodes of vomiting or spitting-up and poor sleeping habits. Less common symptoms include swallowing problems, gagging, sore throat, and poor food intake which may cause an infant to fail to grow and gain weight as expected (failure to thrive). | 345 | Cyclic Vomiting Syndrome |
nord_345_5 | Diagnosis of Cyclic Vomiting Syndrome | A diagnosis of cyclic vomiting syndrome may be suspected based upon a thorough clinical evaluation with the identification of characteristic findings. Diagnostic criteria are currently based upon the consensus criteria of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the Rome IV Committee. The determination of CVS can only be made after other causes of recurrent vomiting have been ruled out. There is no “test” to prove the presence of cyclic vomiting syndrome, although the presence of urine ketosis early in an episode may be helpful. A variety of tests of may be used to rule out other causes of recurrent nausea and vomiting. In particular, it is important to rule out a physical/structural blockage of the intestines, including malrotation, with an upper gastrointestinal series of radiographs. Standard blood chemistries testing is important to detect abnormal levels of sodium and potassium (electrolytes) and well as pancreatitis (lipase). | Diagnosis of Cyclic Vomiting Syndrome. A diagnosis of cyclic vomiting syndrome may be suspected based upon a thorough clinical evaluation with the identification of characteristic findings. Diagnostic criteria are currently based upon the consensus criteria of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the Rome IV Committee. The determination of CVS can only be made after other causes of recurrent vomiting have been ruled out. There is no “test” to prove the presence of cyclic vomiting syndrome, although the presence of urine ketosis early in an episode may be helpful. A variety of tests of may be used to rule out other causes of recurrent nausea and vomiting. In particular, it is important to rule out a physical/structural blockage of the intestines, including malrotation, with an upper gastrointestinal series of radiographs. Standard blood chemistries testing is important to detect abnormal levels of sodium and potassium (electrolytes) and well as pancreatitis (lipase). | 345 | Cyclic Vomiting Syndrome |
nord_345_6 | Therapies of Cyclic Vomiting Syndrome | TreatmentThe treatment of cyclic vomiting syndrome is directed toward preventing, shortening or managing the episodes of nausea and vomiting and reducing symptoms of abdominal pain. Treatment of this disorder is based upon experience and observation as opposed to an evidence-based treatment regimen. Specific therapies should be tailored for each individual patient.Prophylactic therapy is used to prevent episodes from occurring. Some individuals are treated with certain anti-migraine medications, especially amitriptyline, as well as cyproheptadine (in preschool-aged children) or propranolol. Anti-migraine therapies seem particularly effective for individuals with a family history of migraine.Two studies each for coenzyme Q10 and L-carnitine suggest that these mitochondrial-targeted cofactors can be helpful in preventing vomiting episodes. Both are natural substances that can be obtained in the United States and most other countries without a prescription. Co-enzyme Q10 assists in energy production (electron transport) and L-carnitine aids with fuel transport (fat transport) and the clearing of metabolic waste products. In some patients, vomiting episodes become less frequent when these cofactors are used alone. One study suggests that they work best in combination with amitriptyline, and recommends adjusting dosage of all three treatments based on blood levels. Side effects of these cofactors are rare and generally mild; L-carnitine can cause nausea and diarrhea as well as a fish-like odor. Co-enzyme Q10 is available in two forms, ubiquinone and ubiquinol. Studies have shown that ubiquinol is up to five times more bioavailable (absorbable from the intestines) as ubiquinone and is thus preferred. Given this bioavailability, ubiquinol is also more cost effective despite a higher unit cost.Preventive drug therapy is usually recommended for individuals with equal to or more than one episode per two-month period, but can be considered in those with less frequent episodes especially if episodes are prolonged or severe. Although not all experts agree, erythromycin may also be used to reduce the severity of episodes, especially in individuals with CVS and poor stomach pumping. Drugs that prevent seizures (anticonvulsants), especially toparimate and phenobarbital have also been used to prevent episodes from occurring. Aprepitant is recently being used more often for CVS. Treatment of symptoms once they start is generally used when episodes occur less frequently (i.e., less than once every 2 month) or when preventive therapy has not worked. Certain drugs may be used to stop an episode as it is about to begin (abortive therapy). Some affected individuals can sense (e.g. nausea) an episode coming on (warning phase). Drugs used to treat vomiting (anti-emetics) such as ondansetron or granisetron or certain anti-migraine drugs known as triptans may be used to stop an episode if they are administered at the beginning of an episode. About one-half of individuals with CVS respond favorably to attempts to abort or lessen the severity of episodes using sugar-containing intravenous (IV) fluids. In particular, D10-containing (10% sugar) IV fluids may be helpful if given early, although this is not always available and D5-containing fluids at high rates can be substituted. Sugar-containing drinks such as juices or sodas can also be helpful at home.Since individuals respond to medications differently, no one therapy works for all affected individuals. Several attempts using different preventive and abortive therapies may be necessary until an effective regimen is found for an individual patient. In particular, treatment failures are frequently the result of too little drug given too infrequently. For example, although most experts target 0.5 mg per kg body weight per day, amitriptyline is often required 1 to 1.5 mg/kg/day for over a month or two in order to prevent vomiting episodes. Blood levels of amitriptyline can be obtained to check that the dose given is adequate and not excessive.When preventive and abortive therapy does not work, supportive care during an episode may include bed rest in a dimly lit, quiet room. The administration of intravenous fluids to prevent complications such as dehydration may be necessary. Anti-vomiting medications (especially ondansetron at 0.3 to 0.4 mg/kg/dose, maximum dose about 24 mg), ketorolac used for pain and lorazepam for sedation may also be used. When children or adults are asleep, they don’t experience nausea. Deep sleep may also reset their system and shorten the episode. In severe episodes, hospitalization may be necessary.Avoidance of known triggers (when possible) may also help reduce the frequency of episodes. Treatment of underlying commonplace anxiety using cognitive behavioral therapy and stress management (deep breathing) is often the key to improvement and rehabilitation back to school. The support of family is considered essential by clinicians to help deal with the unpredictable, disruptive nature of CVS and the likelihood of a delay in attaining the proper diagnosis. | Therapies of Cyclic Vomiting Syndrome. TreatmentThe treatment of cyclic vomiting syndrome is directed toward preventing, shortening or managing the episodes of nausea and vomiting and reducing symptoms of abdominal pain. Treatment of this disorder is based upon experience and observation as opposed to an evidence-based treatment regimen. Specific therapies should be tailored for each individual patient.Prophylactic therapy is used to prevent episodes from occurring. Some individuals are treated with certain anti-migraine medications, especially amitriptyline, as well as cyproheptadine (in preschool-aged children) or propranolol. Anti-migraine therapies seem particularly effective for individuals with a family history of migraine.Two studies each for coenzyme Q10 and L-carnitine suggest that these mitochondrial-targeted cofactors can be helpful in preventing vomiting episodes. Both are natural substances that can be obtained in the United States and most other countries without a prescription. Co-enzyme Q10 assists in energy production (electron transport) and L-carnitine aids with fuel transport (fat transport) and the clearing of metabolic waste products. In some patients, vomiting episodes become less frequent when these cofactors are used alone. One study suggests that they work best in combination with amitriptyline, and recommends adjusting dosage of all three treatments based on blood levels. Side effects of these cofactors are rare and generally mild; L-carnitine can cause nausea and diarrhea as well as a fish-like odor. Co-enzyme Q10 is available in two forms, ubiquinone and ubiquinol. Studies have shown that ubiquinol is up to five times more bioavailable (absorbable from the intestines) as ubiquinone and is thus preferred. Given this bioavailability, ubiquinol is also more cost effective despite a higher unit cost.Preventive drug therapy is usually recommended for individuals with equal to or more than one episode per two-month period, but can be considered in those with less frequent episodes especially if episodes are prolonged or severe. Although not all experts agree, erythromycin may also be used to reduce the severity of episodes, especially in individuals with CVS and poor stomach pumping. Drugs that prevent seizures (anticonvulsants), especially toparimate and phenobarbital have also been used to prevent episodes from occurring. Aprepitant is recently being used more often for CVS. Treatment of symptoms once they start is generally used when episodes occur less frequently (i.e., less than once every 2 month) or when preventive therapy has not worked. Certain drugs may be used to stop an episode as it is about to begin (abortive therapy). Some affected individuals can sense (e.g. nausea) an episode coming on (warning phase). Drugs used to treat vomiting (anti-emetics) such as ondansetron or granisetron or certain anti-migraine drugs known as triptans may be used to stop an episode if they are administered at the beginning of an episode. About one-half of individuals with CVS respond favorably to attempts to abort or lessen the severity of episodes using sugar-containing intravenous (IV) fluids. In particular, D10-containing (10% sugar) IV fluids may be helpful if given early, although this is not always available and D5-containing fluids at high rates can be substituted. Sugar-containing drinks such as juices or sodas can also be helpful at home.Since individuals respond to medications differently, no one therapy works for all affected individuals. Several attempts using different preventive and abortive therapies may be necessary until an effective regimen is found for an individual patient. In particular, treatment failures are frequently the result of too little drug given too infrequently. For example, although most experts target 0.5 mg per kg body weight per day, amitriptyline is often required 1 to 1.5 mg/kg/day for over a month or two in order to prevent vomiting episodes. Blood levels of amitriptyline can be obtained to check that the dose given is adequate and not excessive.When preventive and abortive therapy does not work, supportive care during an episode may include bed rest in a dimly lit, quiet room. The administration of intravenous fluids to prevent complications such as dehydration may be necessary. Anti-vomiting medications (especially ondansetron at 0.3 to 0.4 mg/kg/dose, maximum dose about 24 mg), ketorolac used for pain and lorazepam for sedation may also be used. When children or adults are asleep, they don’t experience nausea. Deep sleep may also reset their system and shorten the episode. In severe episodes, hospitalization may be necessary.Avoidance of known triggers (when possible) may also help reduce the frequency of episodes. Treatment of underlying commonplace anxiety using cognitive behavioral therapy and stress management (deep breathing) is often the key to improvement and rehabilitation back to school. The support of family is considered essential by clinicians to help deal with the unpredictable, disruptive nature of CVS and the likelihood of a delay in attaining the proper diagnosis. | 345 | Cyclic Vomiting Syndrome |
nord_346_0 | Overview of Cystic Fibrosis | Cystic fibrosis is a genetic disorder that often affects multiple organ systems of the body. Cystic fibrosis is characterized by abnormalities affecting certain glands (exocrine) of the body especially those that produce mucus. Saliva and sweat glands may also be affected. Exocrine glands secrete substances through ducts, either internally (e.g., glands in the lungs) or externally (e.g., sweat glands). In cystic fibrosis, these secretions become abnormally thick and can clog up vital areas of the body causing inflammation, obstruction and infection. The symptoms of cystic fibrosis can vary greatly in number and severity from one individual to another. Common symptoms include breathing (respiratory) abnormalities including a persistent cough, shortness of breath and lung infections; obstruction of the pancreas, which prevents digestive enzymes from reaching the intestines to help break down food and may result in poor growth and poor nutrition; and obstruction of the intestines. Cystic fibrosis is slowly progressive and often causes chronic lung damage, which eventually results in life-threatening complications. Because of improved treatments and new treatment options, the outlook and overall quality of life of individuals with cystic fibrosis has improved and over 50 percent of individuals with the disorder are adults. Cystic fibrosis is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is inherited as an autosomal recessive trait. | Overview of Cystic Fibrosis. Cystic fibrosis is a genetic disorder that often affects multiple organ systems of the body. Cystic fibrosis is characterized by abnormalities affecting certain glands (exocrine) of the body especially those that produce mucus. Saliva and sweat glands may also be affected. Exocrine glands secrete substances through ducts, either internally (e.g., glands in the lungs) or externally (e.g., sweat glands). In cystic fibrosis, these secretions become abnormally thick and can clog up vital areas of the body causing inflammation, obstruction and infection. The symptoms of cystic fibrosis can vary greatly in number and severity from one individual to another. Common symptoms include breathing (respiratory) abnormalities including a persistent cough, shortness of breath and lung infections; obstruction of the pancreas, which prevents digestive enzymes from reaching the intestines to help break down food and may result in poor growth and poor nutrition; and obstruction of the intestines. Cystic fibrosis is slowly progressive and often causes chronic lung damage, which eventually results in life-threatening complications. Because of improved treatments and new treatment options, the outlook and overall quality of life of individuals with cystic fibrosis has improved and over 50 percent of individuals with the disorder are adults. Cystic fibrosis is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is inherited as an autosomal recessive trait. | 346 | Cystic Fibrosis |
nord_346_1 | Symptoms of Cystic Fibrosis | The symptoms of cystic fibrosis result because mucus secretions are abnormally thick and sticky, whereas normally they are thin and slippery and serve as a protective lubricant. Other secreted material such as saliva, sweat and digestive juices may also be affected. These abnormal secretions can clog up vital tubes, ducts and passageways throughout the body.Multiple organ systems may be affected by cystic fibrosis, especially the lungs and pancreas. The intestines, liver, sweat glands and reproductive organs also are frequently affected. The symptoms of cystic fibrosis can vary greatly from one individual to another. Some individuals may only have respiratory problems without other complications. Some individuals may only have a few mild symptoms; others may have serious complications. The severity of specific symptoms also varies. In early life, many individuals may have mild respiratory complications, while others may have serious, life-threatening respiratory complications. Affected individuals will not have all the symptoms discussed below.Cystic fibrosis is often apparent shortly after birth, but before newborn screening, when symptoms were not severe, CF may not have been detected until years later and, in rare cases, even as late as during adulthood. Most cases diagnosed in adulthood have no associated symptoms (asymptomatic) or only very mild symptoms. At this time, newborn screening for CF is provided throughout the United States, and thus it has become much rarer for CF to be newly diagnosed later in life.Affected individuals develop a variety of breathing (respiratory) complications due to the production of thick, sticky mucus that clogs various air passages in the body. Associated symptoms include a persistent cough that often produces mucus or phlegm (productive cough), wheezing, and shortness of breath. Because mucus clogs the airways, bacteria become trapped and accumulate within the lungs and air passages making individuals particularly prone to developing repeated (chronic) respiratory infections that lead to inflammation of the main air passages of the lungs (bronchitis), inflammation of the sinuses (sinusitis) and inflammation of the lungs. Clogging of the airways with mucus may also make it difficult to breath.The immune system of individuals with cystic fibrosis responds to an infection by sending white blood cells to attack the infection. After attacking the infection, white blood cells break down and further clog the airways. Debris from the white blood cells can be very destructive to lung tissue, and is thought to be a major contributor to the lung damage that occurs in cystic fibrosis. Further, this debris tends to be very “sticky,” which adds to the difficulty of its clearance from the lungs. The repeated cycle of infection and immune system response progressively damages the lungs. Chronic mucus blockage and infection of the respiratory passageways may cause them to become abnormally widened (bronchiestasis), which permits more mucus to build up and further increase the risk of infection. Eventually, continued damage to the lungs can cause life-threatening respiratory failure or enlargement and improper function of the lower right chamber (ventricle) of the heart (cor pulmonale). Enlargement of the ventricle occurs because the heart must work harder to try and pump blood through the damaged lungs.In many cases, cystic fibrosis causes pancreatic insufficiency. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps break down sugar. When mucous builds up in the pancreatic ducts, it may block the enzymes from reaching the intestines and helping the breakdown and absorption of food and nutrients. Failure of the body to breakdown and absorb nutrients is called malabsorption and can result in a variety of nutritional deficiencies in affected individuals. In childhood, it may result in failure of an affected child to grow and gain weight at the expected rate for age and sex (failure to thrive). Affected individuals may also have large, loose, foul-smelling stools that contain and excess of fat (steatorrhea) and other nutrients due to malabsorption.The first symptom in 10-20% of cases diagnosed during infancy is meconium ileus -obstruction of the intestines at birth with a thick, tarry substance called meconium. Meconium is the medical term for an infant’s first stool, which is passed shortly after birth.CF causes an abnormality that prevents the absorption of salt from sweat, which results in higher than normal levels of salt in the sweat. Salt depletion may upset the balance of minerals in the body, causing abnormal heart rhythms or the body to overheat.Mucus can also accumulated within the small tubes that carry bile from the liver to the intestines (bile ducts) causing obstruction and inflammation. In some cases, high blood pressure of the major vein that carries blood to the liver from the digestive organs may occur (portal hypertension). Obstruction of the bile ducts can damage the liver, eventually leading to scarring of the liver (cirrhosis). Damage to the liver can potentially become life-threatening.Most boys with cystic fibrosis are born without the small tubes that carry sperm out from the testes (congenital absence of the vas deferens) resulting in infertility. In other cases, male infertility may be caused by underdevelopment (atrophy) or damage (fibrosis) of the vas deferens. In some girls, fertility may be reduced due to the accumulation of abnormal mucus in the cervix and irregular menstrual periods.Additional respiratory symptoms may be associated with cystic fibrosis including the development of small growths in the nose (nasal polyps), coughing up of blood (hemoptysis), recurrent episodes of lung collapse (pneumothorax), and abnormally fast breathing (tachypnea).Additional gastrointestinal symptoms associated with cystic fibrosis may occur including recurrent abdominal pain, bloating (distention) of the abdomen, backflow of the contents of the stomach into the tube (esophagus) that connects the back of the mouth to the stomach (gastroesophageal reflux) and protrusion of part of the rectum through the anus (rectal prolapse). In some cases, the gall bladder may be filled with thick, sticky mucus and fail to function properly. The gall bladder is a small, pear-shaped organ located under the liver that stores bile. Some individuals may develop gall stones.Most individuals with cystic fibrosis develop rounding or flattening (clubbing) of the tips of the fingers or toes.Individuals with cystic fibrosis may be at risk for developing cystic fibrosis-related diabetes mellitus (CFRD). CFRD may occur in some adolescents with cystic fibrosis, although the prevalence increases during adulthood, as the longer patients live with cystic fibrosis, the more likely they are to develop CFRD. The onset of CFRD is slow and individuals may not have symptoms (asymptomatic). CFRD develops due to damage to the pancreas (which limits insulin production) and increased resistance to insulin. CFRD can also worsen lung function in affected individuals.Another specific condition that may develop in individuals with cystic fibrosis is known as distal intestinal obstruction syndrome (DIOS), in which food, mucus and stool clog the intestines. This condition can cause stomach aches, bloating, cramping, nausea and loss of appetite. In severe cases, it may cause pain, vomiting and watery stools. The incidence of DIOS appears to increase with age; most cases tend to occur in adolescents and adults. | Symptoms of Cystic Fibrosis. The symptoms of cystic fibrosis result because mucus secretions are abnormally thick and sticky, whereas normally they are thin and slippery and serve as a protective lubricant. Other secreted material such as saliva, sweat and digestive juices may also be affected. These abnormal secretions can clog up vital tubes, ducts and passageways throughout the body.Multiple organ systems may be affected by cystic fibrosis, especially the lungs and pancreas. The intestines, liver, sweat glands and reproductive organs also are frequently affected. The symptoms of cystic fibrosis can vary greatly from one individual to another. Some individuals may only have respiratory problems without other complications. Some individuals may only have a few mild symptoms; others may have serious complications. The severity of specific symptoms also varies. In early life, many individuals may have mild respiratory complications, while others may have serious, life-threatening respiratory complications. Affected individuals will not have all the symptoms discussed below.Cystic fibrosis is often apparent shortly after birth, but before newborn screening, when symptoms were not severe, CF may not have been detected until years later and, in rare cases, even as late as during adulthood. Most cases diagnosed in adulthood have no associated symptoms (asymptomatic) or only very mild symptoms. At this time, newborn screening for CF is provided throughout the United States, and thus it has become much rarer for CF to be newly diagnosed later in life.Affected individuals develop a variety of breathing (respiratory) complications due to the production of thick, sticky mucus that clogs various air passages in the body. Associated symptoms include a persistent cough that often produces mucus or phlegm (productive cough), wheezing, and shortness of breath. Because mucus clogs the airways, bacteria become trapped and accumulate within the lungs and air passages making individuals particularly prone to developing repeated (chronic) respiratory infections that lead to inflammation of the main air passages of the lungs (bronchitis), inflammation of the sinuses (sinusitis) and inflammation of the lungs. Clogging of the airways with mucus may also make it difficult to breath.The immune system of individuals with cystic fibrosis responds to an infection by sending white blood cells to attack the infection. After attacking the infection, white blood cells break down and further clog the airways. Debris from the white blood cells can be very destructive to lung tissue, and is thought to be a major contributor to the lung damage that occurs in cystic fibrosis. Further, this debris tends to be very “sticky,” which adds to the difficulty of its clearance from the lungs. The repeated cycle of infection and immune system response progressively damages the lungs. Chronic mucus blockage and infection of the respiratory passageways may cause them to become abnormally widened (bronchiestasis), which permits more mucus to build up and further increase the risk of infection. Eventually, continued damage to the lungs can cause life-threatening respiratory failure or enlargement and improper function of the lower right chamber (ventricle) of the heart (cor pulmonale). Enlargement of the ventricle occurs because the heart must work harder to try and pump blood through the damaged lungs.In many cases, cystic fibrosis causes pancreatic insufficiency. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps break down sugar. When mucous builds up in the pancreatic ducts, it may block the enzymes from reaching the intestines and helping the breakdown and absorption of food and nutrients. Failure of the body to breakdown and absorb nutrients is called malabsorption and can result in a variety of nutritional deficiencies in affected individuals. In childhood, it may result in failure of an affected child to grow and gain weight at the expected rate for age and sex (failure to thrive). Affected individuals may also have large, loose, foul-smelling stools that contain and excess of fat (steatorrhea) and other nutrients due to malabsorption.The first symptom in 10-20% of cases diagnosed during infancy is meconium ileus -obstruction of the intestines at birth with a thick, tarry substance called meconium. Meconium is the medical term for an infant’s first stool, which is passed shortly after birth.CF causes an abnormality that prevents the absorption of salt from sweat, which results in higher than normal levels of salt in the sweat. Salt depletion may upset the balance of minerals in the body, causing abnormal heart rhythms or the body to overheat.Mucus can also accumulated within the small tubes that carry bile from the liver to the intestines (bile ducts) causing obstruction and inflammation. In some cases, high blood pressure of the major vein that carries blood to the liver from the digestive organs may occur (portal hypertension). Obstruction of the bile ducts can damage the liver, eventually leading to scarring of the liver (cirrhosis). Damage to the liver can potentially become life-threatening.Most boys with cystic fibrosis are born without the small tubes that carry sperm out from the testes (congenital absence of the vas deferens) resulting in infertility. In other cases, male infertility may be caused by underdevelopment (atrophy) or damage (fibrosis) of the vas deferens. In some girls, fertility may be reduced due to the accumulation of abnormal mucus in the cervix and irregular menstrual periods.Additional respiratory symptoms may be associated with cystic fibrosis including the development of small growths in the nose (nasal polyps), coughing up of blood (hemoptysis), recurrent episodes of lung collapse (pneumothorax), and abnormally fast breathing (tachypnea).Additional gastrointestinal symptoms associated with cystic fibrosis may occur including recurrent abdominal pain, bloating (distention) of the abdomen, backflow of the contents of the stomach into the tube (esophagus) that connects the back of the mouth to the stomach (gastroesophageal reflux) and protrusion of part of the rectum through the anus (rectal prolapse). In some cases, the gall bladder may be filled with thick, sticky mucus and fail to function properly. The gall bladder is a small, pear-shaped organ located under the liver that stores bile. Some individuals may develop gall stones.Most individuals with cystic fibrosis develop rounding or flattening (clubbing) of the tips of the fingers or toes.Individuals with cystic fibrosis may be at risk for developing cystic fibrosis-related diabetes mellitus (CFRD). CFRD may occur in some adolescents with cystic fibrosis, although the prevalence increases during adulthood, as the longer patients live with cystic fibrosis, the more likely they are to develop CFRD. The onset of CFRD is slow and individuals may not have symptoms (asymptomatic). CFRD develops due to damage to the pancreas (which limits insulin production) and increased resistance to insulin. CFRD can also worsen lung function in affected individuals.Another specific condition that may develop in individuals with cystic fibrosis is known as distal intestinal obstruction syndrome (DIOS), in which food, mucus and stool clog the intestines. This condition can cause stomach aches, bloating, cramping, nausea and loss of appetite. In severe cases, it may cause pain, vomiting and watery stools. The incidence of DIOS appears to increase with age; most cases tend to occur in adolescents and adults. | 346 | Cystic Fibrosis |
nord_346_2 | Causes of Cystic Fibrosis | Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This defective gene is inherited as an autosomal recessive trait. 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.Investigators have determined that the CFTR gene is located on the long arm (q) of chromosome 7 (7q31.2). 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 7q31.2” refers to band 31.2 on the long arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The CFTR gene primarily is expressed in cells lining the airways, gastrointestinal tract, pancreas, sweat glands, and genitourinary system. The gene controls the production of a protein that regulates the transfer of chloride and sodium across cell membranes. Accordingly, investigators speculate that inheritance of the defective CFTR gene results in disruption of chloride and sodium transfer, ultimately leading to low levels of certain bodily fluids (dehydration), abnormally thick mucus and other glandular secretions, salt loss, and impaired glandular functioning. | Causes of Cystic Fibrosis. Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This defective gene is inherited as an autosomal recessive trait. 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.Investigators have determined that the CFTR gene is located on the long arm (q) of chromosome 7 (7q31.2). 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 7q31.2” refers to band 31.2 on the long arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The CFTR gene primarily is expressed in cells lining the airways, gastrointestinal tract, pancreas, sweat glands, and genitourinary system. The gene controls the production of a protein that regulates the transfer of chloride and sodium across cell membranes. Accordingly, investigators speculate that inheritance of the defective CFTR gene results in disruption of chloride and sodium transfer, ultimately leading to low levels of certain bodily fluids (dehydration), abnormally thick mucus and other glandular secretions, salt loss, and impaired glandular functioning. | 346 | Cystic Fibrosis |
nord_346_3 | Affects of Cystic Fibrosis | Cystic fibrosis is the most common, life-limiting recessive genetic disorder in Caucasians. Approximately 30,000 people have cystic fibrosis in the United States. One thousand new cases are diagnosed each year, with males and females affected in equal numbers. The disorder occurs predominately among Caucasians, occurring in approximately one of every 3,200 live Caucasian births compared to one in 3,900 live births of all Americans. Among African Americans, CF is manifest in about one in 15-17,000 live births. There is also a small but significant number of Americans of Asian descent who are affected by the disorder.In many cases, CF is apparent soon after birth and most affected individuals are diagnosed by age 3. Approximately 10% of those affected were diagnosed after 18 years of age, but this figure is falling because of the institution of newborn screening. | Affects of Cystic Fibrosis. Cystic fibrosis is the most common, life-limiting recessive genetic disorder in Caucasians. Approximately 30,000 people have cystic fibrosis in the United States. One thousand new cases are diagnosed each year, with males and females affected in equal numbers. The disorder occurs predominately among Caucasians, occurring in approximately one of every 3,200 live Caucasian births compared to one in 3,900 live births of all Americans. Among African Americans, CF is manifest in about one in 15-17,000 live births. There is also a small but significant number of Americans of Asian descent who are affected by the disorder.In many cases, CF is apparent soon after birth and most affected individuals are diagnosed by age 3. Approximately 10% of those affected were diagnosed after 18 years of age, but this figure is falling because of the institution of newborn screening. | 346 | Cystic Fibrosis |
nord_346_4 | Related disorders of Cystic Fibrosis | Symptoms of the following disorders can be similar to those of cystic fibrosis. Comparisons may be useful for a differential diagnosis.Primary ciliary dyskinesia (PCD) is rare disorder involving the tiny, hair-structures that cover many cells of the body. Cilia in the respiratory passageways help to move mucus out of these passageways. In individuals with PCD, the cilia are defective allowing mucus to build up in the airways and respiratory passageways of the body. Symptoms may include inflammation of the sinuses (sinusitis), repeated respiratory infections, and pneumonia and can, consequently, cause progressive lung damage. PCD can also affect the middle ear and the reproductive organs. PCD is inherited as an autosomal recessive trait. (For more information on this disorder, choose “primary ciliary dyskinesia” as your search term in the Rare Disease Database.)Shwachman syndrome is a rare genetic disorder with multiple and varied manifestations. The disorder is typically characterized by signs of insufficient absorption (malabsorption) of fats and other nutrients due to abnormal development of the pancreas (pancreatic insufficiency) and improper functioning of the bone marrow (bone marrow dysfunction), resulting in low levels of circulating blood cells (hematologic abnormalities). Additional characteristic findings may include short stature; abnormal bone development affecting the rib cage and/or bones in the arms and/or legs (metaphyseal dysostosis); and/or liver abnormalities. Shwachman syndrome is believed to be inherited as an autosomal recessive trait. (For more information on this disorder, choose “Shwachman” as your search term in the Rare Disease Database.) | Related disorders of Cystic Fibrosis. Symptoms of the following disorders can be similar to those of cystic fibrosis. Comparisons may be useful for a differential diagnosis.Primary ciliary dyskinesia (PCD) is rare disorder involving the tiny, hair-structures that cover many cells of the body. Cilia in the respiratory passageways help to move mucus out of these passageways. In individuals with PCD, the cilia are defective allowing mucus to build up in the airways and respiratory passageways of the body. Symptoms may include inflammation of the sinuses (sinusitis), repeated respiratory infections, and pneumonia and can, consequently, cause progressive lung damage. PCD can also affect the middle ear and the reproductive organs. PCD is inherited as an autosomal recessive trait. (For more information on this disorder, choose “primary ciliary dyskinesia” as your search term in the Rare Disease Database.)Shwachman syndrome is a rare genetic disorder with multiple and varied manifestations. The disorder is typically characterized by signs of insufficient absorption (malabsorption) of fats and other nutrients due to abnormal development of the pancreas (pancreatic insufficiency) and improper functioning of the bone marrow (bone marrow dysfunction), resulting in low levels of circulating blood cells (hematologic abnormalities). Additional characteristic findings may include short stature; abnormal bone development affecting the rib cage and/or bones in the arms and/or legs (metaphyseal dysostosis); and/or liver abnormalities. Shwachman syndrome is believed to be inherited as an autosomal recessive trait. (For more information on this disorder, choose “Shwachman” as your search term in the Rare Disease Database.) | 346 | Cystic Fibrosis |
nord_346_5 | Diagnosis of Cystic Fibrosis | A diagnosis of cystic fibrosis may be suspected based upon newborn screening, identification of characteristic symptoms (e.g., pulmonary disease, pancreatic insufficiency) or a positive family history. The standard diagnostic test for cystic fibrosis is the sweat test, a painless and simple procedure that measures the amount of salt in the sweat. Genetic testing can identify carriers of the defective gene. In May 2005, the U.S. Food and Drug Administration (FDA) approved the first DNA-based blood test to help detect cystic fibrosis. The Tag-It Cystic Fibrosis Kit directly analyzes human DNA to find genetic variations indicative of the disease. All 50 States have newborn screening for CF. In most states, immunoreactive trypsinogen (IRT) assays are performed on dried blood spots from newborns. Trypsinogen is synthesized in the pancreas and IRT levels are elevated in CF. Abnormal IRT results are followed up with sweat testing and/or molecular genetic (DNA-based) testing to confirm the diagnosis. | Diagnosis of Cystic Fibrosis. A diagnosis of cystic fibrosis may be suspected based upon newborn screening, identification of characteristic symptoms (e.g., pulmonary disease, pancreatic insufficiency) or a positive family history. The standard diagnostic test for cystic fibrosis is the sweat test, a painless and simple procedure that measures the amount of salt in the sweat. Genetic testing can identify carriers of the defective gene. In May 2005, the U.S. Food and Drug Administration (FDA) approved the first DNA-based blood test to help detect cystic fibrosis. The Tag-It Cystic Fibrosis Kit directly analyzes human DNA to find genetic variations indicative of the disease. All 50 States have newborn screening for CF. In most states, immunoreactive trypsinogen (IRT) assays are performed on dried blood spots from newborns. Trypsinogen is synthesized in the pancreas and IRT levels are elevated in CF. Abnormal IRT results are followed up with sweat testing and/or molecular genetic (DNA-based) testing to confirm the diagnosis. | 346 | Cystic Fibrosis |
nord_346_6 | Therapies of Cystic Fibrosis | TreatmentThere is at present no cure for cystic fibrosis. Treatment depends upon the stage of the disease and the specific organs that are involved. Treatment is geared toward reducing the thickness and amount of mucus in the airways, preventing infections, preventing blockage of the intestines and ensuring the proper intake of vitamins and nutrients.Various forms of chest physical therapy, such as applying cupped hands vigorously to the back and chest, helps to dislodge thick mucus from the lungs and maintain clear airways. Some physical therapy techniques require assistance from family members or friends; others can be performed by adults with cystic fibrosis without aid. In some cases, devices such as a mechanical vest may be used to help clear airways. This inflatable vest creates vibrations (high-frequency air waves) that loosen mucus in the chest. Other devices require affected individuals to blow into a tube, which helps loosen and dislodge mucus.Antibiotics may be used to treat lung infections. The antibiotic drugs TOBI (tobramycin) and Cayston (aztreonam) have been approved by the Food and Drug Administration (FDA) for the treatment of bronchopulmonary infections of Pseudomonas aeruginosa (the most common source of chronic lung infection) in individuals with cystic fibrosis.When the gastrointestinal system is involved, affected individuals may need to eat an enriched diet and/or take replacement vitamins, especially vitamins A, D, E and K, which are absorbed when mixed with fatty foods. Also, studies have shown that neonatal screening may provide an opportunity to prevent malnutrition in infants with cystic fibrosis. Pancreatic insufficiency may be treated by enzyme replacement therapy and diet.The drug Pulmozyme (dornase alfa) was approved by the FDA for the treatment of CF in 1993. In clinical trials, this mucus-thinning drug reduced the rate of respiratory infection and improved pulmonary function. FDA approval is limited to those over the age of five years. Pulmozyme is a mucolytic, a drug designed to help thin, loosen and clear mucus.Kalydeco (ivacaftor) was approved by the FDA in 2012 as a treatment for cystic fibrosis arising from the G551D mutation, as it is proven to be effective in patients with this mutation. Kalydeco also has been shown to be effective for adults with cystic fibrosis arising from the R117H-CFTR mutation. The drug targets abnormal chloride trafficking in cystic fibrosis, which is the condition’s underlying cause. It works by increasing the time that activated CFTR channels at the cell surface remain open, allowing for more normal chloride flux in lung tissue.In 2014, Kalydeco was approved for expanded use to treat individuals age six and older who have eight additional cystic fibrosis mutations, which are similar in function to that of the G551D mutation. In 2017, Kalydeco was approved for expanded use to treat a total of 33 CFTR gene mutations.In 2015, Orkambi (a combination of ivacaftor and lumacaftor) was approved to treat patients 12 years and older who have the F508del mutation. Having two copies of this mutation is the leading cause of CF, and this is the first drug approved for the specific mutation. In 2016, Orkambi was approved for CF patients with the F508del mutation aged 6-11 years.In 2018, Symdeko (tezacaftor/ivacaftor) was approved to treat people with CF ages 12 and older who have two copies of the most common mutation in the CFTR gene, F508del, and for people who have one of 26 other specific CF mutations.In 2019, the FDA approved Trikafta (elexacaftor/ivacaftor/tezacaftor) as the first triple combination therapy to treat patients 12 years and older with CF who have at least one F508del mutation in the CFTR gene, which is estimated to be ~90% of the CF population.Medications that widen the bronchial tubes and aid in the clearing of mucus (bronchodilators) may be used in some cases. Albuterol is an example of a bronchodilator. Ibuprofen in high doses has been show to slow the rate of lung function decline in individuals with cystic fibrosis. Treatment of individuals with cystic fibrosis with hypertonic saline (sterilized, extra-salty water) has shown better mucus clearance and improved lung function in patients 6 years of age or older.In severe cases of cystic fibrosis, a lung transplant may be necessary. A decision concerning lung transplant is made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors. It is essential for patients to demonstrate their ability to be adherent to their prescribed cystic fibrosis therapies before transplant, because lack of adherence to anti-rejection therapy following transplantation can lead to a rapid death.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Cystic Fibrosis. TreatmentThere is at present no cure for cystic fibrosis. Treatment depends upon the stage of the disease and the specific organs that are involved. Treatment is geared toward reducing the thickness and amount of mucus in the airways, preventing infections, preventing blockage of the intestines and ensuring the proper intake of vitamins and nutrients.Various forms of chest physical therapy, such as applying cupped hands vigorously to the back and chest, helps to dislodge thick mucus from the lungs and maintain clear airways. Some physical therapy techniques require assistance from family members or friends; others can be performed by adults with cystic fibrosis without aid. In some cases, devices such as a mechanical vest may be used to help clear airways. This inflatable vest creates vibrations (high-frequency air waves) that loosen mucus in the chest. Other devices require affected individuals to blow into a tube, which helps loosen and dislodge mucus.Antibiotics may be used to treat lung infections. The antibiotic drugs TOBI (tobramycin) and Cayston (aztreonam) have been approved by the Food and Drug Administration (FDA) for the treatment of bronchopulmonary infections of Pseudomonas aeruginosa (the most common source of chronic lung infection) in individuals with cystic fibrosis.When the gastrointestinal system is involved, affected individuals may need to eat an enriched diet and/or take replacement vitamins, especially vitamins A, D, E and K, which are absorbed when mixed with fatty foods. Also, studies have shown that neonatal screening may provide an opportunity to prevent malnutrition in infants with cystic fibrosis. Pancreatic insufficiency may be treated by enzyme replacement therapy and diet.The drug Pulmozyme (dornase alfa) was approved by the FDA for the treatment of CF in 1993. In clinical trials, this mucus-thinning drug reduced the rate of respiratory infection and improved pulmonary function. FDA approval is limited to those over the age of five years. Pulmozyme is a mucolytic, a drug designed to help thin, loosen and clear mucus.Kalydeco (ivacaftor) was approved by the FDA in 2012 as a treatment for cystic fibrosis arising from the G551D mutation, as it is proven to be effective in patients with this mutation. Kalydeco also has been shown to be effective for adults with cystic fibrosis arising from the R117H-CFTR mutation. The drug targets abnormal chloride trafficking in cystic fibrosis, which is the condition’s underlying cause. It works by increasing the time that activated CFTR channels at the cell surface remain open, allowing for more normal chloride flux in lung tissue.In 2014, Kalydeco was approved for expanded use to treat individuals age six and older who have eight additional cystic fibrosis mutations, which are similar in function to that of the G551D mutation. In 2017, Kalydeco was approved for expanded use to treat a total of 33 CFTR gene mutations.In 2015, Orkambi (a combination of ivacaftor and lumacaftor) was approved to treat patients 12 years and older who have the F508del mutation. Having two copies of this mutation is the leading cause of CF, and this is the first drug approved for the specific mutation. In 2016, Orkambi was approved for CF patients with the F508del mutation aged 6-11 years.In 2018, Symdeko (tezacaftor/ivacaftor) was approved to treat people with CF ages 12 and older who have two copies of the most common mutation in the CFTR gene, F508del, and for people who have one of 26 other specific CF mutations.In 2019, the FDA approved Trikafta (elexacaftor/ivacaftor/tezacaftor) as the first triple combination therapy to treat patients 12 years and older with CF who have at least one F508del mutation in the CFTR gene, which is estimated to be ~90% of the CF population.Medications that widen the bronchial tubes and aid in the clearing of mucus (bronchodilators) may be used in some cases. Albuterol is an example of a bronchodilator. Ibuprofen in high doses has been show to slow the rate of lung function decline in individuals with cystic fibrosis. Treatment of individuals with cystic fibrosis with hypertonic saline (sterilized, extra-salty water) has shown better mucus clearance and improved lung function in patients 6 years of age or older.In severe cases of cystic fibrosis, a lung transplant may be necessary. A decision concerning lung transplant is made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors. It is essential for patients to demonstrate their ability to be adherent to their prescribed cystic fibrosis therapies before transplant, because lack of adherence to anti-rejection therapy following transplantation can lead to a rapid death.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 346 | Cystic Fibrosis |
nord_347_0 | Overview of Cysticercosis | SummaryCysticercosis is caused by the pork tapeworm Taenia solium. Cysticercosis is most seen in endemic regions (Central and South America, sub-Saharan Africa, and Asia (including China, southeast Asia, and India)), where 10 to 20 percent of individuals have evidence of the disease. Cysticercosis can also be found in non-endemic regions in immigrant populations, or in people who have traveled to endemic regions. Cysticercosis can affect anyone at any age. The symptoms of cysticercosis depend on where the infection is in the body, the cyst burden, and the host’s immune response to the infection. Cysts in the nervous system can cause symptoms such as seizures, headache, dizziness, nausea, vomiting, altered mental status, altered vision, accumulation of excessive fluid (cerebrospinal fluid) in the skull (hydrocephalus), and inflammation of the tissue surrounding the brain (arachnoiditis). Cysts in the eye can cause visual disturbances or vision loss, limited eye movement, inflammation in the eye (uveitis), or inflammation of the retina (retinitis). Cysts that develop outside of the nervous system usually do not cause symptoms (asymptomatic), though small hard lumps (nodules) may develop under the skin but will eventually disappear. Treatment of cysticercosis depends on the location of the infection in the body, and is individualized for each person. Cysticercosis located outside of the nervous system usually does not require specific treatment. The treatment for cysticercosis located within the nervous system (neurocysticercosis) consists of antiparasitic therapy, corticosteroids, antiepileptic drugs, and/or surgery.IntroductionThe pork tapeworm (Taenia solium) is a parasite that can cause two types of infections in humans: taeniasis, and cysticercosis. Taeniasis is an intestinal infection with the adult form of the pork tapeworm, resulting from the ingestion of undercooked pork. Conversely, cysticercosis arises from the ingestion of the pork tapeworm’s eggs through fecal-oral contamination, and involves the development of cysts throughout the body, but not in the intestinal tract. This report focuses on cysticercosis, and not taeniasis.The names of the clinical syndromes of cysticercosis depend on where the cyst(s) are in the body. The development of cysts can happen in many tissues throughout the body. Thus, the nomenclature for cysticercosis can be confusing. The following is a brief review of the terminology used:If the cysts are located outside the nervous system, then it is called extraneural cysticercosis. Extraneural cysticercosis occurs most commonly in subcutaneous tissue, muscle tissue or heart (cardiac) tissue. If the cysts are in the nervous system, then it is called neurocysticercosis (NCC). In NCC, a cyst can either be located within specific brain tissues (parenchymal neurocysticercosis) or it can be located outside of these specific tissues (extraparenchymal neurocysticercosis). Extraparenchymal forms include cyst development in the fluid filled regions of the brain (intraventricular cysticercosis), in the space surrounding the brain (subarachnoid cysticercosis), in or around the spinal cord (spinal cysticercosis), and in the eye (ophthalmic cysticercosis). Some forms of subarachnoid cysticercosis are termed racemose cysticercosis and are very rare.Cysticercosis can affect anyone at any age, but the clinical onset in most patients is between the ages of 10 and 40 years old. Symptoms can appear weeks to years after becoming infected with the eggs of the pork tapeworm (T. solium). Most symptoms appear when the cysts start dying. If the cysts are viable, they can “disguise” themselves from the host’s immune system causing only mild symptoms. Few symptoms can arise directly from the presence of the cyst itself. When cysts die, however, it activates the immune system to react against it, and there is a large inflammatory reaction. This inflammation may cause seizures and headache. Cysts can also block the flow of fluid generated in the brain, resulting in increased pressure, puts pressure on the brain and causes symptoms like headache, nausea, dizziness, altered vision etc. | Overview of Cysticercosis. SummaryCysticercosis is caused by the pork tapeworm Taenia solium. Cysticercosis is most seen in endemic regions (Central and South America, sub-Saharan Africa, and Asia (including China, southeast Asia, and India)), where 10 to 20 percent of individuals have evidence of the disease. Cysticercosis can also be found in non-endemic regions in immigrant populations, or in people who have traveled to endemic regions. Cysticercosis can affect anyone at any age. The symptoms of cysticercosis depend on where the infection is in the body, the cyst burden, and the host’s immune response to the infection. Cysts in the nervous system can cause symptoms such as seizures, headache, dizziness, nausea, vomiting, altered mental status, altered vision, accumulation of excessive fluid (cerebrospinal fluid) in the skull (hydrocephalus), and inflammation of the tissue surrounding the brain (arachnoiditis). Cysts in the eye can cause visual disturbances or vision loss, limited eye movement, inflammation in the eye (uveitis), or inflammation of the retina (retinitis). Cysts that develop outside of the nervous system usually do not cause symptoms (asymptomatic), though small hard lumps (nodules) may develop under the skin but will eventually disappear. Treatment of cysticercosis depends on the location of the infection in the body, and is individualized for each person. Cysticercosis located outside of the nervous system usually does not require specific treatment. The treatment for cysticercosis located within the nervous system (neurocysticercosis) consists of antiparasitic therapy, corticosteroids, antiepileptic drugs, and/or surgery.IntroductionThe pork tapeworm (Taenia solium) is a parasite that can cause two types of infections in humans: taeniasis, and cysticercosis. Taeniasis is an intestinal infection with the adult form of the pork tapeworm, resulting from the ingestion of undercooked pork. Conversely, cysticercosis arises from the ingestion of the pork tapeworm’s eggs through fecal-oral contamination, and involves the development of cysts throughout the body, but not in the intestinal tract. This report focuses on cysticercosis, and not taeniasis.The names of the clinical syndromes of cysticercosis depend on where the cyst(s) are in the body. The development of cysts can happen in many tissues throughout the body. Thus, the nomenclature for cysticercosis can be confusing. The following is a brief review of the terminology used:If the cysts are located outside the nervous system, then it is called extraneural cysticercosis. Extraneural cysticercosis occurs most commonly in subcutaneous tissue, muscle tissue or heart (cardiac) tissue. If the cysts are in the nervous system, then it is called neurocysticercosis (NCC). In NCC, a cyst can either be located within specific brain tissues (parenchymal neurocysticercosis) or it can be located outside of these specific tissues (extraparenchymal neurocysticercosis). Extraparenchymal forms include cyst development in the fluid filled regions of the brain (intraventricular cysticercosis), in the space surrounding the brain (subarachnoid cysticercosis), in or around the spinal cord (spinal cysticercosis), and in the eye (ophthalmic cysticercosis). Some forms of subarachnoid cysticercosis are termed racemose cysticercosis and are very rare.Cysticercosis can affect anyone at any age, but the clinical onset in most patients is between the ages of 10 and 40 years old. Symptoms can appear weeks to years after becoming infected with the eggs of the pork tapeworm (T. solium). Most symptoms appear when the cysts start dying. If the cysts are viable, they can “disguise” themselves from the host’s immune system causing only mild symptoms. Few symptoms can arise directly from the presence of the cyst itself. When cysts die, however, it activates the immune system to react against it, and there is a large inflammatory reaction. This inflammation may cause seizures and headache. Cysts can also block the flow of fluid generated in the brain, resulting in increased pressure, puts pressure on the brain and causes symptoms like headache, nausea, dizziness, altered vision etc. | 347 | Cysticercosis |
nord_347_1 | Symptoms of Cysticercosis | Symptoms usually appear years after becoming infection with the eggs of the pork tapeworm (T. solium). Symptoms may last for many years if medical treatment is not received.The symptoms of cysticercosis depend on where the infection is in the body, the cyst burden, and the host’s immune response to the infection. Thus, symptoms vary from case to case. The symptoms described below are categorized based on the location of the infection in the body.Most people with cysticercosis have nervous system involvement (neurocysticercosis). The symptoms of neurocysticercosis vary and are nonspecific. The symptoms of neurocysticercosis depend on if the cysts are in specific brain tissues (parenchymal neurocysticercosis) or if the cysts are outside of these tissues (extraparenchymal neurocysticercosis). An individual can either have parenchymal or extraparenchymal neurocysticercosis or both forms at the same time. Parenchymal neurocysticercosis is the most common form of cysticercosis, occurring in greater than 60 percent of people. Most individuals with parenchymal neurocysticercosis do not have symptoms (asymptomatic). The most common symptom in parenchymal neurocysticercosis is seizures, occurring in 50-80 percent of individuals with parenchymal neurocysticercosis. Some people may have one seizure, while others may have multiple. Having multiple seizures is more common in individuals who have multiple cysts instead of just one cyst. Headaches are also common and a range of neurologic symptoms can rarely occur. Rarely, individuals with a high level of exposure can acquire hundreds of cysts in the brain, which leads to an intense immune response, causing intense swelling of the brain (cysticercal encephalitis), which is associated with seizures, mental confusion, headache, nausea and vomiting, and occasional fever. This is usually seen in children or women under 30 years old. Cysticercal encephalitis can occur spontaneously, or as a result of antiparasitic therapy.Extraparenchymal neurocysticercosis is more common in adults than in children and carries a higher risk for complication or death compared to parenchymal neurocysticercosis, though it is much rarer. Extraparenchymal neurocysticercosis forms include cyst development in the fluid filled regions of the brain (intraventricular cysticercosis), in the space surrounding the brain (subarachnoid cysticercosis), in or around the spinal cord (spinal cysticercosis), and in the eye (ophthalmic cysticercosis). Though the symptoms depend on which form of extraparenchymal neurocysticercosis an individual has, common symptoms to all forms of extraparenchymal neurocysticercosis include altered mental status, and high pressure in the brain (elevated intracranial pressure) due to an accumulation of excessive fluid (cerebrospinal fluid) in the skull (hydrocephalus), which causes headaches, nausea, and vomiting. In some cases, individuals who develop hydrocephalus often, in turn, develop swelling of the optic disc (papilledema). Papilledema may cause blurred or double vision.Symptoms of intraventricular and subarachnoid cysticercosis include headache, nausea and vomiting, dizziness, altered mental status, altered vision, and, rarely, a constellation of findings involving the eyes, mainly the inability to move the eyes upwards and downwards (Parinaud syndrome). In some cases, subarachnoid cysticercosis can cause swelling of a tissue that surrounds the brain (arachnoiditis), which can lead to neck stiffness, intolerance to bright light, and headache (these three symptoms together are termed meningeal signs), stroke, and hydrocephalus. In a rare form of subarachnoid cysticercosis called racemose cysticercosis, there is an accumulation of cysts at the base of the brain, which could result in mental deterioration, coma, and life-threatening complications. Spinal cysticercosis is rare and occurs in about 1 percent of patients with cysticercosis. Symptoms include a shooting, burning, numbness, or sense of weakness in a particular area of the body (radicular pain), or an abnormal sensation of tingling or pricking commonly described as “pins and needles” (paresthesia). Ophthalmic cysticercosis arises when cysts form in the eyes. It occurs in approximately 1 to 3 percent of cysticercosis cases. Many people with ophthalmic cysticercosis are asymptomatic. Symptoms include visual disturbances or vision loss, inflammation in the eye (uveitis), inflammation of the retina (retinitis), limited eye movement, protrusion of the eyeball (proptosis), recurrent eye pain, double vision (diplopia), and symptoms related to the nerve that transmits visual information from the eyes to the brain (optic nerve), such as vision loss in one eye, and/or flashing lights. Rarely, the part of the eye responsible for image formation (retina) can detach (retinal detachment), which can threaten vision and needs to be treated quickly. If the cysts are located outside the nervous system, in places such as subcutaneous tissue, muscle tissue or heart (cardiac) tissue, then it is called extraneural cysticercosis. Individuals with extraneural cysticercosis usually do not have symptoms (asymptomatic). Occasionally, individuals with subcutaneous cysticercosis may have small hard lumps (nodules) that are painless in the arms and chest. These nodules will become swollen and painful right before they begin to disappear. In rare cases, a very large number of cysts can cause enlarged limbs. Rarely, if there are many cysts within a muscle, muscle weakness (myopathy) can develop. Heart involvement (cardiac cysticerci) is usually asymptomatic, but occasionally, there can be heartbeat abnormalities (arrythmias and/or conduction abnormalities). | Symptoms of Cysticercosis. Symptoms usually appear years after becoming infection with the eggs of the pork tapeworm (T. solium). Symptoms may last for many years if medical treatment is not received.The symptoms of cysticercosis depend on where the infection is in the body, the cyst burden, and the host’s immune response to the infection. Thus, symptoms vary from case to case. The symptoms described below are categorized based on the location of the infection in the body.Most people with cysticercosis have nervous system involvement (neurocysticercosis). The symptoms of neurocysticercosis vary and are nonspecific. The symptoms of neurocysticercosis depend on if the cysts are in specific brain tissues (parenchymal neurocysticercosis) or if the cysts are outside of these tissues (extraparenchymal neurocysticercosis). An individual can either have parenchymal or extraparenchymal neurocysticercosis or both forms at the same time. Parenchymal neurocysticercosis is the most common form of cysticercosis, occurring in greater than 60 percent of people. Most individuals with parenchymal neurocysticercosis do not have symptoms (asymptomatic). The most common symptom in parenchymal neurocysticercosis is seizures, occurring in 50-80 percent of individuals with parenchymal neurocysticercosis. Some people may have one seizure, while others may have multiple. Having multiple seizures is more common in individuals who have multiple cysts instead of just one cyst. Headaches are also common and a range of neurologic symptoms can rarely occur. Rarely, individuals with a high level of exposure can acquire hundreds of cysts in the brain, which leads to an intense immune response, causing intense swelling of the brain (cysticercal encephalitis), which is associated with seizures, mental confusion, headache, nausea and vomiting, and occasional fever. This is usually seen in children or women under 30 years old. Cysticercal encephalitis can occur spontaneously, or as a result of antiparasitic therapy.Extraparenchymal neurocysticercosis is more common in adults than in children and carries a higher risk for complication or death compared to parenchymal neurocysticercosis, though it is much rarer. Extraparenchymal neurocysticercosis forms include cyst development in the fluid filled regions of the brain (intraventricular cysticercosis), in the space surrounding the brain (subarachnoid cysticercosis), in or around the spinal cord (spinal cysticercosis), and in the eye (ophthalmic cysticercosis). Though the symptoms depend on which form of extraparenchymal neurocysticercosis an individual has, common symptoms to all forms of extraparenchymal neurocysticercosis include altered mental status, and high pressure in the brain (elevated intracranial pressure) due to an accumulation of excessive fluid (cerebrospinal fluid) in the skull (hydrocephalus), which causes headaches, nausea, and vomiting. In some cases, individuals who develop hydrocephalus often, in turn, develop swelling of the optic disc (papilledema). Papilledema may cause blurred or double vision.Symptoms of intraventricular and subarachnoid cysticercosis include headache, nausea and vomiting, dizziness, altered mental status, altered vision, and, rarely, a constellation of findings involving the eyes, mainly the inability to move the eyes upwards and downwards (Parinaud syndrome). In some cases, subarachnoid cysticercosis can cause swelling of a tissue that surrounds the brain (arachnoiditis), which can lead to neck stiffness, intolerance to bright light, and headache (these three symptoms together are termed meningeal signs), stroke, and hydrocephalus. In a rare form of subarachnoid cysticercosis called racemose cysticercosis, there is an accumulation of cysts at the base of the brain, which could result in mental deterioration, coma, and life-threatening complications. Spinal cysticercosis is rare and occurs in about 1 percent of patients with cysticercosis. Symptoms include a shooting, burning, numbness, or sense of weakness in a particular area of the body (radicular pain), or an abnormal sensation of tingling or pricking commonly described as “pins and needles” (paresthesia). Ophthalmic cysticercosis arises when cysts form in the eyes. It occurs in approximately 1 to 3 percent of cysticercosis cases. Many people with ophthalmic cysticercosis are asymptomatic. Symptoms include visual disturbances or vision loss, inflammation in the eye (uveitis), inflammation of the retina (retinitis), limited eye movement, protrusion of the eyeball (proptosis), recurrent eye pain, double vision (diplopia), and symptoms related to the nerve that transmits visual information from the eyes to the brain (optic nerve), such as vision loss in one eye, and/or flashing lights. Rarely, the part of the eye responsible for image formation (retina) can detach (retinal detachment), which can threaten vision and needs to be treated quickly. If the cysts are located outside the nervous system, in places such as subcutaneous tissue, muscle tissue or heart (cardiac) tissue, then it is called extraneural cysticercosis. Individuals with extraneural cysticercosis usually do not have symptoms (asymptomatic). Occasionally, individuals with subcutaneous cysticercosis may have small hard lumps (nodules) that are painless in the arms and chest. These nodules will become swollen and painful right before they begin to disappear. In rare cases, a very large number of cysts can cause enlarged limbs. Rarely, if there are many cysts within a muscle, muscle weakness (myopathy) can develop. Heart involvement (cardiac cysticerci) is usually asymptomatic, but occasionally, there can be heartbeat abnormalities (arrythmias and/or conduction abnormalities). | 347 | Cysticercosis |
nord_347_2 | Causes of Cysticercosis | Cysticercosis is an infection in both humans and pigs. Pigs acquire the infection through the ingestion of segments of the pork tapeworm (proglottids), infected human feces, or food contaminated by infected human feces. Following ingestions, the embryos hatch in the small intestine, get into the blood stream, and travel through the pig’s body to the brain, muscle, and/or other tissues. After three to eight weeks, a fluid filled cyst with an invaginated scolex (tissue cysticerci) develops in the tissue where the embryo travelled. A human will develop an intestinal infection of the adult pork tapeworm (taeniasis) after consuming undercooked pork that contained cysticerci. Thus, for a human to acquire taeniasis, the pork they consumed needs to have had the infection. Once a human ingests the infected pork, the scolex evaginates and attaches to the human small intestine by its suckers. Segments (proglottids) begin to grow from the scolex, and the result is a growing adult tapeworm. Adult tapeworms can live in the small intestine for years and grow to be very big, in some cases up to 7 meters. The proglottids produces eggs which are shed in human stool. These eggs can be ingested by pigs via the fecal-oral route, where the eggs will hatch in the pig, and the cycle continues as described above. Additionally, these eggs can be ingested by humans via the fecal-oral route. Humans can ingest the eggs in a multitude of ways. The most common method is within a household of an asymptomatic adult pork tapeworm carrier. Other methods include, but are not limited to, produce irrigated with water contaminated with human feces containing the eggs, drinking unsafe water contaminated with eggs, lack of handwashing after using the toilet, fertilization of vegetables with human waste. When a human ingests the eggs, the eggs will hatch, and the larvae will enter the bloodstream, and then distribute to one or more sites over a period of three to eight weeks, and then form cysts (cysticerci). Cysticerci may occur simultaneously in more than one site, or as single cyst. Cysticerci can develop in any organ, but develop most commonly in the subcutaneous tissues, brain and eyes. These cysts cause serious complications (sequalae) if they form in the brain. Cysts located in the nervous system results in neurocysticercosis. Cysts located outside of the nervous system, in subcutaneous tissue, muscle tissue or heart (cardiac) tissue, results in extraneural cysticercosis. The reason cysts develop is because it allows the parasite to evade the host’s immune response and survive. Cysts can survive for years, but will eventually die and degenerate, which provokes the host’s immune system, causing swelling/inflammation of the tissues surrounding the cyst. The pressure arising from the swelling causes symptoms of the infection, though symptoms can also arise directly from the presence of the cyst itself. After the cyst has degenerated and died, the site heals and becomes a nonviable calcified granuloma. It is important to emphasize that cysticercosis is not acquired directly by eating infected undercooked pork. Instead, eating infected undercooked pork causes taeniasis, since infected pork contains the cysts that will develop into adult pork tapeworms in humans. Infected pork does not contain the eggs that cause cysticercosis. Having taeniasis does not automatically mean also having cysticercosis. Some but not all adult pork tapeworm carriers develop cysticercosis. The only way to acquire cysticercosis is by ingestion of the eggs via fecal-oral route. It should also be noted that someone with cysticercosis cannot spread the disease to other people. It is only someone with taeniasis who can release the eggs via stool, and subsequent fecal-oral ingestion of these eggs that will result in cysticercosis. | Causes of Cysticercosis. Cysticercosis is an infection in both humans and pigs. Pigs acquire the infection through the ingestion of segments of the pork tapeworm (proglottids), infected human feces, or food contaminated by infected human feces. Following ingestions, the embryos hatch in the small intestine, get into the blood stream, and travel through the pig’s body to the brain, muscle, and/or other tissues. After three to eight weeks, a fluid filled cyst with an invaginated scolex (tissue cysticerci) develops in the tissue where the embryo travelled. A human will develop an intestinal infection of the adult pork tapeworm (taeniasis) after consuming undercooked pork that contained cysticerci. Thus, for a human to acquire taeniasis, the pork they consumed needs to have had the infection. Once a human ingests the infected pork, the scolex evaginates and attaches to the human small intestine by its suckers. Segments (proglottids) begin to grow from the scolex, and the result is a growing adult tapeworm. Adult tapeworms can live in the small intestine for years and grow to be very big, in some cases up to 7 meters. The proglottids produces eggs which are shed in human stool. These eggs can be ingested by pigs via the fecal-oral route, where the eggs will hatch in the pig, and the cycle continues as described above. Additionally, these eggs can be ingested by humans via the fecal-oral route. Humans can ingest the eggs in a multitude of ways. The most common method is within a household of an asymptomatic adult pork tapeworm carrier. Other methods include, but are not limited to, produce irrigated with water contaminated with human feces containing the eggs, drinking unsafe water contaminated with eggs, lack of handwashing after using the toilet, fertilization of vegetables with human waste. When a human ingests the eggs, the eggs will hatch, and the larvae will enter the bloodstream, and then distribute to one or more sites over a period of three to eight weeks, and then form cysts (cysticerci). Cysticerci may occur simultaneously in more than one site, or as single cyst. Cysticerci can develop in any organ, but develop most commonly in the subcutaneous tissues, brain and eyes. These cysts cause serious complications (sequalae) if they form in the brain. Cysts located in the nervous system results in neurocysticercosis. Cysts located outside of the nervous system, in subcutaneous tissue, muscle tissue or heart (cardiac) tissue, results in extraneural cysticercosis. The reason cysts develop is because it allows the parasite to evade the host’s immune response and survive. Cysts can survive for years, but will eventually die and degenerate, which provokes the host’s immune system, causing swelling/inflammation of the tissues surrounding the cyst. The pressure arising from the swelling causes symptoms of the infection, though symptoms can also arise directly from the presence of the cyst itself. After the cyst has degenerated and died, the site heals and becomes a nonviable calcified granuloma. It is important to emphasize that cysticercosis is not acquired directly by eating infected undercooked pork. Instead, eating infected undercooked pork causes taeniasis, since infected pork contains the cysts that will develop into adult pork tapeworms in humans. Infected pork does not contain the eggs that cause cysticercosis. Having taeniasis does not automatically mean also having cysticercosis. Some but not all adult pork tapeworm carriers develop cysticercosis. The only way to acquire cysticercosis is by ingestion of the eggs via fecal-oral route. It should also be noted that someone with cysticercosis cannot spread the disease to other people. It is only someone with taeniasis who can release the eggs via stool, and subsequent fecal-oral ingestion of these eggs that will result in cysticercosis. | 347 | Cysticercosis |
nord_347_3 | Affects of Cysticercosis | Cysticercosis can affect anyone at any age and affects males and females in equal numbers. Cysticercosis is most seen in endemic regions (Central and South America, sub-Saharan Africa, and Asia (including China, southeast Asia, and India)), where 10 to 20 percent of individuals have evidence of the disease. Within these endemic regions, cysticercosis is most common in rural areas, where pigs roam freely and eat human feces, and where sanitary conditions are less than optimal. Cysticercosis can also be found in non-endemic regions, especially where there are high numbers of immigrants, or in people who have traveled to endemic regions and to countries where sanitation may be substandard and where the water supply may be unsafe. Individuals with no history of pork consumption or travel to endemic areas can also develop cysticercosis, via household contacts of people with an adult pork tapeworm infection (taeniasis). Neurocysticercosis is the most common parasitic central nervous system infection worldwide. In endemic areas, approximately 30% of people with seizure disorders have neuroimaging abnormalities consistent with neurocysticercosis.Cysticercosis cases have risen in the United States due to increased immigration from endemic areas. In the United States from 2003 to 2012, there were more than 18,000 hospitalizations for neurocysticercosis.
Approximately 2,000 cases per year are diagnosed in the United States. 846 patients with cysticercosis were reported in Europe between 1990 and 2011. 324 of these cases were from abroad, 74.4% in migrants and 17.6% in European travelers. | Affects of Cysticercosis. Cysticercosis can affect anyone at any age and affects males and females in equal numbers. Cysticercosis is most seen in endemic regions (Central and South America, sub-Saharan Africa, and Asia (including China, southeast Asia, and India)), where 10 to 20 percent of individuals have evidence of the disease. Within these endemic regions, cysticercosis is most common in rural areas, where pigs roam freely and eat human feces, and where sanitary conditions are less than optimal. Cysticercosis can also be found in non-endemic regions, especially where there are high numbers of immigrants, or in people who have traveled to endemic regions and to countries where sanitation may be substandard and where the water supply may be unsafe. Individuals with no history of pork consumption or travel to endemic areas can also develop cysticercosis, via household contacts of people with an adult pork tapeworm infection (taeniasis). Neurocysticercosis is the most common parasitic central nervous system infection worldwide. In endemic areas, approximately 30% of people with seizure disorders have neuroimaging abnormalities consistent with neurocysticercosis.Cysticercosis cases have risen in the United States due to increased immigration from endemic areas. In the United States from 2003 to 2012, there were more than 18,000 hospitalizations for neurocysticercosis.
Approximately 2,000 cases per year are diagnosed in the United States. 846 patients with cysticercosis were reported in Europe between 1990 and 2011. 324 of these cases were from abroad, 74.4% in migrants and 17.6% in European travelers. | 347 | Cysticercosis |
nord_347_4 | Related disorders of Cysticercosis | Tapeworms can be acquired from various uncooked meats, including beef and fish, but only pork tapeworms appear to produce larvae capable of invading human muscle and forming cysts.The following disorders can resemble the images of the nervous system (neuroimaging) in individuals with cysticercosis:Single nonenhancing cystic lesion occurs with arachnoid cysts, porencephaly, cerebellar cystic astrocytoma, cystic echinococcosis and colloid cyst of the third ventricle. Several nonenhancing cystic lesions occur with cancer spreading to the brain (multiple metastases). Enhancing lesions occur with tuberculosis, paracoccidioidomycosis, toxoplasmosis, lymphoma, early glioma, metastatic or primary brain tumor, and arteriovenous malformation. Calcifications occur with tuberous sclerosis, tuberculosis, cytomegalovirus infection, and toxoplasmosis. Arachnoiditis with ventricular enlargement can be seen in tuberculous and fungal meningitis. | Related disorders of Cysticercosis. Tapeworms can be acquired from various uncooked meats, including beef and fish, but only pork tapeworms appear to produce larvae capable of invading human muscle and forming cysts.The following disorders can resemble the images of the nervous system (neuroimaging) in individuals with cysticercosis:Single nonenhancing cystic lesion occurs with arachnoid cysts, porencephaly, cerebellar cystic astrocytoma, cystic echinococcosis and colloid cyst of the third ventricle. Several nonenhancing cystic lesions occur with cancer spreading to the brain (multiple metastases). Enhancing lesions occur with tuberculosis, paracoccidioidomycosis, toxoplasmosis, lymphoma, early glioma, metastatic or primary brain tumor, and arteriovenous malformation. Calcifications occur with tuberous sclerosis, tuberculosis, cytomegalovirus infection, and toxoplasmosis. Arachnoiditis with ventricular enlargement can be seen in tuberculous and fungal meningitis. | 347 | Cysticercosis |
nord_347_5 | Diagnosis of Cysticercosis | Cysticercosis should be suspected in individuals with seizures and/or symptoms of increased pressure in the brain (increased intracranial pressure). The diagnosis of cysticercosis is made based on the combination of characteristic signs and symptoms obtained via a detailed patient history, neuroimaging findings, and exposure to risk factors, such as living in an endemic region, household exposure to a carrier of the adult pork tapeworm infection (taeniasis), or a history of prolonged travel or residence in an endemic region. Neuroimaging studies should include computed tomography (CT), and magnetic resonance imaging (MRI). A special blood test that looks at the immune system (serologic testing with enzyme-linked immunotransfer blot) is recommended as a confirmatory test in people who are suspected of having neurocysticercosis. Very rarely, if the neuroimaging and serology are unable to make the diagnosis, a piece of the suspected infected brain tissue is taken (biopsy) and examined by a specialist (pathologist) to look for neurocysticercosis. Clinical Testing and Work-UpInitial evaluation should include a detailed history and physical examination, and neuroimaging studies (CT and MRI). In individuals with diagnostic neuroimaging findings, symptomatic treatment should be started right away (such as medications for seizures or surgery for elevated pressures. However, specific antiparasitic therapy is never an emergency.All people with diagnosed cysticercosis should receive an eye examination (ophthalmic examination) before beginning treatment to look for ophthalmic cysticercosis. People that will be treated with a prolonged course of steroids should undergo screening for latent tuberculosis infection as well as screening for the parasitic infection caused by the S. stercoralis roundworm (strongyloidiasis). Patients with cysts located outside of the nervous system (extraneural cysticercosis) should undergo imaging of the brain to look for cysts in the nervous system (neurocysticercosis). | Diagnosis of Cysticercosis. Cysticercosis should be suspected in individuals with seizures and/or symptoms of increased pressure in the brain (increased intracranial pressure). The diagnosis of cysticercosis is made based on the combination of characteristic signs and symptoms obtained via a detailed patient history, neuroimaging findings, and exposure to risk factors, such as living in an endemic region, household exposure to a carrier of the adult pork tapeworm infection (taeniasis), or a history of prolonged travel or residence in an endemic region. Neuroimaging studies should include computed tomography (CT), and magnetic resonance imaging (MRI). A special blood test that looks at the immune system (serologic testing with enzyme-linked immunotransfer blot) is recommended as a confirmatory test in people who are suspected of having neurocysticercosis. Very rarely, if the neuroimaging and serology are unable to make the diagnosis, a piece of the suspected infected brain tissue is taken (biopsy) and examined by a specialist (pathologist) to look for neurocysticercosis. Clinical Testing and Work-UpInitial evaluation should include a detailed history and physical examination, and neuroimaging studies (CT and MRI). In individuals with diagnostic neuroimaging findings, symptomatic treatment should be started right away (such as medications for seizures or surgery for elevated pressures. However, specific antiparasitic therapy is never an emergency.All people with diagnosed cysticercosis should receive an eye examination (ophthalmic examination) before beginning treatment to look for ophthalmic cysticercosis. People that will be treated with a prolonged course of steroids should undergo screening for latent tuberculosis infection as well as screening for the parasitic infection caused by the S. stercoralis roundworm (strongyloidiasis). Patients with cysts located outside of the nervous system (extraneural cysticercosis) should undergo imaging of the brain to look for cysts in the nervous system (neurocysticercosis). | 347 | Cysticercosis |
nord_347_6 | Therapies of Cysticercosis | TreatmentThe treatment of cysticercosis depends on the location of the infection in the body. Cysticercosis located outside of the nervous system is usually benign does not need to be treated. There are medications available to treat cysticercosis for those who do need treatment. The treatment for cysticercosis located within the nervous system (neurocysticercosis) consists of antiparasitic therapy, corticosteroids, antiepileptic drugs, and/or surgery. Treatment is always individualized for each patient. Antiparasitic drugs have been reported to destroy many of parasites and improve outcomes in some cases. The antiparasitic drugs used are albendazole alone or a combination of albendazole and praziquantel. Albendazole was approved by the Food and Drug Administration (FDA) for the treatment of cysticercosis in 1996. Initiation of antiparasitic drugs is never urgent and symptom management of seizures and/or increased intracranial pressure is the priority. As such, pregnant women are often able to delay antiparasitic therapy until after pregnancy. An eye examination (ophthalmic examination) must be obtained before beginning antiparasitic treatment to look for cysts in the eye (ophthalmic cysticercosis). If cysts in the eye are found, antiparasitic drugs should not be initiated as it can threaten vision. The treatment for ophthalmic cysticercosis is surgical removal of the eye cyst(s). As well, antiparasitic therapy is not to be used (contraindicated) in individuals with higher than normal pressure in the brain (increased intracranial pressure). Antiparasitic drugs can cause a temporary inflammatory reaction which can increase neurocysticercosis symptoms, mainly headaches, during the first week of treatment. Corticosteroids should always be administered alongside antiparasitic therapy to decrease this side effect. Corticosteroids are used in patients with cysticercosis to prevent the increase in transient symptoms caused by antiparasitic drugs, and to manage fluid build-up in the brain (cerebral edema) which causes increased intracranial pressure. Dexamethasone or prednisone are often the corticosteroid used, and work by decreasing inflammation. Antiepileptic drugs (AEDs) are used to treat seizures due to neurocysticercosis. The choice of which antiepileptic drug to use depends on cost, drug interactions, and potential side effects. Phenytoin and carbamazepine are often used. In pregnant women, AEDs dangerous for the unborn baby (teratogens) must be avoided. A variety of surgical techniques may be used to treat certain individuals with cysticercosis. An accumulation of excessive fluid (cerebrospinal fluid) within the skull (hydrocephalus) may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Surgical excision of cysts may be performed in certain cases. Cysticerci affecting the eyes may also be treated surgically. | Therapies of Cysticercosis. TreatmentThe treatment of cysticercosis depends on the location of the infection in the body. Cysticercosis located outside of the nervous system is usually benign does not need to be treated. There are medications available to treat cysticercosis for those who do need treatment. The treatment for cysticercosis located within the nervous system (neurocysticercosis) consists of antiparasitic therapy, corticosteroids, antiepileptic drugs, and/or surgery. Treatment is always individualized for each patient. Antiparasitic drugs have been reported to destroy many of parasites and improve outcomes in some cases. The antiparasitic drugs used are albendazole alone or a combination of albendazole and praziquantel. Albendazole was approved by the Food and Drug Administration (FDA) for the treatment of cysticercosis in 1996. Initiation of antiparasitic drugs is never urgent and symptom management of seizures and/or increased intracranial pressure is the priority. As such, pregnant women are often able to delay antiparasitic therapy until after pregnancy. An eye examination (ophthalmic examination) must be obtained before beginning antiparasitic treatment to look for cysts in the eye (ophthalmic cysticercosis). If cysts in the eye are found, antiparasitic drugs should not be initiated as it can threaten vision. The treatment for ophthalmic cysticercosis is surgical removal of the eye cyst(s). As well, antiparasitic therapy is not to be used (contraindicated) in individuals with higher than normal pressure in the brain (increased intracranial pressure). Antiparasitic drugs can cause a temporary inflammatory reaction which can increase neurocysticercosis symptoms, mainly headaches, during the first week of treatment. Corticosteroids should always be administered alongside antiparasitic therapy to decrease this side effect. Corticosteroids are used in patients with cysticercosis to prevent the increase in transient symptoms caused by antiparasitic drugs, and to manage fluid build-up in the brain (cerebral edema) which causes increased intracranial pressure. Dexamethasone or prednisone are often the corticosteroid used, and work by decreasing inflammation. Antiepileptic drugs (AEDs) are used to treat seizures due to neurocysticercosis. The choice of which antiepileptic drug to use depends on cost, drug interactions, and potential side effects. Phenytoin and carbamazepine are often used. In pregnant women, AEDs dangerous for the unborn baby (teratogens) must be avoided. A variety of surgical techniques may be used to treat certain individuals with cysticercosis. An accumulation of excessive fluid (cerebrospinal fluid) within the skull (hydrocephalus) may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Surgical excision of cysts may be performed in certain cases. Cysticerci affecting the eyes may also be treated surgically. | 347 | Cysticercosis |
nord_348_0 | Overview of Cystinosis | SummaryCystinosis is a rare, multisystem genetic disorder characterized by the accumulation of an amino acid called cystine in different tissues and organs of the body including the kidneys, eyes, muscles, liver, pancreas and brain. Generally, cystinosis is broken down into three different forms known as nephropathic cystinosis, intermediate cystinosis and non-nephropathic (or ocular) cystinosis. The age of onset, symptoms, and severity of cystinosis can vary greatly from one person to another. Nephropathic cystinosis presents in infancy and is the most common and severe form. Early detection and prompt treatment are critical in slowing the development and progression of symptoms associated with cystinosis. The kidneys and eyes are the two organs most often affected. Individuals with nephropathic or intermediate cystinosis ultimately require a kidney transplant. Non-nephropathic cystinosis only affects the corneas of the eyes. Cystinosis is caused by mutations of the CTNS gene and is inherited as an autosomal recessive disease.IntroductionCystinosis was first described in the medical literature in 1903 by Abderhalden. Cystinosis is classified as a lysosomal storage disorder. Lysosomes are membrane bound compartments within cells that break down certain nutrients such as fats, proteins and carbohydrates. Lysosomes are the primary digestive unit within cells. Some enzymes within lysosomes break down (metabolize) these nutrients, while other proteins transport the leftover metabolic products (such as cystine) out of the lysosome. In the case of cystinosis, the lack of such a specific transporter causes cystine to accumulate in lysosomes of cells throughout the body. Cystine forms crystals (crystallizes) in many types of cells and slowly damages affected organs. | Overview of Cystinosis. SummaryCystinosis is a rare, multisystem genetic disorder characterized by the accumulation of an amino acid called cystine in different tissues and organs of the body including the kidneys, eyes, muscles, liver, pancreas and brain. Generally, cystinosis is broken down into three different forms known as nephropathic cystinosis, intermediate cystinosis and non-nephropathic (or ocular) cystinosis. The age of onset, symptoms, and severity of cystinosis can vary greatly from one person to another. Nephropathic cystinosis presents in infancy and is the most common and severe form. Early detection and prompt treatment are critical in slowing the development and progression of symptoms associated with cystinosis. The kidneys and eyes are the two organs most often affected. Individuals with nephropathic or intermediate cystinosis ultimately require a kidney transplant. Non-nephropathic cystinosis only affects the corneas of the eyes. Cystinosis is caused by mutations of the CTNS gene and is inherited as an autosomal recessive disease.IntroductionCystinosis was first described in the medical literature in 1903 by Abderhalden. Cystinosis is classified as a lysosomal storage disorder. Lysosomes are membrane bound compartments within cells that break down certain nutrients such as fats, proteins and carbohydrates. Lysosomes are the primary digestive unit within cells. Some enzymes within lysosomes break down (metabolize) these nutrients, while other proteins transport the leftover metabolic products (such as cystine) out of the lysosome. In the case of cystinosis, the lack of such a specific transporter causes cystine to accumulate in lysosomes of cells throughout the body. Cystine forms crystals (crystallizes) in many types of cells and slowly damages affected organs. | 348 | Cystinosis |
nord_348_1 | Symptoms of Cystinosis | At one time, nephropathic cystinosis was fatal at a very young age. However, the development of a medication known as cysteamine (which lowers the levels of cystine in the cells of the body) and improvements in kidney transplantation have transformed cystinosis from a fatal kidney disorder to a chronic, multisystem disorder with a life expectancy well into adulthood and even beyond 50 years of age.The specific symptoms and severity of cystinosis vary greatly from one person to another based upon several factors including age of onset and whether the disorder is promptly diagnosed and treated. The progression of the disorder can be slowed by early diagnosis and treatment. Eventually, cystinosis can affect all tissues of the body. The age of onset for different symptoms varies greatly.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.NEPHROPATHIC CYSTINOSIS
Nephropathic, or infantile, cystinosis is the most frequent and most severe form of cystinosis. The symptoms of nephropathic cystinosis usually become apparent within the second half of the first year of life. Specific symptoms can be mild or severe based upon each individual case and the age when treatment is started.Growth failure and renal Fanconi syndrome are usually the first noticeable complications of the disorder. Although infants appear normal at birth, by the age of one they generally fall into the third percentile for height and weight. In addition, affected infants may have episodes of vomiting, poor appetite, and feeding difficulties that contribute (along with kidney dysfunction) to nutritional deficiency and failure to gain weight and grow at the expected rate (failure to thrive). On average, growth in untreated children with cystinosis occurs at 60 percent the expected rate.Infants with nephropathic cystinosis develop renal Fanconi syndrome, a rare disorder characterized by kidney dysfunction. The kidneys are two bean-shaped organs located just under the back of the ribcage. The kidneys have several functions, including filtering and excreting waste products from the blood and body, creating certain hormones and helping maintain the balance of certain chemicals in the body such as potassium, sodium, chloride, calcium, magnesium, and other minerals and electrolytes. In nephropathic cystinosis, the kidney tubules fail to reabsorb a variety of needed substances, including the compounds mentioned above as well as amino acids, water, phosphate, glucose, carnitine, certain proteins and electrolytes. Consequently, affected individuals have abnormally low levels of many of these substances in the body.Symptoms of renal Fanconi syndrome usually become apparent between 6 and 12 months of age and may include excessive thirst (polydipsia), excessive production and passage of urine (polyuria), electrolyte imbalances, vomiting, and dehydration with or without fever. Dehydration can be severe in some affected individuals.The renal Fanconi syndrome can also cause hypophosphatemic rickets. In this disorder, because the kidneys are unable to reabsorb phosphate from the urine, the body leaches phosphate from the bones to maintain blood levels of phosphate; this results in progressive softening and weakening of the bone (rickets). Rickets can cause bone deformity and can delay walking, because it is painful. Affected children may walk gingerly. Kidney dysfunction can also cause excessive amounts of calcium to be lost from the body through the urine (hypercalciuric hypocalcemia). Low levels of calcium can cause intermittent muscle spasms (tetany) and, rarely in cystinosis, seizures.If left untreated, the filtering function of the kidney will continue to deteriorate, eventually progressing to kidney failure at about 10 years of age. Treatment with medications that lower cystine levels can slow or stop the progression of kidney disease and delay the need for a kidney transplant into the teen-age years, the 20s or later. Any existing kidney damage that occurs before diagnosis (and therefore before treatment) is irreversible.Extrarenal Symptoms
Children with nephropathic cystinosis may also develop symptoms unrelated to the kidneys (extrarenal symptoms). Again, these findings are highly variable and an affected child will not develop all of the symptoms discussed below. Specific extrarenal symptoms vary greatly depending upon the age that treatment is begun and the specific organs that become involved; those organs can include the eyes, bone marrow, liver, pancreas, spleen, intestine, brain, thyroid, muscles and testes.At any age, children may develop an abnormal sensitivity to light (photophobia) and irritation due to the formation of cystine crystals in the cornea. The severity of photophobia can vary. In some untreated individuals, pain and recurrent corneal erosions may develop.Around the age of 10, affected children may also develop deficiency of thyroid hormone production (hypothyroidism) due to cystine accumulation in the thyroid. The thyroid is a butterfly-shaped gland located at the base of the neck. The thyroid secretes hormones into the bloodstream that influence certain activities of the body such as growth, maturation and the rate of metabolism. Symptoms of hypothyroidism are highly variable, but may include fatigue, feeling cold, dry skin, constipation and depression.As a group, children with nephropathic cystinosis do not produce normal amounts of tears, sweat or saliva. Tear production may be diminished causing the eyes to dry out. An impaired ability to sweat can potentially cause total exhaustion or collapse due to heat (heat prostration).Puberty may be delayed by one or two years. Untreated males experience hypogonadism, in which the testes produce reduced amounts of testosterone. Testosterone plays a key role in growth and the development of male secondary sexual characteristics during puberty. Males are generally infertile.Intelligence is usually normal, although many children experience learning disabilities. Some children may have problems with processing visual information, short-term visual memory, difficulties identifying common objects by touch (tactile recognition) and an inability to visually recognize the spatial relationships among objects (poor visuospatial skills). An example of visuospatial skills is distance and depth perception. Issues with motor speed and sustained attention have also been reported. Some affected children display behavioral and psychosocial issues, which are common in children dealing with chronic illnesses. IQ levels, while in the normal range, may be lower than would be expected based upon the IQ levels of parents and siblings.Children with nephropathic cystinosis may have mildly altered facial features (craniofacial dysmorphology). Delayed dental development and delayed eruption of permanent teeth can also occur. Some affected individuals may develop increased pressure of cerebrospinal fluid within the brain (intracranial hypertension), which can cause headaches and swelling of the optic disc (papilledema).Late-Onset Abnormalities
The increased longevity of individuals with nephropathic cystinosis has revealed that additional complications affecting organs other than the kidneys can occur later in life. These complications develop due to the chronic accumulation of cystine crystals in individuals who have not been adequately treated by cysteamine, although they have undergone a kidney transplant. These additional complications generally develop between 20 and 40 years of age.Accumulation of cystine in muscle tissue can cause muscle disease (myopathy) leading to progressive weakness and wasting of affected muscles. This usually begins in the hands and progresses to the arms, shoulders, and neck. Impairment of muscles in the throat can lead to swallowing and feeding difficulties. Involvement of chest muscles can result in decreased lung function.A wide variety of gastrointestinal symptoms can develop including enlargement of the liver (hepatomegaly), high blood pressure of the main vein of the liver (portal hypertension), enlargement of the spleen (splenomegaly), gastroesophageal reflux, ulcers, inflammation of the esophagus (esophagitis), and dysfunction of the muscles of the gastrointestinal tract (dysmotility). Unusual additional symptoms include poor fat absorption causing diarrhea, inflammatory bowel disease, tearing of the bowel causing the contents of the intestines to flow into the abdominal cavity (bowel perforation), and inflammation of the peritoneum (peritonitis), which is the membrane that lines the abdominal wall and organs.High blood pressure (hypertension), coronary artery atherosclerosis, and blood clotting abnormalities are complications of the renal disease associated with cystinosis.Additional findings include metabolic bone disease and an inability to properly digest food due to a lack of digestive enzymes normally produced by the pancreas (pancreatic exocrine insufficiency). Adults with cystinosis may also develop eye abnormalities including spasm of the eyelids (blepharospasm), band keratopathy and pigmentary retinopathy. Band keratopathy refers to the accumulation of calcium deposits in a band across the central surface of the cornea, which can cause pain and decreased clarity of vision (visual acuity). Pigmentary retinopathy is characterized by progressive degeneration of the retina, the thin layer of nerve cells that line the inner surface of the back of the eyes. The retina senses light and converts it to nerve signals, which are then relayed to the brain through the optic nerve. Pigmentary retinopathy can impair night and color vision and, eventually, can contribute to overall reduced clarity of vision.Although uncommon, brain dysfunction occurs in some older adults with cystinosis. The exact reason this occurs is unknown. Specific symptoms will vary, but some affected individuals may experience a decline in both motor and mental capabilities. In very rare cases, neurological dysfunction can progress to dementia.Individuals with nephropathic cystinosis appear to have a higher rate of diabetes than the general population because of destruction of the pancreas by cystine accumulation.INTERMEDIATE CYSTINOSIS
Also known as nephropathic juvenile cystinosis or adolescent cystinosis, this form of cystinosis is characterized by all of the signs and symptoms of nephropathic cystinosis described above. However, onset of these symptoms does not occur until later, perhaps at 8-20 years of age. Generally, the symptoms are less severe than in the classical infantile nephropathic form and have a slower progression. If untreated, end-stage renal failure in intermediate cystinosis usually develops at some point between 15 and 25 years of age. There is a spectrum of disease severity in cystinosis, with overlap of the infantile and intermediate forms.NON-NEPHROPATHIC CYSTINOSIS
Also known as ocular or “benign” cystinosis, this form usually affects adults during middle age; it was once called adult cystinosis. Kidney disease does not occur in these individuals. The disorder appears to affect only the eyes. Untreated individuals with non-nephropathic cystinosis eventually develop photophobia due to cystine crystal accumulation in the eyes. | Symptoms of Cystinosis. At one time, nephropathic cystinosis was fatal at a very young age. However, the development of a medication known as cysteamine (which lowers the levels of cystine in the cells of the body) and improvements in kidney transplantation have transformed cystinosis from a fatal kidney disorder to a chronic, multisystem disorder with a life expectancy well into adulthood and even beyond 50 years of age.The specific symptoms and severity of cystinosis vary greatly from one person to another based upon several factors including age of onset and whether the disorder is promptly diagnosed and treated. The progression of the disorder can be slowed by early diagnosis and treatment. Eventually, cystinosis can affect all tissues of the body. The age of onset for different symptoms varies greatly.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.NEPHROPATHIC CYSTINOSIS
Nephropathic, or infantile, cystinosis is the most frequent and most severe form of cystinosis. The symptoms of nephropathic cystinosis usually become apparent within the second half of the first year of life. Specific symptoms can be mild or severe based upon each individual case and the age when treatment is started.Growth failure and renal Fanconi syndrome are usually the first noticeable complications of the disorder. Although infants appear normal at birth, by the age of one they generally fall into the third percentile for height and weight. In addition, affected infants may have episodes of vomiting, poor appetite, and feeding difficulties that contribute (along with kidney dysfunction) to nutritional deficiency and failure to gain weight and grow at the expected rate (failure to thrive). On average, growth in untreated children with cystinosis occurs at 60 percent the expected rate.Infants with nephropathic cystinosis develop renal Fanconi syndrome, a rare disorder characterized by kidney dysfunction. The kidneys are two bean-shaped organs located just under the back of the ribcage. The kidneys have several functions, including filtering and excreting waste products from the blood and body, creating certain hormones and helping maintain the balance of certain chemicals in the body such as potassium, sodium, chloride, calcium, magnesium, and other minerals and electrolytes. In nephropathic cystinosis, the kidney tubules fail to reabsorb a variety of needed substances, including the compounds mentioned above as well as amino acids, water, phosphate, glucose, carnitine, certain proteins and electrolytes. Consequently, affected individuals have abnormally low levels of many of these substances in the body.Symptoms of renal Fanconi syndrome usually become apparent between 6 and 12 months of age and may include excessive thirst (polydipsia), excessive production and passage of urine (polyuria), electrolyte imbalances, vomiting, and dehydration with or without fever. Dehydration can be severe in some affected individuals.The renal Fanconi syndrome can also cause hypophosphatemic rickets. In this disorder, because the kidneys are unable to reabsorb phosphate from the urine, the body leaches phosphate from the bones to maintain blood levels of phosphate; this results in progressive softening and weakening of the bone (rickets). Rickets can cause bone deformity and can delay walking, because it is painful. Affected children may walk gingerly. Kidney dysfunction can also cause excessive amounts of calcium to be lost from the body through the urine (hypercalciuric hypocalcemia). Low levels of calcium can cause intermittent muscle spasms (tetany) and, rarely in cystinosis, seizures.If left untreated, the filtering function of the kidney will continue to deteriorate, eventually progressing to kidney failure at about 10 years of age. Treatment with medications that lower cystine levels can slow or stop the progression of kidney disease and delay the need for a kidney transplant into the teen-age years, the 20s or later. Any existing kidney damage that occurs before diagnosis (and therefore before treatment) is irreversible.Extrarenal Symptoms
Children with nephropathic cystinosis may also develop symptoms unrelated to the kidneys (extrarenal symptoms). Again, these findings are highly variable and an affected child will not develop all of the symptoms discussed below. Specific extrarenal symptoms vary greatly depending upon the age that treatment is begun and the specific organs that become involved; those organs can include the eyes, bone marrow, liver, pancreas, spleen, intestine, brain, thyroid, muscles and testes.At any age, children may develop an abnormal sensitivity to light (photophobia) and irritation due to the formation of cystine crystals in the cornea. The severity of photophobia can vary. In some untreated individuals, pain and recurrent corneal erosions may develop.Around the age of 10, affected children may also develop deficiency of thyroid hormone production (hypothyroidism) due to cystine accumulation in the thyroid. The thyroid is a butterfly-shaped gland located at the base of the neck. The thyroid secretes hormones into the bloodstream that influence certain activities of the body such as growth, maturation and the rate of metabolism. Symptoms of hypothyroidism are highly variable, but may include fatigue, feeling cold, dry skin, constipation and depression.As a group, children with nephropathic cystinosis do not produce normal amounts of tears, sweat or saliva. Tear production may be diminished causing the eyes to dry out. An impaired ability to sweat can potentially cause total exhaustion or collapse due to heat (heat prostration).Puberty may be delayed by one or two years. Untreated males experience hypogonadism, in which the testes produce reduced amounts of testosterone. Testosterone plays a key role in growth and the development of male secondary sexual characteristics during puberty. Males are generally infertile.Intelligence is usually normal, although many children experience learning disabilities. Some children may have problems with processing visual information, short-term visual memory, difficulties identifying common objects by touch (tactile recognition) and an inability to visually recognize the spatial relationships among objects (poor visuospatial skills). An example of visuospatial skills is distance and depth perception. Issues with motor speed and sustained attention have also been reported. Some affected children display behavioral and psychosocial issues, which are common in children dealing with chronic illnesses. IQ levels, while in the normal range, may be lower than would be expected based upon the IQ levels of parents and siblings.Children with nephropathic cystinosis may have mildly altered facial features (craniofacial dysmorphology). Delayed dental development and delayed eruption of permanent teeth can also occur. Some affected individuals may develop increased pressure of cerebrospinal fluid within the brain (intracranial hypertension), which can cause headaches and swelling of the optic disc (papilledema).Late-Onset Abnormalities
The increased longevity of individuals with nephropathic cystinosis has revealed that additional complications affecting organs other than the kidneys can occur later in life. These complications develop due to the chronic accumulation of cystine crystals in individuals who have not been adequately treated by cysteamine, although they have undergone a kidney transplant. These additional complications generally develop between 20 and 40 years of age.Accumulation of cystine in muscle tissue can cause muscle disease (myopathy) leading to progressive weakness and wasting of affected muscles. This usually begins in the hands and progresses to the arms, shoulders, and neck. Impairment of muscles in the throat can lead to swallowing and feeding difficulties. Involvement of chest muscles can result in decreased lung function.A wide variety of gastrointestinal symptoms can develop including enlargement of the liver (hepatomegaly), high blood pressure of the main vein of the liver (portal hypertension), enlargement of the spleen (splenomegaly), gastroesophageal reflux, ulcers, inflammation of the esophagus (esophagitis), and dysfunction of the muscles of the gastrointestinal tract (dysmotility). Unusual additional symptoms include poor fat absorption causing diarrhea, inflammatory bowel disease, tearing of the bowel causing the contents of the intestines to flow into the abdominal cavity (bowel perforation), and inflammation of the peritoneum (peritonitis), which is the membrane that lines the abdominal wall and organs.High blood pressure (hypertension), coronary artery atherosclerosis, and blood clotting abnormalities are complications of the renal disease associated with cystinosis.Additional findings include metabolic bone disease and an inability to properly digest food due to a lack of digestive enzymes normally produced by the pancreas (pancreatic exocrine insufficiency). Adults with cystinosis may also develop eye abnormalities including spasm of the eyelids (blepharospasm), band keratopathy and pigmentary retinopathy. Band keratopathy refers to the accumulation of calcium deposits in a band across the central surface of the cornea, which can cause pain and decreased clarity of vision (visual acuity). Pigmentary retinopathy is characterized by progressive degeneration of the retina, the thin layer of nerve cells that line the inner surface of the back of the eyes. The retina senses light and converts it to nerve signals, which are then relayed to the brain through the optic nerve. Pigmentary retinopathy can impair night and color vision and, eventually, can contribute to overall reduced clarity of vision.Although uncommon, brain dysfunction occurs in some older adults with cystinosis. The exact reason this occurs is unknown. Specific symptoms will vary, but some affected individuals may experience a decline in both motor and mental capabilities. In very rare cases, neurological dysfunction can progress to dementia.Individuals with nephropathic cystinosis appear to have a higher rate of diabetes than the general population because of destruction of the pancreas by cystine accumulation.INTERMEDIATE CYSTINOSIS
Also known as nephropathic juvenile cystinosis or adolescent cystinosis, this form of cystinosis is characterized by all of the signs and symptoms of nephropathic cystinosis described above. However, onset of these symptoms does not occur until later, perhaps at 8-20 years of age. Generally, the symptoms are less severe than in the classical infantile nephropathic form and have a slower progression. If untreated, end-stage renal failure in intermediate cystinosis usually develops at some point between 15 and 25 years of age. There is a spectrum of disease severity in cystinosis, with overlap of the infantile and intermediate forms.NON-NEPHROPATHIC CYSTINOSIS
Also known as ocular or “benign” cystinosis, this form usually affects adults during middle age; it was once called adult cystinosis. Kidney disease does not occur in these individuals. The disorder appears to affect only the eyes. Untreated individuals with non-nephropathic cystinosis eventually develop photophobia due to cystine crystal accumulation in the eyes. | 348 | Cystinosis |
nord_348_2 | Causes of Cystinosis | All types of cystinosis are caused by mutations of the CTNS gene. The disease is inherited in an autosomal recessive fashion. Recessive genetic disorders occur when an individual inherits a mutation in the same gene 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. Carriers for cystinosis (e.g., parents of affected individuals) never have symptoms of the disease. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.Investigators have determined that the CTNS gene is located on the short arm (p) of chromosome 17 (17p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human 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 17p13” refers to band 13 on the short arm of chromosome 17. The numbered bands specify the approximate location of the thousands of genes that are present on each chromosome.The CTNS gene contains instructions for producing (encoding) a protein called cystinosin that is required to transport the amino acid cystine out of lysosomes and into the rest of a cell. Lysosomes break down (degrade) certain proteins into their component amino acids such as cystine. Cystine is then transported out of the lysosome by cystinosin. Deficient levels of functional cystinosin result in the accumulation (storage) of cystine in the lysosomes of various tissues and organs of the body. The accumulated cystine forms crystals, which eventually damage the affected organs. | Causes of Cystinosis. All types of cystinosis are caused by mutations of the CTNS gene. The disease is inherited in an autosomal recessive fashion. Recessive genetic disorders occur when an individual inherits a mutation in the same gene 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. Carriers for cystinosis (e.g., parents of affected individuals) never have symptoms of the disease. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.Investigators have determined that the CTNS gene is located on the short arm (p) of chromosome 17 (17p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human 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 17p13” refers to band 13 on the short arm of chromosome 17. The numbered bands specify the approximate location of the thousands of genes that are present on each chromosome.The CTNS gene contains instructions for producing (encoding) a protein called cystinosin that is required to transport the amino acid cystine out of lysosomes and into the rest of a cell. Lysosomes break down (degrade) certain proteins into their component amino acids such as cystine. Cystine is then transported out of the lysosome by cystinosin. Deficient levels of functional cystinosin result in the accumulation (storage) of cystine in the lysosomes of various tissues and organs of the body. The accumulated cystine forms crystals, which eventually damage the affected organs. | 348 | Cystinosis |
nord_348_3 | Affects of Cystinosis | Cystinosis affects males and females in equal numbers. The disorder is estimated to occur in 1 in 100,000-200,000 people in the general population. Cystinosis has been reported worldwide, in all ethnic groups. Cystinosis is the most common cause of renal Fanconi syndrome in children and accounts for approximately 5 percent of all childhood cases of kidney failure. | Affects of Cystinosis. Cystinosis affects males and females in equal numbers. The disorder is estimated to occur in 1 in 100,000-200,000 people in the general population. Cystinosis has been reported worldwide, in all ethnic groups. Cystinosis is the most common cause of renal Fanconi syndrome in children and accounts for approximately 5 percent of all childhood cases of kidney failure. | 348 | Cystinosis |
nord_348_4 | Related disorders of Cystinosis | Symptoms of the following disorders can be similar to those of cystinosis. Comparisons may be useful for a differential diagnosis.Many different disorders can cause renal Fanconi syndrome in children including Lowe syndrome, Wilson disease, tyrosinemia type I, galactosemia, and glycogen storage diseases. Additional disorders that may have symptoms similar to those found in cystinosis include Bartter’s syndrome and diabetes insipidus. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are several types of metabolic disorders in which secondary accumulation of certain substances such as fats and carbohydrates occurs in the body. These disorders include galactosemia, sialidosis, Gaucher disease, galactosialidosis, Wolman disease, cholesteryl ester storage disease, the mucopolysaccharidoses and other lysosomal storage disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Cystinosis. Symptoms of the following disorders can be similar to those of cystinosis. Comparisons may be useful for a differential diagnosis.Many different disorders can cause renal Fanconi syndrome in children including Lowe syndrome, Wilson disease, tyrosinemia type I, galactosemia, and glycogen storage diseases. Additional disorders that may have symptoms similar to those found in cystinosis include Bartter’s syndrome and diabetes insipidus. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are several types of metabolic disorders in which secondary accumulation of certain substances such as fats and carbohydrates occurs in the body. These disorders include galactosemia, sialidosis, Gaucher disease, galactosialidosis, Wolman disease, cholesteryl ester storage disease, the mucopolysaccharidoses and other lysosomal storage disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 348 | Cystinosis |
nord_348_5 | Diagnosis of Cystinosis | A diagnosis of cystinosis is based upon identification of characteristic symptoms (e.g., symptoms of renal Fanconi syndrome), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A prompt diagnosis of cystinosis is critical to maximize the preventive and therapeutic benefits of cystine depleting medications.Clinical Testing and Work-Up
A diagnosis of cystinosis can be confirmed by measuring cystine levels in certain white blood cells (“polymorphonuclear leukocytes”).Urinary examination may reveal excess loss of nutrients including minerals, electrolytes, amino acids, carnitine and water, which is indicative of renal Fanconi syndrome.A physician may use a special microscope called a slit lamp to view the eyes through high magnification, which can reveal cystine crystals in the cornea. This is diagnostic if performed by an experienced ophthalmologist.
A diagnosis of cystinosis can be confirmed by molecular genetic testing, which can identify the characteristic CTNS gene mutation that causes the disorder. Molecular genetic testing is available through a commercial laboratory.Prenatal diagnosis is available for families with a known risk for having a baby with cystinosis. Cystine levels can be measured in cells obtained from the fluid that surrounds the developing fetus (amniotic fluid). A test known as chorionic villus sampling can also be used to obtain a prenatal diagnosis of cystinosis. Chorionic villi are thin, hair-like structures found on the placenta. These cells can be examined to detect elevated levels of cystine. | Diagnosis of Cystinosis. A diagnosis of cystinosis is based upon identification of characteristic symptoms (e.g., symptoms of renal Fanconi syndrome), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A prompt diagnosis of cystinosis is critical to maximize the preventive and therapeutic benefits of cystine depleting medications.Clinical Testing and Work-Up
A diagnosis of cystinosis can be confirmed by measuring cystine levels in certain white blood cells (“polymorphonuclear leukocytes”).Urinary examination may reveal excess loss of nutrients including minerals, electrolytes, amino acids, carnitine and water, which is indicative of renal Fanconi syndrome.A physician may use a special microscope called a slit lamp to view the eyes through high magnification, which can reveal cystine crystals in the cornea. This is diagnostic if performed by an experienced ophthalmologist.
A diagnosis of cystinosis can be confirmed by molecular genetic testing, which can identify the characteristic CTNS gene mutation that causes the disorder. Molecular genetic testing is available through a commercial laboratory.Prenatal diagnosis is available for families with a known risk for having a baby with cystinosis. Cystine levels can be measured in cells obtained from the fluid that surrounds the developing fetus (amniotic fluid). A test known as chorionic villus sampling can also be used to obtain a prenatal diagnosis of cystinosis. Chorionic villi are thin, hair-like structures found on the placenta. These cells can be examined to detect elevated levels of cystine. | 348 | Cystinosis |
nord_348_6 | Therapies of Cystinosis | Treatment
The treatment of cystinosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), eye specialists (ophthalmologists), digestive disorder specialists (gastroenterologists), psychologists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Nephropathic and intermediate cystinosis were once progressively fatal disorders, with a lifespan for the infantile form of less than 10 years. However, the development of cystine depleting therapies along with improvements in kidney transplantation have extended the lifespan well into adulthood.Cystine Depleting Therapy
In 1994, the Food and Drug Administration (FDA) approved cysteamine bitartrate (Cystagon) for the treatment of individuals with cystinosis. In 2013, the FDA approved Procysb, an extended-release form of cysteamine. Cysteamine is a cystine-depleting agent that can greatly lower cystine levels within cells. Therapy with cysteamine slows the development and progression of kidney damage and enhances growth in children. Cysteamine can significantly delay the need for a kidney transplant. Some individuals who underwent early, diligent treatment with cysteamine were able to delay a kidney transplant into their 20’s or longer.Therapy with cysteamine should be begin immediately after diagnosis to prevent or slow kidney damage. Cysteamine should be continued throughout life because studies have shown that long-standing treatment can prevent many of the non-renal, late onset complications of cystinosis.Cysteamine smells and tastes foul, which can be unpleasant for patients. Therapy with oral cysteamine can cause nausea, vomiting and gastrointestinal discomfort. Cysteamine also causes excess secretion of stomach acids. Some individuals taking cysteamine may need to take proton pump inhibitors such as omeprazole to reduce the production of stomach acid, helping to improve gastrointestinal symptoms.Cysteamine is taken orally, but it does not reach the cornea effectively and, therefore, fails to eliminate cystine crystals from the cornea. Cysteamine ophthalmic (Cystaran and Cystadrops) are approved by the FDA to treat corneal cystine crystal accumulation associated with cystinosis. Symptomatic Therapy
Renal Fanconi syndrome is treated with a high intake of fluids and electrolytes to prevent excessive reduction of body water (dehydration). Sodium bicarbonate, sodium citrate, magnesium and potassium may be administered to help to maintain normal electrolyte balance. Angiotensin-converting enzyme (ACE) inhibitors are sometimes used with the hope of slowing the progression of the renal disease.Indomethacin is an anti-inflammatory medication that is sometimes used to reduce urinary losses of water and electrolytes; it may also help to improve growth rate. If affected individuals take indomethacin, they must be closely monitored with respect to their renal function.Phosphates and vitamin D are often given to correct impaired reabsorption of phosphate into the blood and prevent rickets. Carnitine may be prescribed for some pre-transplant individuals to improve muscle strength.Proper nutrition is vitally important to ensure that affected infants and children maximize their growth potential. Growth hormone therapy has significantly improved growth in many patients. L-thyroxine is used to treat hypothyroidism, insulin is used to treat insulin-dependent diabetes and testosterone is used to treat males with underactive testicular function (hypogonadism) so that secondary sexual characteristics will develop. Infertility will not respond to testosterone treatment.Ocular symptoms of cystinosis can be treated with avoidance of bright light, sunglasses and lubrication. In extremely rare cases, a corneal transplant may be necessary. This is usually required only for individuals with large band keratopathies or those suffering from pain due to repeated corneal erosions.Some infants and children with cystinosis (e.g., those with dysphagia, poor nutrition and increased risk of aspiration) may require the implantation of a gastronomy tube. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the direct intake of food and/or medicine.Speech and language therapy may be beneficial for some patients. Genetic counseling is recommended for affected individuals and their families.Renal Transplantation
Despite early and prompt treatment, individuals with infantile and intermediate cystinosis eventually develop end stage renal disease (ESRD), requiring a kidney transplant. Initially, an affected individual may undergo dialysis. Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney, filtering waste products from the bloodstream and helping to maintain proper levels of essential chemicals such as potassium. ESRD is not reversible so individuals will eventually require a kidney transplant. The rate of progression of kidney dysfunction to ESRD can vary greatly from one individual to another. Individuals with cystinosis generally respond very well to a kidney transplant, which can cure renal Fanconi syndrome because cystine does not accumulate in the donated kidney. However, cystine still accumulates in other tissues and organs of the body. | Therapies of Cystinosis. Treatment
The treatment of cystinosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), eye specialists (ophthalmologists), digestive disorder specialists (gastroenterologists), psychologists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Nephropathic and intermediate cystinosis were once progressively fatal disorders, with a lifespan for the infantile form of less than 10 years. However, the development of cystine depleting therapies along with improvements in kidney transplantation have extended the lifespan well into adulthood.Cystine Depleting Therapy
In 1994, the Food and Drug Administration (FDA) approved cysteamine bitartrate (Cystagon) for the treatment of individuals with cystinosis. In 2013, the FDA approved Procysb, an extended-release form of cysteamine. Cysteamine is a cystine-depleting agent that can greatly lower cystine levels within cells. Therapy with cysteamine slows the development and progression of kidney damage and enhances growth in children. Cysteamine can significantly delay the need for a kidney transplant. Some individuals who underwent early, diligent treatment with cysteamine were able to delay a kidney transplant into their 20’s or longer.Therapy with cysteamine should be begin immediately after diagnosis to prevent or slow kidney damage. Cysteamine should be continued throughout life because studies have shown that long-standing treatment can prevent many of the non-renal, late onset complications of cystinosis.Cysteamine smells and tastes foul, which can be unpleasant for patients. Therapy with oral cysteamine can cause nausea, vomiting and gastrointestinal discomfort. Cysteamine also causes excess secretion of stomach acids. Some individuals taking cysteamine may need to take proton pump inhibitors such as omeprazole to reduce the production of stomach acid, helping to improve gastrointestinal symptoms.Cysteamine is taken orally, but it does not reach the cornea effectively and, therefore, fails to eliminate cystine crystals from the cornea. Cysteamine ophthalmic (Cystaran and Cystadrops) are approved by the FDA to treat corneal cystine crystal accumulation associated with cystinosis. Symptomatic Therapy
Renal Fanconi syndrome is treated with a high intake of fluids and electrolytes to prevent excessive reduction of body water (dehydration). Sodium bicarbonate, sodium citrate, magnesium and potassium may be administered to help to maintain normal electrolyte balance. Angiotensin-converting enzyme (ACE) inhibitors are sometimes used with the hope of slowing the progression of the renal disease.Indomethacin is an anti-inflammatory medication that is sometimes used to reduce urinary losses of water and electrolytes; it may also help to improve growth rate. If affected individuals take indomethacin, they must be closely monitored with respect to their renal function.Phosphates and vitamin D are often given to correct impaired reabsorption of phosphate into the blood and prevent rickets. Carnitine may be prescribed for some pre-transplant individuals to improve muscle strength.Proper nutrition is vitally important to ensure that affected infants and children maximize their growth potential. Growth hormone therapy has significantly improved growth in many patients. L-thyroxine is used to treat hypothyroidism, insulin is used to treat insulin-dependent diabetes and testosterone is used to treat males with underactive testicular function (hypogonadism) so that secondary sexual characteristics will develop. Infertility will not respond to testosterone treatment.Ocular symptoms of cystinosis can be treated with avoidance of bright light, sunglasses and lubrication. In extremely rare cases, a corneal transplant may be necessary. This is usually required only for individuals with large band keratopathies or those suffering from pain due to repeated corneal erosions.Some infants and children with cystinosis (e.g., those with dysphagia, poor nutrition and increased risk of aspiration) may require the implantation of a gastronomy tube. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the direct intake of food and/or medicine.Speech and language therapy may be beneficial for some patients. Genetic counseling is recommended for affected individuals and their families.Renal Transplantation
Despite early and prompt treatment, individuals with infantile and intermediate cystinosis eventually develop end stage renal disease (ESRD), requiring a kidney transplant. Initially, an affected individual may undergo dialysis. Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney, filtering waste products from the bloodstream and helping to maintain proper levels of essential chemicals such as potassium. ESRD is not reversible so individuals will eventually require a kidney transplant. The rate of progression of kidney dysfunction to ESRD can vary greatly from one individual to another. Individuals with cystinosis generally respond very well to a kidney transplant, which can cure renal Fanconi syndrome because cystine does not accumulate in the donated kidney. However, cystine still accumulates in other tissues and organs of the body. | 348 | Cystinosis |
nord_349_0 | Overview of Cystinuria | Cystinuria is an inherited metabolic disorder characterized by excessive amounts of undissolved cystine in the urine, as well as three chemically similar amino acids: arginine, lysine, and ornithine. Excess cystine in the urine can lead to the formation of crystals and stones (calculi) in the kidney, bladder, and/or urinary tract (ureters). Some people with cystinuria do not form stones, while others frequently form stones. | Overview of Cystinuria. Cystinuria is an inherited metabolic disorder characterized by excessive amounts of undissolved cystine in the urine, as well as three chemically similar amino acids: arginine, lysine, and ornithine. Excess cystine in the urine can lead to the formation of crystals and stones (calculi) in the kidney, bladder, and/or urinary tract (ureters). Some people with cystinuria do not form stones, while others frequently form stones. | 349 | Cystinuria |
nord_349_1 | Symptoms of Cystinuria | People with cystinuria excrete abnormally high levels of cystine in the urine. The level of cystine is so high that it remains undissolved in the urine. The amino acids lysine, arginine, and ornithine are also excreted in massive amounts by people with this disorder, but they dissolve more readily in the urine and are not associated with any particular symptoms.The initial symptom of cystinuria is usually sharp pain in the lower back or side of the abdomen (renal colic). Other symptoms may include blood in the urine (hematuria), obstruction of the urinary tract, and/or infections of the urinary tract. Frequent recurrences ultimately may lead to kidney damage.People with cystinuria typically produce jagged stones that are small, though some form very large stones. Stones may be accompanied by urinary “gravel,” which consists of yellowish-brown hexagonal crystals. All patients with urinary stones should be screened for cystinuria. | Symptoms of Cystinuria. People with cystinuria excrete abnormally high levels of cystine in the urine. The level of cystine is so high that it remains undissolved in the urine. The amino acids lysine, arginine, and ornithine are also excreted in massive amounts by people with this disorder, but they dissolve more readily in the urine and are not associated with any particular symptoms.The initial symptom of cystinuria is usually sharp pain in the lower back or side of the abdomen (renal colic). Other symptoms may include blood in the urine (hematuria), obstruction of the urinary tract, and/or infections of the urinary tract. Frequent recurrences ultimately may lead to kidney damage.People with cystinuria typically produce jagged stones that are small, though some form very large stones. Stones may be accompanied by urinary “gravel,” which consists of yellowish-brown hexagonal crystals. All patients with urinary stones should be screened for cystinuria. | 349 | Cystinuria |
nord_349_2 | Causes of Cystinuria | Cystinuria is caused by changes (mutations) in the SLC3A1 and SLC7A9 genes. These mutations result in the abnormal transport of cystine in the kidney and this leads to the symptoms of cystinuria. Cystinuria is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. People who are carriers of these genes typically have slightly elevated levels of cystine and lysine in the urine. The full implications of being a carrier are not known and require further investigation. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Cystinuria. Cystinuria is caused by changes (mutations) in the SLC3A1 and SLC7A9 genes. These mutations result in the abnormal transport of cystine in the kidney and this leads to the symptoms of cystinuria. Cystinuria is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. People who are carriers of these genes typically have slightly elevated levels of cystine and lysine in the urine. The full implications of being a carrier are not known and require further investigation. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | 349 | Cystinuria |
nord_349_3 | Affects of Cystinuria | Cystinuria is an inherited metabolic disorder that affects males and females in equal numbers. Symptoms of this disorder typically begin between 10 and 30 years of age, although elevated cystine excretion may be found in infancy. The disorder occurs in approximately 1 in 7,000 to 1 in 10,000 people in the United States. The prevalence of cystinuria varies in different countries. | Affects of Cystinuria. Cystinuria is an inherited metabolic disorder that affects males and females in equal numbers. Symptoms of this disorder typically begin between 10 and 30 years of age, although elevated cystine excretion may be found in infancy. The disorder occurs in approximately 1 in 7,000 to 1 in 10,000 people in the United States. The prevalence of cystinuria varies in different countries. | 349 | Cystinuria |
nord_349_4 | Related disorders of Cystinuria | Symptoms of the following disorders can be similar to those of cystinuria. Comparisons may be useful for a differential diagnosis:Kidney stones are hard deposits of minerals and salts that form inside the kidneys. Kidney stones form when urine contains more crystal-forming substances such as calcium, oxalate and uric acid than the fluid in the urine can dilute. Signs and symptoms of kidney stones can include severe, sharp pain in the side and back, below the ribs; pain that radiates to the lower abdomen and groin; pain that comes in waves and fluctuates in intensity; and pain or burning sensation while urinating.Cystinosis is a rare inherited disorder of cystine transport characterized by the accumulation of cystine within the cells of the body, especially in the kidneys and eyes. Symptoms of this disorder include the excretion of abnormally large volumes of urine (polyuria), abnormally low levels of circulating potassium (hypokalemia), and/or renal tubular failure. The accumulation of cystine in the eyes may result in an increased sensitivity to light (photophobia), headache, and/or itching and burning of the eyes. Symptoms usually begin during infancy. (For more information on this disorder, choose “cystinosis” as your search term in the Rare Disease Database.) | Related disorders of Cystinuria. Symptoms of the following disorders can be similar to those of cystinuria. Comparisons may be useful for a differential diagnosis:Kidney stones are hard deposits of minerals and salts that form inside the kidneys. Kidney stones form when urine contains more crystal-forming substances such as calcium, oxalate and uric acid than the fluid in the urine can dilute. Signs and symptoms of kidney stones can include severe, sharp pain in the side and back, below the ribs; pain that radiates to the lower abdomen and groin; pain that comes in waves and fluctuates in intensity; and pain or burning sensation while urinating.Cystinosis is a rare inherited disorder of cystine transport characterized by the accumulation of cystine within the cells of the body, especially in the kidneys and eyes. Symptoms of this disorder include the excretion of abnormally large volumes of urine (polyuria), abnormally low levels of circulating potassium (hypokalemia), and/or renal tubular failure. The accumulation of cystine in the eyes may result in an increased sensitivity to light (photophobia), headache, and/or itching and burning of the eyes. Symptoms usually begin during infancy. (For more information on this disorder, choose “cystinosis” as your search term in the Rare Disease Database.) | 349 | Cystinuria |
nord_349_5 | Diagnosis of Cystinuria | People with cystinuria have cystine crystals in their urine that can be identified by looking at the urine under a microscope. Additionally, patients with cystinuria typically produce stones that are 100% cystine, which can be analyzed at special laboratories. Finally, cystinuria can be diagnosed through genetic testing, which may be available at medical centers that specialize in kidney stone diseases. | Diagnosis of Cystinuria. People with cystinuria have cystine crystals in their urine that can be identified by looking at the urine under a microscope. Additionally, patients with cystinuria typically produce stones that are 100% cystine, which can be analyzed at special laboratories. Finally, cystinuria can be diagnosed through genetic testing, which may be available at medical centers that specialize in kidney stone diseases. | 349 | Cystinuria |
nord_349_6 | Therapies of Cystinuria | The primary objective of treatment for cystinuria is to reduce the cystine concentration in the urine. Consumption of large amounts of fluid both day and night maintains a high volume of urine and reduces cystine concentration in the urine. Making the urine more alkaline (alkalization) helps cystine to dissolve more readily in the urine and may also prevent the formation of stones. Drugs that may be prescribed to make the urine more alkaline include potassium citrate and acetazolamide. This treatment is accompanied by dietary salt and animal protein restriction.The orphan drug alpha-mercaptopropionyl glycine, also known as tiopronin (Thiola) has been approved as a treatment for cystinuria. This drug has been shown to make cystine more soluble in patients with cystinuria and reduce the risk of crystal and stone formation.
Another approach to the treatment of cystinuria is administration of d-penicillamine, although there are some risks of side effects with this drug. D-penicillamine promotes the formation of cystine in a different chemical form (mixed disulfide), which is more soluble in the urine and is excreted. This medication is rarely prescribed now because tiopronin is at least as effective and has fewer side effects. Another medicine that is used at times is captopril.Kidney and/or bladder surgery sometimes becomes necessary, but stones commonly recur. Small stones may pass spontaneously on their own with high fluid intake and, if needed, pain medications. If spontaneous stone passage is unsuccessful, stones may be removed by a special procedure. The surgeon can view the stones through an illuminated optic instrument inserted in the urethra and passed up into the upper urinary tract. The stones are then removed with special instruments (endoscopic basket extraction). Laser techniques are also used to dissolve stones in the bladder and/or kidneys that are caused by cystinuria. Ultrasound waves have been used to break up stones but are not as effective for cystine stones.Genetic counseling is recommended for patients and their families. Other treatment is symptomatic and supportive. | Therapies of Cystinuria. The primary objective of treatment for cystinuria is to reduce the cystine concentration in the urine. Consumption of large amounts of fluid both day and night maintains a high volume of urine and reduces cystine concentration in the urine. Making the urine more alkaline (alkalization) helps cystine to dissolve more readily in the urine and may also prevent the formation of stones. Drugs that may be prescribed to make the urine more alkaline include potassium citrate and acetazolamide. This treatment is accompanied by dietary salt and animal protein restriction.The orphan drug alpha-mercaptopropionyl glycine, also known as tiopronin (Thiola) has been approved as a treatment for cystinuria. This drug has been shown to make cystine more soluble in patients with cystinuria and reduce the risk of crystal and stone formation.
Another approach to the treatment of cystinuria is administration of d-penicillamine, although there are some risks of side effects with this drug. D-penicillamine promotes the formation of cystine in a different chemical form (mixed disulfide), which is more soluble in the urine and is excreted. This medication is rarely prescribed now because tiopronin is at least as effective and has fewer side effects. Another medicine that is used at times is captopril.Kidney and/or bladder surgery sometimes becomes necessary, but stones commonly recur. Small stones may pass spontaneously on their own with high fluid intake and, if needed, pain medications. If spontaneous stone passage is unsuccessful, stones may be removed by a special procedure. The surgeon can view the stones through an illuminated optic instrument inserted in the urethra and passed up into the upper urinary tract. The stones are then removed with special instruments (endoscopic basket extraction). Laser techniques are also used to dissolve stones in the bladder and/or kidneys that are caused by cystinuria. Ultrasound waves have been used to break up stones but are not as effective for cystine stones.Genetic counseling is recommended for patients and their families. Other treatment is symptomatic and supportive. | 349 | Cystinuria |
nord_350_0 | Overview of Cytochrome C Oxidase Deficiency | Cytochrome C Oxidase deficiency is a very rare inherited metabolic disorder characterized by deficiency of the enzyme cytochrome C oxidase (COX), or Complex IV, an essential enzyme that is active in the subcellular structures that help to regulate energy production (mitochondria). Deficiency of COX may be limited (localized) to the tissues of the skeletal muscles or may affect several tissues, such as the heart, kidney, liver, brain, and/or connective tissue (fibroblasts); in other cases, the COX deficiency may be generalized (systemic). Four distinct forms of Cytochrome C Oxidase deficiency have been identifed. The first form of this disorder is known as COX deficiency, benign infantile mitochondrial myopathy. Affected infants exhibit many of the same symptoms as those with the more severe infantile form of the disease; however, because the COX deficiency is limited (localized) to tissues of the skeletal muscles, they typically do not have heart or kidney dysfunction.In the second type of the disease, known as COX deficiency, infantile mitochondrial myopathy, because the COX deficiency affects tissues of the skeletal muscles as well as several other tissues, the disorder may be characterized by a generalized weakness of skeletal muscles (myotonia), abnormalities of the heart and kidneys, and/or abnormally high levels of lactic acid in the blood (lactic acidosis). De Toni-Fanconi-Debre syndrome may also be present and may include excessive thirst, excessive urination, and excessive excretion of glucose, phosphates, amino acids, bicarbonate, calcium and water in the urine.The third form of COX deficiency, known as Leigh's disease (subacute necrotizing encephalomyelopathy), is thought to be a generalized (systemic) form of COX deficiency. Leigh's disease is characterized by progressive degeneration of the brain and dysfunction of other organs of the body including the heart, kidneys, muscles, and liver. Symptoms may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh's disease progresses, symptoms may also include generalized weakness; loss of muscle tone (hypotonia); and/or episodes of lactic acidosis.In the fourth form of COX deficiency, known as COX deficiency French-Canadian type, the COX deficiency affects tissues of the skeletal muscles, connective tissue, and, in particular, the brain (Leigh's disease) and the liver. Affected infants and children may demonstrate developmental delays, diminished muscle tone (hypotonia), crossing of the eyes (strabismus), Leigh's disease, and/or episodes of lactic acidosis. Most cases of COX deficiency are inherited in an autosomal recessive pattern. Rarely, COX deficiency occurs as the result of a new or inherited abnormality (mutation) in a mitochondrial gene. | Overview of Cytochrome C Oxidase Deficiency. Cytochrome C Oxidase deficiency is a very rare inherited metabolic disorder characterized by deficiency of the enzyme cytochrome C oxidase (COX), or Complex IV, an essential enzyme that is active in the subcellular structures that help to regulate energy production (mitochondria). Deficiency of COX may be limited (localized) to the tissues of the skeletal muscles or may affect several tissues, such as the heart, kidney, liver, brain, and/or connective tissue (fibroblasts); in other cases, the COX deficiency may be generalized (systemic). Four distinct forms of Cytochrome C Oxidase deficiency have been identifed. The first form of this disorder is known as COX deficiency, benign infantile mitochondrial myopathy. Affected infants exhibit many of the same symptoms as those with the more severe infantile form of the disease; however, because the COX deficiency is limited (localized) to tissues of the skeletal muscles, they typically do not have heart or kidney dysfunction.In the second type of the disease, known as COX deficiency, infantile mitochondrial myopathy, because the COX deficiency affects tissues of the skeletal muscles as well as several other tissues, the disorder may be characterized by a generalized weakness of skeletal muscles (myotonia), abnormalities of the heart and kidneys, and/or abnormally high levels of lactic acid in the blood (lactic acidosis). De Toni-Fanconi-Debre syndrome may also be present and may include excessive thirst, excessive urination, and excessive excretion of glucose, phosphates, amino acids, bicarbonate, calcium and water in the urine.The third form of COX deficiency, known as Leigh's disease (subacute necrotizing encephalomyelopathy), is thought to be a generalized (systemic) form of COX deficiency. Leigh's disease is characterized by progressive degeneration of the brain and dysfunction of other organs of the body including the heart, kidneys, muscles, and liver. Symptoms may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh's disease progresses, symptoms may also include generalized weakness; loss of muscle tone (hypotonia); and/or episodes of lactic acidosis.In the fourth form of COX deficiency, known as COX deficiency French-Canadian type, the COX deficiency affects tissues of the skeletal muscles, connective tissue, and, in particular, the brain (Leigh's disease) and the liver. Affected infants and children may demonstrate developmental delays, diminished muscle tone (hypotonia), crossing of the eyes (strabismus), Leigh's disease, and/or episodes of lactic acidosis. Most cases of COX deficiency are inherited in an autosomal recessive pattern. Rarely, COX deficiency occurs as the result of a new or inherited abnormality (mutation) in a mitochondrial gene. | 350 | Cytochrome C Oxidase Deficiency |
nord_350_1 | Symptoms of Cytochrome C Oxidase Deficiency | Cytochrome C Oxidase (COX) deficiency is a very rare inherited metabolic disorder characterized by a deficiency of the enzyme cytochrome C oxidase or Complex IV. Cytochrome C oxidase is an essential enzyme that is active in subcellular structures that help to regulate energy production (mitochondria). Four distinct forms of Cytochrome C Oxidase deficiency have been identified. The range and severity of symptoms varies greatly from case to case.In the first form of this disorder, known as COX deficiency type benign infantile mitochondrial myopathy, deficiency of cytochrome C oxidase may be limited (localized) to the tissues of the skeletal muscles. Therefore, although affected infants may exhibit many of the same symptoms as those associated with the severe infantile form of the disease, the heart and kidneys are not affected. Affected infants with this form of the disorder may experience episodes characterized by the presence of abnormally high levels of lactic acid in the blood (lactic acidosis). If untreated, life-threatening complications (e.g., respiratory failure) may occur. With appropriate, intensive treatment, recovery from this form of COX deficiency may occur spontaneously within the first few years of life.In the second form of the disorder, COX deficiency type infantile mitochondrial myopathy, deficiency of cytochrome C oxidase affects tissues of the skeletal muscles as well as several other tissues, such as the heart, kidney, liver, brain, and/or connective tissue (fibroblasts). Symptoms associated with this form of the disease typically begin within the first three to four weeks of life. Such symptoms may include generalized muscle weakness as well as heart problems (cardiomyopathy) and kidney dysfunction. Affected infants may also fail to gain weight at the expected rate (failure to thrive) and/or exhibit a weak cry; difficulties sucking, swallowing, and/or breathing; and/or “floppiness” or poor muscle tone (hypotonia). In addition, infants with COX deficiency may experience episodes of lactic acidosis, possibly leading to impairment of respiratory and kidney function. Other symptoms may result from a specific defect in the kidneys that leads to de Toni-Fanconi-Debre syndrome, a condition that causes kidney dysfunction and involves excessive urinary excretion of glucose, phosphates, amino acids, bicarbonate, calcium, and water. Symptoms due to de Toni-Fanconi-Debre syndrome may include excessive thirst (polydipsia) and excessive urination (polyuria).Leigh’s disease, also known as subacute necrotizing encephalomyelopathy, is thought to be a generalized (systemic) form of COX deficiency. This form of the disorder is characterized by progressive degeneration of the brain and dysfunction of other organs of the body including the heart, kidneys, muscles, and/or liver. Symptoms generally begin between three months and two years of age. The most predominant symptoms of Leigh’s disease involve the brain and spinal cord (central nervous system). In most affected infants, the first noticeable signs may include loss of previously acquired motor skills or loss of head control and poor sucking ability. These symptoms may be accompanied by a profound loss of appetite, vomiting, irritability, continuous crying, and/or possible seizure activity. If the onset is later in childhood (i.e., 2 years), affected children may experience difficulty articulating words (dysarthria) and coordinating voluntary movements such as walking or running (ataxia). Previously acquired intellectual skills may diminish and mental retardation may also occur. (For more complete details on this disorder, please see NORD’s disease report on Leigh’s disease. To obtain this information, choose “Leigh” as your search term in the Rare Disease Database.)In the fourth form of COX deficiency, known as COX deficiency French-Canadian type, deficiency of cytochrome C oxidase affects tissues of the skeletal muscles, connective tissue (fibroblasts), and, in particular, tissues of the brain (Leigh’s disease) and liver. However, tissues of the kidney and heart demonstrate near normal cytochrome C oxidase activity. Affected infants and children may demonstrate developmental delays, diminished muscle tone (hypotonia), slight facial abnormalities (mild facial dysmorphism), Leigh’s disease, crossing of the eyes (strabismus), impaired ability to control voluntary movements (ataxia), fatty accumulation within and degeneration of the liver (microvesicular steatosis), and/or episodes of lactic acidosis, which may lead to life-threatening complications such as respiratory and kidney failure. | Symptoms of Cytochrome C Oxidase Deficiency. Cytochrome C Oxidase (COX) deficiency is a very rare inherited metabolic disorder characterized by a deficiency of the enzyme cytochrome C oxidase or Complex IV. Cytochrome C oxidase is an essential enzyme that is active in subcellular structures that help to regulate energy production (mitochondria). Four distinct forms of Cytochrome C Oxidase deficiency have been identified. The range and severity of symptoms varies greatly from case to case.In the first form of this disorder, known as COX deficiency type benign infantile mitochondrial myopathy, deficiency of cytochrome C oxidase may be limited (localized) to the tissues of the skeletal muscles. Therefore, although affected infants may exhibit many of the same symptoms as those associated with the severe infantile form of the disease, the heart and kidneys are not affected. Affected infants with this form of the disorder may experience episodes characterized by the presence of abnormally high levels of lactic acid in the blood (lactic acidosis). If untreated, life-threatening complications (e.g., respiratory failure) may occur. With appropriate, intensive treatment, recovery from this form of COX deficiency may occur spontaneously within the first few years of life.In the second form of the disorder, COX deficiency type infantile mitochondrial myopathy, deficiency of cytochrome C oxidase affects tissues of the skeletal muscles as well as several other tissues, such as the heart, kidney, liver, brain, and/or connective tissue (fibroblasts). Symptoms associated with this form of the disease typically begin within the first three to four weeks of life. Such symptoms may include generalized muscle weakness as well as heart problems (cardiomyopathy) and kidney dysfunction. Affected infants may also fail to gain weight at the expected rate (failure to thrive) and/or exhibit a weak cry; difficulties sucking, swallowing, and/or breathing; and/or “floppiness” or poor muscle tone (hypotonia). In addition, infants with COX deficiency may experience episodes of lactic acidosis, possibly leading to impairment of respiratory and kidney function. Other symptoms may result from a specific defect in the kidneys that leads to de Toni-Fanconi-Debre syndrome, a condition that causes kidney dysfunction and involves excessive urinary excretion of glucose, phosphates, amino acids, bicarbonate, calcium, and water. Symptoms due to de Toni-Fanconi-Debre syndrome may include excessive thirst (polydipsia) and excessive urination (polyuria).Leigh’s disease, also known as subacute necrotizing encephalomyelopathy, is thought to be a generalized (systemic) form of COX deficiency. This form of the disorder is characterized by progressive degeneration of the brain and dysfunction of other organs of the body including the heart, kidneys, muscles, and/or liver. Symptoms generally begin between three months and two years of age. The most predominant symptoms of Leigh’s disease involve the brain and spinal cord (central nervous system). In most affected infants, the first noticeable signs may include loss of previously acquired motor skills or loss of head control and poor sucking ability. These symptoms may be accompanied by a profound loss of appetite, vomiting, irritability, continuous crying, and/or possible seizure activity. If the onset is later in childhood (i.e., 2 years), affected children may experience difficulty articulating words (dysarthria) and coordinating voluntary movements such as walking or running (ataxia). Previously acquired intellectual skills may diminish and mental retardation may also occur. (For more complete details on this disorder, please see NORD’s disease report on Leigh’s disease. To obtain this information, choose “Leigh” as your search term in the Rare Disease Database.)In the fourth form of COX deficiency, known as COX deficiency French-Canadian type, deficiency of cytochrome C oxidase affects tissues of the skeletal muscles, connective tissue (fibroblasts), and, in particular, tissues of the brain (Leigh’s disease) and liver. However, tissues of the kidney and heart demonstrate near normal cytochrome C oxidase activity. Affected infants and children may demonstrate developmental delays, diminished muscle tone (hypotonia), slight facial abnormalities (mild facial dysmorphism), Leigh’s disease, crossing of the eyes (strabismus), impaired ability to control voluntary movements (ataxia), fatty accumulation within and degeneration of the liver (microvesicular steatosis), and/or episodes of lactic acidosis, which may lead to life-threatening complications such as respiratory and kidney failure. | 350 | Cytochrome C Oxidase Deficiency |
nord_350_2 | Causes of Cytochrome C Oxidase Deficiency | Researchers believe that most cases of Cytochrome C Oxidase deficiency are inherited in an autosomal recessive pattern. (For example, research seems to indicate that COX deficiency French-Canadian type has a recessive mode of inheritance.) 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.Rarely, COX deficiency occurs as the result of a new or inherited mutation in a mitochondrial gene. Mitochondria, found by the hundreds within most cells of the body, regulate the production of cellular energy and carry the genetic blueprints for this process within their own unique DNA. The enzyme cytochrome C oxidase is comprised of 13 subunits, three of which are thought to be encoded by the mitochondrial DNA (mtDNA), while the remaining subunits are encoded by the DNA of the nucleus.Mutations affecting the genes for mitochondria (mtDNA) are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization. As a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Some affected individuals have a new mtDNA mutation that was not inherited.As cells divide, the number of normal mtDNA and mutated mtDNA are distributed in an unpredictable fashion among different tissues. Consequently, mutated mtDNA accumulates at different rates among different tissues in the same individual. Thus, family members who have the identical mutation in mtDNA may exhibit a variety of different symptoms and signs at different times and to varying degrees of severity. | Causes of Cytochrome C Oxidase Deficiency. Researchers believe that most cases of Cytochrome C Oxidase deficiency are inherited in an autosomal recessive pattern. (For example, research seems to indicate that COX deficiency French-Canadian type has a recessive mode of inheritance.) 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.Rarely, COX deficiency occurs as the result of a new or inherited mutation in a mitochondrial gene. Mitochondria, found by the hundreds within most cells of the body, regulate the production of cellular energy and carry the genetic blueprints for this process within their own unique DNA. The enzyme cytochrome C oxidase is comprised of 13 subunits, three of which are thought to be encoded by the mitochondrial DNA (mtDNA), while the remaining subunits are encoded by the DNA of the nucleus.Mutations affecting the genes for mitochondria (mtDNA) are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization. As a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Some affected individuals have a new mtDNA mutation that was not inherited.As cells divide, the number of normal mtDNA and mutated mtDNA are distributed in an unpredictable fashion among different tissues. Consequently, mutated mtDNA accumulates at different rates among different tissues in the same individual. Thus, family members who have the identical mutation in mtDNA may exhibit a variety of different symptoms and signs at different times and to varying degrees of severity. | 350 | Cytochrome C Oxidase Deficiency |
nord_350_3 | Affects of Cytochrome C Oxidase Deficiency | Cytochrome C Oxidase (COX) Deficiency is a very rare metabolic disorder that appears to affect males and females in equal numbers. The overall incidence rates of various forms of the disorder (i.e., infantile mitochondrial myopathic forms and Leigh’s disease) are unclear. However, COX deficiency French-Canadian type has been reported in the French-Canadian population of the Saguenay-Lac-Saint-Jean region of northeastern Quebec with an estimated incidence of 1 in 2,473 births.In most cases of the infantile mitochondrial myopathic forms of this disorder, onset occurs within the first month of life. Leigh’s disease usually becomes apparent between three months and two years of age. COX deficiency French-Canadian type also tends to become apparent during infancy or childhood. However, in some rare cases, symptoms of COX deficiency may not develop until adolescence or adulthood. | Affects of Cytochrome C Oxidase Deficiency. Cytochrome C Oxidase (COX) Deficiency is a very rare metabolic disorder that appears to affect males and females in equal numbers. The overall incidence rates of various forms of the disorder (i.e., infantile mitochondrial myopathic forms and Leigh’s disease) are unclear. However, COX deficiency French-Canadian type has been reported in the French-Canadian population of the Saguenay-Lac-Saint-Jean region of northeastern Quebec with an estimated incidence of 1 in 2,473 births.In most cases of the infantile mitochondrial myopathic forms of this disorder, onset occurs within the first month of life. Leigh’s disease usually becomes apparent between three months and two years of age. COX deficiency French-Canadian type also tends to become apparent during infancy or childhood. However, in some rare cases, symptoms of COX deficiency may not develop until adolescence or adulthood. | 350 | Cytochrome C Oxidase Deficiency |
nord_350_4 | Related disorders of Cytochrome C Oxidase Deficiency | Symptoms of the following disorders may be similar to those of Cytochrome C Oxidase deficiency. Comparisons may be useful for a differential diagnosis:MELAS syndrome, one of a group of rare disorders known as mitochondrial encephalomyopathies, is characterized by recurring, stroke-like episodes in which there are sudden headaches followed by vomiting and seizures. Short stature, an accumulation of lactic acid in the blood (lactic acidosis), and muscular weakness on one side of the body (hemiparesis) are typically present. Visual symptoms may include impaired vision or blindness in one half of the visual field (hemianopsia) and/or blindness due to lesions in the area of the brain involved with vision (cortical blindness). MELAS syndrome is thought to be inherited due to abnormal changes in genetic material (mutation) found within mitochondria (mtDNA). (For more information on this disorder, choose “MELAS” as your search term in the Rare Disease Database.)Kearns-Sayre syndrome is a rare neuromuscular disorder characterized by three primary findings: progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), leading to chronic inflammation, progressive degeneration, and wearing away of certain eye structures (pigmentary degeneration of the retina); and heart disease (cardiomyopathy) such as heart block. Other findings may include muscle weakness, short stature, hearing loss, and/or impaired ability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). Kearns-Sayre syndrome belongs (in part) to that group of rare neuromuscular disorders known as mitochondrial encephalomyopathies. In these disorders, abnormally high numbers of defective mitochondria are present. In approximately 80 percent of cases of Kearns-Sayre syndrome, tests will reveal missing genetic material (deletions) involving the unique DNA in mitochondria (mtDNA). (For more information on this disorder, choose “Kearns-Sayre” as your search term in the Rare Disease Database.)MERRF syndrome (myoclonus epilepsy associated with ragged-red fibers) is one of a group of rare neuromuscular disorders known as mitochondrial encephalomyopathies. The most characteristic symptom of MERRF syndrome is myoclonic seizures, which are usually sudden, brief, jerking spasms that can affect the arms and legs (limbs) or the entire body. An impairment in the ability to coordinate movements (ataxia) as well as an accumulation of lactic acid in the blood (lactic acidosis) may also be present in affected individuals. Difficulty speaking (dysarthria), optic atrophy, short stature, hearing loss, dementia, and involuntary jerking of the eyes (nystagmus) may also occur. MERRF syndrome is thought to be inherited due to abnormal changes in genetic material (mutations) found within mitochondria (mtDNA). (For more information on this disorder, choose “MERRF” as your search term in the Rare Disease Database.)Dilated Cardiomyopathy (DCM) which can lead to heart failure has also been linked to COX deficiency. Because of the heart’s high energy demands, COX’s role in mitochondrial energy supply is critical for cardiac function. Although DCM has diverse etiologies, evidence for COX deficiency has been reported as early as 1990. Later studies have described functionally important genetic COX mutations associated with DCM. Cardiac biopsies from people with DCM found reduced COX expression (subunit IV mRNA and protein) which correlated with decreased cardiac function. The relevance and importance of COX deficiency in the area of DCM, however, awaits further more definitive studies.There are additional mitochondrial disorders that may be characterized by symptoms similar to those associated with COX deficiency. (For more information on these disorders, choose “mitochondria” as your search term in the Rare Disease Database.) | Related disorders of Cytochrome C Oxidase Deficiency. Symptoms of the following disorders may be similar to those of Cytochrome C Oxidase deficiency. Comparisons may be useful for a differential diagnosis:MELAS syndrome, one of a group of rare disorders known as mitochondrial encephalomyopathies, is characterized by recurring, stroke-like episodes in which there are sudden headaches followed by vomiting and seizures. Short stature, an accumulation of lactic acid in the blood (lactic acidosis), and muscular weakness on one side of the body (hemiparesis) are typically present. Visual symptoms may include impaired vision or blindness in one half of the visual field (hemianopsia) and/or blindness due to lesions in the area of the brain involved with vision (cortical blindness). MELAS syndrome is thought to be inherited due to abnormal changes in genetic material (mutation) found within mitochondria (mtDNA). (For more information on this disorder, choose “MELAS” as your search term in the Rare Disease Database.)Kearns-Sayre syndrome is a rare neuromuscular disorder characterized by three primary findings: progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), leading to chronic inflammation, progressive degeneration, and wearing away of certain eye structures (pigmentary degeneration of the retina); and heart disease (cardiomyopathy) such as heart block. Other findings may include muscle weakness, short stature, hearing loss, and/or impaired ability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). Kearns-Sayre syndrome belongs (in part) to that group of rare neuromuscular disorders known as mitochondrial encephalomyopathies. In these disorders, abnormally high numbers of defective mitochondria are present. In approximately 80 percent of cases of Kearns-Sayre syndrome, tests will reveal missing genetic material (deletions) involving the unique DNA in mitochondria (mtDNA). (For more information on this disorder, choose “Kearns-Sayre” as your search term in the Rare Disease Database.)MERRF syndrome (myoclonus epilepsy associated with ragged-red fibers) is one of a group of rare neuromuscular disorders known as mitochondrial encephalomyopathies. The most characteristic symptom of MERRF syndrome is myoclonic seizures, which are usually sudden, brief, jerking spasms that can affect the arms and legs (limbs) or the entire body. An impairment in the ability to coordinate movements (ataxia) as well as an accumulation of lactic acid in the blood (lactic acidosis) may also be present in affected individuals. Difficulty speaking (dysarthria), optic atrophy, short stature, hearing loss, dementia, and involuntary jerking of the eyes (nystagmus) may also occur. MERRF syndrome is thought to be inherited due to abnormal changes in genetic material (mutations) found within mitochondria (mtDNA). (For more information on this disorder, choose “MERRF” as your search term in the Rare Disease Database.)Dilated Cardiomyopathy (DCM) which can lead to heart failure has also been linked to COX deficiency. Because of the heart’s high energy demands, COX’s role in mitochondrial energy supply is critical for cardiac function. Although DCM has diverse etiologies, evidence for COX deficiency has been reported as early as 1990. Later studies have described functionally important genetic COX mutations associated with DCM. Cardiac biopsies from people with DCM found reduced COX expression (subunit IV mRNA and protein) which correlated with decreased cardiac function. The relevance and importance of COX deficiency in the area of DCM, however, awaits further more definitive studies.There are additional mitochondrial disorders that may be characterized by symptoms similar to those associated with COX deficiency. (For more information on these disorders, choose “mitochondria” as your search term in the Rare Disease Database.) | 350 | Cytochrome C Oxidase Deficiency |
nord_350_5 | Diagnosis of Cytochrome C Oxidase Deficiency | Cytochrome C Oxidase (COX) deficiency may be diagnosed after birth (postnatally) based upon a thorough clinical evaluation, characteristic findings, a detailed patient history, and a variety of specialized tests. According to the medical literature, a diagnosis of COX deficiency should be considered in infants or children who exhibit episodes of lactic acidosis.Specialized laboratory studies may be performed to help confirm such a diagnosis including enzyme tests (assays) of connective tissue cells (fibroblasts) that may reveal reduced activity of the cytochrome C oxidase enzyme. In addition, muscle biopsy studies may reveal “ragged-red fibers” (a striking, unique abnormality of muscle tissue that is apparent when viewed under a microscope) that demonstrate markedly reduced levels of COX activity as well as alterations or abnormalities of the mitochondrial structure. Other laboratory tests may include specialized staining techniques that reveal which subunits of the COX enzyme are affected.In infants with COX deficiency type infantile mitochondrial myopathy who also exhibit de Toni-Fanconi-Debre syndrome, laboratory studies may reveal signs of kidney dysfunction including abnormally high levels of glucose, phosphates, amino acids, bicarbonate, calcium, and water in the blood.The diagnosis of the Leigh’s disease form of COX deficiency may be aided by advanced imaging techniques. Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain may reveal abnormalities of certain areas of the brain (e.g., the brain stem, cerebellum, basal ganglia). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain’s tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the brain. In addition, laboratory studies may reveal a generalized reduction of cytochrome C oxidase enzyme activity within tissues cells of the brain, skeletal muscle, connective tissue (fibroblasts), heart, liver, and kidneys. Laboratory tests may also demonstrate high levels of acidic waste products in the blood (lactic acidosis).In individuals with COX deficiency French-Canadian type, laboratory studies and advanced imaging tests may reveal findings characteristic of the Leigh’s disease form of COX deficiency. In addition, enzyme assays may demonstrate that the severity of reduced cytochrome C oxidase enzyme activity varies greatly in various tissue cells. For example, whereas assays may reveal almost normal levels of COX activity in the heart and kidneys, COX enzyme activity may be approximately 50 percent of normal within skeletal muscle and connective tissue cells (fibroblasts) and severely reduced in brain and liver tissue cells. In addition, imaging studies or other tests may reveal abnormal fatty accumulation within and degeneration of the liver (microvesicular steatosis).Molecular genetic testing is available to identify some of the nuclear and mitochondrial gene mutations associated with COX deficiency. | Diagnosis of Cytochrome C Oxidase Deficiency. Cytochrome C Oxidase (COX) deficiency may be diagnosed after birth (postnatally) based upon a thorough clinical evaluation, characteristic findings, a detailed patient history, and a variety of specialized tests. According to the medical literature, a diagnosis of COX deficiency should be considered in infants or children who exhibit episodes of lactic acidosis.Specialized laboratory studies may be performed to help confirm such a diagnosis including enzyme tests (assays) of connective tissue cells (fibroblasts) that may reveal reduced activity of the cytochrome C oxidase enzyme. In addition, muscle biopsy studies may reveal “ragged-red fibers” (a striking, unique abnormality of muscle tissue that is apparent when viewed under a microscope) that demonstrate markedly reduced levels of COX activity as well as alterations or abnormalities of the mitochondrial structure. Other laboratory tests may include specialized staining techniques that reveal which subunits of the COX enzyme are affected.In infants with COX deficiency type infantile mitochondrial myopathy who also exhibit de Toni-Fanconi-Debre syndrome, laboratory studies may reveal signs of kidney dysfunction including abnormally high levels of glucose, phosphates, amino acids, bicarbonate, calcium, and water in the blood.The diagnosis of the Leigh’s disease form of COX deficiency may be aided by advanced imaging techniques. Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain may reveal abnormalities of certain areas of the brain (e.g., the brain stem, cerebellum, basal ganglia). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain’s tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the brain. In addition, laboratory studies may reveal a generalized reduction of cytochrome C oxidase enzyme activity within tissues cells of the brain, skeletal muscle, connective tissue (fibroblasts), heart, liver, and kidneys. Laboratory tests may also demonstrate high levels of acidic waste products in the blood (lactic acidosis).In individuals with COX deficiency French-Canadian type, laboratory studies and advanced imaging tests may reveal findings characteristic of the Leigh’s disease form of COX deficiency. In addition, enzyme assays may demonstrate that the severity of reduced cytochrome C oxidase enzyme activity varies greatly in various tissue cells. For example, whereas assays may reveal almost normal levels of COX activity in the heart and kidneys, COX enzyme activity may be approximately 50 percent of normal within skeletal muscle and connective tissue cells (fibroblasts) and severely reduced in brain and liver tissue cells. In addition, imaging studies or other tests may reveal abnormal fatty accumulation within and degeneration of the liver (microvesicular steatosis).Molecular genetic testing is available to identify some of the nuclear and mitochondrial gene mutations associated with COX deficiency. | 350 | Cytochrome C Oxidase Deficiency |
nord_350_6 | Therapies of Cytochrome C Oxidase Deficiency | Treatment
Treatment of all forms of COX deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected child’s treatments. Such specialists may include pediatricians; physicians who diagnose and treat abnormalities of the kidneys (nephrologists), musculoskeletal system (orthopedists), heart (cardiologists), lungs (pulmonologists), nervous system (neurologists), and/or liver (hepatologists); and/or other health care professionals. In the case of benign infantile mitochondrial myopathy, it is important that early diagnosis and intensive treatment be pursued until spontaneous recovery is realized.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Cytochrome C Oxidase Deficiency. Treatment
Treatment of all forms of COX deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected child’s treatments. Such specialists may include pediatricians; physicians who diagnose and treat abnormalities of the kidneys (nephrologists), musculoskeletal system (orthopedists), heart (cardiologists), lungs (pulmonologists), nervous system (neurologists), and/or liver (hepatologists); and/or other health care professionals. In the case of benign infantile mitochondrial myopathy, it is important that early diagnosis and intensive treatment be pursued until spontaneous recovery is realized.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 350 | Cytochrome C Oxidase Deficiency |
nord_351_0 | Overview of Cytomegalovirus Infection | Cytomegalovirus infection (CMV) is a viral infection that rarely causes obvious illness. The virus that causes CMV is part of the herpes virus family and, like other herpes viruses, may become dormant for a period of time and then be reactivated. CMV affects young children mainly, but it is estimated that by age 30 in the United States, half of all adults are, or have been, infected. The virus can pass from an infected, pregnant mother to her child through the shared blood supply (umbilical cord).Physicians recognize three clinical forms of CMV. These include: (1) CMV inclusion disease of the newborn, which ranges in severity from being without symptoms to being a severe disease affecting the liver, spleen and central nervous system, with possible developmental disabilities; (2) Acute acquired CMV infection, which is similar to infectious mononucleosis and characterized by fever, a feeling of being not quite right (malaise), skeletal-muscular pain and the absence of a sore throat; (3) CMV in immuno-compromised persons (for instance, people who have had organ transplants or who have HIV) with increased risk for difficult eye infections (CMV retinitis), gastrointestinal CMV, and encephalitis. | Overview of Cytomegalovirus Infection. Cytomegalovirus infection (CMV) is a viral infection that rarely causes obvious illness. The virus that causes CMV is part of the herpes virus family and, like other herpes viruses, may become dormant for a period of time and then be reactivated. CMV affects young children mainly, but it is estimated that by age 30 in the United States, half of all adults are, or have been, infected. The virus can pass from an infected, pregnant mother to her child through the shared blood supply (umbilical cord).Physicians recognize three clinical forms of CMV. These include: (1) CMV inclusion disease of the newborn, which ranges in severity from being without symptoms to being a severe disease affecting the liver, spleen and central nervous system, with possible developmental disabilities; (2) Acute acquired CMV infection, which is similar to infectious mononucleosis and characterized by fever, a feeling of being not quite right (malaise), skeletal-muscular pain and the absence of a sore throat; (3) CMV in immuno-compromised persons (for instance, people who have had organ transplants or who have HIV) with increased risk for difficult eye infections (CMV retinitis), gastrointestinal CMV, and encephalitis. | 351 | Cytomegalovirus Infection |
nord_351_1 | Symptoms of Cytomegalovirus Infection | Most of those who are infected with CMV (children or adult) do not develop symptoms. When symptoms are present, there may be a great range in the type and severity of symptoms experienced. Among the 10 to 20% of infants who do have symptoms, they may range from such benign signs as the presence of CMV in the urine to dangerous conditions such as hemorrhagic anemia, liver damage and central nervous sytem (CNS) damage. Infants born with a severe form of the disease typically have a low birth weight and develop a fever, hepatitis with jaundice, and hemorrhagic manifestations such as purpura. Hepatosplenomegaly (enlargement of liver and spleen), thrombocytopenia (decrease in number of blood platelets), chorioretinitis (inflammation of the choroid and retina), microcephaly (abnormal smallness of the head), and periventricular cerebral calcification may be present. Psychomotor retardation (development of motor defects and psychic abnormalities), spastic diplegia (spastic paralysis on both sides of body), blindness, deafness, or seizures may develop. Even though the cytomegalovirus infection may not at times be apparent in some infants, it may later cause hearing defects in these children.Acquired cytomegalovirus infections are often asymptomatic (there are no symptoms apparent). An acute illness with fever, termed cytomegalovirus mononucleosis or cytomegalovirus hepatitis, may result from contact through medical treatment or from spontaneous contact with cytomegalovirus. Postperfusion syndrome develops two to four weeks after transfusion with fresh blood containing CMV and is characterized by fever lasting two to three weeks, hepatitis of variable degrees with or without jaundice, a characteristic atypical lymphocytosis (excess of lymph cells in the blood or in any effusion) resembling that of infectious mononucleosis, and occasionally a rash. CMV infection in patients with malignancy or receiving immunosuppressive therapy may cause pulmonary, gastrointestinal or renal (kidney) involvement. This complication is of major importance in some reported transplantation series in which immunosuppressive therapy is utilized.Cytomegalovirus retinitis may occur in some people with impaired immune systems due to AIDS, cytotoxic chemotherapy, or long-term immunosuppression. Some affected individuals may experience blurred vision, decreased visual activity, progressive visual impairment, and a defect of vision in a defined area in one or both eyes (scotomas). | Symptoms of Cytomegalovirus Infection. Most of those who are infected with CMV (children or adult) do not develop symptoms. When symptoms are present, there may be a great range in the type and severity of symptoms experienced. Among the 10 to 20% of infants who do have symptoms, they may range from such benign signs as the presence of CMV in the urine to dangerous conditions such as hemorrhagic anemia, liver damage and central nervous sytem (CNS) damage. Infants born with a severe form of the disease typically have a low birth weight and develop a fever, hepatitis with jaundice, and hemorrhagic manifestations such as purpura. Hepatosplenomegaly (enlargement of liver and spleen), thrombocytopenia (decrease in number of blood platelets), chorioretinitis (inflammation of the choroid and retina), microcephaly (abnormal smallness of the head), and periventricular cerebral calcification may be present. Psychomotor retardation (development of motor defects and psychic abnormalities), spastic diplegia (spastic paralysis on both sides of body), blindness, deafness, or seizures may develop. Even though the cytomegalovirus infection may not at times be apparent in some infants, it may later cause hearing defects in these children.Acquired cytomegalovirus infections are often asymptomatic (there are no symptoms apparent). An acute illness with fever, termed cytomegalovirus mononucleosis or cytomegalovirus hepatitis, may result from contact through medical treatment or from spontaneous contact with cytomegalovirus. Postperfusion syndrome develops two to four weeks after transfusion with fresh blood containing CMV and is characterized by fever lasting two to three weeks, hepatitis of variable degrees with or without jaundice, a characteristic atypical lymphocytosis (excess of lymph cells in the blood or in any effusion) resembling that of infectious mononucleosis, and occasionally a rash. CMV infection in patients with malignancy or receiving immunosuppressive therapy may cause pulmonary, gastrointestinal or renal (kidney) involvement. This complication is of major importance in some reported transplantation series in which immunosuppressive therapy is utilized.Cytomegalovirus retinitis may occur in some people with impaired immune systems due to AIDS, cytotoxic chemotherapy, or long-term immunosuppression. Some affected individuals may experience blurred vision, decreased visual activity, progressive visual impairment, and a defect of vision in a defined area in one or both eyes (scotomas). | 351 | Cytomegalovirus Infection |
nord_351_2 | Causes of Cytomegalovirus Infection | Cytomegalovirus infection is caused by the human cytomegaloviruses (also known as “salivary gland viruses”). These are a subgroup of infective agents closely related to the herpes group of viruses. Like other herpes viruses, they may remain latent for years in people. | Causes of Cytomegalovirus Infection. Cytomegalovirus infection is caused by the human cytomegaloviruses (also known as “salivary gland viruses”). These are a subgroup of infective agents closely related to the herpes group of viruses. Like other herpes viruses, they may remain latent for years in people. | 351 | Cytomegalovirus Infection |
nord_351_3 | Affects of Cytomegalovirus Infection | Cytomegalovirus infection has increased in the United States in recent years, possibly because of the increased use of daycare facilities. Recent studies of the percent of children with CMV virus in daycare facilities compared to the percent of children with CMV who are cared for at home found that about 60% of the children in daycare facilities have CMV compared to only 20% of the children cared for at home. If a woman is infected during pregnancy, fetal infections known as cytomegalic inclusion disease (CID) can occur.According to the American Academy of Pediatrics, eighty-seven percent of children with CID develop complications. Thirty-one percent have serious sensorineural hearing loss, and sixty-two percent have some degree of mental retardation.Perinatal CMV infection is common. It occurs in eight to thirteen percent of healthy newborns in the United States, and fourteen to eighteen percent of sick or premature infants. Healthy full-term infants rarely have symptoms and are at lesser risk of long-term effects. In contrast, symptoms are common in premature and sick full-term infants and may include pneumonia, hepatitis, hemolytic anemia, thrombocytopenia, and fever. | Affects of Cytomegalovirus Infection. Cytomegalovirus infection has increased in the United States in recent years, possibly because of the increased use of daycare facilities. Recent studies of the percent of children with CMV virus in daycare facilities compared to the percent of children with CMV who are cared for at home found that about 60% of the children in daycare facilities have CMV compared to only 20% of the children cared for at home. If a woman is infected during pregnancy, fetal infections known as cytomegalic inclusion disease (CID) can occur.According to the American Academy of Pediatrics, eighty-seven percent of children with CID develop complications. Thirty-one percent have serious sensorineural hearing loss, and sixty-two percent have some degree of mental retardation.Perinatal CMV infection is common. It occurs in eight to thirteen percent of healthy newborns in the United States, and fourteen to eighteen percent of sick or premature infants. Healthy full-term infants rarely have symptoms and are at lesser risk of long-term effects. In contrast, symptoms are common in premature and sick full-term infants and may include pneumonia, hepatitis, hemolytic anemia, thrombocytopenia, and fever. | 351 | Cytomegalovirus Infection |
nord_351_4 | Related disorders of Cytomegalovirus Infection | The CMV virus is closely related to the herpes group of viruses. (For more information on Cytomegalovirus Infection and other herpes viruses, use “CMV” and “Herpes” as your search terms in the Rare Disease Database.) | Related disorders of Cytomegalovirus Infection. The CMV virus is closely related to the herpes group of viruses. (For more information on Cytomegalovirus Infection and other herpes viruses, use “CMV” and “Herpes” as your search terms in the Rare Disease Database.) | 351 | Cytomegalovirus Infection |
nord_351_5 | Diagnosis of Cytomegalovirus Infection | Diagnosis of Cytomegalovirus Infection. | 351 | Cytomegalovirus Infection |
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nord_351_6 | Therapies of Cytomegalovirus Infection | CMV infections can be controlled by drug therapy but, as yet, cannot be cured. Two drugs that keep the infection from getting worse are ganciclovir and foscarnet. These are delivered intravenously, and treatment must continue over a long period of time. A tablet form of ganciclovir, approved for CMV infections of the eye, has become available.Further, ganciclovir, delivered in the form of an intravitreal implant (Vitrasert Implant) is available as a means of providing long-term delivery of the drug o the eye. This delivery system requires a minor operation on the eye(s) in order to implant the delivery system. This form of delivery lasts for 3 to 6 months before it must be repeated.CMV infections arising in the course of an organ transplant are now treated with cytomegalovirus immune globulin intravenous (human) (CMV IGIV). CMV IGIV is an intravenous immune globulin enriched in antibodies against cytomegalovirus (CMV). It is approved by the U.S. Food and Drug Administration (FDA) as a preventive measure (prophylaxis) against CMV disease associated with transplantation of the kidney, lung, liver, pancreas, and heart. | Therapies of Cytomegalovirus Infection. CMV infections can be controlled by drug therapy but, as yet, cannot be cured. Two drugs that keep the infection from getting worse are ganciclovir and foscarnet. These are delivered intravenously, and treatment must continue over a long period of time. A tablet form of ganciclovir, approved for CMV infections of the eye, has become available.Further, ganciclovir, delivered in the form of an intravitreal implant (Vitrasert Implant) is available as a means of providing long-term delivery of the drug o the eye. This delivery system requires a minor operation on the eye(s) in order to implant the delivery system. This form of delivery lasts for 3 to 6 months before it must be repeated.CMV infections arising in the course of an organ transplant are now treated with cytomegalovirus immune globulin intravenous (human) (CMV IGIV). CMV IGIV is an intravenous immune globulin enriched in antibodies against cytomegalovirus (CMV). It is approved by the U.S. Food and Drug Administration (FDA) as a preventive measure (prophylaxis) against CMV disease associated with transplantation of the kidney, lung, liver, pancreas, and heart. | 351 | Cytomegalovirus Infection |
nord_352_0 | Overview of Dandy Walker Malformation | Dandy-Walker malformation (DWM) is a brain malformation that occurs during embryonic development of the cerebellum and 4th ventricle. The cerebellum is the area of the brain that helps coordinate movement, and is also involved with cognition and behavior. The 4th ventricle is a space around the cerebellum that channels fluid from inside to around the outside of the brain. DWM is characterized by underdevelopment (small size and abnormal position) of the middle part of the cerebellum known as the cerebellar vermis, cystic enlargement of the 4th ventricle and enlargement of the base of the skull (posterior fossa). DWM is sometimes (20-80%) associated with hydrocephalus, in which blockage of the normal flow of spinal fluid leads to excessive amounts of fluid accumulating in and around the brain. This leads to abnormally high pressure within the skull and swelling of the head, and can lead to neurological impairment. | Overview of Dandy Walker Malformation. Dandy-Walker malformation (DWM) is a brain malformation that occurs during embryonic development of the cerebellum and 4th ventricle. The cerebellum is the area of the brain that helps coordinate movement, and is also involved with cognition and behavior. The 4th ventricle is a space around the cerebellum that channels fluid from inside to around the outside of the brain. DWM is characterized by underdevelopment (small size and abnormal position) of the middle part of the cerebellum known as the cerebellar vermis, cystic enlargement of the 4th ventricle and enlargement of the base of the skull (posterior fossa). DWM is sometimes (20-80%) associated with hydrocephalus, in which blockage of the normal flow of spinal fluid leads to excessive amounts of fluid accumulating in and around the brain. This leads to abnormally high pressure within the skull and swelling of the head, and can lead to neurological impairment. | 352 | Dandy Walker Malformation |
nord_352_1 | Symptoms of Dandy Walker Malformation | The symptoms of Dandy Walker syndrome typically include developmental delay, low tone (hypotonia) or later high tone (spasticity), poor coordination and balance (ataxia), and sometimes enlarged head circumference and increased pressure within the skull due to hydrocephalus. Mental retardation occurs in fewer than half, most often in those with severe hydrocephalus, chromosome abnormalities or other birth defects. Seizures occur in 15-30% of those affected. Respiratory control centers in the brainstem are sometimes affected and can lead to respiratory failure, again most likely with severe hydrocephalus. The age at diagnosis varies depending on the onset and severity of hydrocephalus, and presence of other birth defects or medical problems.The clinical presentation and imaging features of DWM overlap with isolated cerebellar vermis hypoplasia (CVH) and mega-cisterna magna (MCM), and these have been classified together as a spectrum of anomalies known as the Dandy-Walker complex. But emerging experience suggests that this is an oversimplification that may contribute to inaccurate information about both outcome and genetic risks. CVH consists of a small vermis without the striking upward rotation of the vermis, cystic enlargement of the 4th ventricle or enlarged posterior fossa that characterize typical DWM. This malformation has also been called the “Dandy-Walker variant”, a potentially confusing term. The available data regarding outcome is limited, but this is often more severe than in typical DWM. MCM is characterized by an enlarged posterior fossa despite normal or very nearly normal size of the cerebellum. The increased size is associated with an enlarged fluid collection beneath and often behind the cerebellum. This has been reported as a normal variant, but emerging experience suggests that it may be associated with developmental disabilities although these are usually less severe than seen in DWM or CVH. The uncertainty in prognosis for these three overlapping conditions is accounted for by both natural variability and difficulty in distinguishing them. | Symptoms of Dandy Walker Malformation. The symptoms of Dandy Walker syndrome typically include developmental delay, low tone (hypotonia) or later high tone (spasticity), poor coordination and balance (ataxia), and sometimes enlarged head circumference and increased pressure within the skull due to hydrocephalus. Mental retardation occurs in fewer than half, most often in those with severe hydrocephalus, chromosome abnormalities or other birth defects. Seizures occur in 15-30% of those affected. Respiratory control centers in the brainstem are sometimes affected and can lead to respiratory failure, again most likely with severe hydrocephalus. The age at diagnosis varies depending on the onset and severity of hydrocephalus, and presence of other birth defects or medical problems.The clinical presentation and imaging features of DWM overlap with isolated cerebellar vermis hypoplasia (CVH) and mega-cisterna magna (MCM), and these have been classified together as a spectrum of anomalies known as the Dandy-Walker complex. But emerging experience suggests that this is an oversimplification that may contribute to inaccurate information about both outcome and genetic risks. CVH consists of a small vermis without the striking upward rotation of the vermis, cystic enlargement of the 4th ventricle or enlarged posterior fossa that characterize typical DWM. This malformation has also been called the “Dandy-Walker variant”, a potentially confusing term. The available data regarding outcome is limited, but this is often more severe than in typical DWM. MCM is characterized by an enlarged posterior fossa despite normal or very nearly normal size of the cerebellum. The increased size is associated with an enlarged fluid collection beneath and often behind the cerebellum. This has been reported as a normal variant, but emerging experience suggests that it may be associated with developmental disabilities although these are usually less severe than seen in DWM or CVH. The uncertainty in prognosis for these three overlapping conditions is accounted for by both natural variability and difficulty in distinguishing them. | 352 | Dandy Walker Malformation |
nord_352_2 | Causes of Dandy Walker Malformation | DWM results from defects in early embryonic development of the cerebellum and surrounding structures. A few patients have chromosome abnormalities including deletion of chromosome 3q24.3 (the location of the first DWM genes, known as ZIC1 and ZIC4), 6p25 or 13q32.2-q33.2, or duplication of 9p. In the remainder, it is probably due to other more complex genetic and perhaps environmental factors (teratogens) as the recurrence risk in siblings less than 5%. A few examples of affected siblings with isolated Dandy-Walker malformation have been reported, suggesting autosomal recessive or X-linked inheritance, but most of these are probably CVH and not typical DWM. In these families, the recurrence risk is higher, up to 25%. DWM may also occur as part of a genetic syndrome that includes multiple birth defects, such as the PHACES syndrome of facial hemangioma, heart and sternal defects and DWM. Many other syndromes and chromosome abnormalities have been reported with DWM, but most of these appear to have CVH rather than typical DWM. | Causes of Dandy Walker Malformation. DWM results from defects in early embryonic development of the cerebellum and surrounding structures. A few patients have chromosome abnormalities including deletion of chromosome 3q24.3 (the location of the first DWM genes, known as ZIC1 and ZIC4), 6p25 or 13q32.2-q33.2, or duplication of 9p. In the remainder, it is probably due to other more complex genetic and perhaps environmental factors (teratogens) as the recurrence risk in siblings less than 5%. A few examples of affected siblings with isolated Dandy-Walker malformation have been reported, suggesting autosomal recessive or X-linked inheritance, but most of these are probably CVH and not typical DWM. In these families, the recurrence risk is higher, up to 25%. DWM may also occur as part of a genetic syndrome that includes multiple birth defects, such as the PHACES syndrome of facial hemangioma, heart and sternal defects and DWM. Many other syndromes and chromosome abnormalities have been reported with DWM, but most of these appear to have CVH rather than typical DWM. | 352 | Dandy Walker Malformation |
nord_352_3 | Affects of Dandy Walker Malformation | The frequency of Dandy Walker malformation in the US is approximately 1 per 25,000 -35,000 live births and affects more females than males. | Affects of Dandy Walker Malformation. The frequency of Dandy Walker malformation in the US is approximately 1 per 25,000 -35,000 live births and affects more females than males. | 352 | Dandy Walker Malformation |
nord_352_4 | Related disorders of Dandy Walker Malformation | Symptoms of the following disorders can be similar to those of Dandy-Walker malformation. Comparisons may be useful for a differential diagnosis:Hydrocephalus is a condition in which abnormally widened (dilated) cerebral spaces in the brain (ventricles) inhibit the normal flow of cerebrospinal fluid (CSF). The cerebrospinal fluid accumulates in the skull and puts pressure on the brain tissue. An enlarged head in infants and increased cerebrospinal fluid pressure are frequent findings but are not necessary for the diagnosis of hydrocephalus. There are several different forms of hydrocephalus: communicating hydrocephalus, non-communicating hydrocephalus or obstructive hydrocephalus, internal hydrocephalus, normal pressure hydrocephalus, and benign hydrocephalus. (For more information on this disorder, choose “hydrocephalus” as your search term in the Rare Disease Database.)Walker-Warburg syndrome (WWS) is a rare genetic multisystem disorder characterized by muscle disease and brain and eye abnormalities. The specific symptoms and severity of WWS vary greatly from case to case. The most consistent features are a smooth appearance of the surface of the brain due to lack of normal folds (lissencephaly), malformations of other brain structures (cerebellum and brain stem), various developmental abnormalities of the eyes, and progressive degeneration and weakness of the voluntary muscles (congenital muscular dystrophy). WWS is considered to be a form of muscular dystrophy and is inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “Walker Warburg” as your search term in the Rare Disease Database.) | Related disorders of Dandy Walker Malformation. Symptoms of the following disorders can be similar to those of Dandy-Walker malformation. Comparisons may be useful for a differential diagnosis:Hydrocephalus is a condition in which abnormally widened (dilated) cerebral spaces in the brain (ventricles) inhibit the normal flow of cerebrospinal fluid (CSF). The cerebrospinal fluid accumulates in the skull and puts pressure on the brain tissue. An enlarged head in infants and increased cerebrospinal fluid pressure are frequent findings but are not necessary for the diagnosis of hydrocephalus. There are several different forms of hydrocephalus: communicating hydrocephalus, non-communicating hydrocephalus or obstructive hydrocephalus, internal hydrocephalus, normal pressure hydrocephalus, and benign hydrocephalus. (For more information on this disorder, choose “hydrocephalus” as your search term in the Rare Disease Database.)Walker-Warburg syndrome (WWS) is a rare genetic multisystem disorder characterized by muscle disease and brain and eye abnormalities. The specific symptoms and severity of WWS vary greatly from case to case. The most consistent features are a smooth appearance of the surface of the brain due to lack of normal folds (lissencephaly), malformations of other brain structures (cerebellum and brain stem), various developmental abnormalities of the eyes, and progressive degeneration and weakness of the voluntary muscles (congenital muscular dystrophy). WWS is considered to be a form of muscular dystrophy and is inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “Walker Warburg” as your search term in the Rare Disease Database.) | 352 | Dandy Walker Malformation |
nord_352_5 | Diagnosis of Dandy Walker Malformation | Dandy Walker malformation is diagnosed with the use of ultrasound, CT and MRI. Prenatal diagnosis of Dandy-Walker malformation is sometimes made by ultrasound or fetal MRI. | Diagnosis of Dandy Walker Malformation. Dandy Walker malformation is diagnosed with the use of ultrasound, CT and MRI. Prenatal diagnosis of Dandy-Walker malformation is sometimes made by ultrasound or fetal MRI. | 352 | Dandy Walker Malformation |
nord_352_6 | Therapies of Dandy Walker Malformation | TreatmentHydrocephalus associated with Dandy Walker syndrome is treated with surgery to insert a tube to redirect the fluid that surrounds the brain and to assist fluid drainage into other parts of the body that can absorb the fluid.A supportive team approach for children with Dandy-Waller malformation is often warranted and may include special education, physical therapy and other medical, social or vocational services.Genetic counseling is recommended for families that have a child with Dandy Walker malformation. | Therapies of Dandy Walker Malformation. TreatmentHydrocephalus associated with Dandy Walker syndrome is treated with surgery to insert a tube to redirect the fluid that surrounds the brain and to assist fluid drainage into other parts of the body that can absorb the fluid.A supportive team approach for children with Dandy-Waller malformation is often warranted and may include special education, physical therapy and other medical, social or vocational services.Genetic counseling is recommended for families that have a child with Dandy Walker malformation. | 352 | Dandy Walker Malformation |
nord_353_0 | Overview of Danon Disease | Danon disease is a rare genetic disorder characterized by an X-linked dominant inheritance pattern, so males are more severely affected than females. Among boys, the key features are diseased heart muscle (cardiomyopathy), weakness of the body muscles (skeletal myopathy) and intellectual disability ranging from mild learning problems to overt intellectual disability. In many males, the disease progresses until a heart transplant is required or death occurs in the second to third decade of life. Females are also affected, although usually more mildly, and often onset is delayed until they reach adulthood. However, some females will progress to being considered for cardiac transplantation during their second decade of life, similar to what is observed in males. Other features include heart arrhythmias, which can lead to a need for medications or a pacemaker, and eye disease affecting the retina; the retinal disease does not always affect vision, especially early in the disease. Danon disease is not usually evident at birth unless blood tests are done in a suspected case (i.e., a son born to a mother known to have the disease). | Overview of Danon Disease. Danon disease is a rare genetic disorder characterized by an X-linked dominant inheritance pattern, so males are more severely affected than females. Among boys, the key features are diseased heart muscle (cardiomyopathy), weakness of the body muscles (skeletal myopathy) and intellectual disability ranging from mild learning problems to overt intellectual disability. In many males, the disease progresses until a heart transplant is required or death occurs in the second to third decade of life. Females are also affected, although usually more mildly, and often onset is delayed until they reach adulthood. However, some females will progress to being considered for cardiac transplantation during their second decade of life, similar to what is observed in males. Other features include heart arrhythmias, which can lead to a need for medications or a pacemaker, and eye disease affecting the retina; the retinal disease does not always affect vision, especially early in the disease. Danon disease is not usually evident at birth unless blood tests are done in a suspected case (i.e., a son born to a mother known to have the disease). | 353 | Danon Disease |
nord_353_1 | Symptoms of Danon Disease | Symptoms of Danon disease vary from person to person and depend on gender. Boys usually show early signs of muscle problems (difficulty sitting or walking), and motor skills may be awkward or delayed. Intellectual disability is usually noticed by parents and/or teachers and can be quite mild. The development of heart disease can lead to further fatigue and shortness of breath. Visual complaints are also prevalent with serious color vision disturbances and near-complete loss of retinal pigment in some patients.In general, young girls may have no symptoms and will report normal muscle strength and have normal intellect. As females age, symptoms of heart disease can begin to develop, and many adult women will experience arrhythmias and may develop progressive heart failure and be considered for cardiac transplantation. Muscle symptoms are reported by some girls and women, but overt findings of frank muscle weakness are usually absent. Visual complaints may also be reported in women and can be an early feature of the disease, although manifestations are less severe than in men.Clinical researchers believe that the skeletal muscle involvement in Danon disease preferentially involves the muscles of the back, shoulder, upper legs and the neck muscles. These are the proximal muscles; that is, those closest to the center of the body. Symptoms of weakness in these muscles can include back pain and difficulty raising one’s arms over the head, getting out of a chair or walking up steps. In a young boy, these problems may be suggested by problems meeting motor milestones (sitting, crawling, and walking, running). An experienced neurologist can recognize the extent of muscle disease by performing a physical examination. Increasingly it is apparent that for some patients the muscle disease progresses over time and some older males may require assistance devices (walkers, wheelchairs).The diseased heart muscle (cardiomyopathy) can lead to a thickened, stiff heart (hypertrophic cardiomyopathy) or to an enlarged heart (dilated cardiomyopathy). Hypertrophic cardiomyopathy is more common in males (approximately 90% hypertrophic and 10% dilated), whereas females are more apt to show features of dilated cardiomyopathy (approximately 50% hypertrophic and 50% dilated). Sometimes the cardiomyopathy can be the first sign of disease in male children. In both instances, problems with heart function and symptoms of heart failure (shortness of breath, fatigue, fluid gain) can occur. Death from heart disease seems to more occur frequently in males, especially as they reach the second and third decades of life. Heart transplantation has been performed successfully and can greatly improve symptoms and extend life. Implantable cardiac defibrillators are used to manage heart arrhythmias and should probably be considered when arrhythmia and cardiomyopathy develop.The extent of intellectual disability in affected males has been described in some epidemiological studies. Most boys will be mildly affected cognitively, usually allowing them to achieve the ability to read, hold jobs, form relationships and live independently. Furthermore, providing education and learning support may help some boys improve their intellectual functioning. In women, intellect appears to be normal, although very little information in the literature addresses this question.Less prevalent symptoms might also include liver and lung involvement, although these have not been studied extensively and might be secondary to muscle involvement (e.g., serum liver enzyme elevation and respiratory muscle weakness). Some speculation also exists on psychiatric disease, with some case reports detailing depression, psychosis, suicidal ideation and attention-deficit hyperactivity disorder in Danon disease patients. However, it is unclear if psychiatric episodes are related to Danon disease.Males with Danon disease typically have abnormalities on certain laboratory tests. The creatine kinase (CPK) level in the blood is often elevated and reflects ongoing muscle damage. The CPK is usually elevated in males but is usually normal in females who have Danon disease. Abnormalities in liver enzyme tests are common in males; in some boys, these are mistakenly interpreted as a sign of primary liver disease rather than a reflection of skeletal muscle dysfunction; frank liver dysfunction has not been well-described in Danon disease. The electrocardiogram (ECG), which measures electrical impulses made by the heart, is often abnormal. This abnormality in conduction and electrical impulse is also known as an arrhythmia. Frequently, an arrhythmia called Wolff-Parkinson-White syndrome, or a pre-excitation syndrome will be seen on the ECG. An examination of the retina by an experienced eye doctor (ophthalmologist) will often detect changes in the pigment of the retina. This can be a useful sign in women, as the retinal changes appear to precede other symptoms of the disease in some females. | Symptoms of Danon Disease. Symptoms of Danon disease vary from person to person and depend on gender. Boys usually show early signs of muscle problems (difficulty sitting or walking), and motor skills may be awkward or delayed. Intellectual disability is usually noticed by parents and/or teachers and can be quite mild. The development of heart disease can lead to further fatigue and shortness of breath. Visual complaints are also prevalent with serious color vision disturbances and near-complete loss of retinal pigment in some patients.In general, young girls may have no symptoms and will report normal muscle strength and have normal intellect. As females age, symptoms of heart disease can begin to develop, and many adult women will experience arrhythmias and may develop progressive heart failure and be considered for cardiac transplantation. Muscle symptoms are reported by some girls and women, but overt findings of frank muscle weakness are usually absent. Visual complaints may also be reported in women and can be an early feature of the disease, although manifestations are less severe than in men.Clinical researchers believe that the skeletal muscle involvement in Danon disease preferentially involves the muscles of the back, shoulder, upper legs and the neck muscles. These are the proximal muscles; that is, those closest to the center of the body. Symptoms of weakness in these muscles can include back pain and difficulty raising one’s arms over the head, getting out of a chair or walking up steps. In a young boy, these problems may be suggested by problems meeting motor milestones (sitting, crawling, and walking, running). An experienced neurologist can recognize the extent of muscle disease by performing a physical examination. Increasingly it is apparent that for some patients the muscle disease progresses over time and some older males may require assistance devices (walkers, wheelchairs).The diseased heart muscle (cardiomyopathy) can lead to a thickened, stiff heart (hypertrophic cardiomyopathy) or to an enlarged heart (dilated cardiomyopathy). Hypertrophic cardiomyopathy is more common in males (approximately 90% hypertrophic and 10% dilated), whereas females are more apt to show features of dilated cardiomyopathy (approximately 50% hypertrophic and 50% dilated). Sometimes the cardiomyopathy can be the first sign of disease in male children. In both instances, problems with heart function and symptoms of heart failure (shortness of breath, fatigue, fluid gain) can occur. Death from heart disease seems to more occur frequently in males, especially as they reach the second and third decades of life. Heart transplantation has been performed successfully and can greatly improve symptoms and extend life. Implantable cardiac defibrillators are used to manage heart arrhythmias and should probably be considered when arrhythmia and cardiomyopathy develop.The extent of intellectual disability in affected males has been described in some epidemiological studies. Most boys will be mildly affected cognitively, usually allowing them to achieve the ability to read, hold jobs, form relationships and live independently. Furthermore, providing education and learning support may help some boys improve their intellectual functioning. In women, intellect appears to be normal, although very little information in the literature addresses this question.Less prevalent symptoms might also include liver and lung involvement, although these have not been studied extensively and might be secondary to muscle involvement (e.g., serum liver enzyme elevation and respiratory muscle weakness). Some speculation also exists on psychiatric disease, with some case reports detailing depression, psychosis, suicidal ideation and attention-deficit hyperactivity disorder in Danon disease patients. However, it is unclear if psychiatric episodes are related to Danon disease.Males with Danon disease typically have abnormalities on certain laboratory tests. The creatine kinase (CPK) level in the blood is often elevated and reflects ongoing muscle damage. The CPK is usually elevated in males but is usually normal in females who have Danon disease. Abnormalities in liver enzyme tests are common in males; in some boys, these are mistakenly interpreted as a sign of primary liver disease rather than a reflection of skeletal muscle dysfunction; frank liver dysfunction has not been well-described in Danon disease. The electrocardiogram (ECG), which measures electrical impulses made by the heart, is often abnormal. This abnormality in conduction and electrical impulse is also known as an arrhythmia. Frequently, an arrhythmia called Wolff-Parkinson-White syndrome, or a pre-excitation syndrome will be seen on the ECG. An examination of the retina by an experienced eye doctor (ophthalmologist) will often detect changes in the pigment of the retina. This can be a useful sign in women, as the retinal changes appear to precede other symptoms of the disease in some females. | 353 | Danon Disease |
nord_353_2 | Causes of Danon Disease | Danon disease is caused by a change (mutation or variant) in a gene called LAMP2. To date, there are over 160 different variants in the LAMP2 gene identified in case reports and databases that could lead to Danon disease. Variants that lead to a complete absence of the LAMP2 protein have been shown to be most detrimental in terms of prognosis. Other variants that lead to a partial LAMP2 protein deficiency maybe less severe clinically.In many instances the disease is inherited from a parent, typically the mother who is far more apt to remain healthy enough to reach reproductive age than the typically affected male. Without a heart transplant, only a few males may be healthy enough to father their own children. New genetic variants (sporadic mutations) could also account for the first case in a family, but these have not been widely reported. Affected mothers have a 50% chance to pass on the gene variant to each of their children (both sons and daughters). Affected fathers who are healthy enough to have children will pass on the variant to all of their daughters and none of their sons. This pattern of inheritance is consistent with what occurs in other X-linked genetic conditions.Since females have two X chromosomes (and males have one), females are somewhat protected from the effects of the gene variants that cause Danon disease. This is explained by the fact that each woman with Danon disease has one X chromosome with a Danon disease gene variant and one X chromosome where the LAMP2 gene is functioning normally. The X chromosome with the normal LAMP2 gene protects females and explains, in part, the less severe symptoms and the delay in onset of symptoms until adulthood.The genetic characteristics of this gene (LAMP2) are transmitted in an X-linked dominant pattern.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is turned off. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.X-linked dominant disorders, like Danon disease, are also caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive. In the case of Danon disease, males can survive to adulthood, however, their medical problems and the typical need for heart transplantation likely limits their ability to have children.The function of the LAMP2 protein (made from the LAMP2 gene) is not well understood. It appears that the LAMP2 protein is important for the function of the cell’s lysosomes. Lysosomes, often compared to waste disposal plants, are small structures inside cells that are responsible for breaking down certain molecules and compounds in cells. When the lysosomes do not function properly, cellular products accumulate. One such product that may build-up is glycogen and, in some people, the diagnosis of Danon disease is suggested because of excess glycogen seen on a skeletal muscle biopsy. However, it is important to realize that excess glycogen is not always visible on a single muscle biopsy. | Causes of Danon Disease. Danon disease is caused by a change (mutation or variant) in a gene called LAMP2. To date, there are over 160 different variants in the LAMP2 gene identified in case reports and databases that could lead to Danon disease. Variants that lead to a complete absence of the LAMP2 protein have been shown to be most detrimental in terms of prognosis. Other variants that lead to a partial LAMP2 protein deficiency maybe less severe clinically.In many instances the disease is inherited from a parent, typically the mother who is far more apt to remain healthy enough to reach reproductive age than the typically affected male. Without a heart transplant, only a few males may be healthy enough to father their own children. New genetic variants (sporadic mutations) could also account for the first case in a family, but these have not been widely reported. Affected mothers have a 50% chance to pass on the gene variant to each of their children (both sons and daughters). Affected fathers who are healthy enough to have children will pass on the variant to all of their daughters and none of their sons. This pattern of inheritance is consistent with what occurs in other X-linked genetic conditions.Since females have two X chromosomes (and males have one), females are somewhat protected from the effects of the gene variants that cause Danon disease. This is explained by the fact that each woman with Danon disease has one X chromosome with a Danon disease gene variant and one X chromosome where the LAMP2 gene is functioning normally. The X chromosome with the normal LAMP2 gene protects females and explains, in part, the less severe symptoms and the delay in onset of symptoms until adulthood.The genetic characteristics of this gene (LAMP2) are transmitted in an X-linked dominant pattern.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is turned off. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.X-linked dominant disorders, like Danon disease, are also caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive. In the case of Danon disease, males can survive to adulthood, however, their medical problems and the typical need for heart transplantation likely limits their ability to have children.The function of the LAMP2 protein (made from the LAMP2 gene) is not well understood. It appears that the LAMP2 protein is important for the function of the cell’s lysosomes. Lysosomes, often compared to waste disposal plants, are small structures inside cells that are responsible for breaking down certain molecules and compounds in cells. When the lysosomes do not function properly, cellular products accumulate. One such product that may build-up is glycogen and, in some people, the diagnosis of Danon disease is suggested because of excess glycogen seen on a skeletal muscle biopsy. However, it is important to realize that excess glycogen is not always visible on a single muscle biopsy. | 353 | Danon Disease |
nord_353_3 | Affects of Danon Disease | At present, it is thought that Danon disease can affect all ethnic populations. The prevalence of Danon disease is unknown but may be rising due to increased detection from wider availability of LAMP2 gene testing. Histories of affected patients at birth are usually normal. As discussed, males are more severely affected in this X-linked dominant disease. | Affects of Danon Disease. At present, it is thought that Danon disease can affect all ethnic populations. The prevalence of Danon disease is unknown but may be rising due to increased detection from wider availability of LAMP2 gene testing. Histories of affected patients at birth are usually normal. As discussed, males are more severely affected in this X-linked dominant disease. | 353 | Danon Disease |
nord_353_4 | Related disorders of Danon Disease | Until recently, Danon disease and Pompe disease were thought to be closely related because in both conditions, skeletal and cardiac muscles are involved. Under the microscope, Danon disease shows many features (i.e., increased glycogen content), that are typical of Pompe disease. Two main features distinguish the two diseases: 1) the inheritance pattern in Pompe disease is autosomal recessive while that in Danon disease is X-linked dominant, and 2) the enzyme deficient in Pompe disease (acid maltase or acid alpha glucosidase) is present in normal amounts in Danon disease.X-linked myopathy with excessive autophagy is a disorder similar to Danon disease. Currently, it is thought to be a separate disorder, although the gene causing the disorder has not yet been definitively identified. Some studies point to an abnormality in the VMA21 gene as the etiology. Skeletal muscle involvement and elevated CPK are seen. Heart involvement and intellectual disability, commonly seen in Danon disease, appear absent in X-linked myopathy with excessive autophagy. The inheritance pattern is X-linked recessive.Lethal, congenital glycogen storage disease of the heart is caused by genetic variants in a gene called PRKAG2. The disease is severe and characterized by low blood sugar (hypoglycemia), cardiomyopathy, congestive heart failure and an autosomal recessive pattern of inheritance. It is sometimes referred to as glycogen storage disease of the heart, which is a descriptive term and may sometimes include Danon disease.Lastly, infantile autophagic vacuolar myopathy is another disease similar to Danon disease. The causative gene abnormality has not been identified. An X-linked recessive inheritance pattern has been described with infantile onset of lethal cardiomyopathy and skeletal muscle weakness. | Related disorders of Danon Disease. Until recently, Danon disease and Pompe disease were thought to be closely related because in both conditions, skeletal and cardiac muscles are involved. Under the microscope, Danon disease shows many features (i.e., increased glycogen content), that are typical of Pompe disease. Two main features distinguish the two diseases: 1) the inheritance pattern in Pompe disease is autosomal recessive while that in Danon disease is X-linked dominant, and 2) the enzyme deficient in Pompe disease (acid maltase or acid alpha glucosidase) is present in normal amounts in Danon disease.X-linked myopathy with excessive autophagy is a disorder similar to Danon disease. Currently, it is thought to be a separate disorder, although the gene causing the disorder has not yet been definitively identified. Some studies point to an abnormality in the VMA21 gene as the etiology. Skeletal muscle involvement and elevated CPK are seen. Heart involvement and intellectual disability, commonly seen in Danon disease, appear absent in X-linked myopathy with excessive autophagy. The inheritance pattern is X-linked recessive.Lethal, congenital glycogen storage disease of the heart is caused by genetic variants in a gene called PRKAG2. The disease is severe and characterized by low blood sugar (hypoglycemia), cardiomyopathy, congestive heart failure and an autosomal recessive pattern of inheritance. It is sometimes referred to as glycogen storage disease of the heart, which is a descriptive term and may sometimes include Danon disease.Lastly, infantile autophagic vacuolar myopathy is another disease similar to Danon disease. The causative gene abnormality has not been identified. An X-linked recessive inheritance pattern has been described with infantile onset of lethal cardiomyopathy and skeletal muscle weakness. | 353 | Danon Disease |
nord_353_5 | Diagnosis of Danon Disease | Because Danon disease is rare and unfamiliar to most physicians, diagnosis is difficult and takes substantial time. The diagnosis is suggested based on a family history compatible with X-linked dominant inheritance and symptoms in affected relatives (cardiomyopathy, skeletal myopathy, intellectual disability, Wolff-Parkinson White, etc.). Skeletal muscle biopsy is done in some males to determine the cause of muscle weakness. If, while examining the biopsy materials, glycogen buildup and/or empty spaces appear in the cells of the muscle tissue (vacuolization), Danon disease must be considered. This also holds true for the analysis of a heart biopsy. A muscle biopsy that yields evidence of glycogen build-up and empty spaces in the muscle cells are key signs and indications that a diagnosis of Danon disease is a high probability.It is important to recognize that, in early stages of Danon disease, and probably also in women, the muscle biopsy can be non-specific. Thus, a normal or non-specific muscle biopsy does not exclude Danon disease. If other features of Danon disease are present, a non-diagnostic muscle biopsy should not discourage more definitive genetic testing. Patients who appear to have Pompe disease (based on muscle biopsy for instance) but have normal acid maltase activity, should be evaluated for Danon disease. Unexplained hypertrophic cardiomyopathy in males is probably due to Danon disease in some people.Antibodies to the LAMP-2 protein are available and tissue staining (of a muscle biopsy) for the absence of LAMP-2 protein is another potential, but not widely available, diagnostic approach. LAMP-2 antibody testing is likely to be normal in women with Danon disease and if done should be interpreted with caution due to the possibility of a false-negative result.Genetic testing of the LAMP2 gene is currently the gold standard for diagnosis and is available in specialized genetics laboratories. Most genetic variants causing Danon disease predict reduced levels or even absence of the LAMP2 gene product, the LAMP-2 protein. Although the sensitivity of LAMP2 genetic testing is not known at this time, it is the best that is available. The noninvasive nature of DNA-based testing and the inclusion of LAMP2 gene testing in hypertrophic cardiomyopathy genetic diagnostic panels favor this method as the most common route to diagnosis. | Diagnosis of Danon Disease. Because Danon disease is rare and unfamiliar to most physicians, diagnosis is difficult and takes substantial time. The diagnosis is suggested based on a family history compatible with X-linked dominant inheritance and symptoms in affected relatives (cardiomyopathy, skeletal myopathy, intellectual disability, Wolff-Parkinson White, etc.). Skeletal muscle biopsy is done in some males to determine the cause of muscle weakness. If, while examining the biopsy materials, glycogen buildup and/or empty spaces appear in the cells of the muscle tissue (vacuolization), Danon disease must be considered. This also holds true for the analysis of a heart biopsy. A muscle biopsy that yields evidence of glycogen build-up and empty spaces in the muscle cells are key signs and indications that a diagnosis of Danon disease is a high probability.It is important to recognize that, in early stages of Danon disease, and probably also in women, the muscle biopsy can be non-specific. Thus, a normal or non-specific muscle biopsy does not exclude Danon disease. If other features of Danon disease are present, a non-diagnostic muscle biopsy should not discourage more definitive genetic testing. Patients who appear to have Pompe disease (based on muscle biopsy for instance) but have normal acid maltase activity, should be evaluated for Danon disease. Unexplained hypertrophic cardiomyopathy in males is probably due to Danon disease in some people.Antibodies to the LAMP-2 protein are available and tissue staining (of a muscle biopsy) for the absence of LAMP-2 protein is another potential, but not widely available, diagnostic approach. LAMP-2 antibody testing is likely to be normal in women with Danon disease and if done should be interpreted with caution due to the possibility of a false-negative result.Genetic testing of the LAMP2 gene is currently the gold standard for diagnosis and is available in specialized genetics laboratories. Most genetic variants causing Danon disease predict reduced levels or even absence of the LAMP2 gene product, the LAMP-2 protein. Although the sensitivity of LAMP2 genetic testing is not known at this time, it is the best that is available. The noninvasive nature of DNA-based testing and the inclusion of LAMP2 gene testing in hypertrophic cardiomyopathy genetic diagnostic panels favor this method as the most common route to diagnosis. | 353 | Danon Disease |
nord_353_6 | Therapies of Danon Disease | Treatment
The treatment of Danon disease is directed toward the specific symptoms that are apparent in each individual. It requires a team that should include a primary care physician as well as several specialists, including a cardiologist, neurologist, ophthalmologist, geneticist, genetic counselor, rehabilitation physician, educational specialist, and physical therapist. Currently there is no specific therapy that is known to slow the underlying biological problems caused by LAMP-2 protein deficiency.The severity of cardiomyopathy is the major prognostic factor. Imaging studies including echocardiography and cardiac magnetic resonance can assess heart function, extent of hypertrophy, and degree of cardiac fibrosis (formation of scar tissue on the heart). Medications for heart disease should be given when indicated by clinical signs and symptoms. The rapid progression of the cardiomyopathy in some males necessitates prompt consideration for heart transplantation. Early involvement of electrophysiology to study the electrical conduction system of the heart is warranted in patients with arrhythmias. Devices that continuously record the electrical impulses of the heart and can be worn for several days can be used to detect arrhythmias. For symptomatic arrhythmias, early implantation of a cardioverter-defibrillator may be appropriate. Cardiac ablation therapy, which is a technique utilized to destroy the abnormal focus in the heart generating the irregular rhythm, can also be performed. As the disease can progress rapidly in males, consideration for early defibrillator implantation and evaluation for cardiac transplantation are appropriate in males as cardiomyopathy progresses.Assessment of muscle strength, especially the proximal muscles of the shoulder, neck, and legs, should be performed regularly. Physical therapy can be helpful in maintaining muscle strength and flexibility. Intellectual disability should be screened for in males and appropriate educational interventions applied as needed. Regular eye examinations, to track the development and progression of retinal disease, should be considered. Biological relatives who are at risk for Danon disease should be evaluated by a physician for early signs of disease. At a minimum, evaluation of such relatives should include a medical history, physical examination (attention to cardiac, neurological, and ocular exams), CPK testing, ECG and echocardiogram.Genetic consultation and counseling are recommended for all patients and families so that inheritance and reproductive risks are clearly communicated. | Therapies of Danon Disease. Treatment
The treatment of Danon disease is directed toward the specific symptoms that are apparent in each individual. It requires a team that should include a primary care physician as well as several specialists, including a cardiologist, neurologist, ophthalmologist, geneticist, genetic counselor, rehabilitation physician, educational specialist, and physical therapist. Currently there is no specific therapy that is known to slow the underlying biological problems caused by LAMP-2 protein deficiency.The severity of cardiomyopathy is the major prognostic factor. Imaging studies including echocardiography and cardiac magnetic resonance can assess heart function, extent of hypertrophy, and degree of cardiac fibrosis (formation of scar tissue on the heart). Medications for heart disease should be given when indicated by clinical signs and symptoms. The rapid progression of the cardiomyopathy in some males necessitates prompt consideration for heart transplantation. Early involvement of electrophysiology to study the electrical conduction system of the heart is warranted in patients with arrhythmias. Devices that continuously record the electrical impulses of the heart and can be worn for several days can be used to detect arrhythmias. For symptomatic arrhythmias, early implantation of a cardioverter-defibrillator may be appropriate. Cardiac ablation therapy, which is a technique utilized to destroy the abnormal focus in the heart generating the irregular rhythm, can also be performed. As the disease can progress rapidly in males, consideration for early defibrillator implantation and evaluation for cardiac transplantation are appropriate in males as cardiomyopathy progresses.Assessment of muscle strength, especially the proximal muscles of the shoulder, neck, and legs, should be performed regularly. Physical therapy can be helpful in maintaining muscle strength and flexibility. Intellectual disability should be screened for in males and appropriate educational interventions applied as needed. Regular eye examinations, to track the development and progression of retinal disease, should be considered. Biological relatives who are at risk for Danon disease should be evaluated by a physician for early signs of disease. At a minimum, evaluation of such relatives should include a medical history, physical examination (attention to cardiac, neurological, and ocular exams), CPK testing, ECG and echocardiogram.Genetic consultation and counseling are recommended for all patients and families so that inheritance and reproductive risks are clearly communicated. | 353 | Danon Disease |
nord_354_0 | Overview of De Barsy Syndrome | De Barsy syndrome is a rare genetic disorder characterized by eye abnormalities, growth retardation, intellectual disability, a prematurely-aged appearance (progeroid features), and loose (lax), wrinkled, sagging, redundant skin that lacks elasticity (cutis laxa). Distinctive facial features, skeletal malformations, and neurological abnormalities can also occur. The specific symptoms present and the severity of de Barsy syndrome can vary greatly from one individual to another. Some cases of de Barsy syndrome have been linked to mutations in either the PYCR1 or ALDH18A1 genes; in other cases, a specific genetic mutation has not yet been identified. De Barsy syndrome is inherited in an autosomal recessive manner.De Barsy syndrome was first reported in the medical literature by Dr. De Barsy in 1968 in one patient. The disorder is now classified as a form of cutis laxa and also known as autosomal recessive cutis laxa type 3. Cutis laxa is a group of rare disorders that may occur in several inherited (congenital) forms or acquired at some point during life (acquired cutis laxa). This group of disorders involves a wide spectrum of symptoms and signs that result from defects in connective tissue, the material between cells of the body that gives the tissue form and strength. Connective tissue is found throughout the body in muscles, joints, skin and other organs. Cutis laxa is characterized by skin that is loose (lax), wrinkled, sagging, redundant, and lacking elasticity (inelastic). When stretched, inelastic skin returns to place abnormally slowly.Cutis laxa syndromes were once broken down mainly by clinical characteristics, but are now classified based upon the specific mutation present. Consequently, individuals with de Barsy syndrome caused by a PYCR1 mutation are said to have PYCR1-related cutis laxa (autosomal recessive cutis laxa type 3B) and individuals with de Barsy syndrome caused by an ALDH18A1 mutation are said to have ALDH18A1-related cutis laxa (autosomal recessive cutis laxa type 3A). NORD has a general report on cutis laxa that explains the various subtypes and genetics of cutis laxa. For more information, choose “cutis laxa” as your search term in the Rare Disease Database.In ALDH18A1-related de Barsy syndrome, approximately one third of ALDH18A1 mutation carriers show biochemical signs of metabolic disease due to ALDH18A1 related abnormal purine synthesis in blood. Abnormal amino acid levels include variable degrees of decrease in arginine, ornithine, citrulline and sometimes low proline concentrations. Young patients might present with symptoms of elevated levels of ammonia in the blood (hyperammonemia) and secondary urea cycle disturbance. It is extremely important to screen for the specific purine synthesis defect related metabolites in suspected ALDH18A1-related cases. These metabolites are not always abnormal and might show variable degree of abnormalities. Ammonia elevation is usually not exceeding a second fold increase. In case of abnormal results there is a potential dietary and amino acid supplementation therapy. | Overview of De Barsy Syndrome. De Barsy syndrome is a rare genetic disorder characterized by eye abnormalities, growth retardation, intellectual disability, a prematurely-aged appearance (progeroid features), and loose (lax), wrinkled, sagging, redundant skin that lacks elasticity (cutis laxa). Distinctive facial features, skeletal malformations, and neurological abnormalities can also occur. The specific symptoms present and the severity of de Barsy syndrome can vary greatly from one individual to another. Some cases of de Barsy syndrome have been linked to mutations in either the PYCR1 or ALDH18A1 genes; in other cases, a specific genetic mutation has not yet been identified. De Barsy syndrome is inherited in an autosomal recessive manner.De Barsy syndrome was first reported in the medical literature by Dr. De Barsy in 1968 in one patient. The disorder is now classified as a form of cutis laxa and also known as autosomal recessive cutis laxa type 3. Cutis laxa is a group of rare disorders that may occur in several inherited (congenital) forms or acquired at some point during life (acquired cutis laxa). This group of disorders involves a wide spectrum of symptoms and signs that result from defects in connective tissue, the material between cells of the body that gives the tissue form and strength. Connective tissue is found throughout the body in muscles, joints, skin and other organs. Cutis laxa is characterized by skin that is loose (lax), wrinkled, sagging, redundant, and lacking elasticity (inelastic). When stretched, inelastic skin returns to place abnormally slowly.Cutis laxa syndromes were once broken down mainly by clinical characteristics, but are now classified based upon the specific mutation present. Consequently, individuals with de Barsy syndrome caused by a PYCR1 mutation are said to have PYCR1-related cutis laxa (autosomal recessive cutis laxa type 3B) and individuals with de Barsy syndrome caused by an ALDH18A1 mutation are said to have ALDH18A1-related cutis laxa (autosomal recessive cutis laxa type 3A). NORD has a general report on cutis laxa that explains the various subtypes and genetics of cutis laxa. For more information, choose “cutis laxa” as your search term in the Rare Disease Database.In ALDH18A1-related de Barsy syndrome, approximately one third of ALDH18A1 mutation carriers show biochemical signs of metabolic disease due to ALDH18A1 related abnormal purine synthesis in blood. Abnormal amino acid levels include variable degrees of decrease in arginine, ornithine, citrulline and sometimes low proline concentrations. Young patients might present with symptoms of elevated levels of ammonia in the blood (hyperammonemia) and secondary urea cycle disturbance. It is extremely important to screen for the specific purine synthesis defect related metabolites in suspected ALDH18A1-related cases. These metabolites are not always abnormal and might show variable degree of abnormalities. Ammonia elevation is usually not exceeding a second fold increase. In case of abnormal results there is a potential dietary and amino acid supplementation therapy. | 354 | De Barsy Syndrome |
nord_354_1 | Symptoms of De Barsy Syndrome | Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about de Barsy syndrome 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. An extremely wide and varied group of symptoms have been reported in individuals with de Barsy syndrome. The prematurely-aged appearance that commonly affects children with de Barsy syndrome is caused by underdevelopment of the skin and structures in the middle of the face (midface hypoplasia). Loose, sagging, inelastic skin that characterizes cutis laxa contributes to the prematurely-aged appearance. Less often, the skin may be thin and appear translucent so the underlying veins may be easily visible. In some cases, affected individuals may have reduced subcutaneous fat, which is the layer of fat just below the skin’s surface. Infants with de Barsy syndrome may also have distinctive facial features including an unusually prominent forehead (frontal bossing), thin lips, widely spaced eyes (hypertelorism), a small, upturned nose, and large, malformed (dysplastic) ears. Some affected infants may experience delayed closure of the soft spot on top of the skull (delayed closure of the anterior fontanel). The anterior fontanel may be abnormally large as well. In some cases, the circumference of an infant’s or child’s head may be smaller than would be expected based upon age and gender (microcephaly). Affected infants may also have diminished muscle tone (hypotonia) and joints that are abnormally loose (hypermobility) because of lax ligaments and tendons. Skeletal abnormalities may occur including frequent dislocations and partial dislocations (subluxations) including congenital dislocation of the hip, and hands that are stuck in a clenched position (contracture) with thumbs that turned inward (adducted thumbs). A sunken breastbone known as pectus excavatum, low bone mineral density, and weakened, fragile bones (osteoporosis) have also been reported. Ocular abnormalities are also common in de Barsy syndrome and may include clouding of the lenses of the eyes (cataracts) and clouding of the corneas of the eyes (bilateral corneal opacification). The cornea is the clear (transparent) outer layer of the eye that helps let light in. Corneal opacification may not cause any symptoms or it can lead to varying degrees of vision loss. Less common ocular abnormalities include bluish discoloration of the whites of the eyes (blue sclera), nearsightedness (myopia), and eyes that do not line up in the same direction such as crossed-eyes (strabismus).Varying degrees of intellectual disability may also occur, ranging from moderate to severe. Affected infants and children may experience delays in attaining developmental milestones (developmental delays) and have reflex responses that are stronger than normal (hyperreflexia). As affected individuals grow older they may develop seizures and involuntary, slow, writhing movements (athetoid-like movements) of the hands, feet, arms and legs. Growth delays occur before birth and after birth (intrauterine and postnatal growth deficiency). In addition, affected infants may fail to grow and gain weight at the expected rate for age and gender (failure to thrive). Individuals with de Barsy syndrome may display height that is below what would normally be expected based upon age and gender (short stature). Additional symptoms have been reported in some cases including inguinal and umbilical hernias. | Symptoms of De Barsy Syndrome. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about de Barsy syndrome 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. An extremely wide and varied group of symptoms have been reported in individuals with de Barsy syndrome. The prematurely-aged appearance that commonly affects children with de Barsy syndrome is caused by underdevelopment of the skin and structures in the middle of the face (midface hypoplasia). Loose, sagging, inelastic skin that characterizes cutis laxa contributes to the prematurely-aged appearance. Less often, the skin may be thin and appear translucent so the underlying veins may be easily visible. In some cases, affected individuals may have reduced subcutaneous fat, which is the layer of fat just below the skin’s surface. Infants with de Barsy syndrome may also have distinctive facial features including an unusually prominent forehead (frontal bossing), thin lips, widely spaced eyes (hypertelorism), a small, upturned nose, and large, malformed (dysplastic) ears. Some affected infants may experience delayed closure of the soft spot on top of the skull (delayed closure of the anterior fontanel). The anterior fontanel may be abnormally large as well. In some cases, the circumference of an infant’s or child’s head may be smaller than would be expected based upon age and gender (microcephaly). Affected infants may also have diminished muscle tone (hypotonia) and joints that are abnormally loose (hypermobility) because of lax ligaments and tendons. Skeletal abnormalities may occur including frequent dislocations and partial dislocations (subluxations) including congenital dislocation of the hip, and hands that are stuck in a clenched position (contracture) with thumbs that turned inward (adducted thumbs). A sunken breastbone known as pectus excavatum, low bone mineral density, and weakened, fragile bones (osteoporosis) have also been reported. Ocular abnormalities are also common in de Barsy syndrome and may include clouding of the lenses of the eyes (cataracts) and clouding of the corneas of the eyes (bilateral corneal opacification). The cornea is the clear (transparent) outer layer of the eye that helps let light in. Corneal opacification may not cause any symptoms or it can lead to varying degrees of vision loss. Less common ocular abnormalities include bluish discoloration of the whites of the eyes (blue sclera), nearsightedness (myopia), and eyes that do not line up in the same direction such as crossed-eyes (strabismus).Varying degrees of intellectual disability may also occur, ranging from moderate to severe. Affected infants and children may experience delays in attaining developmental milestones (developmental delays) and have reflex responses that are stronger than normal (hyperreflexia). As affected individuals grow older they may develop seizures and involuntary, slow, writhing movements (athetoid-like movements) of the hands, feet, arms and legs. Growth delays occur before birth and after birth (intrauterine and postnatal growth deficiency). In addition, affected infants may fail to grow and gain weight at the expected rate for age and gender (failure to thrive). Individuals with de Barsy syndrome may display height that is below what would normally be expected based upon age and gender (short stature). Additional symptoms have been reported in some cases including inguinal and umbilical hernias. | 354 | De Barsy Syndrome |
nord_354_2 | Causes of De Barsy Syndrome | Some cases of de Barsy syndrome are caused by mutations in either the PYCR1 or ALDH18A1 genes. 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. Some individuals with de Barsy syndrome do not have mutations in either of these genes suggesting that as-yet-unidentified genes cause the disorder. De Barsy syndrome is inherited as an autosomal recessive disorder. 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. Investigators have determined that the PYCR1 gene is located on the long arm of chromosome 17 (17q25.3) and that the ALDH18A1 gene is located on the long arm of chromosome 10 (10q24.1). 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 17q25.3” refers to band 25.3 on the long arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome. | Causes of De Barsy Syndrome. Some cases of de Barsy syndrome are caused by mutations in either the PYCR1 or ALDH18A1 genes. 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. Some individuals with de Barsy syndrome do not have mutations in either of these genes suggesting that as-yet-unidentified genes cause the disorder. De Barsy syndrome is inherited as an autosomal recessive disorder. 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. Investigators have determined that the PYCR1 gene is located on the long arm of chromosome 17 (17q25.3) and that the ALDH18A1 gene is located on the long arm of chromosome 10 (10q24.1). 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 17q25.3” refers to band 25.3 on the long arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome. | 354 | De Barsy Syndrome |
nord_354_3 | Affects of De Barsy Syndrome | De Barsy syndrome affects males and females in equal numbers. Fewer than 50 cases have been reported in the medical literature. The exact incidence and prevalence of this disorder is unknown. Because cases may go misdiagnosed or undiagnosed, determining the true frequency of de Barsy syndrome in the general population is difficult. De Barsy syndrome is usually obvious at birth or early infancy. | Affects of De Barsy Syndrome. De Barsy syndrome affects males and females in equal numbers. Fewer than 50 cases have been reported in the medical literature. The exact incidence and prevalence of this disorder is unknown. Because cases may go misdiagnosed or undiagnosed, determining the true frequency of de Barsy syndrome in the general population is difficult. De Barsy syndrome is usually obvious at birth or early infancy. | 354 | De Barsy Syndrome |
nord_354_4 | Related disorders of De Barsy Syndrome | Symptoms of the following disorders can be similar to those of de Barsy syndrome. Comparisons may be useful for a differential diagnosis.Cutis laxa is a general term for a group of rare disorders that may occur in several inherited (congenital) forms or acquired at some point during life (acquired cutis laxa). This group of disorders involves a wide spectrum of symptoms and signs that result from defects in connective tissue, the material between cells of the body that gives the tissue form and strength. Connective tissue is found throughout the body in muscles, joints, skin and other organs. Cutis laxa is characterized by skin that is loose (lax), wrinkled, sagging, redundant, and lacking elasticity (inelastic). When stretched, inelastic skin returns to place abnormally slowly. The skin around the face, arms, legs and trunk is most commonly affected. The affected skin may be thickened and dark. Abnormal skin may give affected individuals and children a prematurely-aged appearance and they can potentially look much older than their true age. Unlike similar skin disorders, easy bruising and scarring are generally not associated with cutis laxa. The joints are often abnormally loose (hypermobility) because of lax ligaments and tendons. Several inherited forms of the disorder have been identified. Most cases are inherited as either an autosomal dominant or recessive disorder. (For more information on this disorder, choose “cutis laxa” as your search term in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by defects of the major structural protein in the body (collagen). Collagen, a tough, fibrous protein, plays an essential role in holding together and strengthening the tissues of the body. Due to defects of collagen, primary EDS symptoms and findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, stretchy (elastic) skin; and excessive fragility of the skin, small blood vessels, and other bodily tissues and membranes. The different types of EDS were originally categorized in a classification system that used Roman numerals (e.g., EDS I to EDS XI), based upon each form's associated symptoms and findings (clinical evidence) and underlying cause. A revised, simplified classification system has since been described in the medical literature that categorizes EDS into six major subtypes, based upon clinical evidence, underlying biochemical defects, and mode of inheritance. Each subtype of EDS is a distinct hereditary disorder that may affect individuals within certain families (kindreds). In other words, parents with one subtype of EDS will not have children with another EDS subtype. Depending upon the specific subtype present, Ehlers-Danlos syndrome is usually transmitted as an autosomal dominant or autosomal recessive trait. Only certain rare types of EDS include a predisposition for severe cardiovascular issues (such as vascular EDS); other types predominantly alter the skin and joints (e.g. hypermobile EDS). (For more information on this disorder, choose “Ehlers Danlos” as your search term in the Rare Disease Database.)Pseudoxanthoma elasticum, PXE, is an inherited disorder caused by mutations in the ABCC6 transporter gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium and other minerals are deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Individuals with PXE can have excess, wrinkled skin. Unlike individuals with cutis laxa, affected skin in PXE tends to be hyperelastic. Loose joints are also common. Onset can range from early childhood to adulthood. PXE is inherited as an autosomal recessive disorder. (For more information on this disorder, choose “pseudoxanthoma elasticum” as your search term in the Rare Disease Database.)There are many additional disorders in which a prematurely-aged appearance and cutis laxa or similar skin symptoms occur. Such disorders include arterial tortuosity syndrome, Cantu syndrome, SCARF syndrome, Lenz-Majewski hyperostotic dwarfism, Barber-Say syndrome, Hutchinson-Gilford progeria syndrome, Cockayne syndrome, Wiedemann-Rautenstrauch syndrome, Kabuki syndrome, Williams syndrome, Costello syndrome, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome, and ablepharon-macrostomia syndrome. NORD has individual reports on many of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of De Barsy Syndrome. Symptoms of the following disorders can be similar to those of de Barsy syndrome. Comparisons may be useful for a differential diagnosis.Cutis laxa is a general term for a group of rare disorders that may occur in several inherited (congenital) forms or acquired at some point during life (acquired cutis laxa). This group of disorders involves a wide spectrum of symptoms and signs that result from defects in connective tissue, the material between cells of the body that gives the tissue form and strength. Connective tissue is found throughout the body in muscles, joints, skin and other organs. Cutis laxa is characterized by skin that is loose (lax), wrinkled, sagging, redundant, and lacking elasticity (inelastic). When stretched, inelastic skin returns to place abnormally slowly. The skin around the face, arms, legs and trunk is most commonly affected. The affected skin may be thickened and dark. Abnormal skin may give affected individuals and children a prematurely-aged appearance and they can potentially look much older than their true age. Unlike similar skin disorders, easy bruising and scarring are generally not associated with cutis laxa. The joints are often abnormally loose (hypermobility) because of lax ligaments and tendons. Several inherited forms of the disorder have been identified. Most cases are inherited as either an autosomal dominant or recessive disorder. (For more information on this disorder, choose “cutis laxa” as your search term in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by defects of the major structural protein in the body (collagen). Collagen, a tough, fibrous protein, plays an essential role in holding together and strengthening the tissues of the body. Due to defects of collagen, primary EDS symptoms and findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, stretchy (elastic) skin; and excessive fragility of the skin, small blood vessels, and other bodily tissues and membranes. The different types of EDS were originally categorized in a classification system that used Roman numerals (e.g., EDS I to EDS XI), based upon each form's associated symptoms and findings (clinical evidence) and underlying cause. A revised, simplified classification system has since been described in the medical literature that categorizes EDS into six major subtypes, based upon clinical evidence, underlying biochemical defects, and mode of inheritance. Each subtype of EDS is a distinct hereditary disorder that may affect individuals within certain families (kindreds). In other words, parents with one subtype of EDS will not have children with another EDS subtype. Depending upon the specific subtype present, Ehlers-Danlos syndrome is usually transmitted as an autosomal dominant or autosomal recessive trait. Only certain rare types of EDS include a predisposition for severe cardiovascular issues (such as vascular EDS); other types predominantly alter the skin and joints (e.g. hypermobile EDS). (For more information on this disorder, choose “Ehlers Danlos” as your search term in the Rare Disease Database.)Pseudoxanthoma elasticum, PXE, is an inherited disorder caused by mutations in the ABCC6 transporter gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium and other minerals are deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Individuals with PXE can have excess, wrinkled skin. Unlike individuals with cutis laxa, affected skin in PXE tends to be hyperelastic. Loose joints are also common. Onset can range from early childhood to adulthood. PXE is inherited as an autosomal recessive disorder. (For more information on this disorder, choose “pseudoxanthoma elasticum” as your search term in the Rare Disease Database.)There are many additional disorders in which a prematurely-aged appearance and cutis laxa or similar skin symptoms occur. Such disorders include arterial tortuosity syndrome, Cantu syndrome, SCARF syndrome, Lenz-Majewski hyperostotic dwarfism, Barber-Say syndrome, Hutchinson-Gilford progeria syndrome, Cockayne syndrome, Wiedemann-Rautenstrauch syndrome, Kabuki syndrome, Williams syndrome, Costello syndrome, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome, and ablepharon-macrostomia syndrome. NORD has individual reports on many of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | 354 | De Barsy Syndrome |
nord_354_5 | Diagnosis of De Barsy Syndrome | A diagnosis of de Barsy syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Surgical removal and microscopic examination (biopsy) of affected skin can reveal characteristic changes in elastic fibers. Distinguishing between the specific genetic forms of cutis laxa can be difficult. Molecular genetic testing can confirm a diagnosis of an inherited form cutis laxa and establish the specific, underlying subtype in some cases. Molecular genetic testing can detect mutations in specific genes known to cause cutis laxa, but is available only as a diagnostic service at specialized laboratories.As previously stated, it is extremely important to screen for the specific purine synthesis defect related metabolites in suspected ALDH18A1-related cases. These metabolites are not always abnormal and might show variable degree of abnormalities. | Diagnosis of De Barsy Syndrome. A diagnosis of de Barsy syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Surgical removal and microscopic examination (biopsy) of affected skin can reveal characteristic changes in elastic fibers. Distinguishing between the specific genetic forms of cutis laxa can be difficult. Molecular genetic testing can confirm a diagnosis of an inherited form cutis laxa and establish the specific, underlying subtype in some cases. Molecular genetic testing can detect mutations in specific genes known to cause cutis laxa, but is available only as a diagnostic service at specialized laboratories.As previously stated, it is extremely important to screen for the specific purine synthesis defect related metabolites in suspected ALDH18A1-related cases. These metabolites are not always abnormal and might show variable degree of abnormalities. | 354 | De Barsy Syndrome |
nord_354_6 | Therapies of De Barsy Syndrome | TreatmentThe treatment of de Barsy 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, surgeons, dermatologists, orthopedists, neurologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, 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 de Barsy syndrome.Specific therapies for individuals with cutis laxa can include surgery to repair skeletal problems, ocular abnormalities, or hernias. Some individuals elect for plastic (cosmetic) surgery to improve skin symptoms. Results are typically good, but loose, lax skin often recurs.Individuals with ALDH18A1-related de Barsy syndrome who present with hyperammonemia and low arginine, ornithine and citrulline levels should be treated by drugs known as ammonia scavengers as well as supplementation with citrulline or arginine.Early developmental intervention is important to ensure that affected children reach their potential. Physiotherapy may be useful to help prevent contractures. Additional medical, social and/or vocational services including special remedial education may be necessary.Affected individuals should avoid environmental triggers that can worsen cutis laxa or associated symptoms. For example, sunbathing can damage the skin and should be avoided. | Therapies of De Barsy Syndrome. TreatmentThe treatment of de Barsy 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, surgeons, dermatologists, orthopedists, neurologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, 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 de Barsy syndrome.Specific therapies for individuals with cutis laxa can include surgery to repair skeletal problems, ocular abnormalities, or hernias. Some individuals elect for plastic (cosmetic) surgery to improve skin symptoms. Results are typically good, but loose, lax skin often recurs.Individuals with ALDH18A1-related de Barsy syndrome who present with hyperammonemia and low arginine, ornithine and citrulline levels should be treated by drugs known as ammonia scavengers as well as supplementation with citrulline or arginine.Early developmental intervention is important to ensure that affected children reach their potential. Physiotherapy may be useful to help prevent contractures. Additional medical, social and/or vocational services including special remedial education may be necessary.Affected individuals should avoid environmental triggers that can worsen cutis laxa or associated symptoms. For example, sunbathing can damage the skin and should be avoided. | 354 | De Barsy Syndrome |
nord_355_0 | Overview of De Sanctis Cacchione Syndrome | De Sanctis-Cacchione syndrome is an extremely rare disorder characterized by the skin and eye symptoms of xeroderma pigmentosum (XP) occurring in association with neurological abnormalities, mental retardation, unusually short stature (dwarfism), and underdevelopment of the testes or ovaries (hypogonadism). Xeroderma pigmentosum is a group of rare inherited skin disorders characterized by a heightened reaction to ultraviolet light (photosensitivity), skin discolorations, and the possible development of several types of eye disorders and skin cancers. The most common neurological abnormalities associated with De Sanctis- Cacchione syndrome are low intelligence, an abnormally small head (microcephaly), the loss of ability to coordinate voluntary movement (ataxia), and/or absent (areflexia) or weakened (hyporeflexia) reflexes. De Sanctis-Cacchione syndrome is inherited as an autosomal recessive trait. | Overview of De Sanctis Cacchione Syndrome. De Sanctis-Cacchione syndrome is an extremely rare disorder characterized by the skin and eye symptoms of xeroderma pigmentosum (XP) occurring in association with neurological abnormalities, mental retardation, unusually short stature (dwarfism), and underdevelopment of the testes or ovaries (hypogonadism). Xeroderma pigmentosum is a group of rare inherited skin disorders characterized by a heightened reaction to ultraviolet light (photosensitivity), skin discolorations, and the possible development of several types of eye disorders and skin cancers. The most common neurological abnormalities associated with De Sanctis- Cacchione syndrome are low intelligence, an abnormally small head (microcephaly), the loss of ability to coordinate voluntary movement (ataxia), and/or absent (areflexia) or weakened (hyporeflexia) reflexes. De Sanctis-Cacchione syndrome is inherited as an autosomal recessive trait. | 355 | De Sanctis Cacchione Syndrome |
nord_355_1 | Symptoms of De Sanctis Cacchione Syndrome | In De Sanctis-Cacchione syndrome, the earliest symptoms are the skin abnormalities associated with xeroderma pigmentosum (XP) including excessive freckling and blistering occurring after exposure to ultraviolet light (photosensitivity). In some cases, pain and blistering may occur immediately after contact with sunlight. Acute sunburn and persistent redness or inflammation of the skin (erythema) are also early symptoms of De Sanctis-Cacchione syndrome. In most cases of XP, these symptoms may be apparent immediately after birth or by the age of three years. However, in some rare cases, symptoms may not be apparent until later in childhood. In most cases of De Sanctis-Cacchione syndrome, onset is often during infancy. Additional skin symptoms often associated with De Sanctis-Cacchione syndrome include unusually dark (hyperpigmentation) or light (hypopigmentation) areas of skin. In some cases, complete loss of skin color (depigmentation) and/or excessive scarring may occur. Wart-like lesions (actinic keratoses) may develop, as well as small red skin lesions (telangiectasias) that are caused by abnormal widening of tiny blood vessels near the surface of the skin. The skin may also become weak and easily damaged. Degenerative (atrophic) changes may occur and the skin may appear dry and smooth. Most children with De Sanctis-Cacchione syndrome usually have one or more neurological abnormalities; the most frequent is low intelligence. Other abnormalities may include an unusually small head (microcephaly); hearing impairment (sensorineural deafness); absent (areflexia) or weakened (hyporeflexia) reflexes; and/or increased rigidity in some muscles causing stiffness and limitation of movement (spasticity). Affected individuals may also exhibit loss of the ability to coordinate voluntary movements (ataxia) and/or abnormal involuntary movements of the body such as uncontrolled jerky movements combined with slow, writhing movements (choreoathetosis). De Sanctis-Cacchione syndrome is occasionally associated with slow progressive degeneration of part of the brain known as the cerebellum (cerebellar atropy) and/or any of a group of progressive disorders involving degeneration of other parts of the brain (i.e., cortex, basis pontis, and inferior olivary nuclei). This clinical picture is similar to that seen in the hereditary olivopontocerebellar atrophies. Symptoms may include impaired muscle coordination (ataxia), tremors, involuntary movements, and speech disturbances (dysarthria). (For more information on this disorder, choose “Hereditary Olivopontocerebellar Atrophy” as your search term in the Rare Disease Database.) Individuals with De Sanctis-Cacchione syndrome will also exhibit unusually slow development, profound growth delays resulting in short stature (dwarfism), mental retardation, and/or inadequate function of the testes or ovaries (hypogonadism). Benign skin tumors may be associated with De Sanctis-Cacchione syndrome, with onset possible before the age of five. These may include tumors that are pre-malignant or benign (non-cancerous), such as tumors made up of blood vessels (angiomas) and/or rapidly growing tumors often occurring on sun-exposed areas of the skin.Individuals with De Sanctis-Cacchione syndrome may experience an early onset of skin cancer. For example, skin cancers such as malignant melanoma, basal cell carcinoma, and squamous cell carcinoma often occur in individuals with this disorder; the most commonly affected areas are the head, neck, and face. (For more information on these disorders, see the Related Disorders section of this report.) In De Sanctis-Cacchione syndrome, some of the eye symptoms associated with XP may be present. These may include an extreme intolerance to light (photophobia); inflammation of the corneas of the eyes (keratitis); inflammation of the membrane that covers the white portion of the eyes (conjunctivitis); outward facing of the eyelids (ectropion); and/or inward facing of the eyelids (entropion). The severity of symptoms related to the skin and eyes may depend on the amount of exposure to ultraviolet light. | Symptoms of De Sanctis Cacchione Syndrome. In De Sanctis-Cacchione syndrome, the earliest symptoms are the skin abnormalities associated with xeroderma pigmentosum (XP) including excessive freckling and blistering occurring after exposure to ultraviolet light (photosensitivity). In some cases, pain and blistering may occur immediately after contact with sunlight. Acute sunburn and persistent redness or inflammation of the skin (erythema) are also early symptoms of De Sanctis-Cacchione syndrome. In most cases of XP, these symptoms may be apparent immediately after birth or by the age of three years. However, in some rare cases, symptoms may not be apparent until later in childhood. In most cases of De Sanctis-Cacchione syndrome, onset is often during infancy. Additional skin symptoms often associated with De Sanctis-Cacchione syndrome include unusually dark (hyperpigmentation) or light (hypopigmentation) areas of skin. In some cases, complete loss of skin color (depigmentation) and/or excessive scarring may occur. Wart-like lesions (actinic keratoses) may develop, as well as small red skin lesions (telangiectasias) that are caused by abnormal widening of tiny blood vessels near the surface of the skin. The skin may also become weak and easily damaged. Degenerative (atrophic) changes may occur and the skin may appear dry and smooth. Most children with De Sanctis-Cacchione syndrome usually have one or more neurological abnormalities; the most frequent is low intelligence. Other abnormalities may include an unusually small head (microcephaly); hearing impairment (sensorineural deafness); absent (areflexia) or weakened (hyporeflexia) reflexes; and/or increased rigidity in some muscles causing stiffness and limitation of movement (spasticity). Affected individuals may also exhibit loss of the ability to coordinate voluntary movements (ataxia) and/or abnormal involuntary movements of the body such as uncontrolled jerky movements combined with slow, writhing movements (choreoathetosis). De Sanctis-Cacchione syndrome is occasionally associated with slow progressive degeneration of part of the brain known as the cerebellum (cerebellar atropy) and/or any of a group of progressive disorders involving degeneration of other parts of the brain (i.e., cortex, basis pontis, and inferior olivary nuclei). This clinical picture is similar to that seen in the hereditary olivopontocerebellar atrophies. Symptoms may include impaired muscle coordination (ataxia), tremors, involuntary movements, and speech disturbances (dysarthria). (For more information on this disorder, choose “Hereditary Olivopontocerebellar Atrophy” as your search term in the Rare Disease Database.) Individuals with De Sanctis-Cacchione syndrome will also exhibit unusually slow development, profound growth delays resulting in short stature (dwarfism), mental retardation, and/or inadequate function of the testes or ovaries (hypogonadism). Benign skin tumors may be associated with De Sanctis-Cacchione syndrome, with onset possible before the age of five. These may include tumors that are pre-malignant or benign (non-cancerous), such as tumors made up of blood vessels (angiomas) and/or rapidly growing tumors often occurring on sun-exposed areas of the skin.Individuals with De Sanctis-Cacchione syndrome may experience an early onset of skin cancer. For example, skin cancers such as malignant melanoma, basal cell carcinoma, and squamous cell carcinoma often occur in individuals with this disorder; the most commonly affected areas are the head, neck, and face. (For more information on these disorders, see the Related Disorders section of this report.) In De Sanctis-Cacchione syndrome, some of the eye symptoms associated with XP may be present. These may include an extreme intolerance to light (photophobia); inflammation of the corneas of the eyes (keratitis); inflammation of the membrane that covers the white portion of the eyes (conjunctivitis); outward facing of the eyelids (ectropion); and/or inward facing of the eyelids (entropion). The severity of symptoms related to the skin and eyes may depend on the amount of exposure to ultraviolet light. | 355 | De Sanctis Cacchione Syndrome |
nord_355_2 | Causes of De Sanctis Cacchione Syndrome | The symptoms of De Sanctis-Cacchione syndrome occur because of the body's inability to repair damage to the building blocks of genes (DNA). The damage is caused by exposure to ultraviolet light, such as rays of the sun. Everyone has certain connective tissue cells (fibroblasts) that have the ability to repair this damage through a complex process. However, the fibroblasts in people affected by De Sanctis-Cacchione syndrome lack the ability or have a reduced capacity to repair their DNA. In addition, some affected individuals' cells cannot properly repair sunlight-damaged skin. Several forms (subdivisions) of XP have been identified, based on the capacity of the body to repair sunlight-damaged DNA. Any of the subdivisions of XP may occur in De Sanctis-Cacchione syndrome. However, the classic form of XP (xeroderma pigmentosum, stype A) or xeroderma pigmentosum, type D are most often found in association with De Sanctis-Cacchione syndrome. De Sanctis-Cacchione syndrome 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 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%. In approximately 30 percent of the documented cases, individuals affected by De Sanctis-Cacchione syndrome have had parents who were related by blood (consanguineous). 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.Investigators have determined that some cases of De Sanctis-Cacchione syndrome may be caused by disruption or changes (mutations) of a certain gene located on the long arm (q) of chromosome 10 (10q11). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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 10q11” refers to band 11 on the long arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome. | Causes of De Sanctis Cacchione Syndrome. The symptoms of De Sanctis-Cacchione syndrome occur because of the body's inability to repair damage to the building blocks of genes (DNA). The damage is caused by exposure to ultraviolet light, such as rays of the sun. Everyone has certain connective tissue cells (fibroblasts) that have the ability to repair this damage through a complex process. However, the fibroblasts in people affected by De Sanctis-Cacchione syndrome lack the ability or have a reduced capacity to repair their DNA. In addition, some affected individuals' cells cannot properly repair sunlight-damaged skin. Several forms (subdivisions) of XP have been identified, based on the capacity of the body to repair sunlight-damaged DNA. Any of the subdivisions of XP may occur in De Sanctis-Cacchione syndrome. However, the classic form of XP (xeroderma pigmentosum, stype A) or xeroderma pigmentosum, type D are most often found in association with De Sanctis-Cacchione syndrome. De Sanctis-Cacchione syndrome 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 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%. In approximately 30 percent of the documented cases, individuals affected by De Sanctis-Cacchione syndrome have had parents who were related by blood (consanguineous). 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.Investigators have determined that some cases of De Sanctis-Cacchione syndrome may be caused by disruption or changes (mutations) of a certain gene located on the long arm (q) of chromosome 10 (10q11). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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 10q11” refers to band 11 on the long arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome. | 355 | De Sanctis Cacchione Syndrome |
nord_355_3 | Affects of De Sanctis Cacchione Syndrome | De Sanctis-Cacchione syndrome is an extremely rare disorder that affects males and females in equal numbers. Although about 200 cases have been reported in Western medical literature, the exact number of cases of this disorder is not known. Onset of symptoms usually occurs during the first year of life, but in rare cases may appear during early or late childhood. Onset of some neurological symptoms may occur as late as five to 10 years of age or even in the second decade of life. De Sanctis-Cacchione syndrome was first described in the medical literature in 1932. | Affects of De Sanctis Cacchione Syndrome. De Sanctis-Cacchione syndrome is an extremely rare disorder that affects males and females in equal numbers. Although about 200 cases have been reported in Western medical literature, the exact number of cases of this disorder is not known. Onset of symptoms usually occurs during the first year of life, but in rare cases may appear during early or late childhood. Onset of some neurological symptoms may occur as late as five to 10 years of age or even in the second decade of life. De Sanctis-Cacchione syndrome was first described in the medical literature in 1932. | 355 | De Sanctis Cacchione Syndrome |
nord_355_4 | Related disorders of De Sanctis Cacchione Syndrome | Symptoms of the following disorders can be similar to those of De Sanctis-Cacchione syndrome. Comparisons may be useful for a differential diagnosis:Cockayne syndrome is a rare inherited disorder characterized by short stature; distinctive skin abnormalities; characteristic craniofacial malformations and a prematurely aged (progeric) appearance; eye abnormalities resulting in visual impairment; deafness; and/or mental retardation. In individuals with the disorder, eye abnormalities may include gradual deterioration of the nerves of the eyes (optic atrophy), progressive degeneration of the nerve-rich membrane lining the eyes (retinal degeneration), and/or abnormal clouding of the lenses of the eyes (cataracts). In addition, the skin may be abnormally sensitive to sunlight, resulting in scarring, a scaly rash, abnormal pigmentation, and degeneration (atrophy) of affected areas. Individuals with Cockayne syndrome may also have a prematurely aged appearance and characteristic facial abnormalities including a thin nose, sunken eyes, and/or a protruding lower jaw (prognathism). Affected individuals may also have additional physical abnormalities including unusually sparse hair and various skeletal malformations. Cockayne syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Cockayne” as your search term in the Rare Disease Database.)Pigmented xerodermoid is a condition characterized by a late onset of symptoms similar to those of xeroderma pigmentosum. These symptoms may include a heightened reaction to sunlight (photosensitivity); skin discolorations; small red skin lesions (telangiectasias); abnormalities of the eyes; and/or benign (non-cancerous) tumors (angiomas and keratoacanthomas). Affected individuals may experience early onset of some types of skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma, malignant melanoma). Individuals with pigmented xerodermoid can repair DNA damaged by ultraviolet light; however, the post repair process is defective. The cause of pigmented xerodermoid is unknown. However, some scientists believe it may be inherited as an autosomal recessive trait. The following disorders may be associated with De Sanctis-Cacchione syndrome as secondary characteristics. They are not necessary for a differential diagnosis: Malignant melanoma is a form of skin cancer that develops from the melanin cells of the upper layer of the skin (epidermis) or from similar cells that may be found in moles (nevi). In early stages most melanomas do not produce any specific symptoms. Later, they may appear as lesions that do not heal or as existing moles that show changes in size or color. This type of skin cancer eventually spreads to the lower skin levels and adjacent tissue and may result in new tumor growths in vital organs of the body. (For more information on this disorder, choose “Melanoma” as your search term in the Rare Disease Database.) Basal cell carcinomas are tumors that occur on the surface of the skin. They may appear as small, shiny, firm masses of tissues (nodules); flat, scar-like lesions (plaques); or red patches covered by thick, dry, silvery scales. If left untreated, basal cell carcinoma may spread (metastasize) to other parts of the body causing further disease. This type of skin cancer may be difficult to differentiate from psoriasis or localized dermatitis without a biopsy. Overexposure to sunlight or ionizing radiation may cause this type of skin cancer. Squamous cell carcinomas are tumors that usually appear on sun-exposed areas of the skin, but may occur anywhere on the body. This form of skin cancer is characterized by lesions that appear to have a scaly or crusted surface. These lesions may spread to underlying tissues; however, with appropriate treatment, Squamous cell carcinoma is usually curable. (For more information on this disorder, choose “Squamous Cell Carcinoma” as your search term in the Rare Disease Database.) | Related disorders of De Sanctis Cacchione Syndrome. Symptoms of the following disorders can be similar to those of De Sanctis-Cacchione syndrome. Comparisons may be useful for a differential diagnosis:Cockayne syndrome is a rare inherited disorder characterized by short stature; distinctive skin abnormalities; characteristic craniofacial malformations and a prematurely aged (progeric) appearance; eye abnormalities resulting in visual impairment; deafness; and/or mental retardation. In individuals with the disorder, eye abnormalities may include gradual deterioration of the nerves of the eyes (optic atrophy), progressive degeneration of the nerve-rich membrane lining the eyes (retinal degeneration), and/or abnormal clouding of the lenses of the eyes (cataracts). In addition, the skin may be abnormally sensitive to sunlight, resulting in scarring, a scaly rash, abnormal pigmentation, and degeneration (atrophy) of affected areas. Individuals with Cockayne syndrome may also have a prematurely aged appearance and characteristic facial abnormalities including a thin nose, sunken eyes, and/or a protruding lower jaw (prognathism). Affected individuals may also have additional physical abnormalities including unusually sparse hair and various skeletal malformations. Cockayne syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Cockayne” as your search term in the Rare Disease Database.)Pigmented xerodermoid is a condition characterized by a late onset of symptoms similar to those of xeroderma pigmentosum. These symptoms may include a heightened reaction to sunlight (photosensitivity); skin discolorations; small red skin lesions (telangiectasias); abnormalities of the eyes; and/or benign (non-cancerous) tumors (angiomas and keratoacanthomas). Affected individuals may experience early onset of some types of skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma, malignant melanoma). Individuals with pigmented xerodermoid can repair DNA damaged by ultraviolet light; however, the post repair process is defective. The cause of pigmented xerodermoid is unknown. However, some scientists believe it may be inherited as an autosomal recessive trait. The following disorders may be associated with De Sanctis-Cacchione syndrome as secondary characteristics. They are not necessary for a differential diagnosis: Malignant melanoma is a form of skin cancer that develops from the melanin cells of the upper layer of the skin (epidermis) or from similar cells that may be found in moles (nevi). In early stages most melanomas do not produce any specific symptoms. Later, they may appear as lesions that do not heal or as existing moles that show changes in size or color. This type of skin cancer eventually spreads to the lower skin levels and adjacent tissue and may result in new tumor growths in vital organs of the body. (For more information on this disorder, choose “Melanoma” as your search term in the Rare Disease Database.) Basal cell carcinomas are tumors that occur on the surface of the skin. They may appear as small, shiny, firm masses of tissues (nodules); flat, scar-like lesions (plaques); or red patches covered by thick, dry, silvery scales. If left untreated, basal cell carcinoma may spread (metastasize) to other parts of the body causing further disease. This type of skin cancer may be difficult to differentiate from psoriasis or localized dermatitis without a biopsy. Overexposure to sunlight or ionizing radiation may cause this type of skin cancer. Squamous cell carcinomas are tumors that usually appear on sun-exposed areas of the skin, but may occur anywhere on the body. This form of skin cancer is characterized by lesions that appear to have a scaly or crusted surface. These lesions may spread to underlying tissues; however, with appropriate treatment, Squamous cell carcinoma is usually curable. (For more information on this disorder, choose “Squamous Cell Carcinoma” as your search term in the Rare Disease Database.) | 355 | De Sanctis Cacchione Syndrome |
nord_355_5 | Diagnosis of De Sanctis Cacchione Syndrome | The diagnosis of De Sanctis-Cacchione syndrome may be confirmed when xeroderma pigmentosum is found to occur in association with one or more neurological abnormalities, mental retardation, dwarfism, and inadequate function of the testes or ovaries (hypogonadism).Before birth (prenatal) diagnosis of XP may be confirmed through the use of a special procedure called amniocentesis. During this procedure, a sample of the fluid that surrounds the fetus is removed and tests are conducted to determine whether the fetus has XP. This procedure is usually done as part of a screening process for families with a history of XP.A thorough clinical evaluation should be made to determine whether the other symptoms of De Sanctis-Cacchione syndrome are present (i.e., neurological abnormalities, mental retardation, dwarfism, and hypogonadism. This evaluation may include neuroimaging studies, such as magnetic resonance imaging (MRI) and computed tomography (CT) scans.Specialized laboratory tests may be used to confirm a diagnosis of De Sanctis-Cacchione syndrome. These tests can detect defective DNA repair in white blood cells (lymphocytes), liver cells, corneal cells, and skin cells taken from people affected by De Sanctis-Cacchione syndrome. During such tests, the cells are exposed to UV radiation and/or certain cancer producing substances (carcinogens). After exposure to these substances, the defective DNA repair process of these cells becomes apparent. | Diagnosis of De Sanctis Cacchione Syndrome. The diagnosis of De Sanctis-Cacchione syndrome may be confirmed when xeroderma pigmentosum is found to occur in association with one or more neurological abnormalities, mental retardation, dwarfism, and inadequate function of the testes or ovaries (hypogonadism).Before birth (prenatal) diagnosis of XP may be confirmed through the use of a special procedure called amniocentesis. During this procedure, a sample of the fluid that surrounds the fetus is removed and tests are conducted to determine whether the fetus has XP. This procedure is usually done as part of a screening process for families with a history of XP.A thorough clinical evaluation should be made to determine whether the other symptoms of De Sanctis-Cacchione syndrome are present (i.e., neurological abnormalities, mental retardation, dwarfism, and hypogonadism. This evaluation may include neuroimaging studies, such as magnetic resonance imaging (MRI) and computed tomography (CT) scans.Specialized laboratory tests may be used to confirm a diagnosis of De Sanctis-Cacchione syndrome. These tests can detect defective DNA repair in white blood cells (lymphocytes), liver cells, corneal cells, and skin cells taken from people affected by De Sanctis-Cacchione syndrome. During such tests, the cells are exposed to UV radiation and/or certain cancer producing substances (carcinogens). After exposure to these substances, the defective DNA repair process of these cells becomes apparent. | 355 | De Sanctis Cacchione Syndrome |
nord_355_6 | Therapies of De Sanctis Cacchione Syndrome | TreatmentIn individuals with De Sanctis-Cacchione syndrome total protection of the skin from sunlight (e.g., topical sunscreens, sunglasses, double layers of clothing) is necessary to prevent the development of skin lesions and other complications (e.g., skin cancers and some neurological symptoms). Affected individuals with De Sanctis-Cacchione Syndrome must limit outdoor activities during daylight hours to avoid exposure to ultraviolet light. Avoidance of chemical carcinogens, such as those in cigarette smoke, is also recommended.For individuals who have skin cancer, early detection and surgical removal of the lesions is essential. Regular examinations of the skin and eyes by specialists is recommended. Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of De Sanctis Cacchione Syndrome. TreatmentIn individuals with De Sanctis-Cacchione syndrome total protection of the skin from sunlight (e.g., topical sunscreens, sunglasses, double layers of clothing) is necessary to prevent the development of skin lesions and other complications (e.g., skin cancers and some neurological symptoms). Affected individuals with De Sanctis-Cacchione Syndrome must limit outdoor activities during daylight hours to avoid exposure to ultraviolet light. Avoidance of chemical carcinogens, such as those in cigarette smoke, is also recommended.For individuals who have skin cancer, early detection and surgical removal of the lesions is essential. Regular examinations of the skin and eyes by specialists is recommended. Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 355 | De Sanctis Cacchione Syndrome |
nord_356_0 | Overview of Degos Disease | Degos disease is an extremely rare disorder, with only about 200 reported cases worldwide. In affected individuals, arteries of smaller diameter become blocked (occlusive arteriopathy), subsequently restricting the flow of blood to affected areas. Degos disease usually presents with characteristic skin lesions (porcelain-white macules) that may persist for several weeks or even years. Degos disease can occur at any age, with onset of symptoms typically between the age of 20 and 50. In most individuals, the symptoms of Degos disease are limited to the skin, termed benign cutaneous Degos disease. This form of the disease has an excellent prognosis.Other individuals will develop additional symptoms that affect multiple organ systems, in which the disease is then termed systemic Degos disease. Systemic Degos disease can develop suddenly or several years following the development of the benign cutaneous type. Degos disease has a potentially life-threatening prognosis: a 50% risk of death within 2-3 years of symptom emergence. In addition to dermal atrophy, systemic Degos disease is most frequently characterized by lesions in the small intestine, and, less often, other portions of the gastrointestinal tract. Some of these lesions may ultimately perforate. Major symptoms prior to perforation include abdominal pain, diarrhea and/or weight loss. This systemic form of Degos disease can lead to other disabling and potentially life-threatening complications if the central nervous system, heart, or lung are involved.Researchers caution that statistics concerning Degos disease may be inaccurate. Because of its rarity, many affected individuals go undiagnosed. Furthermore, medical reports disproportionately discuss the more serious, systemic form of the disease. It is important to note that about two-thirds of all patients only develop non-life-threatening skin lesions. In addition, recent advances in drug therapy have dramatically improved the potential for recovery of even those severely afflicted by the systemic form of the disease. Most cases reported in the literature were published when no effective treatment option was available. Affected individuals should talk to their physicians and medical team about their specific case and associated symptoms. | Overview of Degos Disease. Degos disease is an extremely rare disorder, with only about 200 reported cases worldwide. In affected individuals, arteries of smaller diameter become blocked (occlusive arteriopathy), subsequently restricting the flow of blood to affected areas. Degos disease usually presents with characteristic skin lesions (porcelain-white macules) that may persist for several weeks or even years. Degos disease can occur at any age, with onset of symptoms typically between the age of 20 and 50. In most individuals, the symptoms of Degos disease are limited to the skin, termed benign cutaneous Degos disease. This form of the disease has an excellent prognosis.Other individuals will develop additional symptoms that affect multiple organ systems, in which the disease is then termed systemic Degos disease. Systemic Degos disease can develop suddenly or several years following the development of the benign cutaneous type. Degos disease has a potentially life-threatening prognosis: a 50% risk of death within 2-3 years of symptom emergence. In addition to dermal atrophy, systemic Degos disease is most frequently characterized by lesions in the small intestine, and, less often, other portions of the gastrointestinal tract. Some of these lesions may ultimately perforate. Major symptoms prior to perforation include abdominal pain, diarrhea and/or weight loss. This systemic form of Degos disease can lead to other disabling and potentially life-threatening complications if the central nervous system, heart, or lung are involved.Researchers caution that statistics concerning Degos disease may be inaccurate. Because of its rarity, many affected individuals go undiagnosed. Furthermore, medical reports disproportionately discuss the more serious, systemic form of the disease. It is important to note that about two-thirds of all patients only develop non-life-threatening skin lesions. In addition, recent advances in drug therapy have dramatically improved the potential for recovery of even those severely afflicted by the systemic form of the disease. Most cases reported in the literature were published when no effective treatment option was available. Affected individuals should talk to their physicians and medical team about their specific case and associated symptoms. | 356 | Degos Disease |
nord_356_1 | Symptoms of Degos Disease | In most people, the initial sign of Degos disease is the development of skin lesions which evolve to a very distinct appearance (see below). Affected individuals develop small, elevated bumps or spots (papules) of varying shapes, typically appearing on the trunk, upper arms and upper legs. At onset, only a few lesions may be present, but over time, the skin often continues to develop lesions, so that ultimately hundreds may appear. The palms of the hands, soles of the feet and face are usually not affected so that lesions may not be apparent to others. Over a period of weeks to months, the lesions typically transition from reddish or pink bumps to flat or depressed porcelain-white lesions with a red rim.In some people, blood vessels of other organ systems are also affected (systemic Degos disease), resulting in serious and potentially life-threatening complications. Individuals who develop systemic Degos disease will not necessarily (and usually does not) develop all the symptoms discussed below.The most common internal organ affected by systemic Degos disease is the gastrointestinal (GI) tract. Gastrointestinal involvement may present anywhere from a few weeks to a few years after the skin lesions develop. In extremely rare cases, gastrointestinal involvement may precede the development of skin lesions.Due to the occlusion (blockage) of blood vessels and restricted blood flow present in Degos disease, lesions can form in the small intestines, resulting in abdominal pain, cramping, nausea, vomiting, diarrhea, bloating, constipation, internal bleeding (hemorrhage) and the passing of blood with bowel movements or vomiting blood. Some affected individuals may experience weakness, fatigue and weight loss from malabsorption of nutrients in the small intestine. The intestinal lesions can tear or rupture (perforate), causing the contents of the intestines to leak into the abdominal cavity (intestinal fistula). This results in inflammation of the membranes lining the abdominal cavity (peritonitis), which is a life-threatening complication and the most common cause of death in Degos patients.Some individuals with systemic Degos disease experience involvement of the central nervous system (CNS). Symptoms of CNS involvement vary depending upon the specific areas affected but may include headaches, dizziness (vertigo), seizures, paralysis (palsy) of cranial nerves, weakness of one side of the body (hemiparesis), ischemic strokes and damage to small areas of cells in the brain due to blocked arteries (cerebral infarcts). Nonspecific neurological symptoms such as memory loss, difficulty communicating (aphasia), pain insensitivity and altered sensations may also occur. CNS involvement Degos disease nearly always indicates severe disease and poor prognosis.In rare cases, additional organ systems that may become involved include the eyes, heart, lungs and bladder. When the eyes are affected, individuals may develop double vision (diplopia), drooping of the eyelids (ptosis), clouding of the lenses of the eyes (cataracts), atrophy of the optic nerve, swelling of the optic nerve (papilledema), partial loss of the field of vision (visual-field defects) and blindness caused by lack of blood flow to the eyes (amaurosis fugax).When the heart is affected, individuals may develop weakness, shortness of breath upon exertion and chest pain. In some cases, inflammation of the sac-like membrane surrounding the heart (pericardium) may occur. This may develop into permanent thickening, resulting in scarring and contracture of the pericardium (constrictive pericarditis).Inflammation of the membranes lining the lungs (pleuritis) and fluid collection around the lungs (pleural effusion) has also been reported. Respiratory failure can eventually occur. | Symptoms of Degos Disease. In most people, the initial sign of Degos disease is the development of skin lesions which evolve to a very distinct appearance (see below). Affected individuals develop small, elevated bumps or spots (papules) of varying shapes, typically appearing on the trunk, upper arms and upper legs. At onset, only a few lesions may be present, but over time, the skin often continues to develop lesions, so that ultimately hundreds may appear. The palms of the hands, soles of the feet and face are usually not affected so that lesions may not be apparent to others. Over a period of weeks to months, the lesions typically transition from reddish or pink bumps to flat or depressed porcelain-white lesions with a red rim.In some people, blood vessels of other organ systems are also affected (systemic Degos disease), resulting in serious and potentially life-threatening complications. Individuals who develop systemic Degos disease will not necessarily (and usually does not) develop all the symptoms discussed below.The most common internal organ affected by systemic Degos disease is the gastrointestinal (GI) tract. Gastrointestinal involvement may present anywhere from a few weeks to a few years after the skin lesions develop. In extremely rare cases, gastrointestinal involvement may precede the development of skin lesions.Due to the occlusion (blockage) of blood vessels and restricted blood flow present in Degos disease, lesions can form in the small intestines, resulting in abdominal pain, cramping, nausea, vomiting, diarrhea, bloating, constipation, internal bleeding (hemorrhage) and the passing of blood with bowel movements or vomiting blood. Some affected individuals may experience weakness, fatigue and weight loss from malabsorption of nutrients in the small intestine. The intestinal lesions can tear or rupture (perforate), causing the contents of the intestines to leak into the abdominal cavity (intestinal fistula). This results in inflammation of the membranes lining the abdominal cavity (peritonitis), which is a life-threatening complication and the most common cause of death in Degos patients.Some individuals with systemic Degos disease experience involvement of the central nervous system (CNS). Symptoms of CNS involvement vary depending upon the specific areas affected but may include headaches, dizziness (vertigo), seizures, paralysis (palsy) of cranial nerves, weakness of one side of the body (hemiparesis), ischemic strokes and damage to small areas of cells in the brain due to blocked arteries (cerebral infarcts). Nonspecific neurological symptoms such as memory loss, difficulty communicating (aphasia), pain insensitivity and altered sensations may also occur. CNS involvement Degos disease nearly always indicates severe disease and poor prognosis.In rare cases, additional organ systems that may become involved include the eyes, heart, lungs and bladder. When the eyes are affected, individuals may develop double vision (diplopia), drooping of the eyelids (ptosis), clouding of the lenses of the eyes (cataracts), atrophy of the optic nerve, swelling of the optic nerve (papilledema), partial loss of the field of vision (visual-field defects) and blindness caused by lack of blood flow to the eyes (amaurosis fugax).When the heart is affected, individuals may develop weakness, shortness of breath upon exertion and chest pain. In some cases, inflammation of the sac-like membrane surrounding the heart (pericardium) may occur. This may develop into permanent thickening, resulting in scarring and contracture of the pericardium (constrictive pericarditis).Inflammation of the membranes lining the lungs (pleuritis) and fluid collection around the lungs (pleural effusion) has also been reported. Respiratory failure can eventually occur. | 356 | Degos Disease |
nord_356_2 | Causes of Degos Disease | Degos disease is caused by multiplication of the cells lining small arteries, resulting in the narrowing or blocking of affected vessels termed arterial occlusion. Areas of severely damaged tissue (necrosis) may appear in locations where these affected arteries restrict blood flow, known as occlusive arteriopathy. The symptoms and severity of Degos disease depend upon the location of the blocked arteries and necrotic lesions (characterized by cell death in tissues).The underlying cause of this cellular multiplication remains unknown, though many theories have been proposed. These possibilities include viral infection, vasculitis (inflammation of the blood vessels), abnormal blood clotting (coagulopathy or a primary disorder of endothelial cells that line the blood vessels) or autoimmunity (whereby the body’s immune system mistakenly attacks healthy tissue).Some cases of Degos disease are believed to be genetic and inherited and follow an autosomal dominant inheritance pattern. Other cases lack any perceived genetic cause. Interestingly, cases of Degos disease with a genetic component are usually limited to the skin (benign cutaneous Degos disease), thus typically giving a better prognosis. In one case a specific variant in a gene was identified which resulted in over-activity of the interferon receptor at cell surfaces.The work of Dr. Cynthia Mago has provided evidence that Degos disease is, at least in part, a C5b-9 / interferon-ɑ- mediated endothelial disease. Both C5b-9 and interferon-ɑ (IFN-ɑ) were found to have extensive expression in affected cutaneous (skin) tissues. Affected individuals have excessive deposits of C5b-9, the membranolytic attack complex, which can result in cell death in areas of attachment of the complex. IFN-ɑ is an innate immune cytokine that manages viral replication rate and shapes immunological responses in the downstream C5b-9 response. It may be an important mechanism in fibrotic changes which can lead to occlusion of small blood vessels.Further research is required to determine the true underlying cause of the disease. | Causes of Degos Disease. Degos disease is caused by multiplication of the cells lining small arteries, resulting in the narrowing or blocking of affected vessels termed arterial occlusion. Areas of severely damaged tissue (necrosis) may appear in locations where these affected arteries restrict blood flow, known as occlusive arteriopathy. The symptoms and severity of Degos disease depend upon the location of the blocked arteries and necrotic lesions (characterized by cell death in tissues).The underlying cause of this cellular multiplication remains unknown, though many theories have been proposed. These possibilities include viral infection, vasculitis (inflammation of the blood vessels), abnormal blood clotting (coagulopathy or a primary disorder of endothelial cells that line the blood vessels) or autoimmunity (whereby the body’s immune system mistakenly attacks healthy tissue).Some cases of Degos disease are believed to be genetic and inherited and follow an autosomal dominant inheritance pattern. Other cases lack any perceived genetic cause. Interestingly, cases of Degos disease with a genetic component are usually limited to the skin (benign cutaneous Degos disease), thus typically giving a better prognosis. In one case a specific variant in a gene was identified which resulted in over-activity of the interferon receptor at cell surfaces.The work of Dr. Cynthia Mago has provided evidence that Degos disease is, at least in part, a C5b-9 / interferon-ɑ- mediated endothelial disease. Both C5b-9 and interferon-ɑ (IFN-ɑ) were found to have extensive expression in affected cutaneous (skin) tissues. Affected individuals have excessive deposits of C5b-9, the membranolytic attack complex, which can result in cell death in areas of attachment of the complex. IFN-ɑ is an innate immune cytokine that manages viral replication rate and shapes immunological responses in the downstream C5b-9 response. It may be an important mechanism in fibrotic changes which can lead to occlusion of small blood vessels.Further research is required to determine the true underlying cause of the disease. | 356 | Degos Disease |
nord_356_3 | Affects of Degos Disease | Since its recognition as a distinct clinical entity by Dr. Degos in 1942, well more than 200 cases of Degos disease have been reported in the medical literature; however, the exact incidence of the disorder is unknown. Many researchers believe that Degos disease is under-diagnosed, making it difficult to determine its true frequency in the general population. Degos disease can affect individuals of any age, with one case reporting an onset as early as 8 months old; however, symptoms most frequently appear between the ages of 20-50. Males have been affected more often than females, with a male predominance of 3:1. One study found that females developed the benign cutaneous form of Degos disease more often than males. | Affects of Degos Disease. Since its recognition as a distinct clinical entity by Dr. Degos in 1942, well more than 200 cases of Degos disease have been reported in the medical literature; however, the exact incidence of the disorder is unknown. Many researchers believe that Degos disease is under-diagnosed, making it difficult to determine its true frequency in the general population. Degos disease can affect individuals of any age, with one case reporting an onset as early as 8 months old; however, symptoms most frequently appear between the ages of 20-50. Males have been affected more often than females, with a male predominance of 3:1. One study found that females developed the benign cutaneous form of Degos disease more often than males. | 356 | Degos Disease |
nord_356_4 | Related disorders of Degos Disease | Related disorders of Degos Disease. | 356 | Degos Disease |
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nord_356_5 | Diagnosis of Degos Disease | Identification of the characteristic skin lesions is typically the first step in the diagnosis of Degos disease. Mature lesions have white centers and pink/red borders due to dilated blood vessels, and are primarily located on the chest, back and upper extremities. Biopsy of affected tissue reveals necrosis (tissue cell death due to lack of blood supply) and blockage of small arterioles. This microscopic examination of affected skin tissue reveals a wedge-shaped area of necrotic tissue, a distinctive change that is characteristic of Degos disease. No specific laboratory test can be used to aid in the diagnosis of Degos disease. Most lab tests return normal results, though anemia may manifest in certain individuals with the systemic form of the disease. Imaging (i.e., MRI, EEG, and EMG) may be used to identify affected areas of the brain and body with systemic Degos disease. Gastrointestinal lesions of Degos, when present, involve the outer (serosal) surface of the bowel, especially the small bowel. As with skin lesions, bowel lesions have a highly characteristic appearance and are best visualized by performance of laparoscopy (endoscopy and colonoscopy are much less sensitive methods to detect these lesions). | Diagnosis of Degos Disease. Identification of the characteristic skin lesions is typically the first step in the diagnosis of Degos disease. Mature lesions have white centers and pink/red borders due to dilated blood vessels, and are primarily located on the chest, back and upper extremities. Biopsy of affected tissue reveals necrosis (tissue cell death due to lack of blood supply) and blockage of small arterioles. This microscopic examination of affected skin tissue reveals a wedge-shaped area of necrotic tissue, a distinctive change that is characteristic of Degos disease. No specific laboratory test can be used to aid in the diagnosis of Degos disease. Most lab tests return normal results, though anemia may manifest in certain individuals with the systemic form of the disease. Imaging (i.e., MRI, EEG, and EMG) may be used to identify affected areas of the brain and body with systemic Degos disease. Gastrointestinal lesions of Degos, when present, involve the outer (serosal) surface of the bowel, especially the small bowel. As with skin lesions, bowel lesions have a highly characteristic appearance and are best visualized by performance of laparoscopy (endoscopy and colonoscopy are much less sensitive methods to detect these lesions). | 356 | Degos Disease |
nord_356_6 | Therapies of Degos Disease | TreatmentDegos Disease should be suspected in any individual with the highly typical skin lesions and diagnosis should be confirmed by skin biopsy and review of the slides by an experienced dermatopathologist. The diagnosis by itself may provoke a great deal of anxiety. This is best addressed by rapid evaluation to exclude evidence of systemic disease. If evidence of systemic disease is detected, evaluation by an expert in Degos Disease is advised as treatment for systemic disease is in a rapid state of evolution. But we are well past the circumstance, described in so many papers in the literature, when diagnosis of systemic disease meant no effective intervention existed.Many articles in medical literature suggest that anti-platelet therapy is warranted even in those with skin-only disease. Evidence of the benefit of this therapy is sparse. All individuals with skin-only disease should be educated as to signs that could signal development of systemic disease. Baseline laparoscopy is the most effective means of establishing or ruling out the presence of gastrointestinal Degos. There are currently no guidelines as to how often this should be repeated in subsequent years, but it certainly should be considered whenever persistent new gastrointestinal symptoms develop. Baseline chest x-ray, echocardiogram, EKG, ophthalmologic examination and brain MRI are also recommended.The use of inhibitors of activation of C5, a complement component, has been lifesaving in multiple individuals with gastrointestinal Degos. Due to the extreme rarity of the disease, no double-blind placebo-controlled study of this therapy has been performed. However, when outcomes are compared to historical “controls”, the many articles in which death is the only outcome of those with gastrointestinal Degos, the change is remarkable (Sattler et al, 2022). The addition of treprostinil, a prostacyclin analogue, has been reported to provide more prolonged effect as compared to use of complement inhibition alone (Shapiro et al). Currently, anti-inteferon therapy is under study for those with Degos involving the central nervous system.All too often individuals with systemic Degos are diagnosed only after catastrophic complications have occurred. Treatment always requires recognition of the disease, and the earlier recognition occurs, the more effective treatment interventions are likely to be in preventing irreversible organ damage or death.Unfortunately, the approaches mentioned above involve the “off-label” use of the medications described. This means they have not been approved by the U.S. Food and Drug Administration (FDA) specifically to treat Degos disease. These agents may be difficult or impossible to access. Delay involved in obtaining approval for drug administration can only negatively impact treatment outcomes. Intensive advocacy is often necessary. Every effort is being made to publish reports of drug efficacy in the medical literature so that access can become easier.Some researchers have advocated for the use of intravenous immunoglobulin (IVIG) as a treatment for affected individuals. IVIG is a treatment technique in which plasma proteins from blood donors are administered via a drip directly into the patient’s bloodstream. This method can be used to treat autoimmune, infectious and idiopathic diseases. More research is necessary to determine the long-term safety and efficacy of such therapies in individuals with Degos disease, as results of this attempted treatment have been inconsistent. | Therapies of Degos Disease. TreatmentDegos Disease should be suspected in any individual with the highly typical skin lesions and diagnosis should be confirmed by skin biopsy and review of the slides by an experienced dermatopathologist. The diagnosis by itself may provoke a great deal of anxiety. This is best addressed by rapid evaluation to exclude evidence of systemic disease. If evidence of systemic disease is detected, evaluation by an expert in Degos Disease is advised as treatment for systemic disease is in a rapid state of evolution. But we are well past the circumstance, described in so many papers in the literature, when diagnosis of systemic disease meant no effective intervention existed.Many articles in medical literature suggest that anti-platelet therapy is warranted even in those with skin-only disease. Evidence of the benefit of this therapy is sparse. All individuals with skin-only disease should be educated as to signs that could signal development of systemic disease. Baseline laparoscopy is the most effective means of establishing or ruling out the presence of gastrointestinal Degos. There are currently no guidelines as to how often this should be repeated in subsequent years, but it certainly should be considered whenever persistent new gastrointestinal symptoms develop. Baseline chest x-ray, echocardiogram, EKG, ophthalmologic examination and brain MRI are also recommended.The use of inhibitors of activation of C5, a complement component, has been lifesaving in multiple individuals with gastrointestinal Degos. Due to the extreme rarity of the disease, no double-blind placebo-controlled study of this therapy has been performed. However, when outcomes are compared to historical “controls”, the many articles in which death is the only outcome of those with gastrointestinal Degos, the change is remarkable (Sattler et al, 2022). The addition of treprostinil, a prostacyclin analogue, has been reported to provide more prolonged effect as compared to use of complement inhibition alone (Shapiro et al). Currently, anti-inteferon therapy is under study for those with Degos involving the central nervous system.All too often individuals with systemic Degos are diagnosed only after catastrophic complications have occurred. Treatment always requires recognition of the disease, and the earlier recognition occurs, the more effective treatment interventions are likely to be in preventing irreversible organ damage or death.Unfortunately, the approaches mentioned above involve the “off-label” use of the medications described. This means they have not been approved by the U.S. Food and Drug Administration (FDA) specifically to treat Degos disease. These agents may be difficult or impossible to access. Delay involved in obtaining approval for drug administration can only negatively impact treatment outcomes. Intensive advocacy is often necessary. Every effort is being made to publish reports of drug efficacy in the medical literature so that access can become easier.Some researchers have advocated for the use of intravenous immunoglobulin (IVIG) as a treatment for affected individuals. IVIG is a treatment technique in which plasma proteins from blood donors are administered via a drip directly into the patient’s bloodstream. This method can be used to treat autoimmune, infectious and idiopathic diseases. More research is necessary to determine the long-term safety and efficacy of such therapies in individuals with Degos disease, as results of this attempted treatment have been inconsistent. | 356 | Degos Disease |
nord_357_0 | Overview of Dejerine-Sottas Syndrome | SummaryDejerine-Sottas syndrome (DSS) is an inherited neurological condition that gradually affects the ability to move. Peripheral nerves are the nerves outside of the brain and spinal cord. These nerves become enlarged or thickened leading to muscle weakness. The condition may progress irregularly and can often be accompanied by pain, weakness, numbness, and a tingling, prickling or burning sensation in the legs. DSS can result in the inability to walk but is not thought to shorten lifespan. This condition does not impact brain function.IntroductionDSS is a historical name for a type of Charcot-Marie-Tooth disease (CMT3). This terminology was used to describe patients with an early onset form of CMT with a marked breakdown (demyelination) of the protective sheath around the long nerves, exposing and endangering the nerves. The availability of genetic testing has resulted in most types of CMT being renamed based on associations with specific genes, but Dejerine-Sottas syndrome is still sometimes used to describe the condition. DSS has also been described as a type of hereditary motor sensory neuropathy (HMSN3) which are rare genetic nerve disorders that impact movement. | Overview of Dejerine-Sottas Syndrome. SummaryDejerine-Sottas syndrome (DSS) is an inherited neurological condition that gradually affects the ability to move. Peripheral nerves are the nerves outside of the brain and spinal cord. These nerves become enlarged or thickened leading to muscle weakness. The condition may progress irregularly and can often be accompanied by pain, weakness, numbness, and a tingling, prickling or burning sensation in the legs. DSS can result in the inability to walk but is not thought to shorten lifespan. This condition does not impact brain function.IntroductionDSS is a historical name for a type of Charcot-Marie-Tooth disease (CMT3). This terminology was used to describe patients with an early onset form of CMT with a marked breakdown (demyelination) of the protective sheath around the long nerves, exposing and endangering the nerves. The availability of genetic testing has resulted in most types of CMT being renamed based on associations with specific genes, but Dejerine-Sottas syndrome is still sometimes used to describe the condition. DSS has also been described as a type of hereditary motor sensory neuropathy (HMSN3) which are rare genetic nerve disorders that impact movement. | 357 | Dejerine-Sottas Syndrome |
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