id
stringlengths 8
11
| title
stringlengths 14
124
| content
stringlengths 0
34k
| contents
stringlengths 20
34k
| nordid
int64 0
1.32k
| rare-disease
stringlengths 4
103
|
|---|---|---|---|---|---|
nord_100_0 | Overview of Argininosuccinic Aciduria | SummaryArgininosuccinic aciduria is a rare genetic disorder characterized by deficiency or lack of the enzyme argininosuccinate lyase (ASL). This enzyme is one of six enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of this argininosuccinate lyase results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Ammonia is a neurotoxin, which means that it damages or inhibits the function of neurons, the cells of the central nervous system. Excess ammonia travels to the central nervous system through the blood, resulting in the symptoms and physical findings associated with the disorder. Affected infants may experience vomiting, refusal to eat, progressive lethargy and coma. Argininosuccinic aciduria is inherited in an autosomal recessive pattern. Symptoms unrelated to high ammonia may occur in some patients because of additional roles of this enzyme in the body.IntroductionUrea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood. | Overview of Argininosuccinic Aciduria. SummaryArgininosuccinic aciduria is a rare genetic disorder characterized by deficiency or lack of the enzyme argininosuccinate lyase (ASL). This enzyme is one of six enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of this argininosuccinate lyase results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Ammonia is a neurotoxin, which means that it damages or inhibits the function of neurons, the cells of the central nervous system. Excess ammonia travels to the central nervous system through the blood, resulting in the symptoms and physical findings associated with the disorder. Affected infants may experience vomiting, refusal to eat, progressive lethargy and coma. Argininosuccinic aciduria is inherited in an autosomal recessive pattern. Symptoms unrelated to high ammonia may occur in some patients because of additional roles of this enzyme in the body.IntroductionUrea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood. | 100 | Argininosuccinic Aciduria |
nord_100_1 | Symptoms of Argininosuccinic Aciduria | The severity and specific symptoms of argininosuccinic aciduria varies from one person to another. A severe form of the disorder, which is characterized by a complete or near complete lack of the ASL enzyme, occurs shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the ASL enzyme, affects some individuals later during infancy or childhood or even adulthood (late-onset form).Symptoms are caused by the accumulation of ammonia in the blood. The severe form occurs within 24-72 hours after birth, usually following a protein feeding. This form is initially characterized by a refusal to eat, lethargy, lack of appetite, vomiting and irritability. Affected infants may also experience seizures, breathing (respiratory) abnormalities, accumulation of fluid in the brain (cerebral edema) and an abnormally large liver (hepatomegaly). Less commonly, some individuals develop progressive liver disease and dysfunction such as the buildup of scar tissue (fibrosis) and cirrhosis. In rare instances, chronic kidney (renal) disease has been reported. Abnormally rapid breathing (tachypnea) may be detected and sometimes is the first sign recognized of elevated ammonia in the blood. As affected individuals grow older, they may have coarse and brittle (friable) hair that breaks off easily and can leave patches of hair loss, a condition known as trichorrhexis nodosa.In some patients, due to high levels of ammonia in the blood (hyperammonemic coma), the disorder may progress to coma. In these patients, argininosuccinic aciduria may potentially result in neurological abnormalities including delays in reaching developmental milestones (developmental delays) and intellectual disability. The severity of such neurological abnormalities is more severe in infants who are in hyperammonemic coma for more than three days. If left untreated, the disorder will result in life-threatening complications. However, even individuals without significant hyperammonemia may develop neurological abnormalities suggesting alternative causes of injury.In infants with partial enzyme deficiency, onset of the disorder may not occur until later during infancy or childhood (late onset form). Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy and vomiting. Affected infants and children may also have dry, brittle hair. Some individuals with the late onset form may not develop any symptoms (asymptomatic).Infants with the mild form may alternate between periods of wellness and hyperammonemia. Episodes of hyperammonemia are usually triggered by acute infection, stress, certain medications or not following the recommended dietary restrictions (e.g., high protein intake or also insufficient, too low protein intake). Other individuals with the mild form may not have any documented episodes of hyperammonemia but can still develop behavioral abnormalities such as attention deficit/hyperactivity disorder, cognitive impairment and learning disabilities.Both the severe and late-onset forms of argininosuccinic aciduria can be associated with long-term complications including liver dysfunction, neurocognitive deficits such as cognitive impairment, seizures, brittle hair and high blood pressure (hypertension). These long-term complications appear to be unrelated to the frequency, length or severity of episodes of hyperammonemia. Increasingly, high blood pressure has been diagnosed in some but not all children and adults with this condition. This may be due to an inability of the body to generate a chemical called nitric oxide. | Symptoms of Argininosuccinic Aciduria. The severity and specific symptoms of argininosuccinic aciduria varies from one person to another. A severe form of the disorder, which is characterized by a complete or near complete lack of the ASL enzyme, occurs shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the ASL enzyme, affects some individuals later during infancy or childhood or even adulthood (late-onset form).Symptoms are caused by the accumulation of ammonia in the blood. The severe form occurs within 24-72 hours after birth, usually following a protein feeding. This form is initially characterized by a refusal to eat, lethargy, lack of appetite, vomiting and irritability. Affected infants may also experience seizures, breathing (respiratory) abnormalities, accumulation of fluid in the brain (cerebral edema) and an abnormally large liver (hepatomegaly). Less commonly, some individuals develop progressive liver disease and dysfunction such as the buildup of scar tissue (fibrosis) and cirrhosis. In rare instances, chronic kidney (renal) disease has been reported. Abnormally rapid breathing (tachypnea) may be detected and sometimes is the first sign recognized of elevated ammonia in the blood. As affected individuals grow older, they may have coarse and brittle (friable) hair that breaks off easily and can leave patches of hair loss, a condition known as trichorrhexis nodosa.In some patients, due to high levels of ammonia in the blood (hyperammonemic coma), the disorder may progress to coma. In these patients, argininosuccinic aciduria may potentially result in neurological abnormalities including delays in reaching developmental milestones (developmental delays) and intellectual disability. The severity of such neurological abnormalities is more severe in infants who are in hyperammonemic coma for more than three days. If left untreated, the disorder will result in life-threatening complications. However, even individuals without significant hyperammonemia may develop neurological abnormalities suggesting alternative causes of injury.In infants with partial enzyme deficiency, onset of the disorder may not occur until later during infancy or childhood (late onset form). Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy and vomiting. Affected infants and children may also have dry, brittle hair. Some individuals with the late onset form may not develop any symptoms (asymptomatic).Infants with the mild form may alternate between periods of wellness and hyperammonemia. Episodes of hyperammonemia are usually triggered by acute infection, stress, certain medications or not following the recommended dietary restrictions (e.g., high protein intake or also insufficient, too low protein intake). Other individuals with the mild form may not have any documented episodes of hyperammonemia but can still develop behavioral abnormalities such as attention deficit/hyperactivity disorder, cognitive impairment and learning disabilities.Both the severe and late-onset forms of argininosuccinic aciduria can be associated with long-term complications including liver dysfunction, neurocognitive deficits such as cognitive impairment, seizures, brittle hair and high blood pressure (hypertension). These long-term complications appear to be unrelated to the frequency, length or severity of episodes of hyperammonemia. Increasingly, high blood pressure has been diagnosed in some but not all children and adults with this condition. This may be due to an inability of the body to generate a chemical called nitric oxide. | 100 | Argininosuccinic Aciduria |
nord_100_2 | Causes of Argininosuccinic Aciduria | Argininosuccinic aciduria is caused by changes (pathogenic variants or mutations) in the ASL gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.Symptoms of argininosuccinic aciduria develop due to the near complete or partial lack of the enzyme argininosuccinate lyase. The ASL gene is responsible for regulating the production of this enzyme. Alterations in the ASL gene lead to low levels of functional argininosuccinate lyase, which is needed to break down nitrogen in the body. Failure to properly break down nitrogen leads to the abnormal accumulation of nitrogen, in the form of ammonia, in the blood (hyperammonemia).Researchers have determined that argininosuccinic aciduria is a more complex metabolic disorder than originally suspected. Affected individuals have developed some of the long-term complications described above (e.g., liver disease, hypertension, neurocognitive issues) despite not having any episodes of hyperammonemia and having an overall good metabolic profile. Researchers theorize that the deficient enzyme, argininosuccinate lyase, may have more roles in the body other than breaking down nitrogen (i.e., its role in the urea cycle) including the production of nitric oxide. More research is necessary to fully understand the complex, underlying mechanisms of argininosuccinic aciduria.Argininosuccinic aciduria is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an 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. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Argininosuccinic Aciduria. Argininosuccinic aciduria is caused by changes (pathogenic variants or mutations) in the ASL gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.Symptoms of argininosuccinic aciduria develop due to the near complete or partial lack of the enzyme argininosuccinate lyase. The ASL gene is responsible for regulating the production of this enzyme. Alterations in the ASL gene lead to low levels of functional argininosuccinate lyase, which is needed to break down nitrogen in the body. Failure to properly break down nitrogen leads to the abnormal accumulation of nitrogen, in the form of ammonia, in the blood (hyperammonemia).Researchers have determined that argininosuccinic aciduria is a more complex metabolic disorder than originally suspected. Affected individuals have developed some of the long-term complications described above (e.g., liver disease, hypertension, neurocognitive issues) despite not having any episodes of hyperammonemia and having an overall good metabolic profile. Researchers theorize that the deficient enzyme, argininosuccinate lyase, may have more roles in the body other than breaking down nitrogen (i.e., its role in the urea cycle) including the production of nitric oxide. More research is necessary to fully understand the complex, underlying mechanisms of argininosuccinic aciduria.Argininosuccinic aciduria is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an 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. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | 100 | Argininosuccinic Aciduria |
nord_100_3 | Affects of Argininosuccinic Aciduria | Argininosuccinic aciduria is a rare disorder that affects fewer than a thousand people in the United States. It is estimated to affect anywhere between approximately one in 70,000 to 1 in 218,000 live births. Males and females are affected in equal numbers. Onset of symptoms usually occurs at birth but may not be noticeable for days or weeks. In some children, onset of symptoms may not occur until later during infancy or childhood.The estimated frequency of urea cycle disorders collectively is approximately one in 30,000. However, because urea cycle disorders like argininosuccinic aciduria often go unrecognized, these disorders are under-diagnosed, making it difficult to determine their true frequency in the general population. | Affects of Argininosuccinic Aciduria. Argininosuccinic aciduria is a rare disorder that affects fewer than a thousand people in the United States. It is estimated to affect anywhere between approximately one in 70,000 to 1 in 218,000 live births. Males and females are affected in equal numbers. Onset of symptoms usually occurs at birth but may not be noticeable for days or weeks. In some children, onset of symptoms may not occur until later during infancy or childhood.The estimated frequency of urea cycle disorders collectively is approximately one in 30,000. However, because urea cycle disorders like argininosuccinic aciduria often go unrecognized, these disorders are under-diagnosed, making it difficult to determine their true frequency in the general population. | 100 | Argininosuccinic Aciduria |
nord_100_4 | Related disorders of Argininosuccinic Aciduria | Symptoms of the following disorders may be similar to those of argininosuccinic aciduria. Comparisons may be useful for a differential diagnosis:Urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some people, life-threatening complications may result. In addition to argininosuccinic aciduria, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Reye syndrome is a rare childhood disorder characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia) and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered using aspirin in children recovering from chicken pox or influenza. Deficiencies of the urea cycle enzymes are thought to play a role in the development of Reye syndrome. Symptoms include vomiting, diarrhea, rapid breathing, irritability, fatigue and behavioral changes. Neurological symptoms may be life-threatening and include seizures, stupor, and coma. (For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.)Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to break down (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy and seizures. If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon. | Related disorders of Argininosuccinic Aciduria. Symptoms of the following disorders may be similar to those of argininosuccinic aciduria. Comparisons may be useful for a differential diagnosis:Urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some people, life-threatening complications may result. In addition to argininosuccinic aciduria, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Reye syndrome is a rare childhood disorder characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia) and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered using aspirin in children recovering from chicken pox or influenza. Deficiencies of the urea cycle enzymes are thought to play a role in the development of Reye syndrome. Symptoms include vomiting, diarrhea, rapid breathing, irritability, fatigue and behavioral changes. Neurological symptoms may be life-threatening and include seizures, stupor, and coma. (For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.)Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to break down (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy and seizures. If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon. | 100 | Argininosuccinic Aciduria |
nord_100_5 | Diagnosis of Argininosuccinic Aciduria | A diagnosis of a urea cycle disorder, such as argininosuccinic aciduria, should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability. All 50 states in the U.S. include argininosuccinic aciduria in newborn screening programs.A diagnosis of argininosuccinic aciduria can be made through a detailed patient/family history, identification of characteristic findings and a variety of specialized tests. Blood tests may reveal excessive amounts of ammonia in the blood, which is the main criterion for a diagnosis of urea cycles disorders including argininosuccinic aciduria. Blood tests may also reveal high levels of an amino acid called citrulline. However, high levels of ammonia or citrulline in the blood may characterize other disorders such as organic acidemias, congenital lactic acidosis and fatty acid oxidation disorders and are also present in other urea cycle disorders.A diagnosis can be confirmed by identifying elevated levels of argininosuccinic acid in blood or urine samples. A diagnosis can also be confirmed by molecular genetic testing, which detects the gene alteration that causes the disorder. | Diagnosis of Argininosuccinic Aciduria. A diagnosis of a urea cycle disorder, such as argininosuccinic aciduria, should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability. All 50 states in the U.S. include argininosuccinic aciduria in newborn screening programs.A diagnosis of argininosuccinic aciduria can be made through a detailed patient/family history, identification of characteristic findings and a variety of specialized tests. Blood tests may reveal excessive amounts of ammonia in the blood, which is the main criterion for a diagnosis of urea cycles disorders including argininosuccinic aciduria. Blood tests may also reveal high levels of an amino acid called citrulline. However, high levels of ammonia or citrulline in the blood may characterize other disorders such as organic acidemias, congenital lactic acidosis and fatty acid oxidation disorders and are also present in other urea cycle disorders.A diagnosis can be confirmed by identifying elevated levels of argininosuccinic acid in blood or urine samples. A diagnosis can also be confirmed by molecular genetic testing, which detects the gene alteration that causes the disorder. | 100 | Argininosuccinic Aciduria |
nord_100_6 | Therapies of Argininosuccinic Aciduria | Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticists, dieticians and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.Genetic counseling is recommended for affected individuals and their families.The treatment of argininosuccinic aciduria is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).Dietary restrictions in individuals with argininosuccinic aciduria are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with argininosuccinic aciduria are placed on a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula (e.g., UCD-1 Ross, or Cyclinex, Mead Johnson), and a calorie supplement without protein is often used (e.g., MJ80056, Mead Johnson).Individuals with argininosuccinic aciduria benefit from treatment with arginine, which helps to promote the excretion of nitrogen (in the form of increased argininosuccinic acid production). Arginine supplementation has shown benefits in improving or reversing changes to the hair, but its impact on the long-term, chronic complications of the disorder are not fully understood. The dose of arginine is often higher than is used in other forms of urea cycle disorder and it is effective in decreasing ammonia in emergent situations of elevated ammonia. However, chronic treatment with high doses of arginine may contribute to liver disease as it produces higher levels of argininosuccinic acid. Therefore, in individuals with liver disease, lower doses should be considered for long term treatment. In this situation, other medications like alternative pathway therapies may be needed. The dose of arginine can be increased during illnesses to clear excess nitrogen and thereby reduce risk of high ammonia. Multiple vitamins, vitamin D, and calcium supplements may also be used in the treatment of argininosuccinic aciduria as some patients may suffer from osteoporosis or low bone mass. This and other systemic complications like high blood pressure may be caused by decreased production of nitric oxide in patients with argininosuccinic aciduria, the addition of low protein foods rich in nitrite and/or supplementation of nutraceuticals that provide nitrite as an independent source may be helpful, although there are no definitive clinical trials that prove this.Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some individuals, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.In some patients, despite early treatment and good metabolic control, affected individuals may develop certain symptoms such as neurocognitive deficiencies, behavior issues such as ADHD, developmental disability and seizures.In addition to dietary restrictions and supplements, individuals with argininosuccinic aciduria are treated by medications that stimulate the removal of nitrogen from the body. These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. This is known as alternative pathway therapy or nitrogen scavenging therapy. This includes sodium benzoate, sodium phenylbutyrate, and glycerol triphenylbutyrate.In 2013, the U.S. Food and Drug Administration (FDA) approved Ravicti (glycerol phenylbutyrate) for the chronic management of urea cycle disorders including argininosuccinic aciduria in affected individuals aged 2 years and older. Ravicti is a liquid therapy that helps to remove ammonia from the body. Ravicti is used in individuals whose disease cannot be managed through a low-protein diet and dietary supplements alone.In 1996, the FDA approved Buphenyl (sodium phenylbutyrate) for chronic management of urea cycle disorders including argininosuccinic aciduria. Buphenyl is a powder therapy that helps to remove ammonia from the body. A generic form of Buphenyl is also now available.Sodium benzoate is a powder that is not FDA approved for treatment urea cycle disorders, but it has been used in chronic treatment of urea cycle disorders. It is not believed to be as effective as Buphenyl or Ravicti based on theoretical considerations, though this has never been tested in patients. A combination of sodium benzoate and phenylbutyrate has been used in some patients who may have problems tolerating the latter but the clinical effectiveness of this combined approach vs. phenylbutyrate alone is unknown.In 2005, the FDA approved the use Ammonul (sodium benzoate and sodium phenylacetate) as an intravenous, rescue therapy for the prevention and treatment of hyperammonemia and associated disease of the brain (encephalopathy) in individuals with urea cycle disorders. This is only used in a hospitalized setting.Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose. As mentioned above, a patient who has been treated on a chronic lower dose of arginine can be given a higher dose during illness either orally (with arginine base) or intravenously (with arginine hydrochloride).In individuals where there is no improvement or where hyperammonemic coma develops, the removal of wastes by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children and adults who are first diagnosed with argininosuccinic aciduria during hyperammonemic coma.In some individuals, a liver transplant may be recommended. This is an option of last resort for specific individuals who have progressive liver disease, experience recurrent medical crises and hospitalizations despite therapy, or who have a poor quality of life.Preventive Care
After diagnosis of argininosuccinic aciduria, steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia and amino acids in the blood. Detection of elevated levels of ammonia may allow treatment before clinical symptoms appear. Monitoring for complications such as high blood pressure, liver inflammation and fibrosis and developmental delay should be closely monitored from the time of diagnosis. | Therapies of Argininosuccinic Aciduria. Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticists, dieticians and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.Genetic counseling is recommended for affected individuals and their families.The treatment of argininosuccinic aciduria is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).Dietary restrictions in individuals with argininosuccinic aciduria are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with argininosuccinic aciduria are placed on a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula (e.g., UCD-1 Ross, or Cyclinex, Mead Johnson), and a calorie supplement without protein is often used (e.g., MJ80056, Mead Johnson).Individuals with argininosuccinic aciduria benefit from treatment with arginine, which helps to promote the excretion of nitrogen (in the form of increased argininosuccinic acid production). Arginine supplementation has shown benefits in improving or reversing changes to the hair, but its impact on the long-term, chronic complications of the disorder are not fully understood. The dose of arginine is often higher than is used in other forms of urea cycle disorder and it is effective in decreasing ammonia in emergent situations of elevated ammonia. However, chronic treatment with high doses of arginine may contribute to liver disease as it produces higher levels of argininosuccinic acid. Therefore, in individuals with liver disease, lower doses should be considered for long term treatment. In this situation, other medications like alternative pathway therapies may be needed. The dose of arginine can be increased during illnesses to clear excess nitrogen and thereby reduce risk of high ammonia. Multiple vitamins, vitamin D, and calcium supplements may also be used in the treatment of argininosuccinic aciduria as some patients may suffer from osteoporosis or low bone mass. This and other systemic complications like high blood pressure may be caused by decreased production of nitric oxide in patients with argininosuccinic aciduria, the addition of low protein foods rich in nitrite and/or supplementation of nutraceuticals that provide nitrite as an independent source may be helpful, although there are no definitive clinical trials that prove this.Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some individuals, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.In some patients, despite early treatment and good metabolic control, affected individuals may develop certain symptoms such as neurocognitive deficiencies, behavior issues such as ADHD, developmental disability and seizures.In addition to dietary restrictions and supplements, individuals with argininosuccinic aciduria are treated by medications that stimulate the removal of nitrogen from the body. These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. This is known as alternative pathway therapy or nitrogen scavenging therapy. This includes sodium benzoate, sodium phenylbutyrate, and glycerol triphenylbutyrate.In 2013, the U.S. Food and Drug Administration (FDA) approved Ravicti (glycerol phenylbutyrate) for the chronic management of urea cycle disorders including argininosuccinic aciduria in affected individuals aged 2 years and older. Ravicti is a liquid therapy that helps to remove ammonia from the body. Ravicti is used in individuals whose disease cannot be managed through a low-protein diet and dietary supplements alone.In 1996, the FDA approved Buphenyl (sodium phenylbutyrate) for chronic management of urea cycle disorders including argininosuccinic aciduria. Buphenyl is a powder therapy that helps to remove ammonia from the body. A generic form of Buphenyl is also now available.Sodium benzoate is a powder that is not FDA approved for treatment urea cycle disorders, but it has been used in chronic treatment of urea cycle disorders. It is not believed to be as effective as Buphenyl or Ravicti based on theoretical considerations, though this has never been tested in patients. A combination of sodium benzoate and phenylbutyrate has been used in some patients who may have problems tolerating the latter but the clinical effectiveness of this combined approach vs. phenylbutyrate alone is unknown.In 2005, the FDA approved the use Ammonul (sodium benzoate and sodium phenylacetate) as an intravenous, rescue therapy for the prevention and treatment of hyperammonemia and associated disease of the brain (encephalopathy) in individuals with urea cycle disorders. This is only used in a hospitalized setting.Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose. As mentioned above, a patient who has been treated on a chronic lower dose of arginine can be given a higher dose during illness either orally (with arginine base) or intravenously (with arginine hydrochloride).In individuals where there is no improvement or where hyperammonemic coma develops, the removal of wastes by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children and adults who are first diagnosed with argininosuccinic aciduria during hyperammonemic coma.In some individuals, a liver transplant may be recommended. This is an option of last resort for specific individuals who have progressive liver disease, experience recurrent medical crises and hospitalizations despite therapy, or who have a poor quality of life.Preventive Care
After diagnosis of argininosuccinic aciduria, steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia and amino acids in the blood. Detection of elevated levels of ammonia may allow treatment before clinical symptoms appear. Monitoring for complications such as high blood pressure, liver inflammation and fibrosis and developmental delay should be closely monitored from the time of diagnosis. | 100 | Argininosuccinic Aciduria |
nord_101_0 | Overview of Aromatic L-Amino Acid Decarboxylase Deficiency | SummaryAromatic l-amino acid decarboxylase (AADC) deficiency is a very rare genetic disorder characterized by decreased activity of aromatic l-amino acid decarboxylase, an enzyme involved in the building (synthesis) of neurotransmitters (dopamine and serotonin), which are responsible for the communication between neurons in the nervous system. Although affected individuals can appear normal at birth, most will develop symptoms during the first months of life. AADC deficiency most commonly leads to decreased muscle tone (hypotonia), movement disorders including abnormal eyes movement (oculogyric crises), developmental delay, restricted growth (failure to thrive), and disruption of the part of the nervous system responsible for unconscious modulation of body functions such as heartbeat (autonomic nervous system). Medication is available to manage the symptoms, but response to treatment greatly varies among affected individuals, and an optimal treatment regimen can be difficult to achieve. There is currently no cure for the disease, but gene therapy has shown potential to improve symptoms in clinical trials. | Overview of Aromatic L-Amino Acid Decarboxylase Deficiency. SummaryAromatic l-amino acid decarboxylase (AADC) deficiency is a very rare genetic disorder characterized by decreased activity of aromatic l-amino acid decarboxylase, an enzyme involved in the building (synthesis) of neurotransmitters (dopamine and serotonin), which are responsible for the communication between neurons in the nervous system. Although affected individuals can appear normal at birth, most will develop symptoms during the first months of life. AADC deficiency most commonly leads to decreased muscle tone (hypotonia), movement disorders including abnormal eyes movement (oculogyric crises), developmental delay, restricted growth (failure to thrive), and disruption of the part of the nervous system responsible for unconscious modulation of body functions such as heartbeat (autonomic nervous system). Medication is available to manage the symptoms, but response to treatment greatly varies among affected individuals, and an optimal treatment regimen can be difficult to achieve. There is currently no cure for the disease, but gene therapy has shown potential to improve symptoms in clinical trials. | 101 | Aromatic L-Amino Acid Decarboxylase Deficiency |
nord_101_1 | Symptoms of Aromatic L-Amino Acid Decarboxylase Deficiency | AADC deficiency is a disorder that manifests early in life. The symptoms can begin during the neonatal period or when the child is a few months old. There is a wide range of possible symptoms and the severity of the disease varies among affected individuals. The two most common symptoms are hypotonia in the trunk and oculogyric crises. These crises are characterized by abnormal rotation of the eyeballs and gaze deviation, uncontrolled movements of the head and neck, muscle spasms, agitation, and irritability. They can last several hours and tend to recur every 2 to 5 days. Other movement disorders can be present such as decreased movements (hypokinesia), increased muscle tone (hypertonia) in the limbs, sustained muscle contraction and abnormal postures (dystonia), involuntary writhing movements (athetosis), involuntary and irregular movements of the hands and feet (chorea), and tremors. Another prominent feature of AADC deficiency is dysfunction of the autonomic nervous system. This part of the nervous system is not under voluntarily control and is notably involved in self-regulation of the body. Dysfunction of the autonomic nervous system can lead to symptoms such as excessive sweating and salivation (hypersalivation), droopy eyelids (ptosis), nasal congestion, temperature instability, low blood pressure (hypotension), and low blood sugar (hypoglycemia). Less common symptoms include seizures, behavioral problems such as irritability and excessive crying, decreased or increased sleep (insomnia and hypersomnia, respectively), and decreased or increased reflexes (hyporeflexia and hyperreflexia, respectively). Another relatively common non-neurologic manifestation is gastrointestinal problems such as diarrhea, constipation, and reflux. Because of the disease itself and as a consequence of the numerous possible symptoms, children with AADC deficiency have developmental delay and are not able to reach normal milestones such as walking and talking, have feeding difficulties and decreased growth (failure to thrive), and are prone to many medical complications. Patients might also have difficulty adapting to those complications as their autonomic nervous system is dysfunctional and can react inappropriately to stressors such as surgery or infections. Many affected children unfortunately do not live through childhood, but some with milder disease do reach adulthood. Importantly, the condition of people living with the disease can deteriorate because of complications, but the symptoms themselves do not tend to worsen with time. Some patients eventually develop cerebral palsy. | Symptoms of Aromatic L-Amino Acid Decarboxylase Deficiency. AADC deficiency is a disorder that manifests early in life. The symptoms can begin during the neonatal period or when the child is a few months old. There is a wide range of possible symptoms and the severity of the disease varies among affected individuals. The two most common symptoms are hypotonia in the trunk and oculogyric crises. These crises are characterized by abnormal rotation of the eyeballs and gaze deviation, uncontrolled movements of the head and neck, muscle spasms, agitation, and irritability. They can last several hours and tend to recur every 2 to 5 days. Other movement disorders can be present such as decreased movements (hypokinesia), increased muscle tone (hypertonia) in the limbs, sustained muscle contraction and abnormal postures (dystonia), involuntary writhing movements (athetosis), involuntary and irregular movements of the hands and feet (chorea), and tremors. Another prominent feature of AADC deficiency is dysfunction of the autonomic nervous system. This part of the nervous system is not under voluntarily control and is notably involved in self-regulation of the body. Dysfunction of the autonomic nervous system can lead to symptoms such as excessive sweating and salivation (hypersalivation), droopy eyelids (ptosis), nasal congestion, temperature instability, low blood pressure (hypotension), and low blood sugar (hypoglycemia). Less common symptoms include seizures, behavioral problems such as irritability and excessive crying, decreased or increased sleep (insomnia and hypersomnia, respectively), and decreased or increased reflexes (hyporeflexia and hyperreflexia, respectively). Another relatively common non-neurologic manifestation is gastrointestinal problems such as diarrhea, constipation, and reflux. Because of the disease itself and as a consequence of the numerous possible symptoms, children with AADC deficiency have developmental delay and are not able to reach normal milestones such as walking and talking, have feeding difficulties and decreased growth (failure to thrive), and are prone to many medical complications. Patients might also have difficulty adapting to those complications as their autonomic nervous system is dysfunctional and can react inappropriately to stressors such as surgery or infections. Many affected children unfortunately do not live through childhood, but some with milder disease do reach adulthood. Importantly, the condition of people living with the disease can deteriorate because of complications, but the symptoms themselves do not tend to worsen with time. Some patients eventually develop cerebral palsy. | 101 | Aromatic L-Amino Acid Decarboxylase Deficiency |
nord_101_2 | Causes of Aromatic L-Amino Acid Decarboxylase Deficiency | AADC deficiency is caused by mutations (changes) in a gene called DDC (which stands for DOPA decarboxylase, another name for AADC). An abnormal DDC gene leads to production of a dysfunctional AADC enzyme that cannot accomplish its normal functions. Enzymes are a type of protein widely present in the body and their role is to facilitate and accelerate (catalyze) chemical reactions that have to take place in order for the body to function correctly. AADC catalyzes chemical reactions responsible for the formation (synthesis) of molecules called neurotransmitters that are essential for proper communication between neurons of the nervous system. The neurotransmitters affected by AADC deficiency are epinephrine and norepinephrine (products of dopamine and involved in the control of the sympathetic nervous system, the “fight or flight” branch of the autonomic nervous system), dopamine (involved in motor control, reward, and motivation), and serotonin (involved in sleep, memory, appetite, and mood). Serotonin is also required for the synthesis of melatonin, which is primarily involved in the regulation of the sleep-wake cycle. Deficiency of those neurotransmitters is responsible for the manifestations of AADC deficiency.AADC deficiency is an autosomal recessive genetic disorder. This type of genetic disorder occurs when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal 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 abnormal 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 is 25%. The risk is the same for males and females. | Causes of Aromatic L-Amino Acid Decarboxylase Deficiency. AADC deficiency is caused by mutations (changes) in a gene called DDC (which stands for DOPA decarboxylase, another name for AADC). An abnormal DDC gene leads to production of a dysfunctional AADC enzyme that cannot accomplish its normal functions. Enzymes are a type of protein widely present in the body and their role is to facilitate and accelerate (catalyze) chemical reactions that have to take place in order for the body to function correctly. AADC catalyzes chemical reactions responsible for the formation (synthesis) of molecules called neurotransmitters that are essential for proper communication between neurons of the nervous system. The neurotransmitters affected by AADC deficiency are epinephrine and norepinephrine (products of dopamine and involved in the control of the sympathetic nervous system, the “fight or flight” branch of the autonomic nervous system), dopamine (involved in motor control, reward, and motivation), and serotonin (involved in sleep, memory, appetite, and mood). Serotonin is also required for the synthesis of melatonin, which is primarily involved in the regulation of the sleep-wake cycle. Deficiency of those neurotransmitters is responsible for the manifestations of AADC deficiency.AADC deficiency is an autosomal recessive genetic disorder. This type of genetic disorder occurs when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal 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 abnormal 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 is 25%. The risk is the same for males and females. | 101 | Aromatic L-Amino Acid Decarboxylase Deficiency |
nord_101_3 | Affects of Aromatic L-Amino Acid Decarboxylase Deficiency | AADC deficiency is an extremely rare disorder; fewer than 150 patients have been reported in the literature. Half of these cases are in Asian individuals, and a fifth are in individuals with Taiwanese ancestry. Males and females seem to be equally affected. AADC deficiency is probably underdiagnosed. The estimated prevalence in the U.S. based on cerebrospinal fluid (CSF) analysis and genetic testing is roughly 1-3:100,000 live newborns. | Affects of Aromatic L-Amino Acid Decarboxylase Deficiency. AADC deficiency is an extremely rare disorder; fewer than 150 patients have been reported in the literature. Half of these cases are in Asian individuals, and a fifth are in individuals with Taiwanese ancestry. Males and females seem to be equally affected. AADC deficiency is probably underdiagnosed. The estimated prevalence in the U.S. based on cerebrospinal fluid (CSF) analysis and genetic testing is roughly 1-3:100,000 live newborns. | 101 | Aromatic L-Amino Acid Decarboxylase Deficiency |
nord_101_4 | Related disorders of Aromatic L-Amino Acid Decarboxylase Deficiency | The symptoms seen in AADC deficiency can be seen in numerous other disorders. Some have a very similar clinical presentation and are mostly differentiated with laboratory testing and medical imaging. Below is a list of some conditions that can present similarly to AADC deficiency, with an emphasis on neurometabolic disorders.Tetrahydrobiopterin (BH4) deficiency is a general term for a group of disorders characterized by abnormalities in the synthesis or regeneration of BH4, a naturally occurring compound that facilitates certain chemical reactions. These disorders usually present within the first six months of life and can be diagnosed through the newborn screening for phenylketonuria (elevated phenylalanine in blood). Affected infants may not grow and gain weight as expected. In the severe forms of BH4 deficiency, symptoms include hypotonia of the trunk, hypertonia of the limbs, decreased body movement (hypokinesia), abnormal muscle contractions (athetosis), seizures, and swallowing difficulties. Small head circumference (microcephaly) is another occasional finding. (For more information on this disorder, choose “tetrahydrobiopterin deficiency” as your search term in the Rare Disease Database.)Sepiapterin reductase deficiency (SRD) is a rare genetic disorder in BH4 metabolism characterized by abnormally low levels of certain neurotransmitters, but it presents without elevated blood phenylalanine concentrations. Symptoms usually become apparent within the first year of life and vary greatly from one person to another. Some individuals develop severe, disabling motor and cognitive deficits while others only experience mild symptoms. Common symptoms include dystonia, developmental delays, hypotonia, and oculogyric crises. Some infants may have microcephaly. (For more information on this disorder, choose “sepiapterin reductase deficiency” as your search term in the Rare Disease Database.)Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare inborn error of metabolism characterized by deficient activity of the SSADH enzyme that disrupts the metabolism of a neurotransmitter called gamma-aminobutyric acid (GABA). Affected individuals can have neurological and neuromuscular symptoms such as intellectual disability, delayed language and motor milestones, hypotonia, seizures, and an impaired ability to coordinate voluntary movements (ataxia). (For more information on this disorder, choose “succinic semialdehyde dehydrogenase deficiency” as your search term in the Rare Disease Database.)Tyrosine hydroxylase deficiency is a rare genetic disorder that involves the synthesis of dopamine and is characterized by a wide spectrum of severity ranging from a mild movement disorder to a life-threatening, neurological disorder. Symptoms of the severe form of tyrosine hydroxylase deficiency are obvious early in infancy and include poor control of voluntary muscles, delays in achieving motor milestones, hypertonia, abnormal rigidity of the arms and legs, hypokinesia, and involuntary muscle spasms that result in slow, stiff movements of the limbs (spasticity). (For more information on this disorder, choose “tyrosine hydroxylase deficiency” as your search term in the Rare Disease Database.)Cerebral palsy is a neurological movement disorder characterized by the lack of muscle control and impairment in the coordination of movements. This disorder is usually a result of injury to the brain during early development in the uterus, at birth, or in the first two years of life. Affected infants have muscle weakness, hypotonia and, later, muscle stiffness (spasticity) and lack of coordination. They may experience developmental delays during the first or second year of life. As with AADC deficiency, this condition is not progressive. (For more information on this disorder, choose “cerebral palsy” as your search term in the Rare Disease Database.) | Related disorders of Aromatic L-Amino Acid Decarboxylase Deficiency. The symptoms seen in AADC deficiency can be seen in numerous other disorders. Some have a very similar clinical presentation and are mostly differentiated with laboratory testing and medical imaging. Below is a list of some conditions that can present similarly to AADC deficiency, with an emphasis on neurometabolic disorders.Tetrahydrobiopterin (BH4) deficiency is a general term for a group of disorders characterized by abnormalities in the synthesis or regeneration of BH4, a naturally occurring compound that facilitates certain chemical reactions. These disorders usually present within the first six months of life and can be diagnosed through the newborn screening for phenylketonuria (elevated phenylalanine in blood). Affected infants may not grow and gain weight as expected. In the severe forms of BH4 deficiency, symptoms include hypotonia of the trunk, hypertonia of the limbs, decreased body movement (hypokinesia), abnormal muscle contractions (athetosis), seizures, and swallowing difficulties. Small head circumference (microcephaly) is another occasional finding. (For more information on this disorder, choose “tetrahydrobiopterin deficiency” as your search term in the Rare Disease Database.)Sepiapterin reductase deficiency (SRD) is a rare genetic disorder in BH4 metabolism characterized by abnormally low levels of certain neurotransmitters, but it presents without elevated blood phenylalanine concentrations. Symptoms usually become apparent within the first year of life and vary greatly from one person to another. Some individuals develop severe, disabling motor and cognitive deficits while others only experience mild symptoms. Common symptoms include dystonia, developmental delays, hypotonia, and oculogyric crises. Some infants may have microcephaly. (For more information on this disorder, choose “sepiapterin reductase deficiency” as your search term in the Rare Disease Database.)Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare inborn error of metabolism characterized by deficient activity of the SSADH enzyme that disrupts the metabolism of a neurotransmitter called gamma-aminobutyric acid (GABA). Affected individuals can have neurological and neuromuscular symptoms such as intellectual disability, delayed language and motor milestones, hypotonia, seizures, and an impaired ability to coordinate voluntary movements (ataxia). (For more information on this disorder, choose “succinic semialdehyde dehydrogenase deficiency” as your search term in the Rare Disease Database.)Tyrosine hydroxylase deficiency is a rare genetic disorder that involves the synthesis of dopamine and is characterized by a wide spectrum of severity ranging from a mild movement disorder to a life-threatening, neurological disorder. Symptoms of the severe form of tyrosine hydroxylase deficiency are obvious early in infancy and include poor control of voluntary muscles, delays in achieving motor milestones, hypertonia, abnormal rigidity of the arms and legs, hypokinesia, and involuntary muscle spasms that result in slow, stiff movements of the limbs (spasticity). (For more information on this disorder, choose “tyrosine hydroxylase deficiency” as your search term in the Rare Disease Database.)Cerebral palsy is a neurological movement disorder characterized by the lack of muscle control and impairment in the coordination of movements. This disorder is usually a result of injury to the brain during early development in the uterus, at birth, or in the first two years of life. Affected infants have muscle weakness, hypotonia and, later, muscle stiffness (spasticity) and lack of coordination. They may experience developmental delays during the first or second year of life. As with AADC deficiency, this condition is not progressive. (For more information on this disorder, choose “cerebral palsy” as your search term in the Rare Disease Database.) | 101 | Aromatic L-Amino Acid Decarboxylase Deficiency |
nord_101_5 | Diagnosis of Aromatic L-Amino Acid Decarboxylase Deficiency | AADC deficiency is a very rare and complex disease with features that overlap with many other disorders (see above). A complete clinical evaluation and a high index of suspicion are required to make the diagnosis. The evaluation of a child with neurodevelopmental delay starts with a perinatal and developmental history and a complete physical examination. Although many tests, such as a complete blood count, measurement of electrolyte levels, and magnetic resonance imaging of the brain are usually performed in the diagnostic workup of a child presenting with neurodevelopmental delay, the laboratory diagnosis of AADC deficiency is centered about four specific tests:1) A lumbar puncture, which is a procedure where a needle is placed in the spinal column of the patient to collect cerebrospinal fluid (CSF). The CSF is then analyzed to identify abnormal levels of certain substances (metabolites) involved in the molecular pathways of neurotransmitter synthesis. The synthesis of neurotransmitters involves a cascade of numerous chemical reactions. In patients with AADC deficiency, the cascade stops where AADC is usually required to catalyze the chemical reactions. As a result, in cases of enzyme deficiency, the metabolites “before” AADC in the chemical reaction cascade will be increased, and those “after” will be decreased. 2) Measurement a specific metabolite 3-O-methyl-dopa (3OMD) in plasma or dried blood spots, which will be increased in patients with the disease.3) Measurement of activity level of the AADC enzyme in the blood (serum), which will be reduced in patients with the disease.4) Genetic testing that can identify disease-causing (pathogenic) mutations in the DDC gene. | Diagnosis of Aromatic L-Amino Acid Decarboxylase Deficiency. AADC deficiency is a very rare and complex disease with features that overlap with many other disorders (see above). A complete clinical evaluation and a high index of suspicion are required to make the diagnosis. The evaluation of a child with neurodevelopmental delay starts with a perinatal and developmental history and a complete physical examination. Although many tests, such as a complete blood count, measurement of electrolyte levels, and magnetic resonance imaging of the brain are usually performed in the diagnostic workup of a child presenting with neurodevelopmental delay, the laboratory diagnosis of AADC deficiency is centered about four specific tests:1) A lumbar puncture, which is a procedure where a needle is placed in the spinal column of the patient to collect cerebrospinal fluid (CSF). The CSF is then analyzed to identify abnormal levels of certain substances (metabolites) involved in the molecular pathways of neurotransmitter synthesis. The synthesis of neurotransmitters involves a cascade of numerous chemical reactions. In patients with AADC deficiency, the cascade stops where AADC is usually required to catalyze the chemical reactions. As a result, in cases of enzyme deficiency, the metabolites “before” AADC in the chemical reaction cascade will be increased, and those “after” will be decreased. 2) Measurement a specific metabolite 3-O-methyl-dopa (3OMD) in plasma or dried blood spots, which will be increased in patients with the disease.3) Measurement of activity level of the AADC enzyme in the blood (serum), which will be reduced in patients with the disease.4) Genetic testing that can identify disease-causing (pathogenic) mutations in the DDC gene. | 101 | Aromatic L-Amino Acid Decarboxylase Deficiency |
nord_101_6 | Therapies of Aromatic L-Amino Acid Decarboxylase Deficiency | Treatment & Management
Although there is currently no cure for AADC deficiency, numerous medications can help manage the symptoms. The optimal medication regimen greatly varies among affected individuals. There is limited scientific evidence for the efficacy of most treatment options due to the rarity of the disease. Each patient needs to have a personalized approach and should be followed by a pediatric neurologist and potentially many other physicians to assist in trials of medications to determine the best combination on a case-by-case basis. Some of the most commonly used treatments include medications to increase the concentration of dopamine in the nervous system (dopamine agonists) or to decrease its degradation (monoamine oxidase B [MAO-B] inhibitors). Vitamin B6 (pyridoxine) or its active form, pyridoxal phosphate (PLP), are often tried, as PLP normally assists AADC in its role as a cofactor and might therefore increase the residual activity of the enzyme. Other medications might be considered depending on the patient. For example, melatonin can be tried for sleep disturbances, and benzodiazepines (a class of medication that acts as central nervous system depressants) or anticholinergics (which counteract activity of acetylcholine, a neurotransmitter) might help patients with oculogyric crises and other motor symptoms. A key factor for the optimal management of AADC deficiency is to adopt a multidisciplinary approach to address the specific needs of the affected individual. Members of the team commonly include physiotherapists, speech therapists, dieticians, psychologists, social workers, and physiatrists (physicians specialized in rehabilitation). | Therapies of Aromatic L-Amino Acid Decarboxylase Deficiency. Treatment & Management
Although there is currently no cure for AADC deficiency, numerous medications can help manage the symptoms. The optimal medication regimen greatly varies among affected individuals. There is limited scientific evidence for the efficacy of most treatment options due to the rarity of the disease. Each patient needs to have a personalized approach and should be followed by a pediatric neurologist and potentially many other physicians to assist in trials of medications to determine the best combination on a case-by-case basis. Some of the most commonly used treatments include medications to increase the concentration of dopamine in the nervous system (dopamine agonists) or to decrease its degradation (monoamine oxidase B [MAO-B] inhibitors). Vitamin B6 (pyridoxine) or its active form, pyridoxal phosphate (PLP), are often tried, as PLP normally assists AADC in its role as a cofactor and might therefore increase the residual activity of the enzyme. Other medications might be considered depending on the patient. For example, melatonin can be tried for sleep disturbances, and benzodiazepines (a class of medication that acts as central nervous system depressants) or anticholinergics (which counteract activity of acetylcholine, a neurotransmitter) might help patients with oculogyric crises and other motor symptoms. A key factor for the optimal management of AADC deficiency is to adopt a multidisciplinary approach to address the specific needs of the affected individual. Members of the team commonly include physiotherapists, speech therapists, dieticians, psychologists, social workers, and physiatrists (physicians specialized in rehabilitation). | 101 | Aromatic L-Amino Acid Decarboxylase Deficiency |
nord_102_0 | Overview of Arterial Tortuosity Syndrome | SummaryArterial tortuosity syndrome (ATS) is an extremely rare genetic disorder characterized by lengthening (elongation) and twisting or distortion (tortuosity) of arteries throughout the body. Arteries are the blood vessels that carry oxygen-rich blood away from the heart. Affected arteries are prone to developing balloon-like bulges (aneurysms) on the wall of the artery, tearing (dissection), or narrowing (stenosis). The main artery that carries blood from the heart and to the rest of the body (aorta) can be affected. The pulmonary arteries are especially prone to narrowing. Additional symptoms affecting connective tissues entering in multiple systems of the body can also be present. Affected individuals may have distinctive facial features that are noticeable at birth or during early childhood. Arterial tortuosity syndrome can potentially cause severe life-threatening complications during infancy or early childhood, although individuals with milder symptoms have also been described. Arterial tortuosity syndrome is caused by mutations in the SLC2A10 gene and is inherited in an autosomal recessive manner.IntroductionArterial tortuosity syndrome is a connective tissue disorder. Connective tissues are the major components of the body forming skeleton, joints, skin, vessels, and other organs. Connective tissues are characterized by the presence of cells included in an extracellular matrix network of a large variety of proteins (i.e., collagens), proteins bound to sugars chains of big dimension (proteoglycans), and sugars (hyaluronic acid, etc.). This complex mesh of molecules gives the tissue form and strength and ensures the passage of nutrients and factors controlling cell growth and proliferation. | Overview of Arterial Tortuosity Syndrome. SummaryArterial tortuosity syndrome (ATS) is an extremely rare genetic disorder characterized by lengthening (elongation) and twisting or distortion (tortuosity) of arteries throughout the body. Arteries are the blood vessels that carry oxygen-rich blood away from the heart. Affected arteries are prone to developing balloon-like bulges (aneurysms) on the wall of the artery, tearing (dissection), or narrowing (stenosis). The main artery that carries blood from the heart and to the rest of the body (aorta) can be affected. The pulmonary arteries are especially prone to narrowing. Additional symptoms affecting connective tissues entering in multiple systems of the body can also be present. Affected individuals may have distinctive facial features that are noticeable at birth or during early childhood. Arterial tortuosity syndrome can potentially cause severe life-threatening complications during infancy or early childhood, although individuals with milder symptoms have also been described. Arterial tortuosity syndrome is caused by mutations in the SLC2A10 gene and is inherited in an autosomal recessive manner.IntroductionArterial tortuosity syndrome is a connective tissue disorder. Connective tissues are the major components of the body forming skeleton, joints, skin, vessels, and other organs. Connective tissues are characterized by the presence of cells included in an extracellular matrix network of a large variety of proteins (i.e., collagens), proteins bound to sugars chains of big dimension (proteoglycans), and sugars (hyaluronic acid, etc.). This complex mesh of molecules gives the tissue form and strength and ensures the passage of nutrients and factors controlling cell growth and proliferation. | 102 | Arterial Tortuosity Syndrome |
nord_102_1 | Symptoms of Arterial Tortuosity Syndrome | Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about ATS is not fully understood. Several factors including the small number of identified affected individuals, 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.Nevertheless, life expectancy seems to be longer than initially observed and in adolescence/adulthood life-threatening cardiovascular events seem to be rare; in adulthood complications commonly observed are chronic systemic and pulmonary hypertension, heart conduction defects, aortic root dilatation, stroke, and intracranial aneurysms. The first few months/years of life appear to be the most critical for possible life-threatening events, particularly complications related to stenosis of the pulmonary arteries (PAS) such as acute respiratory symptoms.It is important to note that affected individuals may not have all of the symptoms discussed below. For example, affected individuals may have uncomplicated arterial tortuosity without extravascular symptoms or only mild ones. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis. The specific symptoms and severity of ATS can vary greatly from one person to another depending, in part, upon the specific arteries that are affected. Usually, large or medium sized arteries are affected such as the aorta, the pulmonary arteries, the carotid artery, and kidney (renal) arteries. In extremely rare cases, blood vessels within the skull can be affected (intracranial arteries). Affected arteries can be abnormally lengthened causing them to become twisted or distorted, possibly forming kinks and loops. The patients with tortuous arteries are prone to aneurysm formation, dissection and ischemic events and other various cardiovascular and respiratory complications. Cardiovascular complications can include high blood pressure of various blood vessels throughout the body (systemic hypertension), enlargement of one of the right chambers (ventricles) of the heart (ventricular hypertrophy), stroke, and tissue death caused by lack of oxygen (infarction). Respiratory complications can include acute respiratory symptoms such as repeated pulmonary infections and difficulty breathing or respiratory distress. Eventually, in severe cases, cardiac or respiratory failure can occur.Individuals with ATS often have distinctive facial features such as an elongated face, beaked nose, highly arched palate, small chin (micrognathia), an abnormally long groove between the nose and upper lip (long philtrum), widely spaced eyes (hypertelorism), downslanted palpebral fissures, eyelids that are abnormally narrowed horizontally (blepharophimosis or periorbital fullness), an abnormally enlarged head (macrocephaly) and a highly arched roof of the mouth (palate) and dental crowding. Less often, individuals may develop progressive changes in the shape of the cornea (keratoconus), resulting in blurred vision and other vision problems.The skin of individuals with ATS may be soft, velvety/silky, and easily stretched (hyperextensible or hyperelastic) to a variable extent. Abnormal scarring due to diminished wound healing can occur with atrophic scars. Skeletal malformations may occur including abnormally long, thin and curved fingers and toes (arachnodactyly), joints that are permanently fixed in a flexed or straightened position (joint contractures especially of knees and elbows), loose (lax) joints, a sunken chest or a chest that protrudes outward, abnormal sideways curvature of the spine (scoliosis), and indentation or protrusion of the chest wall (pectus excavatum/carinatum)Additional symptoms have been reported in individuals with ATS in some cases. Such symptoms include the development of small, sac-like protrusions or bulges (diverticuli) in the genitourinary tract, protrusion of abdominal tissue or part of the small intestines through a bulge or tear in the abdominal muscles near the groin (inguinal hernias), protrusion of part of the stomach into the chest through an opening in the diaphragm (hiatal hernia), softening or weakening of the cartilage of the trachea (tracheomalacia), and decreased muscle tone (generalized hypotonia). | Symptoms of Arterial Tortuosity Syndrome. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about ATS is not fully understood. Several factors including the small number of identified affected individuals, 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.Nevertheless, life expectancy seems to be longer than initially observed and in adolescence/adulthood life-threatening cardiovascular events seem to be rare; in adulthood complications commonly observed are chronic systemic and pulmonary hypertension, heart conduction defects, aortic root dilatation, stroke, and intracranial aneurysms. The first few months/years of life appear to be the most critical for possible life-threatening events, particularly complications related to stenosis of the pulmonary arteries (PAS) such as acute respiratory symptoms.It is important to note that affected individuals may not have all of the symptoms discussed below. For example, affected individuals may have uncomplicated arterial tortuosity without extravascular symptoms or only mild ones. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis. The specific symptoms and severity of ATS can vary greatly from one person to another depending, in part, upon the specific arteries that are affected. Usually, large or medium sized arteries are affected such as the aorta, the pulmonary arteries, the carotid artery, and kidney (renal) arteries. In extremely rare cases, blood vessels within the skull can be affected (intracranial arteries). Affected arteries can be abnormally lengthened causing them to become twisted or distorted, possibly forming kinks and loops. The patients with tortuous arteries are prone to aneurysm formation, dissection and ischemic events and other various cardiovascular and respiratory complications. Cardiovascular complications can include high blood pressure of various blood vessels throughout the body (systemic hypertension), enlargement of one of the right chambers (ventricles) of the heart (ventricular hypertrophy), stroke, and tissue death caused by lack of oxygen (infarction). Respiratory complications can include acute respiratory symptoms such as repeated pulmonary infections and difficulty breathing or respiratory distress. Eventually, in severe cases, cardiac or respiratory failure can occur.Individuals with ATS often have distinctive facial features such as an elongated face, beaked nose, highly arched palate, small chin (micrognathia), an abnormally long groove between the nose and upper lip (long philtrum), widely spaced eyes (hypertelorism), downslanted palpebral fissures, eyelids that are abnormally narrowed horizontally (blepharophimosis or periorbital fullness), an abnormally enlarged head (macrocephaly) and a highly arched roof of the mouth (palate) and dental crowding. Less often, individuals may develop progressive changes in the shape of the cornea (keratoconus), resulting in blurred vision and other vision problems.The skin of individuals with ATS may be soft, velvety/silky, and easily stretched (hyperextensible or hyperelastic) to a variable extent. Abnormal scarring due to diminished wound healing can occur with atrophic scars. Skeletal malformations may occur including abnormally long, thin and curved fingers and toes (arachnodactyly), joints that are permanently fixed in a flexed or straightened position (joint contractures especially of knees and elbows), loose (lax) joints, a sunken chest or a chest that protrudes outward, abnormal sideways curvature of the spine (scoliosis), and indentation or protrusion of the chest wall (pectus excavatum/carinatum)Additional symptoms have been reported in individuals with ATS in some cases. Such symptoms include the development of small, sac-like protrusions or bulges (diverticuli) in the genitourinary tract, protrusion of abdominal tissue or part of the small intestines through a bulge or tear in the abdominal muscles near the groin (inguinal hernias), protrusion of part of the stomach into the chest through an opening in the diaphragm (hiatal hernia), softening or weakening of the cartilage of the trachea (tracheomalacia), and decreased muscle tone (generalized hypotonia). | 102 | Arterial Tortuosity Syndrome |
nord_102_2 | Causes of Arterial Tortuosity Syndrome | Arterial tortuosity syndrome is caused by mutations in the SLC2A10 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.To date, a total of 35 mutations in approximately 80 families have been identified in the SLC2A10 gene. The SLC2A10 gene creates (encodes) a protein known as facilitative glucose transporter 10 (GLUT10) that regulates the transport of sugars (i.e., glucose) and dehydroascorbic acid (DAA), the oxidized form of vitamin C, across cellular membranes. Mutation(s) in SLC2A10 lead to low levels of functional GLUT10 protein in ATS patients. Although the pathogenic mechanism underlying all the SLC2A10 mutations is the loss of GLUT10 function, the specific role of the GLUT10 transporter in the pathogenesis of ATS is still debated.Mutations in the SLC2A10 gene are inherited in an autosomal recessive pattern. 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.In 2015, a study, performed on skin fibroblasts (a type of cell found in connective tissue that synthesizes the extracellular matrix, collagens, and other proteins) derived from ATS patients, showed that the lack of GLUT10 protein perturbs the canonical transforming growth factor beta (TGFβ) pathway and causes the disorganization of different structural proteins (i.e., collagens, elastin, fibronectin, decorin), essential for the structural integrity of several connective tissues including blood vessels wall. In addition, molecular findings, obtained by analyzing all mRNAs in skin fibroblasts of different ATS patients, revealed that the lack of GLUT10 alters TGFβ signaling, extracellular matrix integrity, expression of genes that influence the lipid metabolism, and related to the cellular response against the oxidative stress (maintenance of intracellular redox homeostasis).Moreover, in 2016 it was demonstrated that the GLUT10 is able to transport DAA across cellular endomembranes system (i.e., endoplasmic reticulum, and nuclear envelope). DAA is the oxidized form of vitamin C (ascorbic acid). Vitamin C is an essential nutrient for humans that acts both as a potent antioxidant, which protects cells from oxidative damage by acting as a scavenger of different free radicals, and as a cofactor essential for the function of enzymes (proteins) that are involved in the synthesis (production) of collagens and elastin proteins. The exact manner in which deficient levels of GLUT10 results in the signs and symptoms of ATS is not fully understood, but it is speculated that the decrease of vitamin C inside the cells lacking GLUT10 leads to the altered production of collagens and elastin, the main structural components of the extracellular matrix of connective tissues and of blood vessels, thus affecting the structural integrity of the wall of the main arteries (i.e., aorta, pulmonary arteries). Finally, in 2019 it was demonstrated that the decreased nuclear ascorbate accumulation in dermal fibroblasts from ATS patients is accompanied with altered genomic methylation pattern, strongly suggesting an epigenetic role of ascorbic acid transport in the disease pathomechanism. In view of all these observations, ATS is considered as an ascorbate compartmentalization disorder. | Causes of Arterial Tortuosity Syndrome. Arterial tortuosity syndrome is caused by mutations in the SLC2A10 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.To date, a total of 35 mutations in approximately 80 families have been identified in the SLC2A10 gene. The SLC2A10 gene creates (encodes) a protein known as facilitative glucose transporter 10 (GLUT10) that regulates the transport of sugars (i.e., glucose) and dehydroascorbic acid (DAA), the oxidized form of vitamin C, across cellular membranes. Mutation(s) in SLC2A10 lead to low levels of functional GLUT10 protein in ATS patients. Although the pathogenic mechanism underlying all the SLC2A10 mutations is the loss of GLUT10 function, the specific role of the GLUT10 transporter in the pathogenesis of ATS is still debated.Mutations in the SLC2A10 gene are inherited in an autosomal recessive pattern. 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.In 2015, a study, performed on skin fibroblasts (a type of cell found in connective tissue that synthesizes the extracellular matrix, collagens, and other proteins) derived from ATS patients, showed that the lack of GLUT10 protein perturbs the canonical transforming growth factor beta (TGFβ) pathway and causes the disorganization of different structural proteins (i.e., collagens, elastin, fibronectin, decorin), essential for the structural integrity of several connective tissues including blood vessels wall. In addition, molecular findings, obtained by analyzing all mRNAs in skin fibroblasts of different ATS patients, revealed that the lack of GLUT10 alters TGFβ signaling, extracellular matrix integrity, expression of genes that influence the lipid metabolism, and related to the cellular response against the oxidative stress (maintenance of intracellular redox homeostasis).Moreover, in 2016 it was demonstrated that the GLUT10 is able to transport DAA across cellular endomembranes system (i.e., endoplasmic reticulum, and nuclear envelope). DAA is the oxidized form of vitamin C (ascorbic acid). Vitamin C is an essential nutrient for humans that acts both as a potent antioxidant, which protects cells from oxidative damage by acting as a scavenger of different free radicals, and as a cofactor essential for the function of enzymes (proteins) that are involved in the synthesis (production) of collagens and elastin proteins. The exact manner in which deficient levels of GLUT10 results in the signs and symptoms of ATS is not fully understood, but it is speculated that the decrease of vitamin C inside the cells lacking GLUT10 leads to the altered production of collagens and elastin, the main structural components of the extracellular matrix of connective tissues and of blood vessels, thus affecting the structural integrity of the wall of the main arteries (i.e., aorta, pulmonary arteries). Finally, in 2019 it was demonstrated that the decreased nuclear ascorbate accumulation in dermal fibroblasts from ATS patients is accompanied with altered genomic methylation pattern, strongly suggesting an epigenetic role of ascorbic acid transport in the disease pathomechanism. In view of all these observations, ATS is considered as an ascorbate compartmentalization disorder. | 102 | Arterial Tortuosity Syndrome |
nord_102_3 | Affects of Arterial Tortuosity Syndrome | Arterial tortuosity syndrome affects males and females in equal numbers. Approximately 100 cases have been reported in the medical literature. The exact incidence and prevalence is unknown. The male to female ratio is 1:1. Because affected individuals may go undiagnosed or misdiagnosed, determining the true frequency of arterial tortuosity syndrome in the general population is difficult. Onset is usually in infancy or early childhood. | Affects of Arterial Tortuosity Syndrome. Arterial tortuosity syndrome affects males and females in equal numbers. Approximately 100 cases have been reported in the medical literature. The exact incidence and prevalence is unknown. The male to female ratio is 1:1. Because affected individuals may go undiagnosed or misdiagnosed, determining the true frequency of arterial tortuosity syndrome in the general population is difficult. Onset is usually in infancy or early childhood. | 102 | Arterial Tortuosity Syndrome |
nord_102_4 | Related disorders of Arterial Tortuosity Syndrome | Symptoms of the following disorders can be similar to those of arterial tortuosity syndrome. Comparisons may be useful for a differential diagnosis.Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disorder characterized by a variety of symptoms that overlap with arterial tortuosity syndrome. Individuals with LDS have skeletal and cardiovascular abnormalities. Affected individuals may experience bulging of the wall of the thoracic aorta (aneurysm), tearing (dissection) of the aorta or rupture of the aorta. The aorta in individuals with LDS is prone to tearing or rupturing early in childhood and at a relatively small size. Affected blood vessels tend to follow a very winding course (tortuosity) and aneurysms and tears of blood vessels can occur throughout the entire arterial tree. Additional findings that may occur include long, slender fingers (arachnodactyly), abnormal curvature of the spine (scoliosis), a sunken or protruding chest (pectus excavatum or pectus carinatum), widening of the spinal sac (dural ectasia), and loose joints. Additional symptoms include accumulation of excessive cerebrospinal fluid (CSF) in the skull causing pressure on the tissues of the brain (hydrocephalus), incomplete closure of the roof of the mouth (cleft palate), premature closure of the fibrous joints (sutures) between certain bones of the skull (craniosynostosis), bluish discoloration of the whites of the eyes (blue sclerae), deviation of one of the eyes outward away from the other eye (exotropia) and abnormally formed or unstable joints in the spine of the neck (cervical spine malformation or instability). The fleshy mass (uvula) hanging in the back of the throat may be unusually broad or split (bifid uvula). Characteristic facial features often include widely spaced eyes (hypertelorism), high palate, an abnormally small jaw (micrognathia) that is recessed farther back than normal (retrognathia), and underdeveloped cheek bones (malar hypoplasia). The skin in LDS can be soft with easily visible underlying veins (translucency). The skin also tends to bruise easily and to develop abnormal (wide) scars. People with LDS can be prone to severe allergies and to inflammation of the gastrointestinal tract (eosinophilic esophagitis or colitis). LDS is inherited as an autosomal dominant trait and is caused by mutations in any of the 6 genes that are all known to influence the activity of TGFβ (TGFBR1, TGFBR2, SMAD3, TGFB2,TGFB3, or SMAD2).Marfan syndrome (MFS) is a genetic disorder that affects connective tissues. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), pectus excavatum/carinatum, dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse), and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of MFS vary greatly from person to person. MFS is inherited as an autosomal dominant trait, meaning that only one abnormal copy of the Marfan gene inherited from one parent is sufficient to have the condition. Defects or disruptions (mutations) of the fibrillin-1 (FBN1) gene have been linked to MFS. (For more information on this disorder, choose “Marfan” as your search term in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by defects of the major structural proteins in the body (collagens). Collagens, tough, fibrous proteins, play 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. In the medical literature six major EDS subtypes, and more recently a total of 13 subtypes including very rare forms, based upon clinical evidence, mode of inheritance, and gene involved are reported. Each subtype of EDS is a distinct hereditary disorder that may affect individuals within certain families (kindreds). Depending upon the specific subtype present, EDS 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.)Autosomal recessive Cutis laxa type 1 is a rare autosomal recessive connective tissue disorder characterized by generalized, sagging redundant skin and severe systemic complication including pulmonary emphysema in early life, arterial aneurysms, fibromuscular artery dysplasia and stenosis leading to progressive heart failure. Genitourinary tract diverticuli lead to vesicoureteral reflux and recurrent infections. Less frequent findings include late closure of the fontanel, joint laxity, hip dislocation, inguinal hernia, arachnodactyly, bone fragility, vascular tortuosity and aortic aneurysm. Intelligence is normal.There are many additional disorders in which similar skin symptoms occur. Such disorders include autosomal recessive Cutis laxa type 2 and 3, Menkes 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, Patterson pseudoleprechaunism syndrome, Costello syndrome, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome, and ablepharon-macrostomia syndrome. These disorders have other features that can clearly distinguish them from arterial tortuosity 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 Arterial Tortuosity Syndrome. Symptoms of the following disorders can be similar to those of arterial tortuosity syndrome. Comparisons may be useful for a differential diagnosis.Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disorder characterized by a variety of symptoms that overlap with arterial tortuosity syndrome. Individuals with LDS have skeletal and cardiovascular abnormalities. Affected individuals may experience bulging of the wall of the thoracic aorta (aneurysm), tearing (dissection) of the aorta or rupture of the aorta. The aorta in individuals with LDS is prone to tearing or rupturing early in childhood and at a relatively small size. Affected blood vessels tend to follow a very winding course (tortuosity) and aneurysms and tears of blood vessels can occur throughout the entire arterial tree. Additional findings that may occur include long, slender fingers (arachnodactyly), abnormal curvature of the spine (scoliosis), a sunken or protruding chest (pectus excavatum or pectus carinatum), widening of the spinal sac (dural ectasia), and loose joints. Additional symptoms include accumulation of excessive cerebrospinal fluid (CSF) in the skull causing pressure on the tissues of the brain (hydrocephalus), incomplete closure of the roof of the mouth (cleft palate), premature closure of the fibrous joints (sutures) between certain bones of the skull (craniosynostosis), bluish discoloration of the whites of the eyes (blue sclerae), deviation of one of the eyes outward away from the other eye (exotropia) and abnormally formed or unstable joints in the spine of the neck (cervical spine malformation or instability). The fleshy mass (uvula) hanging in the back of the throat may be unusually broad or split (bifid uvula). Characteristic facial features often include widely spaced eyes (hypertelorism), high palate, an abnormally small jaw (micrognathia) that is recessed farther back than normal (retrognathia), and underdeveloped cheek bones (malar hypoplasia). The skin in LDS can be soft with easily visible underlying veins (translucency). The skin also tends to bruise easily and to develop abnormal (wide) scars. People with LDS can be prone to severe allergies and to inflammation of the gastrointestinal tract (eosinophilic esophagitis or colitis). LDS is inherited as an autosomal dominant trait and is caused by mutations in any of the 6 genes that are all known to influence the activity of TGFβ (TGFBR1, TGFBR2, SMAD3, TGFB2,TGFB3, or SMAD2).Marfan syndrome (MFS) is a genetic disorder that affects connective tissues. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), pectus excavatum/carinatum, dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse), and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of MFS vary greatly from person to person. MFS is inherited as an autosomal dominant trait, meaning that only one abnormal copy of the Marfan gene inherited from one parent is sufficient to have the condition. Defects or disruptions (mutations) of the fibrillin-1 (FBN1) gene have been linked to MFS. (For more information on this disorder, choose “Marfan” as your search term in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by defects of the major structural proteins in the body (collagens). Collagens, tough, fibrous proteins, play 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. In the medical literature six major EDS subtypes, and more recently a total of 13 subtypes including very rare forms, based upon clinical evidence, mode of inheritance, and gene involved are reported. Each subtype of EDS is a distinct hereditary disorder that may affect individuals within certain families (kindreds). Depending upon the specific subtype present, EDS 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.)Autosomal recessive Cutis laxa type 1 is a rare autosomal recessive connective tissue disorder characterized by generalized, sagging redundant skin and severe systemic complication including pulmonary emphysema in early life, arterial aneurysms, fibromuscular artery dysplasia and stenosis leading to progressive heart failure. Genitourinary tract diverticuli lead to vesicoureteral reflux and recurrent infections. Less frequent findings include late closure of the fontanel, joint laxity, hip dislocation, inguinal hernia, arachnodactyly, bone fragility, vascular tortuosity and aortic aneurysm. Intelligence is normal.There are many additional disorders in which similar skin symptoms occur. Such disorders include autosomal recessive Cutis laxa type 2 and 3, Menkes 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, Patterson pseudoleprechaunism syndrome, Costello syndrome, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome, and ablepharon-macrostomia syndrome. These disorders have other features that can clearly distinguish them from arterial tortuosity 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.) | 102 | Arterial Tortuosity Syndrome |
nord_102_5 | Diagnosis of Arterial Tortuosity Syndrome | A diagnosis of ATS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests and SLC2A10 gene molecular analysis.Clinical Testing and WorkupMicroscopic (histologic) examination of affected arteries can reveal disruption of elastic fibers of affected arterial walls.A diagnosis of ATS requires a variety of specialized tests to assess the extent of the disease. Such tests include echocardiography, angiography, magnetic resonance angiography (MRA), and computed tomography (CT) scan. During echocardiography, sound waves are bounced off the heart (echoes), enabling physicians to study cardiac function and motion. Angiographies are traditional x-rays designed to evaluate the health and function of blood vessels. An MRA is done with the same equipment use for magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular structures or tissues within the body. An MRA provides detailed information about blood vessels. In some cases, before the scan, an intravenous line is inserted into a vein to release a special dye (contrast). This contrast highlights the blood vessels, thereby enhancing the results of the scan. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.Molecular genetic testing confirms or excludes a diagnosis of ATS. Molecular genetic testing can detect mutations in the SLC2A10 gene known to cause the disorder but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Arterial Tortuosity Syndrome. A diagnosis of ATS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests and SLC2A10 gene molecular analysis.Clinical Testing and WorkupMicroscopic (histologic) examination of affected arteries can reveal disruption of elastic fibers of affected arterial walls.A diagnosis of ATS requires a variety of specialized tests to assess the extent of the disease. Such tests include echocardiography, angiography, magnetic resonance angiography (MRA), and computed tomography (CT) scan. During echocardiography, sound waves are bounced off the heart (echoes), enabling physicians to study cardiac function and motion. Angiographies are traditional x-rays designed to evaluate the health and function of blood vessels. An MRA is done with the same equipment use for magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular structures or tissues within the body. An MRA provides detailed information about blood vessels. In some cases, before the scan, an intravenous line is inserted into a vein to release a special dye (contrast). This contrast highlights the blood vessels, thereby enhancing the results of the scan. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.Molecular genetic testing confirms or excludes a diagnosis of ATS. Molecular genetic testing can detect mutations in the SLC2A10 gene known to cause the disorder but is available only as a diagnostic service at specialized laboratories. | 102 | Arterial Tortuosity Syndrome |
nord_102_6 | Therapies of Arterial Tortuosity Syndrome | Treatment
The treatment of arterial tortuosity 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, neurologists, cardiologists, pneumologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Based on a literature review, complications have rarely been observed during cardiovascular surgery in ATS patients, and the risk of fatal events should be similar to the general population.Other treatment is symptomatic and supportive and can include surgery to repair hernias, skeletal malformations, or intestinal diverticula.Obstetric aspects of ATS have not been elucidated, to date in literature are reported 4 ATS women with successful pregnancy and uncomplicated deliveries. These data suggest that in ATS, pregnancy can be safely handled with multidisciplinary management including close maternal and fetal surveillance. | Therapies of Arterial Tortuosity Syndrome. Treatment
The treatment of arterial tortuosity 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, neurologists, cardiologists, pneumologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Based on a literature review, complications have rarely been observed during cardiovascular surgery in ATS patients, and the risk of fatal events should be similar to the general population.Other treatment is symptomatic and supportive and can include surgery to repair hernias, skeletal malformations, or intestinal diverticula.Obstetric aspects of ATS have not been elucidated, to date in literature are reported 4 ATS women with successful pregnancy and uncomplicated deliveries. These data suggest that in ATS, pregnancy can be safely handled with multidisciplinary management including close maternal and fetal surveillance. | 102 | Arterial Tortuosity Syndrome |
nord_103_0 | Overview of Arteriovenous Malformation | Arteriovenous malformation (AVM) is a vascular lesion that is a tangle of vessels of varying sizes in which there is one or more direct connections between the arterial and venous circulations. In the lesion there is no capillary bed, which is part of normal tissue. Brain AVMs are often presumed to be congenital, but there is no direct evidence that they form in utero. The distribution of age at detection for brain AVMs is normally-distributed with the mean age in the mid-30’s. Although a small number of AVMs manifest themselves at or shortly after birth, most of them present later in life, and just as likely, form and progress during the later years of life. The lack of capillaries allows blood traveling through the abnormal fistulous connections to flow rapidly. The low resistance of the direct A-V connections, termed fistulas, results in very high flow rates in the vessels leading to and within the AVM. These high flow rates can lower the pressure in the arteries leading to the AVM and to surrounding relatively normal brain tissue. Further, because of the direct A-V connections, the pressure in the arteries, even if somewhat reduced, are transmitted to the veins draining the AVM and surrounding brain, which normally operate at very low pressures. AVM can occur in many different parts of the body, but those located in the central nervous system (brain and spinal cord) can cause problems that affect the brain like other forms of stroke. | Overview of Arteriovenous Malformation. Arteriovenous malformation (AVM) is a vascular lesion that is a tangle of vessels of varying sizes in which there is one or more direct connections between the arterial and venous circulations. In the lesion there is no capillary bed, which is part of normal tissue. Brain AVMs are often presumed to be congenital, but there is no direct evidence that they form in utero. The distribution of age at detection for brain AVMs is normally-distributed with the mean age in the mid-30’s. Although a small number of AVMs manifest themselves at or shortly after birth, most of them present later in life, and just as likely, form and progress during the later years of life. The lack of capillaries allows blood traveling through the abnormal fistulous connections to flow rapidly. The low resistance of the direct A-V connections, termed fistulas, results in very high flow rates in the vessels leading to and within the AVM. These high flow rates can lower the pressure in the arteries leading to the AVM and to surrounding relatively normal brain tissue. Further, because of the direct A-V connections, the pressure in the arteries, even if somewhat reduced, are transmitted to the veins draining the AVM and surrounding brain, which normally operate at very low pressures. AVM can occur in many different parts of the body, but those located in the central nervous system (brain and spinal cord) can cause problems that affect the brain like other forms of stroke. | 103 | Arteriovenous Malformation |
nord_103_1 | Symptoms of Arteriovenous Malformation | Symptoms of AVM occur only after a highly variable amount of damage to the brain or spinal cord has occurred: this ranges from minor symptoms such as headache to devastating rupture with hemorrhagic stroke. A small percentage of AVMs are detected incidentally during investigation of unrelated medical problems and are completely asymptomatic. AVMs cause damage to the brain or spinal cord by several mechanisms: directly reducing oxygen to neurological tissues through (a) a change in vascular pressures; (b) compression of adjacent neural tissue by the abnormal vascular structures of the AVM; (c) bleeding (hemorrhage) into surrounding tissues. Bleeding has several adverse effects including exerting pressure on adjacent neural tissue and also by leaving toxic blood products in contact with neural tissue. Seizures are the presenting symptom in 15-40% of individuals with AVM. Cerebral hemorrhage can occur when an AVM ruptures and a large amount of blood is released into the brain. Brain hemorrhage causes the presenting symptoms in roughly half of patients with a brain AVM. The risk for cerebral hemorrhage in individuals with AVM is approximately 2-4% per year, but there is a very wide range of bleeding risks depending on the anatomic and physiologic characteristics of the AVM. The annualized rates vary from below 1% to as high as 30%. Seizures are the second most important presentation of AVMs. Headache occurs in 10-50% of those with AVM and may be the presenting symptom. There is no tell-tale (pathognomonic) pattern for seizure or headache. Not all of the headaches that bring AVMs to clinical attention are due to the lesion. It is often difficult to know if the headaches are related to the AVM. Other neurological symptoms sometimes occur depending on the location of the AVM. These symptoms can include muscle weakness or paralysis in one area of the body; Symptoms also include, but are not limited to, loss of coordination (ataxia) sometimes leading to difficulty walking; difficulty planning tasks (apraxia); dizziness; vision problems; difficulty speaking or understanding others (aphasia); numbness, tingling or pain; memory problems; mental confusion, hallucinations or dementia. One retrospective study demonstrated that approximately two-thirds of individuals with AVM have a history of mild learning disabilities in childhood or adolescence. Spinal AVMs can present in a number of ways, including sudden and severe back pain that can cause sensory loss, muscle weakness, localized paralysis, or a more gradual onset of neurological problems in sensation or motor function in the extremities. | Symptoms of Arteriovenous Malformation. Symptoms of AVM occur only after a highly variable amount of damage to the brain or spinal cord has occurred: this ranges from minor symptoms such as headache to devastating rupture with hemorrhagic stroke. A small percentage of AVMs are detected incidentally during investigation of unrelated medical problems and are completely asymptomatic. AVMs cause damage to the brain or spinal cord by several mechanisms: directly reducing oxygen to neurological tissues through (a) a change in vascular pressures; (b) compression of adjacent neural tissue by the abnormal vascular structures of the AVM; (c) bleeding (hemorrhage) into surrounding tissues. Bleeding has several adverse effects including exerting pressure on adjacent neural tissue and also by leaving toxic blood products in contact with neural tissue. Seizures are the presenting symptom in 15-40% of individuals with AVM. Cerebral hemorrhage can occur when an AVM ruptures and a large amount of blood is released into the brain. Brain hemorrhage causes the presenting symptoms in roughly half of patients with a brain AVM. The risk for cerebral hemorrhage in individuals with AVM is approximately 2-4% per year, but there is a very wide range of bleeding risks depending on the anatomic and physiologic characteristics of the AVM. The annualized rates vary from below 1% to as high as 30%. Seizures are the second most important presentation of AVMs. Headache occurs in 10-50% of those with AVM and may be the presenting symptom. There is no tell-tale (pathognomonic) pattern for seizure or headache. Not all of the headaches that bring AVMs to clinical attention are due to the lesion. It is often difficult to know if the headaches are related to the AVM. Other neurological symptoms sometimes occur depending on the location of the AVM. These symptoms can include muscle weakness or paralysis in one area of the body; Symptoms also include, but are not limited to, loss of coordination (ataxia) sometimes leading to difficulty walking; difficulty planning tasks (apraxia); dizziness; vision problems; difficulty speaking or understanding others (aphasia); numbness, tingling or pain; memory problems; mental confusion, hallucinations or dementia. One retrospective study demonstrated that approximately two-thirds of individuals with AVM have a history of mild learning disabilities in childhood or adolescence. Spinal AVMs can present in a number of ways, including sudden and severe back pain that can cause sensory loss, muscle weakness, localized paralysis, or a more gradual onset of neurological problems in sensation or motor function in the extremities. | 103 | Arteriovenous Malformation |
nord_103_2 | Causes of Arteriovenous Malformation | AVM are often attributed to result from an error in embryonic or fetal development, but there is no direct evidence of this assertion. No environmental risk factors have been identified for neurological AVM. AVM does not usually run in families, but somewhere on the order of 5% of AVMs may be due to autosomal dominant inheritance of a genetic mutation, most commonly hereditary hemorrhagic telangiectasia or the capillary malformation-AVM syndrome. AVM can rarely be associated with certain syndromes such as Wyburn-Mason syndrome. | Causes of Arteriovenous Malformation. AVM are often attributed to result from an error in embryonic or fetal development, but there is no direct evidence of this assertion. No environmental risk factors have been identified for neurological AVM. AVM does not usually run in families, but somewhere on the order of 5% of AVMs may be due to autosomal dominant inheritance of a genetic mutation, most commonly hereditary hemorrhagic telangiectasia or the capillary malformation-AVM syndrome. AVM can rarely be associated with certain syndromes such as Wyburn-Mason syndrome. | 103 | Arteriovenous Malformation |
nord_103_3 | Affects of Arteriovenous Malformation | AVM affects males and females in equal numbers. There does not appear to be an increased risk for particular ethnic and racial groups. The best estimates for new detection of an AVM are 1 per 100,000 population per year (about 3000 new cases detected per year in the U.S.) The population prevalence is about 10 per 100,000, i.e., there are probably about 30,000 individuals in the U.S. who harbor an AVM or have had an AVM that was treated. They occur throughout life, but the peak onset of symptoms is 35-40 years of age. | Affects of Arteriovenous Malformation. AVM affects males and females in equal numbers. There does not appear to be an increased risk for particular ethnic and racial groups. The best estimates for new detection of an AVM are 1 per 100,000 population per year (about 3000 new cases detected per year in the U.S.) The population prevalence is about 10 per 100,000, i.e., there are probably about 30,000 individuals in the U.S. who harbor an AVM or have had an AVM that was treated. They occur throughout life, but the peak onset of symptoms is 35-40 years of age. | 103 | Arteriovenous Malformation |
nord_103_4 | Related disorders of Arteriovenous Malformation | Symptoms of the following disorders can be similar to those of arteriovenous malformation. Comparisons may be useful for a differential diagnosis: Cavernous malformations are dilated blood vessels that are characterized by multiple distended “caverns” of blood that flow very slowly. The blood-filled vascular spaces are surrounded by blood vessel walls that do not have enough smooth muscle and stretchable material (elastin), so they are weak and get distended. Cavernous malformations can be located anywhere in the body, most commonly in the central nervous system and skin. (For more information about this disorder, choose “cavernous” as your search term in the Rare Disease Database.) | Related disorders of Arteriovenous Malformation. Symptoms of the following disorders can be similar to those of arteriovenous malformation. Comparisons may be useful for a differential diagnosis: Cavernous malformations are dilated blood vessels that are characterized by multiple distended “caverns” of blood that flow very slowly. The blood-filled vascular spaces are surrounded by blood vessel walls that do not have enough smooth muscle and stretchable material (elastin), so they are weak and get distended. Cavernous malformations can be located anywhere in the body, most commonly in the central nervous system and skin. (For more information about this disorder, choose “cavernous” as your search term in the Rare Disease Database.) | 103 | Arteriovenous Malformation |
nord_103_5 | Diagnosis of Arteriovenous Malformation | A variety of imaging studies are used to diagnose AVM. Noninvasive imaging technologies that are used to diagnose AVM are computed axial tomography (CT) and magnetic resonance imaging (MRI). CT is particularly useful in identifying a hemorrhage but can identify only large AVM. MRI is necessary for the initial diagnosis of AVM. Magnetic resonance angiography (MRA) can be used to determine the pattern and speed of blood flow through AVM but can miss small lesions.The current gold standard for diagnosis is X-ray angiography. This test is usually performed by placing a small tube (catheter) in the femoral artery, a large artery in the groin. A contrast agent that highlights blood vessels is injected into the blood vessels that supply the brain, then X-rays can reveal the structure of blood vessels in and around the lesion. The results of the angiogram help to determine the most appropriate treatment. An angiogram is often needed for treatment planning. | Diagnosis of Arteriovenous Malformation. A variety of imaging studies are used to diagnose AVM. Noninvasive imaging technologies that are used to diagnose AVM are computed axial tomography (CT) and magnetic resonance imaging (MRI). CT is particularly useful in identifying a hemorrhage but can identify only large AVM. MRI is necessary for the initial diagnosis of AVM. Magnetic resonance angiography (MRA) can be used to determine the pattern and speed of blood flow through AVM but can miss small lesions.The current gold standard for diagnosis is X-ray angiography. This test is usually performed by placing a small tube (catheter) in the femoral artery, a large artery in the groin. A contrast agent that highlights blood vessels is injected into the blood vessels that supply the brain, then X-rays can reveal the structure of blood vessels in and around the lesion. The results of the angiogram help to determine the most appropriate treatment. An angiogram is often needed for treatment planning. | 103 | Arteriovenous Malformation |
nord_103_6 | Therapies of Arteriovenous Malformation | TreatmentThere is no specific medical therapy currently available, but this is an area of active research. There are some promising medical therapies for AVMs outside of the brain that might one day be adapted for use to treat brain AVMs. Medications can be used to control the headaches, pain or seizures associated with AVM. Surgery may or may not be recommended on a case-by-case basis based on the estimated risks and benefits. Surgery is often necessary because if an AVM is left untreated there is a risk for hemorrhage. Three types of surgery are used for AVM, either alone or in combination. Conventional surgery (microsurgical resection) to remove the AVM is appropriate if the lesion is located in an accessible area that does not involve critically important functional areas and is relatively small in size. Endovascular embolization is a surgical technique in which the AVM is blocked off so that blood can no longer flow through it. This technique is sometimes all that is necessary to cure the AVM but often it is used as a first step prior to other types of surgery. Most North American practitioners do not use embolization as a sole therapy. Radiosurgery is a procedure in which a high dose of radiation is focused on the AVM, which sets off a gradual process that eventually closes the vessels in the lesion. Patients are not protected from spontaneous bleeding during the period of several years that it takes for closure. | Therapies of Arteriovenous Malformation. TreatmentThere is no specific medical therapy currently available, but this is an area of active research. There are some promising medical therapies for AVMs outside of the brain that might one day be adapted for use to treat brain AVMs. Medications can be used to control the headaches, pain or seizures associated with AVM. Surgery may or may not be recommended on a case-by-case basis based on the estimated risks and benefits. Surgery is often necessary because if an AVM is left untreated there is a risk for hemorrhage. Three types of surgery are used for AVM, either alone or in combination. Conventional surgery (microsurgical resection) to remove the AVM is appropriate if the lesion is located in an accessible area that does not involve critically important functional areas and is relatively small in size. Endovascular embolization is a surgical technique in which the AVM is blocked off so that blood can no longer flow through it. This technique is sometimes all that is necessary to cure the AVM but often it is used as a first step prior to other types of surgery. Most North American practitioners do not use embolization as a sole therapy. Radiosurgery is a procedure in which a high dose of radiation is focused on the AVM, which sets off a gradual process that eventually closes the vessels in the lesion. Patients are not protected from spontaneous bleeding during the period of several years that it takes for closure. | 103 | Arteriovenous Malformation |
nord_104_0 | Overview of Arteritis, Takayasu | Takayasu arteritis is a rare disorder characterized by the progressive inflammation of one or more of the larger arteries leading from the heart. The main artery of the heart (aorta) and the pulmonary (lung) artery, among others, may be affected. When this disorder causes progressive inflammation of many arteries, it is known as polyarteritis. One of the consequences of polyarteritis is the reduction of blood flow to any of several organs and/or arms and legs. Arteries in the head and arms may be affected, and this can result in the loss of the major pulse points in the body. Some people with Takayasu arteritis have irregular narrowing of portions of the large arteries (segmental stenosis) and abnormal backward flow of blood from the aorta into the left ventricle of the heart (aortic regurgitation). Other patients may have symptoms of ballooning and weakening (aneurysm) of the wall of a major vessel. | Overview of Arteritis, Takayasu. Takayasu arteritis is a rare disorder characterized by the progressive inflammation of one or more of the larger arteries leading from the heart. The main artery of the heart (aorta) and the pulmonary (lung) artery, among others, may be affected. When this disorder causes progressive inflammation of many arteries, it is known as polyarteritis. One of the consequences of polyarteritis is the reduction of blood flow to any of several organs and/or arms and legs. Arteries in the head and arms may be affected, and this can result in the loss of the major pulse points in the body. Some people with Takayasu arteritis have irregular narrowing of portions of the large arteries (segmental stenosis) and abnormal backward flow of blood from the aorta into the left ventricle of the heart (aortic regurgitation). Other patients may have symptoms of ballooning and weakening (aneurysm) of the wall of a major vessel. | 104 | Arteritis, Takayasu |
nord_104_1 | Symptoms of Arteritis, Takayasu | About half of the patients with Takayasu arteritis display a general feeling of weakness (malaise). In addition, patients may complain of muscle aches (myalgias), and joint pain (arthralgias). Progressive obstructive arterial disease and narrowing of the arteries (stenosis) may follow the initial phase of the disease. When the aorta and the major arteries in the neck (carotid arteries) are affected by Takayasu arteritis, the patient usually experiences lightheadedness, dizziness, and brief moments of unconsciousness (syncope). These symptoms are the result of a decrease in blood supply to the brain (cerebral ischemia). The pulses that are normally found in the neck and on the temples (carotid and superficial temporal pulses) may be absent. Most often, progression of the arteritis is slow so that there is sufficient time to develop adequate alternate circulation (collateral or secondary circulation). People with Takayasu arteritis may develop impairment of heart and brain function due to the insufficient flow of blood to these organs. In some cases an artery may rupture due to weakness of the vessels' wall (aneurysm), and/or difficulty speaking (aphasia) may occur. Other symptoms may include episodes of blindness, dim vision, and an abnormal sensitivity to light (photophobia). Involvement of the arteries in the neck (brachial involvement) may cause weakness in the arms and weakness and cramps in the legs (claudication), cool skin, and the absence of pulses in the wrists (radial). Blood pressure may be very difficult to measure.Intermittent attacks of decreased blood flow to the hands and feet (Raynaud's phenomenon) typically occur in people with Takayasu arteritis. Additional symptoms may include heart murmurs (systolic) and inflammation of the blood vessels that result in nodules under the skin that are red and tender (erythema nodosum). Sometimes people with Takayasu arteritis experience cloudiness of the lens of the eyes (cataracts) at an early age, and there may be progressive weakness in the muscles and soft tissues of the face. | Symptoms of Arteritis, Takayasu. About half of the patients with Takayasu arteritis display a general feeling of weakness (malaise). In addition, patients may complain of muscle aches (myalgias), and joint pain (arthralgias). Progressive obstructive arterial disease and narrowing of the arteries (stenosis) may follow the initial phase of the disease. When the aorta and the major arteries in the neck (carotid arteries) are affected by Takayasu arteritis, the patient usually experiences lightheadedness, dizziness, and brief moments of unconsciousness (syncope). These symptoms are the result of a decrease in blood supply to the brain (cerebral ischemia). The pulses that are normally found in the neck and on the temples (carotid and superficial temporal pulses) may be absent. Most often, progression of the arteritis is slow so that there is sufficient time to develop adequate alternate circulation (collateral or secondary circulation). People with Takayasu arteritis may develop impairment of heart and brain function due to the insufficient flow of blood to these organs. In some cases an artery may rupture due to weakness of the vessels' wall (aneurysm), and/or difficulty speaking (aphasia) may occur. Other symptoms may include episodes of blindness, dim vision, and an abnormal sensitivity to light (photophobia). Involvement of the arteries in the neck (brachial involvement) may cause weakness in the arms and weakness and cramps in the legs (claudication), cool skin, and the absence of pulses in the wrists (radial). Blood pressure may be very difficult to measure.Intermittent attacks of decreased blood flow to the hands and feet (Raynaud's phenomenon) typically occur in people with Takayasu arteritis. Additional symptoms may include heart murmurs (systolic) and inflammation of the blood vessels that result in nodules under the skin that are red and tender (erythema nodosum). Sometimes people with Takayasu arteritis experience cloudiness of the lens of the eyes (cataracts) at an early age, and there may be progressive weakness in the muscles and soft tissues of the face. | 104 | Arteritis, Takayasu |
nord_104_2 | Causes of Arteritis, Takayasu | The exact cause of Takayasu arteritis is not known. Certain laboratory findings, such as elevated levels of globulins and the presence in serum of unusual antibodies, suggest a defect in the immune system and a possible autoimmune association. Autoimmune disorders are caused when the body's natural defenses (e.g., antibodies) against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.It is thought that takayasu arteritis may also run in families and occurs with greater frequency in certain races. Studies have shown increased frequency of takayasu arteritis in Asians who have a particular antigen on chromosome 6 (HLA-Bw52). There appears to be an increase of this disorder in North Americans who carry a particular HLA (HLA-DR4). Infectious agents such as bacteria and viruses do not appear to play a role in the cause of this disorder. It may be that some people are genetically predisposed to this disease. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease.Other studies have suggested that at least some cases of Takayasu arteritis may be inherited as an autosomal recessive genetic 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. In recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is twenty-five percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. | Causes of Arteritis, Takayasu. The exact cause of Takayasu arteritis is not known. Certain laboratory findings, such as elevated levels of globulins and the presence in serum of unusual antibodies, suggest a defect in the immune system and a possible autoimmune association. Autoimmune disorders are caused when the body's natural defenses (e.g., antibodies) against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.It is thought that takayasu arteritis may also run in families and occurs with greater frequency in certain races. Studies have shown increased frequency of takayasu arteritis in Asians who have a particular antigen on chromosome 6 (HLA-Bw52). There appears to be an increase of this disorder in North Americans who carry a particular HLA (HLA-DR4). Infectious agents such as bacteria and viruses do not appear to play a role in the cause of this disorder. It may be that some people are genetically predisposed to this disease. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease.Other studies have suggested that at least some cases of Takayasu arteritis may be inherited as an autosomal recessive genetic 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. In recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is twenty-five percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. | 104 | Arteritis, Takayasu |
nord_104_3 | Affects of Arteritis, Takayasu | Takayasu arteritis is a rare disorder that affects more females than males. Approximately 80 to 90 percent of the cases affect females. This disorder is common in Japan, and occurs throughout the Orient. Takayasu arteritis has been reported in India and South America. The symptoms of this disorder typically begin between 15 and 35 years of age although it can affect children as well. It is estimated that between 2 and 3 new cases per million are recorded in the USA population per year. | Affects of Arteritis, Takayasu. Takayasu arteritis is a rare disorder that affects more females than males. Approximately 80 to 90 percent of the cases affect females. This disorder is common in Japan, and occurs throughout the Orient. Takayasu arteritis has been reported in India and South America. The symptoms of this disorder typically begin between 15 and 35 years of age although it can affect children as well. It is estimated that between 2 and 3 new cases per million are recorded in the USA population per year. | 104 | Arteritis, Takayasu |
nord_104_4 | Related disorders of Arteritis, Takayasu | Symptoms of the following disorders can be similar to those of Takayasu arteritis. Comparisons may be useful for a differential diagnosis:Giant cell arteritis is a generalized vascular disorder characterized by inflammation of the arteries resulting from the accumulation of granular tissue. This causes abnormal changes in the walls of the arteries. Inflammation is generally confined to the different branches of the aortic arch, particularly the temporal arteries. Symptoms may begin suddenly or there may be a gradual onset of low-grade fever, joint stiffness, and weakness. In some cases people may have a sore throat, cough, and/or hoarseness. Involvement of the temporal arteries may result in headache, throbbing or stabbing sensation in the temples, and scalp tenderness. (For more information on this disorder, choose “giant cell arteritis” as your search term in the Rare Disease Database.)Polymyalgia rheumatica is a rare inflammatory disorder characterized by muscle pain, stiffness, and generalized symptoms that include fatigue and fever. This disorder usually responds well to treatment with nonsteroidal anti-inflammatory drugs. Polymyalgia rheumatica generally starts abruptly with pain and stiffness in the neck, shoulders, upper arms, hips, and/or legs. Other symptoms may include a profound loss of weight (anorexia), weakness, and/or depression. (For more information on this disorder, choose “polymyalgia rheumatica” as your search term in the Rare Disease Database.)Polymyalgia nodosa (PAN) is a rare inflammatory systemic disease of the arteries characterized by the presence of lesions (granular nodules) along the length of small and medium-sized arteries. The initial symptoms may include fever, chills, fatigue, and/or weight loss. People with this disorder may also experience abdominal pain, tingling sensations in the hands and feet (peripheral neuropathy), skin eruptions, joint pain, and/or generalized muscle pain. Polymyalgia nodosa may cause narrowing of arteries that results in a lack of oxygen to various organs (ischemia), and blood clots. (For more information on this disorder, choose “polymyalgia nodosa” as your search term in the Rare Disease Database.) | Related disorders of Arteritis, Takayasu. Symptoms of the following disorders can be similar to those of Takayasu arteritis. Comparisons may be useful for a differential diagnosis:Giant cell arteritis is a generalized vascular disorder characterized by inflammation of the arteries resulting from the accumulation of granular tissue. This causes abnormal changes in the walls of the arteries. Inflammation is generally confined to the different branches of the aortic arch, particularly the temporal arteries. Symptoms may begin suddenly or there may be a gradual onset of low-grade fever, joint stiffness, and weakness. In some cases people may have a sore throat, cough, and/or hoarseness. Involvement of the temporal arteries may result in headache, throbbing or stabbing sensation in the temples, and scalp tenderness. (For more information on this disorder, choose “giant cell arteritis” as your search term in the Rare Disease Database.)Polymyalgia rheumatica is a rare inflammatory disorder characterized by muscle pain, stiffness, and generalized symptoms that include fatigue and fever. This disorder usually responds well to treatment with nonsteroidal anti-inflammatory drugs. Polymyalgia rheumatica generally starts abruptly with pain and stiffness in the neck, shoulders, upper arms, hips, and/or legs. Other symptoms may include a profound loss of weight (anorexia), weakness, and/or depression. (For more information on this disorder, choose “polymyalgia rheumatica” as your search term in the Rare Disease Database.)Polymyalgia nodosa (PAN) is a rare inflammatory systemic disease of the arteries characterized by the presence of lesions (granular nodules) along the length of small and medium-sized arteries. The initial symptoms may include fever, chills, fatigue, and/or weight loss. People with this disorder may also experience abdominal pain, tingling sensations in the hands and feet (peripheral neuropathy), skin eruptions, joint pain, and/or generalized muscle pain. Polymyalgia nodosa may cause narrowing of arteries that results in a lack of oxygen to various organs (ischemia), and blood clots. (For more information on this disorder, choose “polymyalgia nodosa” as your search term in the Rare Disease Database.) | 104 | Arteritis, Takayasu |
nord_104_5 | Diagnosis of Arteritis, Takayasu | In addition to a complete medical history and careful physical examination, any of several imaging techniques are used to evaluate the condition of the blood vessels. These include:X-ray examination to see the location and seriousness of any damage to the arteries; magnetic resonance imaging (MRI) in order to isolate and indicate vessel narrowing or aneurysms; computer axial tomography (CAT) scans to determine what damage, if any, has affected an organ of the body; and angiography, which permits the physician to see the interior of the artery to help determine the type of treatment. | Diagnosis of Arteritis, Takayasu. In addition to a complete medical history and careful physical examination, any of several imaging techniques are used to evaluate the condition of the blood vessels. These include:X-ray examination to see the location and seriousness of any damage to the arteries; magnetic resonance imaging (MRI) in order to isolate and indicate vessel narrowing or aneurysms; computer axial tomography (CAT) scans to determine what damage, if any, has affected an organ of the body; and angiography, which permits the physician to see the interior of the artery to help determine the type of treatment. | 104 | Arteritis, Takayasu |
nord_104_6 | Therapies of Arteritis, Takayasu | TreatmentWhen the diagnosis of Takayasu arteritis is suspected, treatment should begin quickly to avoid serious complications such as the blockage of arteries and/or blindness. Corticosteroid drugs usually control initial local and systemic symptoms. Prednisone and prednisolone, the preferred corticosteroids, work rapidly to reduce symptoms. However some patients are resistant to prednisone and its derivatives. The dosage of the corticosteroids is reduced over time but treatment may last for 2 years or longer to prevent recurrence. Takayasu arteritis must be carefully monitored through blood tests (sedimentation rate).Reconstructive vascular surgery, including cardiac by-pass surgery, may be helpful in selected patients with Takayasu arteritis. The surgery may provide new pathways for the arterial circulation, bypassing those vessels that have narrowed. The blood thinning drug, heparin, may be given to those patients who experience episodes of decreased blood supply to various parts of the body (ischemia). | Therapies of Arteritis, Takayasu. TreatmentWhen the diagnosis of Takayasu arteritis is suspected, treatment should begin quickly to avoid serious complications such as the blockage of arteries and/or blindness. Corticosteroid drugs usually control initial local and systemic symptoms. Prednisone and prednisolone, the preferred corticosteroids, work rapidly to reduce symptoms. However some patients are resistant to prednisone and its derivatives. The dosage of the corticosteroids is reduced over time but treatment may last for 2 years or longer to prevent recurrence. Takayasu arteritis must be carefully monitored through blood tests (sedimentation rate).Reconstructive vascular surgery, including cardiac by-pass surgery, may be helpful in selected patients with Takayasu arteritis. The surgery may provide new pathways for the arterial circulation, bypassing those vessels that have narrowed. The blood thinning drug, heparin, may be given to those patients who experience episodes of decreased blood supply to various parts of the body (ischemia). | 104 | Arteritis, Takayasu |
nord_105_0 | Overview of Arthritis, Infectious | Infectious arthritis is an inflammation of one or more joints that occurs as a result of infection by bacteria, viruses or, less frequently, fungi or parasites. The symptoms of Infectious arthritis depend upon which agent has caused the infection but symptoms often include fever, chills, general weakness, and headaches, followed by inflammation and painful swelling of one or more joints of the body.Most often, the infection begins at some other location in the body and travels via the bloodstream to the joint. Less commonly, the infection starts in the joint in the course of a surgical procedure, injection or other action. | Overview of Arthritis, Infectious. Infectious arthritis is an inflammation of one or more joints that occurs as a result of infection by bacteria, viruses or, less frequently, fungi or parasites. The symptoms of Infectious arthritis depend upon which agent has caused the infection but symptoms often include fever, chills, general weakness, and headaches, followed by inflammation and painful swelling of one or more joints of the body.Most often, the infection begins at some other location in the body and travels via the bloodstream to the joint. Less commonly, the infection starts in the joint in the course of a surgical procedure, injection or other action. | 105 | Arthritis, Infectious |
nord_105_1 | Symptoms of Arthritis, Infectious | The symptoms of infectious arthritis depend upon which agent has caused the infection. The symptoms usually include fever (which may be quite high), chills, general weakness and headaches, followed by inflammation of one or more joints. The affected joint or joints often become very painful, swollen, slightly red and stiff within a few hours or days. Rapid onset of symptoms may indicate that a bacterium is the cause. In a few people, however, the infection develops slowly, over a period of months or even years. This slower developing infection is more often the result of a viral or fungal infection than a bacterial one.Infectious arthritis that affects one joint is often, but not always, bacterial in origin. Occasionally, multiple joints may be involved. Bacterial infections appear to most often affect the larger joints: knees, ankles, shoulders, hips, elbows or wrists. The infection occurs less commonly in other, smaller joints as well. For people who already have some form of arthritis, especially rheumatoid arthritis, the infection may seem like a flare-up of their existing condition.Symptoms of infectious arthritis caused by a virus vary with the virus involved. Usually, viral arthritic infections develop more gradually and are more widespread than are bacterial infections, affecting several joints. However, some viral infections may develop quickly and affect only a few joints. In Lyme disease (one form of infectious arthritis), joint inflammation usually occurs several weeks after onset of other symptoms. (For more information on Lyme Disease, choose “Lyme” as your search term in the Rare Disease Database.) | Symptoms of Arthritis, Infectious. The symptoms of infectious arthritis depend upon which agent has caused the infection. The symptoms usually include fever (which may be quite high), chills, general weakness and headaches, followed by inflammation of one or more joints. The affected joint or joints often become very painful, swollen, slightly red and stiff within a few hours or days. Rapid onset of symptoms may indicate that a bacterium is the cause. In a few people, however, the infection develops slowly, over a period of months or even years. This slower developing infection is more often the result of a viral or fungal infection than a bacterial one.Infectious arthritis that affects one joint is often, but not always, bacterial in origin. Occasionally, multiple joints may be involved. Bacterial infections appear to most often affect the larger joints: knees, ankles, shoulders, hips, elbows or wrists. The infection occurs less commonly in other, smaller joints as well. For people who already have some form of arthritis, especially rheumatoid arthritis, the infection may seem like a flare-up of their existing condition.Symptoms of infectious arthritis caused by a virus vary with the virus involved. Usually, viral arthritic infections develop more gradually and are more widespread than are bacterial infections, affecting several joints. However, some viral infections may develop quickly and affect only a few joints. In Lyme disease (one form of infectious arthritis), joint inflammation usually occurs several weeks after onset of other symptoms. (For more information on Lyme Disease, choose “Lyme” as your search term in the Rare Disease Database.) | 105 | Arthritis, Infectious |
nord_105_2 | Causes of Arthritis, Infectious | Any disease-causing microbe may infect a joint. Bacteria are most often responsible, typically producing an acute arthritic attack. In young children the most common bacteria are staphylococci, haemophilus influenzae, and gram- negative bacilli. Older children and adults are most commonly infected with gonococci, staphylococci, streptococci or pneumococci. Acute infectious arthritis at any age may be associated with rubella, mumps or hepatitis B infections. Fungi and fungi-like bacteria such as mycobacterium tuberculosis, etc may cause chronic infectious arthritis. People with rheumatoid arthritis and chronically inflamed joints are particularly susceptible to infectious arthritis. | Causes of Arthritis, Infectious. Any disease-causing microbe may infect a joint. Bacteria are most often responsible, typically producing an acute arthritic attack. In young children the most common bacteria are staphylococci, haemophilus influenzae, and gram- negative bacilli. Older children and adults are most commonly infected with gonococci, staphylococci, streptococci or pneumococci. Acute infectious arthritis at any age may be associated with rubella, mumps or hepatitis B infections. Fungi and fungi-like bacteria such as mycobacterium tuberculosis, etc may cause chronic infectious arthritis. People with rheumatoid arthritis and chronically inflamed joints are particularly susceptible to infectious arthritis. | 105 | Arthritis, Infectious |
nord_105_3 | Affects of Arthritis, Infectious | Infectious arthritis can affect people of all ages and both sexes. About half of all cases involve adults over the age of 60. The incidence is reported as 2-10 cases per 100,000 of general population. For patients with immunologic disorders, the incidence increases to about 30-70 cases per 100,000 people. In gonococcal arthritis, the disorder is found in three times as many women as men. | Affects of Arthritis, Infectious. Infectious arthritis can affect people of all ages and both sexes. About half of all cases involve adults over the age of 60. The incidence is reported as 2-10 cases per 100,000 of general population. For patients with immunologic disorders, the incidence increases to about 30-70 cases per 100,000 people. In gonococcal arthritis, the disorder is found in three times as many women as men. | 105 | Arthritis, Infectious |
nord_105_4 | Related disorders of Arthritis, Infectious | Rheumatoid Arthritis is a chronic disease characterized by usually symmetric inflammation of the peripheral joints, which can eventually result in progressive destruction of joints. Generalized symptoms may also be present.Reiter's syndrome is arthritis associated with nonbacterial urethritis and conjunctivitis, usually seen in genetically susceptible males following recent sexual exposure. (For more information, choose “Reiter” as your search term in the Rare Disease Database.)Psoriatic Arthritis is a rheumatoid-like arthritis associated with psoriasis of the skin or nails and a negative RA serology; HLA-B27 antigen is present in most patients. (For more information, choose “Psoriatic Arthritis” as your search term in the Rare Disease Database.)Ankylosing Spondylitis (Marie-Struempell disease) is a chronic progressive form of arthritis distinguished by inflammation and eventual immobility (ankylosis) of a number of joints, primarily involving the spine and paraspinal structures. (For more information, choose “Spondylitis” as your search term in the Rare Disease Database.)Osteoarthritis (OA; Degenerative Joint Disease, DJD) is the most common form of arthritis, characterized by degenerative loss of joint cartilage, bony sclerosis beneath the cartilage, and bone proliferation at the joint margins. Secondary synovial tissue inflammation is common. | Related disorders of Arthritis, Infectious. Rheumatoid Arthritis is a chronic disease characterized by usually symmetric inflammation of the peripheral joints, which can eventually result in progressive destruction of joints. Generalized symptoms may also be present.Reiter's syndrome is arthritis associated with nonbacterial urethritis and conjunctivitis, usually seen in genetically susceptible males following recent sexual exposure. (For more information, choose “Reiter” as your search term in the Rare Disease Database.)Psoriatic Arthritis is a rheumatoid-like arthritis associated with psoriasis of the skin or nails and a negative RA serology; HLA-B27 antigen is present in most patients. (For more information, choose “Psoriatic Arthritis” as your search term in the Rare Disease Database.)Ankylosing Spondylitis (Marie-Struempell disease) is a chronic progressive form of arthritis distinguished by inflammation and eventual immobility (ankylosis) of a number of joints, primarily involving the spine and paraspinal structures. (For more information, choose “Spondylitis” as your search term in the Rare Disease Database.)Osteoarthritis (OA; Degenerative Joint Disease, DJD) is the most common form of arthritis, characterized by degenerative loss of joint cartilage, bony sclerosis beneath the cartilage, and bone proliferation at the joint margins. Secondary synovial tissue inflammation is common. | 105 | Arthritis, Infectious |
nord_105_5 | Diagnosis of Arthritis, Infectious | A thorough history and physical examination are essential for diagnosis. Blood tests as well as tests of the fluid commonly found in the joints are essential for identification of the infecting agent and to confirm diagnosis. Once the infecting agent is known, an appropriate course of treatment may be designed. | Diagnosis of Arthritis, Infectious. A thorough history and physical examination are essential for diagnosis. Blood tests as well as tests of the fluid commonly found in the joints are essential for identification of the infecting agent and to confirm diagnosis. Once the infecting agent is known, an appropriate course of treatment may be designed. | 105 | Arthritis, Infectious |
nord_105_6 | Therapies of Arthritis, Infectious | TreatmentEarly treatment is required in order to stop the spread of the infection and to avoid destruction of the joint. Successful treatment depends on early and appropriate use of antibiotics. However, examination and culture of the joint fluid should be started before therapy.The choice of antibiotic depends on the bacterial agent involved. If no organism is present and a gonococcal infection is suspected, penicillin-G is commonly used for treatment. Most clinicians prefer not to inject an antibiotic directly into a joint in order to avoid synovitis. Treatment usually is continued for at least two weeks after all symptoms and signs of inflammation have disappeared.Fluid from the joint may be cultured to confirm that the infection is gone. If a decrease of symptoms and sterilization of the joint fluid are not apparent after 48 hours of treatment, the choice and dose of the antibiotic may need to be adjusted. Surgical drainage may be indicated when needle aspiration of the joint is difficult, as in hip infections, or if the infection is not controlled after 48 hours. Splinting, in order to rest and to protect the joint, may be useful during the acute stage. Physical therapy is often useful in building up muscle strength preventing stiffness or restoring mobility.For viral infections, non-steroidal anti-inflammatories may be used to moderate pain and symptoms.Antibiotic treatment for mycobacterial or fungal arthritis is usually the same as for other serious infections by these agents. | Therapies of Arthritis, Infectious. TreatmentEarly treatment is required in order to stop the spread of the infection and to avoid destruction of the joint. Successful treatment depends on early and appropriate use of antibiotics. However, examination and culture of the joint fluid should be started before therapy.The choice of antibiotic depends on the bacterial agent involved. If no organism is present and a gonococcal infection is suspected, penicillin-G is commonly used for treatment. Most clinicians prefer not to inject an antibiotic directly into a joint in order to avoid synovitis. Treatment usually is continued for at least two weeks after all symptoms and signs of inflammation have disappeared.Fluid from the joint may be cultured to confirm that the infection is gone. If a decrease of symptoms and sterilization of the joint fluid are not apparent after 48 hours of treatment, the choice and dose of the antibiotic may need to be adjusted. Surgical drainage may be indicated when needle aspiration of the joint is difficult, as in hip infections, or if the infection is not controlled after 48 hours. Splinting, in order to rest and to protect the joint, may be useful during the acute stage. Physical therapy is often useful in building up muscle strength preventing stiffness or restoring mobility.For viral infections, non-steroidal anti-inflammatories may be used to moderate pain and symptoms.Antibiotic treatment for mycobacterial or fungal arthritis is usually the same as for other serious infections by these agents. | 105 | Arthritis, Infectious |
nord_106_0 | Overview of Arthrogryposis Multiplex Congenita | Arthrogryposis is a general or descriptive term for the development of nonprogressive contractures affecting one or more areas of the body prior to birth (congenitally). A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. When congenital contractures occur only in one body area, it is not referred to as arthrogryposis but rather an isolated congenital contracture. The most common form of an isolated congenital contracture is clubfoot. When arthrogryposis affects two or more different areas of the body, it may be referred to as arthrogryposis multiplex congenita (AMC). The most common form of AMC is amyoplasia. Arthrogryposis and arthrogryposis multiplex congenita are sometimes used interchangeably.The symptoms of AMC are present at birth (congenital). However, specific symptoms and physical findings can differ greatly in range and severity from one person to another, even within a family. In most cases, affected infants have contractures of various joints. The joints of the legs and arms are usually affected; the legs are affected more often than the arms. The joints of the shoulders, elbows, knees, wrists, ankles, fingers, toes, and/or hips are also commonly affected. In addition, the jaws and back may also be affected in individuals with AMC. In most cases, AMC occurs randomly, for no apparent reason (sporadic). More than 400 different conditions can cause isolated or multiple contractures and the causes, genetics, specific symptoms, and severity of these disorders vary dramatically. Mutations in over 400 genes have been identified as responsible for different types of arthrogryposis. These can be grouped by tissue, affected part of a cell involved, and function. | Overview of Arthrogryposis Multiplex Congenita. Arthrogryposis is a general or descriptive term for the development of nonprogressive contractures affecting one or more areas of the body prior to birth (congenitally). A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. When congenital contractures occur only in one body area, it is not referred to as arthrogryposis but rather an isolated congenital contracture. The most common form of an isolated congenital contracture is clubfoot. When arthrogryposis affects two or more different areas of the body, it may be referred to as arthrogryposis multiplex congenita (AMC). The most common form of AMC is amyoplasia. Arthrogryposis and arthrogryposis multiplex congenita are sometimes used interchangeably.The symptoms of AMC are present at birth (congenital). However, specific symptoms and physical findings can differ greatly in range and severity from one person to another, even within a family. In most cases, affected infants have contractures of various joints. The joints of the legs and arms are usually affected; the legs are affected more often than the arms. The joints of the shoulders, elbows, knees, wrists, ankles, fingers, toes, and/or hips are also commonly affected. In addition, the jaws and back may also be affected in individuals with AMC. In most cases, AMC occurs randomly, for no apparent reason (sporadic). More than 400 different conditions can cause isolated or multiple contractures and the causes, genetics, specific symptoms, and severity of these disorders vary dramatically. Mutations in over 400 genes have been identified as responsible for different types of arthrogryposis. These can be grouped by tissue, affected part of a cell involved, and function. | 106 | Arthrogryposis Multiplex Congenita |
nord_106_1 | Symptoms of Arthrogryposis Multiplex Congenita | The most common universal symptom of AMC is limited or absent movement around small and large joints (contractures). The contractures are present at birth (congenital). The muscles of the affected limbs may be underdeveloped (hypoplastic), resulting in a tube-shaped limb with a soft, doughy feeling. Soft tissue webbing may develop over the affected joints.In addition to joint abnormalities, other findings occur with greater frequency in individuals with AMC. These include abnormally slender and fragile long bones of the arms and legs and cleft palate, a condition in which the roof of the mouth fails to fuse together leaving a groove across the top of the mouth. In males, the testes may fail to descend into the scrotum (cryptorchidism). Intelligence may or may not be affected. Approximately one-third of individuals with AMC may have structural or functional abnormalities of the central nervous system.Additional symptoms associated with AMC are related to the underlying disorder that causes the condition in each individual. The specific symptoms and their severity can vary dramatically based upon the underlying cause. Two of the most common forms of AMC are amyoplasia and a group of genetic disorders called the distal arthrogryposes.Amyoplasia is the most common form of AMC. Amyoplasia is a disorder characterized by multiple contractures of the joints. The shoulders may be internally rotated and drawn inward (adducted), the elbows are usually extended, and the wrists are usually flexed. In most affected individuals, the fingers are flexed and stiff. Although in most reports, the distal joints (i.e., those joints farthest away from the center of the body) are usually more severely affected, the shoulders and hips (which are proximal joints) often have significant contractures. Affected individuals usually have severe clubfoot. Some affected individuals may have dislocated hips. In some cases, a birthmark (a splotchy reddish birthmark also called a “stork mark”) may be found at birth on the face. Individuals with amyoplasia usually have normal intelligence, no significant craniofacial abnormalities, and no other serious abnormalities of internal organs (visceral abnormalities). However, about 10% of individuals with amyoplasia have abdominal abnormalities such as gastroschisis (a condition in which a hole is present in the wall of the abdomen allowing the intestines to intrude out of the abdominal space) or intestinal atresia (blockage of the intestine). Another 10% have squashed or missing distal fingers or toes. Amyoplasia is common in one of monozygotic twins. Amyoplasia appears to be sporadic and not recur in families. The diagnosis of amyoplasia is clinical at this time. The distal arthrogryposes are a specific subgroup of AMC. This subgroup is characterized by multiple congenital contractures. Common symptoms include contractures of two or more areas of the body, less involvement of the proximal joints (those joints closest to the center of the body), and highly variable expressivity, which means that specific symptoms vary greatly even among individuals with the same disorder and even in the same family. At least 10 different forms of distal arthrogryposis have been identified including Freeman-Sheldon syndrome, Gordon syndrome, trismus-pseudocamptodactyly syndrome, multiple pterygium syndrome and Sheldon-Hall syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Most types of distal arthrogryposis have associated known gene mutations. | Symptoms of Arthrogryposis Multiplex Congenita. The most common universal symptom of AMC is limited or absent movement around small and large joints (contractures). The contractures are present at birth (congenital). The muscles of the affected limbs may be underdeveloped (hypoplastic), resulting in a tube-shaped limb with a soft, doughy feeling. Soft tissue webbing may develop over the affected joints.In addition to joint abnormalities, other findings occur with greater frequency in individuals with AMC. These include abnormally slender and fragile long bones of the arms and legs and cleft palate, a condition in which the roof of the mouth fails to fuse together leaving a groove across the top of the mouth. In males, the testes may fail to descend into the scrotum (cryptorchidism). Intelligence may or may not be affected. Approximately one-third of individuals with AMC may have structural or functional abnormalities of the central nervous system.Additional symptoms associated with AMC are related to the underlying disorder that causes the condition in each individual. The specific symptoms and their severity can vary dramatically based upon the underlying cause. Two of the most common forms of AMC are amyoplasia and a group of genetic disorders called the distal arthrogryposes.Amyoplasia is the most common form of AMC. Amyoplasia is a disorder characterized by multiple contractures of the joints. The shoulders may be internally rotated and drawn inward (adducted), the elbows are usually extended, and the wrists are usually flexed. In most affected individuals, the fingers are flexed and stiff. Although in most reports, the distal joints (i.e., those joints farthest away from the center of the body) are usually more severely affected, the shoulders and hips (which are proximal joints) often have significant contractures. Affected individuals usually have severe clubfoot. Some affected individuals may have dislocated hips. In some cases, a birthmark (a splotchy reddish birthmark also called a “stork mark”) may be found at birth on the face. Individuals with amyoplasia usually have normal intelligence, no significant craniofacial abnormalities, and no other serious abnormalities of internal organs (visceral abnormalities). However, about 10% of individuals with amyoplasia have abdominal abnormalities such as gastroschisis (a condition in which a hole is present in the wall of the abdomen allowing the intestines to intrude out of the abdominal space) or intestinal atresia (blockage of the intestine). Another 10% have squashed or missing distal fingers or toes. Amyoplasia is common in one of monozygotic twins. Amyoplasia appears to be sporadic and not recur in families. The diagnosis of amyoplasia is clinical at this time. The distal arthrogryposes are a specific subgroup of AMC. This subgroup is characterized by multiple congenital contractures. Common symptoms include contractures of two or more areas of the body, less involvement of the proximal joints (those joints closest to the center of the body), and highly variable expressivity, which means that specific symptoms vary greatly even among individuals with the same disorder and even in the same family. At least 10 different forms of distal arthrogryposis have been identified including Freeman-Sheldon syndrome, Gordon syndrome, trismus-pseudocamptodactyly syndrome, multiple pterygium syndrome and Sheldon-Hall syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Most types of distal arthrogryposis have associated known gene mutations. | 106 | Arthrogryposis Multiplex Congenita |
nord_106_2 | Causes of Arthrogryposis Multiplex Congenita | The cause of AMC depends on the specific type. For many types, the cause is not fully understood. Arthrogryposis or AMC is not a specific diagnosis, but a physical finding that can be associated with numerous disorders and conditions. AMC is thought to be related to decreased movement in utero, which can have multiple causes. Neurologic and muscle problems may well be the most common causes of decreased fetal movement, but connective tissue disorders, maternal illness, and limited space are also common causes. Some cases of AMC occur as part of rare genetic disorders that are inherited. Some cases of AMC are related to multiple factors including genetic and environmental ones (multifactorial inheritance).AMC may occur as part of certain single-gene disorders that can be inherited as autosomal recessive, autosomal dominant or X-linked traits. AMC may also occur as part of chromosomal disorders (e.g., trisomy 18, many microdeletions and microduplications). AMC can also occur as part of certain connective tissue disorders. In addition, some cases of AMC may occur due to abnormalities or disorders associated with improper developmental of the central nervous system or the peripheral nervous system or as part of intrinsic muscle disorders. These disorders may be genetic or may occur due to environmental factors.The primary underlying mechanism that leads to congenital contractures is believed to be decreased fetal movement during development. The joints begin to develop in a fetus around five or six weeks into pregnancy. Motion is essential for the proper development of fetal joints. A lack of fetal movement allows for excess connective tissue to form around the joints, which can result in the joint becoming fixed and/or limiting the movement of a joint. In theory, any factor that diminishes or restricts fetal movement can cause congenital contractures. Such factors would include fetal crowding (in which there is not enough room for the fetus to move around) such as when there are multiple births or uterine structural abnormalities. Restricted fetal movement can also occur secondary to maternal disorders including viral infections, drug use, trauma or other maternal illness. Low levels of amniotic fluid around the fetus (oligohydramnios) have also been linked to decreased fetal movement.Amyoplasia, the most common form of AMC, occurs randomly (sporadically). The distal arthrogryposes, another common form of AMC, are usually inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) only in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.Central and peripheral nervous system disorders that are associated with AMC include a condition in which the brain and spinal cord do not close before birth (meningomyelocele), the spinal muscular atrophies, and disorders in which there is incomplete development of certain portions of the brain (e.g., anencephaly, hydranencephaly or holoprosencephaly). Most of these disorders develop due to multiple factors including genetic and environmental ones (multifactorial inheritance).Less often, AMC may be associated with certain muscle disorders including the muscular dystrophies, certain mitochondrial disorders and a variety of genetic muscle disorders that are present at birth (congenital myopathies). Such disorders are usually inherited.Abnormalities affecting the development of connective tissue can cause AMC as well. Connective tissue is the material between the cells of the body that gives tissues form and strength. The abnormal development of connective tissue in the joints can restrict fetal movements, potentially causing multiple contractures. A lack of joint development or the abnormal fusion of bones (synostosis) that are normally separate have also been associated with multiple congenital contractures. Several disorders, which are associated with abnormalities of connective tissue development, have been associated with multiple congenital contractures including diastrophic dysplasia, metatropic dwarfism, popliteal pterygium syndrome and Larsen syndrome.AMC can also be seen associated with severe hypotonia (lax muscles with little strength). In many cases of AMC, the exact underlying cause of the contractures cannot be identified. | Causes of Arthrogryposis Multiplex Congenita. The cause of AMC depends on the specific type. For many types, the cause is not fully understood. Arthrogryposis or AMC is not a specific diagnosis, but a physical finding that can be associated with numerous disorders and conditions. AMC is thought to be related to decreased movement in utero, which can have multiple causes. Neurologic and muscle problems may well be the most common causes of decreased fetal movement, but connective tissue disorders, maternal illness, and limited space are also common causes. Some cases of AMC occur as part of rare genetic disorders that are inherited. Some cases of AMC are related to multiple factors including genetic and environmental ones (multifactorial inheritance).AMC may occur as part of certain single-gene disorders that can be inherited as autosomal recessive, autosomal dominant or X-linked traits. AMC may also occur as part of chromosomal disorders (e.g., trisomy 18, many microdeletions and microduplications). AMC can also occur as part of certain connective tissue disorders. In addition, some cases of AMC may occur due to abnormalities or disorders associated with improper developmental of the central nervous system or the peripheral nervous system or as part of intrinsic muscle disorders. These disorders may be genetic or may occur due to environmental factors.The primary underlying mechanism that leads to congenital contractures is believed to be decreased fetal movement during development. The joints begin to develop in a fetus around five or six weeks into pregnancy. Motion is essential for the proper development of fetal joints. A lack of fetal movement allows for excess connective tissue to form around the joints, which can result in the joint becoming fixed and/or limiting the movement of a joint. In theory, any factor that diminishes or restricts fetal movement can cause congenital contractures. Such factors would include fetal crowding (in which there is not enough room for the fetus to move around) such as when there are multiple births or uterine structural abnormalities. Restricted fetal movement can also occur secondary to maternal disorders including viral infections, drug use, trauma or other maternal illness. Low levels of amniotic fluid around the fetus (oligohydramnios) have also been linked to decreased fetal movement.Amyoplasia, the most common form of AMC, occurs randomly (sporadically). The distal arthrogryposes, another common form of AMC, are usually inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) only in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.Central and peripheral nervous system disorders that are associated with AMC include a condition in which the brain and spinal cord do not close before birth (meningomyelocele), the spinal muscular atrophies, and disorders in which there is incomplete development of certain portions of the brain (e.g., anencephaly, hydranencephaly or holoprosencephaly). Most of these disorders develop due to multiple factors including genetic and environmental ones (multifactorial inheritance).Less often, AMC may be associated with certain muscle disorders including the muscular dystrophies, certain mitochondrial disorders and a variety of genetic muscle disorders that are present at birth (congenital myopathies). Such disorders are usually inherited.Abnormalities affecting the development of connective tissue can cause AMC as well. Connective tissue is the material between the cells of the body that gives tissues form and strength. The abnormal development of connective tissue in the joints can restrict fetal movements, potentially causing multiple contractures. A lack of joint development or the abnormal fusion of bones (synostosis) that are normally separate have also been associated with multiple congenital contractures. Several disorders, which are associated with abnormalities of connective tissue development, have been associated with multiple congenital contractures including diastrophic dysplasia, metatropic dwarfism, popliteal pterygium syndrome and Larsen syndrome.AMC can also be seen associated with severe hypotonia (lax muscles with little strength). In many cases of AMC, the exact underlying cause of the contractures cannot be identified. | 106 | Arthrogryposis Multiplex Congenita |
nord_106_3 | Affects of Arthrogryposis Multiplex Congenita | The number of males and females affected by AMC is approximately equal. The condition has been reported in individuals of Asian, African and European descent. Isolated congenital contractures affect approximately 1 in 500 individuals in the general population. AMC affects approximately 1 in 3,000 individuals. AMC is, by definition, present at birth (congenital). | Affects of Arthrogryposis Multiplex Congenita. The number of males and females affected by AMC is approximately equal. The condition has been reported in individuals of Asian, African and European descent. Isolated congenital contractures affect approximately 1 in 500 individuals in the general population. AMC affects approximately 1 in 3,000 individuals. AMC is, by definition, present at birth (congenital). | 106 | Arthrogryposis Multiplex Congenita |
nord_106_4 | Related disorders of Arthrogryposis Multiplex Congenita | Related disorders of Arthrogryposis Multiplex Congenita. | 106 | Arthrogryposis Multiplex Congenita |
|
nord_106_5 | Diagnosis of Arthrogryposis Multiplex Congenita | A diagnosis of AMC is made based upon identification of characteristic symptoms (e.g., multiple congenital contractures), a detailed patient history, and a thorough clinical evaluation. Certain tests may be necessary to determine the underlying cause of AMC including nerve conduction, electromyography and muscle biopsy, which can help diagnose neuropathic or myopathic disorders. A nerve conduction study measures how rapidly nerves carry an electrical impulse. An electromyography is a test that records electrical activity in skeletal voluntary muscles at rest and during muscle contraction. A biopsy is a procedure in which a small amount of affected tissue (e.g., muscle) is removed and studied under a microscopic to detect characteristic changes or findings that can aid in obtaining a diagnosis. Imaging studies of the central nervous system (CNS) and comparative genomic hybridization (CGH) array, microarray, and exome studies may also be useful studies in making diagnoses. Because of the many mutations that can lead to arthrogryposis, whole genome sequencing is often required (preferable in both parents for comparison as well) to make a diagnosis. | Diagnosis of Arthrogryposis Multiplex Congenita. A diagnosis of AMC is made based upon identification of characteristic symptoms (e.g., multiple congenital contractures), a detailed patient history, and a thorough clinical evaluation. Certain tests may be necessary to determine the underlying cause of AMC including nerve conduction, electromyography and muscle biopsy, which can help diagnose neuropathic or myopathic disorders. A nerve conduction study measures how rapidly nerves carry an electrical impulse. An electromyography is a test that records electrical activity in skeletal voluntary muscles at rest and during muscle contraction. A biopsy is a procedure in which a small amount of affected tissue (e.g., muscle) is removed and studied under a microscopic to detect characteristic changes or findings that can aid in obtaining a diagnosis. Imaging studies of the central nervous system (CNS) and comparative genomic hybridization (CGH) array, microarray, and exome studies may also be useful studies in making diagnoses. Because of the many mutations that can lead to arthrogryposis, whole genome sequencing is often required (preferable in both parents for comparison as well) to make a diagnosis. | 106 | Arthrogryposis Multiplex Congenita |
nord_106_6 | Therapies of Arthrogryposis Multiplex Congenita | Treatment
The treatment of AMC is directed toward the specific findings that are apparent in each individual. A multidisciplinary approach is best. Standard physical therapy, which can improve joint motion and avoid muscle atrophy in the newborn period is beneficial. Gentle joint manipulation and stretching exercises may also be beneficial. Removable splints for the knees and feet that permit regular muscle movement and exercise are also recommended. Serial casting to mobilize stiff joints is helpful. In some cases, surgery may be necessary to achieve better positioning and increase the range of motion in certain joints, especially the ankles, knees, hips, elbows, or wrists. In rare cases, tendon transfers have been performed to improve muscle function. Tendons are the tissue by which muscle is attached to bone. A multidisciplinary approach is desirable for best long term results, including pediatrician, neurologist, orthopedist, rehabilitation physician and therapist, and medical geneticist. Genetic counseling may be recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Arthrogryposis Multiplex Congenita. Treatment
The treatment of AMC is directed toward the specific findings that are apparent in each individual. A multidisciplinary approach is best. Standard physical therapy, which can improve joint motion and avoid muscle atrophy in the newborn period is beneficial. Gentle joint manipulation and stretching exercises may also be beneficial. Removable splints for the knees and feet that permit regular muscle movement and exercise are also recommended. Serial casting to mobilize stiff joints is helpful. In some cases, surgery may be necessary to achieve better positioning and increase the range of motion in certain joints, especially the ankles, knees, hips, elbows, or wrists. In rare cases, tendon transfers have been performed to improve muscle function. Tendons are the tissue by which muscle is attached to bone. A multidisciplinary approach is desirable for best long term results, including pediatrician, neurologist, orthopedist, rehabilitation physician and therapist, and medical geneticist. Genetic counseling may be recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 106 | Arthrogryposis Multiplex Congenita |
nord_107_0 | Overview of ASAH1-Related Disorders | ASAH1-related disorders are an extremely rare group of disorders caused by an alteration (mutation) in the ASAH1 gene. Alterations in this gene result in a deficiency of the enzyme acid ceramidase. Enzymes are specialized proteins that act to bring about biochemical reactions in the body. The acid ceramidase enzyme is required to help break down certain fatty substances – called ceramides – in the body. Because the activity of this enzyme is reduced, these fatty substances build up abnormally in the cells and tissues of the body. This can cause a variety of signs and symptoms based on where the fatty substance builds up and how much of it builds up. The most common form of ASAH1-related disorder is called Farber disease, which can present in several different ways. The most common presentation is characterized by the three main symptoms: small bumps beneath the skin (subcutaneous nodules), joint disease, and hoarseness of voice. Some people will have additional symptoms, or different symptoms, that can include heart (cardiac), neurological, or breathing problems. A specific form of ASAH1-related disorder is called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), which is characterized by muscle weakness and degeneration, specifically in the legs, as well as seizures. ASAH1-related disorders can be best thought of as a spectrum of disease that can affect one person very differently from how it affects another person. This is true even for members of the same family. The signs, severity, and age of onset of symptoms can all be very different and can range from mild to severe. ASAH1-related disorders are inherited in an autosomal recessive manner. IntroductionASAH1-related disorders are part of a group of hereditary metabolic diseases known as lysosomal storage disorders (LSDs). Lysosomes function as the primary digestive and recycling units within cells. Enzymes within lysosomes break down or digest particular cellular components, such carbohydrates, proteins and fats to their basic units which can then be recycled. Healthy cells and organs are constantly breaking down, recycling and building new cellular components. In individuals with these disorders, including ASAH1-related disorders, a deficiency of or improper functioning of lysosomal enzymes leads to an abnormal accumulation of particular substances such as fatty material called lipids. When cells cannot breakdown these fatty substances they can accumulate within various tissues of the body, such as the bones, joints, brain, heart, spleen, or liver and lead to the symptoms that affected individuals have. | Overview of ASAH1-Related Disorders. ASAH1-related disorders are an extremely rare group of disorders caused by an alteration (mutation) in the ASAH1 gene. Alterations in this gene result in a deficiency of the enzyme acid ceramidase. Enzymes are specialized proteins that act to bring about biochemical reactions in the body. The acid ceramidase enzyme is required to help break down certain fatty substances – called ceramides – in the body. Because the activity of this enzyme is reduced, these fatty substances build up abnormally in the cells and tissues of the body. This can cause a variety of signs and symptoms based on where the fatty substance builds up and how much of it builds up. The most common form of ASAH1-related disorder is called Farber disease, which can present in several different ways. The most common presentation is characterized by the three main symptoms: small bumps beneath the skin (subcutaneous nodules), joint disease, and hoarseness of voice. Some people will have additional symptoms, or different symptoms, that can include heart (cardiac), neurological, or breathing problems. A specific form of ASAH1-related disorder is called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), which is characterized by muscle weakness and degeneration, specifically in the legs, as well as seizures. ASAH1-related disorders can be best thought of as a spectrum of disease that can affect one person very differently from how it affects another person. This is true even for members of the same family. The signs, severity, and age of onset of symptoms can all be very different and can range from mild to severe. ASAH1-related disorders are inherited in an autosomal recessive manner. IntroductionASAH1-related disorders are part of a group of hereditary metabolic diseases known as lysosomal storage disorders (LSDs). Lysosomes function as the primary digestive and recycling units within cells. Enzymes within lysosomes break down or digest particular cellular components, such carbohydrates, proteins and fats to their basic units which can then be recycled. Healthy cells and organs are constantly breaking down, recycling and building new cellular components. In individuals with these disorders, including ASAH1-related disorders, a deficiency of or improper functioning of lysosomal enzymes leads to an abnormal accumulation of particular substances such as fatty material called lipids. When cells cannot breakdown these fatty substances they can accumulate within various tissues of the body, such as the bones, joints, brain, heart, spleen, or liver and lead to the symptoms that affected individuals have. | 107 | ASAH1-Related Disorders |
nord_107_1 | Symptoms of ASAH1-Related Disorders | Although researchers have been able to establish clear syndromes with characteristic or “core” symptoms, much about these LSDs is not fully understood. Several factors including the small number of identified cases, the lack of large clinical natural history studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis. ASAH1-related disorders are also highly variable. This means how they affect one person can be significantly different from how they affect another person. ASAH1-related disorders can cause life-threatening complications in infants, or symptoms can develop in infancy and progressively worsen in children to varying degrees. In some people, the disorder may not be diagnosed until adulthood. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis. The specific signs and symptoms, the age of onset, the progression and severity of the disorder, and the specific organ systems that are affected will vary from one person to another. Farber disease is the name used for the most common presentation of an ASAH1-related disorder. Sometimes, Farber disease is broken down into subtypes based on age of onset and specific symptoms and severity. However, the current thinking is that these disorders are best thought of as a spectrum of disease ranging from mild forms that can go undiagnosed into adulthood to forms that cause severe, even life-threatening complications in infancy. Farber Disease Type 1The classic form, sometimes called Farber disease type 1, is characterized by three main symptoms – skin nodules, joint disease, and hoarseness. Skin nodules are small lumps of cells and fat found just beneath the surface of the skin. These nodules can occur anywhere, but most often occur by the joints or mechanical pressure points, which are spots on the body that are especially sensitive to the application of pressure. Over time, the nodules may thicken and increase in number. These nodules are called lipogranulomas. Granulomas are nodules of inflamed tissue that are produced in response to a foreign substance or infection. In ASAH1-related disorders, this is in response to the abnormal buildup of fatty material (lipids) in the body. Joint disease is characterized by swollen, stiff and painful joints that slowly worsen in severity. This can lead to progressive deformity of the affected joints. The wrists, elbows, hands, knees, and feet are most commonly affected. In severe instances, contractures may occur. A contracture is a condition in which a joint becomes permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint. Hoarseness is also a common finding in Farber disease. Hoarseness is caused by the formation of nodules within the larynx. The larynx, which is also called the voice box, is the hollow organ at the top of the throat that contains the vocal cords. Affected infants may have a weak cry. As children age, they may have difficulty speaking clearly or easily (dysphonia), or they may be unable to speak (aphonia). In some instances, nodules may affect the epiglottis. The epiglottis is a flap cartilage found in the back of the throat. When a person swallows, the epiglottis moves and covers the windpipe. This prevents food from “going down the wrong tube” and into the lungs. When nodules affect the epiglottis, swelling may occur and affected individuals may have trouble breathing and feeding. This can be severe. The classic form of Farber disease can progress to cause lung and heart problems and problems with the brain and nervous system. Lung problems can include noisy breathing (stridor) when a child is breathing out (exhaling), labored or difficulty breathing, pneumonia, lung infection, and severe breathing problems (respiratory distress) that can be life-threatening. Neurological findings can be broad and differ greatly among affected individuals. Some children may experience delays in reaching developmental milestones (developmental delays). This can progress to cause intellectual disability. Diminished muscle tone (hypotonia) and muscle weakness and degeneration (atrophy) can also occur and can progress to cause severe complications. Eventually, affected individuals may need assistance or walk or require a wheelchair. Sometimes, problems with the eyes may develop including the formation of cherry red spots. This condition occurs when the macular cells of the eye deteriorate, exposing the underlying choroid. The choroid is the middle layer of the eye that consists of blood vessels that supply blood to the retina. Additional findings include the formations of nodules in the membrane lining the inner surface of the eyelids (conjunctiva), a poor ability to focus on (fixate on) objects, and rapid, involuntary eye movements (nystagmus). Some individuals develop abnormal enlargement of the liver and spleen (hepatomegaly). Farber Disease Type 2 This form is also characterized by the classic triad described above. Neurological problems can be present, but are usually less severe than seen in type 1. Seizures can also occur, and increase in frequency over time. Farber Disease Type 3 The main symptom of this form is joint disease. Affected individuals develop swelling and pain in the affected joints that can progress to cause contractures. About half of affected individuals develop neurological problems and this form can be associated with below average IQ scores (cognitive deficit). Farber Disease Type 4 This is a severe form of the disorder in which fatty substances build up in various organs of the body causing severe enlargement such as severe enlargement of the liver and spleen. The disorder is usually fatal within the first days to weeks of life. Farber Disease Type 5 This form of the disorder is characterized by normal development for about 6 months to 1 year of age. Eventually, affected infants develop a variety of neurological problems and can lose previously acquired skills (regression) including speech. Seizures, which are resistant to treatment, can develop. There can also be partial paralysis of the legs (paraparesis). Skin nodules may occur and are usually mild. The lungs are usually not affected. Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME) This is a distinct form of ASAH1-related disorders that is characterized by muscle weakness and seizures that are known as progressive myoclonic epilepsy. Muscle weakness starts in the proximal muscles of the legs, which are those closest to the center of the body (e.g. the muscles of the thighs) and progresses to affect the distal muscles, which are those further away from the center of the body (e.g. those of the lower legs). Affected individuals may be clumsy and fall frequently. Eventually, affected individuals have trouble walking or walk in a waddling manner (waddling gait). Over time, some individuals may require assistive devices like a cane to help them walk or, eventually, a wheelchair. Progressive myoclonic epilepsy often occurs later in childhood after the development of muscle weakness and may be characterized by myoclonic and atonic seizures. Myoclonic seizures cause rapid, brief muscle contractions that cause sudden jerky or twitching movements. Jerking or spasms of the arms, jerking movements that occur when a person tries to voluntary move a muscle (action myoclonus), or jerking movements or spasms of the eyelids can occur. Atonic seizures are characterized by a sudden loss of muscle tone so that the head and body may go limp. Some affected individuals develop additional symptoms including involuntary, rhythmic, movements of a body part (tremors), neurological problems that can lead to lower-than-average IQ scores (cognitive decline), or sensorineural hearing loss, which is hearing loss that occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain, and is not caused by problems with the ear itself. Children with spinal muscular atrophy and progressive myoclonic epilepsy have not developed characteristic skin nodules associated with Farber disease. However, at least one child report in the medical literature had symptoms that overlapped between Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy. | Symptoms of ASAH1-Related Disorders. Although researchers have been able to establish clear syndromes with characteristic or “core” symptoms, much about these LSDs is not fully understood. Several factors including the small number of identified cases, the lack of large clinical natural history studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis. ASAH1-related disorders are also highly variable. This means how they affect one person can be significantly different from how they affect another person. ASAH1-related disorders can cause life-threatening complications in infants, or symptoms can develop in infancy and progressively worsen in children to varying degrees. In some people, the disorder may not be diagnosed until adulthood. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis. The specific signs and symptoms, the age of onset, the progression and severity of the disorder, and the specific organ systems that are affected will vary from one person to another. Farber disease is the name used for the most common presentation of an ASAH1-related disorder. Sometimes, Farber disease is broken down into subtypes based on age of onset and specific symptoms and severity. However, the current thinking is that these disorders are best thought of as a spectrum of disease ranging from mild forms that can go undiagnosed into adulthood to forms that cause severe, even life-threatening complications in infancy. Farber Disease Type 1The classic form, sometimes called Farber disease type 1, is characterized by three main symptoms – skin nodules, joint disease, and hoarseness. Skin nodules are small lumps of cells and fat found just beneath the surface of the skin. These nodules can occur anywhere, but most often occur by the joints or mechanical pressure points, which are spots on the body that are especially sensitive to the application of pressure. Over time, the nodules may thicken and increase in number. These nodules are called lipogranulomas. Granulomas are nodules of inflamed tissue that are produced in response to a foreign substance or infection. In ASAH1-related disorders, this is in response to the abnormal buildup of fatty material (lipids) in the body. Joint disease is characterized by swollen, stiff and painful joints that slowly worsen in severity. This can lead to progressive deformity of the affected joints. The wrists, elbows, hands, knees, and feet are most commonly affected. In severe instances, contractures may occur. A contracture is a condition in which a joint becomes permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint. Hoarseness is also a common finding in Farber disease. Hoarseness is caused by the formation of nodules within the larynx. The larynx, which is also called the voice box, is the hollow organ at the top of the throat that contains the vocal cords. Affected infants may have a weak cry. As children age, they may have difficulty speaking clearly or easily (dysphonia), or they may be unable to speak (aphonia). In some instances, nodules may affect the epiglottis. The epiglottis is a flap cartilage found in the back of the throat. When a person swallows, the epiglottis moves and covers the windpipe. This prevents food from “going down the wrong tube” and into the lungs. When nodules affect the epiglottis, swelling may occur and affected individuals may have trouble breathing and feeding. This can be severe. The classic form of Farber disease can progress to cause lung and heart problems and problems with the brain and nervous system. Lung problems can include noisy breathing (stridor) when a child is breathing out (exhaling), labored or difficulty breathing, pneumonia, lung infection, and severe breathing problems (respiratory distress) that can be life-threatening. Neurological findings can be broad and differ greatly among affected individuals. Some children may experience delays in reaching developmental milestones (developmental delays). This can progress to cause intellectual disability. Diminished muscle tone (hypotonia) and muscle weakness and degeneration (atrophy) can also occur and can progress to cause severe complications. Eventually, affected individuals may need assistance or walk or require a wheelchair. Sometimes, problems with the eyes may develop including the formation of cherry red spots. This condition occurs when the macular cells of the eye deteriorate, exposing the underlying choroid. The choroid is the middle layer of the eye that consists of blood vessels that supply blood to the retina. Additional findings include the formations of nodules in the membrane lining the inner surface of the eyelids (conjunctiva), a poor ability to focus on (fixate on) objects, and rapid, involuntary eye movements (nystagmus). Some individuals develop abnormal enlargement of the liver and spleen (hepatomegaly). Farber Disease Type 2 This form is also characterized by the classic triad described above. Neurological problems can be present, but are usually less severe than seen in type 1. Seizures can also occur, and increase in frequency over time. Farber Disease Type 3 The main symptom of this form is joint disease. Affected individuals develop swelling and pain in the affected joints that can progress to cause contractures. About half of affected individuals develop neurological problems and this form can be associated with below average IQ scores (cognitive deficit). Farber Disease Type 4 This is a severe form of the disorder in which fatty substances build up in various organs of the body causing severe enlargement such as severe enlargement of the liver and spleen. The disorder is usually fatal within the first days to weeks of life. Farber Disease Type 5 This form of the disorder is characterized by normal development for about 6 months to 1 year of age. Eventually, affected infants develop a variety of neurological problems and can lose previously acquired skills (regression) including speech. Seizures, which are resistant to treatment, can develop. There can also be partial paralysis of the legs (paraparesis). Skin nodules may occur and are usually mild. The lungs are usually not affected. Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME) This is a distinct form of ASAH1-related disorders that is characterized by muscle weakness and seizures that are known as progressive myoclonic epilepsy. Muscle weakness starts in the proximal muscles of the legs, which are those closest to the center of the body (e.g. the muscles of the thighs) and progresses to affect the distal muscles, which are those further away from the center of the body (e.g. those of the lower legs). Affected individuals may be clumsy and fall frequently. Eventually, affected individuals have trouble walking or walk in a waddling manner (waddling gait). Over time, some individuals may require assistive devices like a cane to help them walk or, eventually, a wheelchair. Progressive myoclonic epilepsy often occurs later in childhood after the development of muscle weakness and may be characterized by myoclonic and atonic seizures. Myoclonic seizures cause rapid, brief muscle contractions that cause sudden jerky or twitching movements. Jerking or spasms of the arms, jerking movements that occur when a person tries to voluntary move a muscle (action myoclonus), or jerking movements or spasms of the eyelids can occur. Atonic seizures are characterized by a sudden loss of muscle tone so that the head and body may go limp. Some affected individuals develop additional symptoms including involuntary, rhythmic, movements of a body part (tremors), neurological problems that can lead to lower-than-average IQ scores (cognitive decline), or sensorineural hearing loss, which is hearing loss that occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain, and is not caused by problems with the ear itself. Children with spinal muscular atrophy and progressive myoclonic epilepsy have not developed characteristic skin nodules associated with Farber disease. However, at least one child report in the medical literature had symptoms that overlapped between Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy. | 107 | ASAH1-Related Disorders |
nord_107_2 | Causes of ASAH1-Related Disorders | ASAH1-related disorders are caused by variations (mutations) in the ASAH1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The ASAH1 gene contains instructions for creating (encoding) an enzyme called acid ceramidase. This enzyme is essential for breaking down (hydrolysis) of a class of fatty substances called ceramides. There are many different ceramides in cells; they serve many normal functions. Because of the altered gene, people with this disorder have low activity levels of this enzyme, which means that ceramides build up abnormally in the various organ systems in the body, damaging the affected areas. Where and how much ceramide builds up can vary, which is why there are so many different the ways the disorder can appear in a person. ASAH1-related disorders are inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. | Causes of ASAH1-Related Disorders. ASAH1-related disorders are caused by variations (mutations) in the ASAH1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The ASAH1 gene contains instructions for creating (encoding) an enzyme called acid ceramidase. This enzyme is essential for breaking down (hydrolysis) of a class of fatty substances called ceramides. There are many different ceramides in cells; they serve many normal functions. Because of the altered gene, people with this disorder have low activity levels of this enzyme, which means that ceramides build up abnormally in the various organ systems in the body, damaging the affected areas. Where and how much ceramide builds up can vary, which is why there are so many different the ways the disorder can appear in a person. ASAH1-related disorders are inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. | 107 | ASAH1-Related Disorders |
nord_107_3 | Affects of ASAH1-Related Disorders | ASAH1-related disorders are extremely rare disorders. They affect males and females in equal numbers. Fewer than 200 individuals have been described in the medical literature. However, rare disorders like ASAH1-related disorders often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. | Affects of ASAH1-Related Disorders. ASAH1-related disorders are extremely rare disorders. They affect males and females in equal numbers. Fewer than 200 individuals have been described in the medical literature. However, rare disorders like ASAH1-related disorders often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. | 107 | ASAH1-Related Disorders |
nord_107_4 | Related disorders of ASAH1-Related Disorders | Symptoms of the following disorders can be similar to those of ASAH-1-related disorders. Comparisons may be useful for a differential diagnosis. Some individuals with ASAH1-related disorders will have signs and symptoms similar to those seen in juvenile idiopathic arthritis, rheumatoid arthritis, juvenile hyaline fibromatosis, and multicentric histiocytosis. Individuals with spinal muscular atrophy with progressive myoclonic epilepsy may have signs and symptoms to those seen in spinal muscular atrophy, Lafora disease, Unverricht-Lundborg disease, and MERFF syndrome. (For more information on these disorders, choose the exact disorder name as your search term in the Rare Disease Database.) | Related disorders of ASAH1-Related Disorders. Symptoms of the following disorders can be similar to those of ASAH-1-related disorders. Comparisons may be useful for a differential diagnosis. Some individuals with ASAH1-related disorders will have signs and symptoms similar to those seen in juvenile idiopathic arthritis, rheumatoid arthritis, juvenile hyaline fibromatosis, and multicentric histiocytosis. Individuals with spinal muscular atrophy with progressive myoclonic epilepsy may have signs and symptoms to those seen in spinal muscular atrophy, Lafora disease, Unverricht-Lundborg disease, and MERFF syndrome. (For more information on these disorders, choose the exact disorder name as your search term in the Rare Disease Database.) | 107 | ASAH1-Related Disorders |
nord_107_5 | Diagnosis of ASAH1-Related Disorders | A diagnosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected in infants or children with characteristic early signs. Clinical Testing and WorkupIndividuals suspected of an ASAH1-related disorder will be tested to determine whether the activity of the enzyme, acid ceramidase, is reduced or absent. Certain cells, specifically certain white blood cells (peripheral blood leukocytes) or connective tissue cells (fibroblasts) will be used to assess how much acid ceramidase activity is present. In people with an ASAH1-related disorder, these tests, known as enzyme assays, will show a reduction in enzyme activity. Peripheral blood leukocytes are white blood cells that are drawn from the blood. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory. Molecular genetic testing is often used to confirm a diagnosis. Molecular genetic testing can detect diseases-causing alterations (mutations) in the ASAH1 gene known to cause these disorders. In fact, some Farber patients have been identified in this manner. They had a variety of related symptoms and genomic sequencing confirmed that they had harmful variants in the ASAH1 gene. | Diagnosis of ASAH1-Related Disorders. A diagnosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected in infants or children with characteristic early signs. Clinical Testing and WorkupIndividuals suspected of an ASAH1-related disorder will be tested to determine whether the activity of the enzyme, acid ceramidase, is reduced or absent. Certain cells, specifically certain white blood cells (peripheral blood leukocytes) or connective tissue cells (fibroblasts) will be used to assess how much acid ceramidase activity is present. In people with an ASAH1-related disorder, these tests, known as enzyme assays, will show a reduction in enzyme activity. Peripheral blood leukocytes are white blood cells that are drawn from the blood. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory. Molecular genetic testing is often used to confirm a diagnosis. Molecular genetic testing can detect diseases-causing alterations (mutations) in the ASAH1 gene known to cause these disorders. In fact, some Farber patients have been identified in this manner. They had a variety of related symptoms and genomic sequencing confirmed that they had harmful variants in the ASAH1 gene. | 107 | ASAH1-Related Disorders |
nord_107_6 | Therapies of ASAH1-Related Disorders | Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists), neurologists, physicians who specialize in the diagnosis and treatment of disorders of the bones and skeleton (orthopedists), physicians who specialize in the diagnosis and treatment of eye disorders (ophthalmologists), physicians who specialize in the diagnosis and treatment of skin disorders (dermatologists), speech pathologists, physical therapists, pain specialists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. There is presently no cure for ASAH1-related disorders and there are no standardized treatment protocols or guidelines for affected individuals. To date, treatment is aimed at the specific symptoms that are present in each individual. Seizures may be treated with drugs that reduce the seizure occurrence (anti-epileptics). Some infants may need to undergo surgical removal of nodules that form in the airways or mouth cavity. Sometimes, a tracheostomy may be required. This is the creation of a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. Some affected children may need a gastrostomy tube, in which a small, thin tube that is inserted into the stomach through a small cut in the abdomen to allow the passage of food and liquid. Anti-inflammatory medications and physical therapy can help to reduce or improve mobility issues and pain associated with joint disease. Surgery may be necessary for the removal of nodules in the hand. Individuals with SMA-PME may be treated with anti-seizure mediations, standard medications for the treatment of tremors, a gastrostomy tube, and standard treatment for scoliosis. Some individuals may require breathing (respiratory) therapy and standard therapy for treating recurrent pneumonia. Sometimes, noninvasive ventilatory support or a tracheostomy may be necessary. Some individuals may require assistive devices to walk including special shoes, walkers, or wheelchairs. Following an initial diagnosis, it is recommended that a developmental assessment be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Periodic reassessments and adjustment of services should be provided with all children. A developmental pediatrician can help with management of behavioral issues and medication considerations. | Therapies of ASAH1-Related Disorders. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists), neurologists, physicians who specialize in the diagnosis and treatment of disorders of the bones and skeleton (orthopedists), physicians who specialize in the diagnosis and treatment of eye disorders (ophthalmologists), physicians who specialize in the diagnosis and treatment of skin disorders (dermatologists), speech pathologists, physical therapists, pain specialists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. There is presently no cure for ASAH1-related disorders and there are no standardized treatment protocols or guidelines for affected individuals. To date, treatment is aimed at the specific symptoms that are present in each individual. Seizures may be treated with drugs that reduce the seizure occurrence (anti-epileptics). Some infants may need to undergo surgical removal of nodules that form in the airways or mouth cavity. Sometimes, a tracheostomy may be required. This is the creation of a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. Some affected children may need a gastrostomy tube, in which a small, thin tube that is inserted into the stomach through a small cut in the abdomen to allow the passage of food and liquid. Anti-inflammatory medications and physical therapy can help to reduce or improve mobility issues and pain associated with joint disease. Surgery may be necessary for the removal of nodules in the hand. Individuals with SMA-PME may be treated with anti-seizure mediations, standard medications for the treatment of tremors, a gastrostomy tube, and standard treatment for scoliosis. Some individuals may require breathing (respiratory) therapy and standard therapy for treating recurrent pneumonia. Sometimes, noninvasive ventilatory support or a tracheostomy may be necessary. Some individuals may require assistive devices to walk including special shoes, walkers, or wheelchairs. Following an initial diagnosis, it is recommended that a developmental assessment be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Periodic reassessments and adjustment of services should be provided with all children. A developmental pediatrician can help with management of behavioral issues and medication considerations. | 107 | ASAH1-Related Disorders |
nord_108_0 | Overview of Asherman’s Syndrome | Asherman's syndrome is a rare, acquired, gynecological disorder of the uterus. It is characterized by the bonding of scar tissue that lines the walls of the uterus, which decreases the volume of the uterine cavity. The bonding of uterine scar tissue (intrauterine adhesions or synechiae) may occur as a result of surgical scraping or cleaning of tissue from the uterine wall (dilatation and curettage [D and C]), infections of the endometrium (e.g., genital tuberculosis), or other factors. Asherman's syndrome can be severe (greater than 75% of the front and back walls of the uterus can fuse together) to moderate and mild, where only smaller portions of the uterine wall fuses together. Patients can experience a range of symptoms depending on the severity of the disease, including reduced menstrual flow, increased cramping and abdominal pain, eventual stoppage of menstrual cycles (amenorrhea), and, in some women, infertility. Current treatment options include hysteroscopic surgery as well as preventive (Foley catheter) and restorative therapies (hormone treatment). Newer options like stem cell treatments are also currently being explored to treat severe cases of Asherman’s syndrome. | Overview of Asherman’s Syndrome. Asherman's syndrome is a rare, acquired, gynecological disorder of the uterus. It is characterized by the bonding of scar tissue that lines the walls of the uterus, which decreases the volume of the uterine cavity. The bonding of uterine scar tissue (intrauterine adhesions or synechiae) may occur as a result of surgical scraping or cleaning of tissue from the uterine wall (dilatation and curettage [D and C]), infections of the endometrium (e.g., genital tuberculosis), or other factors. Asherman's syndrome can be severe (greater than 75% of the front and back walls of the uterus can fuse together) to moderate and mild, where only smaller portions of the uterine wall fuses together. Patients can experience a range of symptoms depending on the severity of the disease, including reduced menstrual flow, increased cramping and abdominal pain, eventual stoppage of menstrual cycles (amenorrhea), and, in some women, infertility. Current treatment options include hysteroscopic surgery as well as preventive (Foley catheter) and restorative therapies (hormone treatment). Newer options like stem cell treatments are also currently being explored to treat severe cases of Asherman’s syndrome. | 108 | Asherman’s Syndrome |
nord_108_1 | Symptoms of Asherman’s Syndrome | Most patients with Asherman’s syndrome experience menstrual blood flow that is sparse (hypomenorrhea) or absent (amenorrhea) along with increased cramping and abdominal pain. Some patients may experience interrupted menstrual blood flow with substantial pain, while others may not have any abnormal changes to their menstrual cycle or experience any pain. Recurrent miscarriages and/or infertility may also be signs of Asherman’s syndrome. In more severe cases, adhesion of uterine scar tissue can also lead to either a partial or full blockage of the uterus or cervical canal that can cause retrograde menstruation (menstruation blood that flows backwards into the fallopian tubes instead of being expelled from the body). | Symptoms of Asherman’s Syndrome. Most patients with Asherman’s syndrome experience menstrual blood flow that is sparse (hypomenorrhea) or absent (amenorrhea) along with increased cramping and abdominal pain. Some patients may experience interrupted menstrual blood flow with substantial pain, while others may not have any abnormal changes to their menstrual cycle or experience any pain. Recurrent miscarriages and/or infertility may also be signs of Asherman’s syndrome. In more severe cases, adhesion of uterine scar tissue can also lead to either a partial or full blockage of the uterus or cervical canal that can cause retrograde menstruation (menstruation blood that flows backwards into the fallopian tubes instead of being expelled from the body). | 108 | Asherman’s Syndrome |
nord_108_2 | Causes of Asherman’s Syndrome | Asherman’s syndrome is most commonly caused by trauma to the uterus through surgical scraping or cleaning of the uterine wall (dilatation and curettage, also known as D & C). D & C is generally performed to clear the uterine lining following a miscarriage or abortion or to treat certain uterine conditions such as heavy bleeding. D & C after a miscarriage is one of the highest risk factors for Asherman’s syndrome. The scraping of the uterine lining following this procedure can lead to scar tissue that can adhere, leading to Asherman’s syndrome. Other types of surgery to the uterus such as removal of fibroids or polyps or surgical repair of structural defects in the uterus can cause scar tissue formation which is also a risk factor for Asherman’s syndrome. Factors that trigger inflammation in the uterus known as endometriosis and sporadic inflammation of the uterus have been linked to Asherman’s syndrome. Infection and inflammation of the uterus caused by bacteria (genital tuberculosis) and parasites such as blood flukes are also risk factors for Asherman’s syndrome. | Causes of Asherman’s Syndrome. Asherman’s syndrome is most commonly caused by trauma to the uterus through surgical scraping or cleaning of the uterine wall (dilatation and curettage, also known as D & C). D & C is generally performed to clear the uterine lining following a miscarriage or abortion or to treat certain uterine conditions such as heavy bleeding. D & C after a miscarriage is one of the highest risk factors for Asherman’s syndrome. The scraping of the uterine lining following this procedure can lead to scar tissue that can adhere, leading to Asherman’s syndrome. Other types of surgery to the uterus such as removal of fibroids or polyps or surgical repair of structural defects in the uterus can cause scar tissue formation which is also a risk factor for Asherman’s syndrome. Factors that trigger inflammation in the uterus known as endometriosis and sporadic inflammation of the uterus have been linked to Asherman’s syndrome. Infection and inflammation of the uterus caused by bacteria (genital tuberculosis) and parasites such as blood flukes are also risk factors for Asherman’s syndrome. | 108 | Asherman’s Syndrome |
nord_108_3 | Affects of Asherman’s Syndrome | Since Asherman’s syndrome involves changes in the uterus, it is limited to the female population. While exact statistics on the prevalence of this condition are not known, the highest frequency of this condition has been reported in Israel, Greece, and South America. Overall, occurrence of Asherman’s syndrome does not seem to be related to any factor associated with geographic location. Genetic predisposition in patients to Asherman’s syndrome has not been identified. Women who have suffered miscarriages or underwent D & C in the first month postpartum have a higher risk for the condition. | Affects of Asherman’s Syndrome. Since Asherman’s syndrome involves changes in the uterus, it is limited to the female population. While exact statistics on the prevalence of this condition are not known, the highest frequency of this condition has been reported in Israel, Greece, and South America. Overall, occurrence of Asherman’s syndrome does not seem to be related to any factor associated with geographic location. Genetic predisposition in patients to Asherman’s syndrome has not been identified. Women who have suffered miscarriages or underwent D & C in the first month postpartum have a higher risk for the condition. | 108 | Asherman’s Syndrome |
nord_108_4 | Related disorders of Asherman’s Syndrome | Symptoms of the following disorders can be similar to those of Asherman’s syndrome. Comparisons may be useful for a differential diagnosis:Primary amenorrhea is the absence of menstruation by the age of 15 or three years after the first signs of breast development. This is most often due to abnormal hypothalamic gonadotropic-releasing hormone levels (GnRH, sex cell growth hormone) Symptoms include incomplete or underdeveloped external genitalia and breasts, ovarian deficiency, and underactive pituitary.Secondary amenorrhea, which can occur in Asherman’s syndrome, is when the absence of menstruation of more than three cycles occurs in women who have previously menstruated, which may be due to scraping of the uterine wall (D&C) or acute endometritis.Endometriosis is a prevalent inflammatory condition that can cause Asherman’s syndrome. It is caused by an inability to shed the tissue buildup of the uterus (endometrium) before menstruation. Symptoms may include lower back or thigh pain, or excessive pain during the menstrual cycle.Pelvic inflammatory disease (PID) is the infection of the fallopian tubes, cervix, uterus or ovaries. It is transmitted by sexual intercourse, childbirth or abortion and occurs most often in young women. Polycystic ovarian syndrome (PCOS) is a rare reproductive disorder affecting young women. It is characterized by absent or abnormal menstruation, sterility, mild signs of secondary male sex characteristics and sometimes obesity. | Related disorders of Asherman’s Syndrome. Symptoms of the following disorders can be similar to those of Asherman’s syndrome. Comparisons may be useful for a differential diagnosis:Primary amenorrhea is the absence of menstruation by the age of 15 or three years after the first signs of breast development. This is most often due to abnormal hypothalamic gonadotropic-releasing hormone levels (GnRH, sex cell growth hormone) Symptoms include incomplete or underdeveloped external genitalia and breasts, ovarian deficiency, and underactive pituitary.Secondary amenorrhea, which can occur in Asherman’s syndrome, is when the absence of menstruation of more than three cycles occurs in women who have previously menstruated, which may be due to scraping of the uterine wall (D&C) or acute endometritis.Endometriosis is a prevalent inflammatory condition that can cause Asherman’s syndrome. It is caused by an inability to shed the tissue buildup of the uterus (endometrium) before menstruation. Symptoms may include lower back or thigh pain, or excessive pain during the menstrual cycle.Pelvic inflammatory disease (PID) is the infection of the fallopian tubes, cervix, uterus or ovaries. It is transmitted by sexual intercourse, childbirth or abortion and occurs most often in young women. Polycystic ovarian syndrome (PCOS) is a rare reproductive disorder affecting young women. It is characterized by absent or abnormal menstruation, sterility, mild signs of secondary male sex characteristics and sometimes obesity. | 108 | Asherman’s Syndrome |
nord_108_5 | Diagnosis of Asherman’s Syndrome | Asherman’s syndrome is usually diagnosed through imaging the size and shape of the uterus. The gold standard for diagnosis is a scope and camera tool called a hysteroscope that is inserted into the uterus to display a real-time view of the uterine cavity. Unfortunately, hyperscopes are not readily available in most gynecologist offices. Consequently, Asherman syndrome may be underdiagnosed since it cannot be effectively detected by routine examinations or by more standard diagnostic scans such as ultrasound. Another common diagnostic method for Asherman’s syndrome is hysterosalpingography which involves the injection of a contrasting fluid into the uterus in order for an X-ray image to be generated. Hysterosalpingography allows for the imaging of the uterine cavity shape which may be abnormal in the presence of intrauterine adhesions. Other common imaging tools such as ultrasound and magnetic resonance imaging (MRI]) cannot usually detect Asherman’s syndrome and remain supplementary diagnostic tools. | Diagnosis of Asherman’s Syndrome. Asherman’s syndrome is usually diagnosed through imaging the size and shape of the uterus. The gold standard for diagnosis is a scope and camera tool called a hysteroscope that is inserted into the uterus to display a real-time view of the uterine cavity. Unfortunately, hyperscopes are not readily available in most gynecologist offices. Consequently, Asherman syndrome may be underdiagnosed since it cannot be effectively detected by routine examinations or by more standard diagnostic scans such as ultrasound. Another common diagnostic method for Asherman’s syndrome is hysterosalpingography which involves the injection of a contrasting fluid into the uterus in order for an X-ray image to be generated. Hysterosalpingography allows for the imaging of the uterine cavity shape which may be abnormal in the presence of intrauterine adhesions. Other common imaging tools such as ultrasound and magnetic resonance imaging (MRI]) cannot usually detect Asherman’s syndrome and remain supplementary diagnostic tools. | 108 | Asherman’s Syndrome |
nord_108_6 | Therapies of Asherman’s Syndrome | Therapies for Asherman’s syndrome focus on restoring the uterus to its original size and shape. The therapies can be divided into three primary approaches: treatment – hysteroscopic surgery, re-adhesion prevention, and uterus restoration therapies. Mild cases of Asherman’s syndrome may only require surgical treatment, while more severe cases may require all three approaches. Most cases of Asherman’s syndrome can be cured with treatment.TreatmentThe most common treatment for Asherman’s syndrome is hysteroscopic surgery (hysteroscopes plus scissors or other cutting instruments) to cut the adhesions of the uterine wall. The hysteroscope allows the doctor a magnified and the direct view of the uterus for precise cutting of the uterine adhesions. Most hysteroscopic surgery can be done in an outpatient setting. The treatment of the severe cases of Asherman’s syndrome can be more challenging, as the cavity may be completely blocked or too narrow to allow the insertion of the hysteroscope inside the cervix.Re-Adhesion PreventionSeveral procedures have been developed to prevent re-adhesion of the uterine wall following hysteroscopic surgery, since the scar tissue may re-adhere. The Foley catheter was one of first devices developed to separate the uterine walls to prevent the recurrent adhesions. A Foley catheter can be inserted in the uterine cavity for 5 to 7 days with a bag for removing drainage from the uterus. Another method to prevent adhesions from reoccurring is a uterine balloon stent made from silicon and shaped to fill the uterine cavity. Finally, application of certain chemicals such as hyaluronic acid has been shown to help prevent uterine re-adhesion. Although the mechanism is not completely understood, it is believed that hyaluronic acid acts as a temporary barrier to prevent re-adhesion and may also promote tissue repair.Uterus Restoration TherapyHormone therapy such as estrogen supplements have been proposed to help enhance tissue repair and restore the lining of the uterus. While some studies have suggested that estrogen therapy may enhance repair and growth of cells in the uterine wall, more clinical studies are being performed to confirm the value of estrogen therapy for treatment of Asherman’s syndrome. Antibiotics are also often prescribed following hysteroscopic surgery. While antibiotics do not directly prevent re-adhesion, they help prevent infections and inflammation that may damage the uterus and trigger re-adhesion of the uterine walls. | Therapies of Asherman’s Syndrome. Therapies for Asherman’s syndrome focus on restoring the uterus to its original size and shape. The therapies can be divided into three primary approaches: treatment – hysteroscopic surgery, re-adhesion prevention, and uterus restoration therapies. Mild cases of Asherman’s syndrome may only require surgical treatment, while more severe cases may require all three approaches. Most cases of Asherman’s syndrome can be cured with treatment.TreatmentThe most common treatment for Asherman’s syndrome is hysteroscopic surgery (hysteroscopes plus scissors or other cutting instruments) to cut the adhesions of the uterine wall. The hysteroscope allows the doctor a magnified and the direct view of the uterus for precise cutting of the uterine adhesions. Most hysteroscopic surgery can be done in an outpatient setting. The treatment of the severe cases of Asherman’s syndrome can be more challenging, as the cavity may be completely blocked or too narrow to allow the insertion of the hysteroscope inside the cervix.Re-Adhesion PreventionSeveral procedures have been developed to prevent re-adhesion of the uterine wall following hysteroscopic surgery, since the scar tissue may re-adhere. The Foley catheter was one of first devices developed to separate the uterine walls to prevent the recurrent adhesions. A Foley catheter can be inserted in the uterine cavity for 5 to 7 days with a bag for removing drainage from the uterus. Another method to prevent adhesions from reoccurring is a uterine balloon stent made from silicon and shaped to fill the uterine cavity. Finally, application of certain chemicals such as hyaluronic acid has been shown to help prevent uterine re-adhesion. Although the mechanism is not completely understood, it is believed that hyaluronic acid acts as a temporary barrier to prevent re-adhesion and may also promote tissue repair.Uterus Restoration TherapyHormone therapy such as estrogen supplements have been proposed to help enhance tissue repair and restore the lining of the uterus. While some studies have suggested that estrogen therapy may enhance repair and growth of cells in the uterine wall, more clinical studies are being performed to confirm the value of estrogen therapy for treatment of Asherman’s syndrome. Antibiotics are also often prescribed following hysteroscopic surgery. While antibiotics do not directly prevent re-adhesion, they help prevent infections and inflammation that may damage the uterus and trigger re-adhesion of the uterine walls. | 108 | Asherman’s Syndrome |
nord_109_0 | Overview of Asherson’s Syndrome | Asherson's syndrome is an extremely rare autoimmune disorder characterized by the development, over a period of hours, days or weeks, of rapidly progressive blood clots affecting multiple organ systems of the body. Conditions such as infections, immunizations, wounds caused due to physical trauma and failure in the anticoagulation mechanism of the body usually act as “triggers”.The syndrome is particularly common among patients with antiphospholipid syndrome who experience a cessation of the anticoagulation mechanism rleated to recurrent bleeding in the body. It is usually seen in patients who have previously suffered from a simple/classic episode of antiphospholipid syndrome. It is not known why patients of antiphospholipid syndrome often have the tendency to be “catapulted” into a serious or fatal multiorgan failure, while the same triggers in other individuals may only result in recurrent large vessel thrombosis. The symptoms are also aptly observed in patients during pregnancy or in the weeks after childbirth (puerperium) and may follow the HELLP syndrome or be associated with malignancies. Symptoms vary from case to case depending upon the specific organ systems involved. Asherson's syndrome can rapidly result in life-threatening multiorgan failure.Asherson's syndrome is a severe variant of antiphospholipid syndrome (APS), an autoimmune disorder in which blood clots occur in relation to the presence of antiphospholipid antibodies in the body. Antibodies are specialized proteins produced by the body's immune system to fight infection. In autoimmune disorders, antibodies mistakenly attack healthy tissue. In APS and Asherson's syndrome, antibodies mistakenly attack certain proteins that bind to phospholipids, which are fat molecules that are involved in the proper function of cell membranes. Phospholipids are found throughout the body. The reason these antibodies attack these proteins and the process by which they cause blood clots to form is not known.Asherson's syndrome may occur in individuals who have primary or secondary APS or in individuals with lupus or other autoimmune disorders. In some cases, no previous history of these disorders may be present. The exact cause of Asherson's syndrome is unknown. | Overview of Asherson’s Syndrome. Asherson's syndrome is an extremely rare autoimmune disorder characterized by the development, over a period of hours, days or weeks, of rapidly progressive blood clots affecting multiple organ systems of the body. Conditions such as infections, immunizations, wounds caused due to physical trauma and failure in the anticoagulation mechanism of the body usually act as “triggers”.The syndrome is particularly common among patients with antiphospholipid syndrome who experience a cessation of the anticoagulation mechanism rleated to recurrent bleeding in the body. It is usually seen in patients who have previously suffered from a simple/classic episode of antiphospholipid syndrome. It is not known why patients of antiphospholipid syndrome often have the tendency to be “catapulted” into a serious or fatal multiorgan failure, while the same triggers in other individuals may only result in recurrent large vessel thrombosis. The symptoms are also aptly observed in patients during pregnancy or in the weeks after childbirth (puerperium) and may follow the HELLP syndrome or be associated with malignancies. Symptoms vary from case to case depending upon the specific organ systems involved. Asherson's syndrome can rapidly result in life-threatening multiorgan failure.Asherson's syndrome is a severe variant of antiphospholipid syndrome (APS), an autoimmune disorder in which blood clots occur in relation to the presence of antiphospholipid antibodies in the body. Antibodies are specialized proteins produced by the body's immune system to fight infection. In autoimmune disorders, antibodies mistakenly attack healthy tissue. In APS and Asherson's syndrome, antibodies mistakenly attack certain proteins that bind to phospholipids, which are fat molecules that are involved in the proper function of cell membranes. Phospholipids are found throughout the body. The reason these antibodies attack these proteins and the process by which they cause blood clots to form is not known.Asherson's syndrome may occur in individuals who have primary or secondary APS or in individuals with lupus or other autoimmune disorders. In some cases, no previous history of these disorders may be present. The exact cause of Asherson's syndrome is unknown. | 109 | Asherson’s Syndrome |
nord_109_1 | Symptoms of Asherson’s Syndrome | The symptoms of Asherson's syndrome are caused by complications resulting from the development of multiple blood clots (thromboses) in the body. Multiple blood clots may form in a matter of hours, days or weeks, potentially causing life-threatening multiorgan failure. Specific symptoms vary depending upon what organ systems are involved. The kidneys, stomach, lungs, heart, skin and central nervous system are commonly affected. Involvement of the kidneys may result in kidney dysfunction and associated symptoms such as low urine production and high blood pressure (hypertension). Involvement of the lungs (pulmonary system) may result in adult respiratory distress syndrome, a severe lung disorder characterized by difficulties (dyspnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). Additional pulmonary symptoms may include (pulmonary embolism).Blotchy reddish patches of discolored skin, a condition known as livedo reticularis, bruising, and the loss of living tissue (gangrene) may develop. Central nervous system symptoms may include stroke (cerebral infarction), seizures, and a condition characterized by altered brain structure and function (encephalopathy).If the heart is involved, symptoms may include inflammation and thickening of the valves of the heart (valvar heart disease) potentially resulting in complication such as mitral valve regurgitation (MVR). In MVR, the mitral valve does not shut properly allowing blood to flow backward into the heart. Affected individuals may also experience chest pain (angina) and the possibility of a heart attack (myocardial infarction). Additional organ systems may be involved including the gastrointestinal system, resulting in abdominal pain and cramping; the adrenal and pituitary glands resulting in hormone imbalances and low blood pressure; and the bone marrow resulting in low levels of red blood cells (anemia) and platelets (thrombocytopenia). | Symptoms of Asherson’s Syndrome. The symptoms of Asherson's syndrome are caused by complications resulting from the development of multiple blood clots (thromboses) in the body. Multiple blood clots may form in a matter of hours, days or weeks, potentially causing life-threatening multiorgan failure. Specific symptoms vary depending upon what organ systems are involved. The kidneys, stomach, lungs, heart, skin and central nervous system are commonly affected. Involvement of the kidneys may result in kidney dysfunction and associated symptoms such as low urine production and high blood pressure (hypertension). Involvement of the lungs (pulmonary system) may result in adult respiratory distress syndrome, a severe lung disorder characterized by difficulties (dyspnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). Additional pulmonary symptoms may include (pulmonary embolism).Blotchy reddish patches of discolored skin, a condition known as livedo reticularis, bruising, and the loss of living tissue (gangrene) may develop. Central nervous system symptoms may include stroke (cerebral infarction), seizures, and a condition characterized by altered brain structure and function (encephalopathy).If the heart is involved, symptoms may include inflammation and thickening of the valves of the heart (valvar heart disease) potentially resulting in complication such as mitral valve regurgitation (MVR). In MVR, the mitral valve does not shut properly allowing blood to flow backward into the heart. Affected individuals may also experience chest pain (angina) and the possibility of a heart attack (myocardial infarction). Additional organ systems may be involved including the gastrointestinal system, resulting in abdominal pain and cramping; the adrenal and pituitary glands resulting in hormone imbalances and low blood pressure; and the bone marrow resulting in low levels of red blood cells (anemia) and platelets (thrombocytopenia). | 109 | Asherson’s Syndrome |
nord_109_2 | Causes of Asherson’s Syndrome | Asherson's syndrome is a rare autoimmune disorder. Autoimmune disorders are caused when the body natural defenses (antibodies, lymphocytes, etc.) against invading organisms suddenly begin to attack perfectly healthy tissue. Researchers believe that multiple factors including genetic and environmental factors play a role in the development of autoimmune disorders. Asherson's syndrome is a variant of antiphospholipid syndrome, which is characterized by the presence of certain antibodies in the body and the development of blood clots. The antibodies that are present in both antiphospholipid syndrome and Asherson's syndrome are known as antiphospholipid antibodies. There are several different types of antiphospholipid antibodies. Two types are most prevalent lupus anticoagulant and anticardiolipin antibodies. These antibodies were originally thought to attack phospholipids, fatty molecules that are a normal part of cell membranes found throughout the body. However, researchers now know that these antibodies mostly target certain blood proteins that bind to phospholipids. The two most common proteins affected are beta2-glycoprotein and prothrombin. The exact mechanism by which these antibodies eventually lead to the development of blood clots is not known. Asherson's syndrome may develop in individuals who already have primary or secondary antiphospholipid syndrome. It may also develop in individuals without a previous history of these disorders. The exact cause of Asherson's is unknown. In some cases, researchers have identified a precipitating event or “trigger” that plays a role in the development of the multiple blood clots that characterize this disorder. The main trigger is infection. Additional triggers are trauma including trauma caused by invasive surgical procedures, withdrawal of anti-clotting medication, pregnancy, and certain underlying malignancies (cancers). | Causes of Asherson’s Syndrome. Asherson's syndrome is a rare autoimmune disorder. Autoimmune disorders are caused when the body natural defenses (antibodies, lymphocytes, etc.) against invading organisms suddenly begin to attack perfectly healthy tissue. Researchers believe that multiple factors including genetic and environmental factors play a role in the development of autoimmune disorders. Asherson's syndrome is a variant of antiphospholipid syndrome, which is characterized by the presence of certain antibodies in the body and the development of blood clots. The antibodies that are present in both antiphospholipid syndrome and Asherson's syndrome are known as antiphospholipid antibodies. There are several different types of antiphospholipid antibodies. Two types are most prevalent lupus anticoagulant and anticardiolipin antibodies. These antibodies were originally thought to attack phospholipids, fatty molecules that are a normal part of cell membranes found throughout the body. However, researchers now know that these antibodies mostly target certain blood proteins that bind to phospholipids. The two most common proteins affected are beta2-glycoprotein and prothrombin. The exact mechanism by which these antibodies eventually lead to the development of blood clots is not known. Asherson's syndrome may develop in individuals who already have primary or secondary antiphospholipid syndrome. It may also develop in individuals without a previous history of these disorders. The exact cause of Asherson's is unknown. In some cases, researchers have identified a precipitating event or “trigger” that plays a role in the development of the multiple blood clots that characterize this disorder. The main trigger is infection. Additional triggers are trauma including trauma caused by invasive surgical procedures, withdrawal of anti-clotting medication, pregnancy, and certain underlying malignancies (cancers). | 109 | Asherson’s Syndrome |
nord_109_3 | Affects of Asherson’s Syndrome | Approximately 300 individuals have been identified with Asherson's syndrome since the disorder was first defined in the medical literature in 1992. More women have been affected than men. The disorder can occur at any age, although most cases have been reported in young adults. | Affects of Asherson’s Syndrome. Approximately 300 individuals have been identified with Asherson's syndrome since the disorder was first defined in the medical literature in 1992. More women have been affected than men. The disorder can occur at any age, although most cases have been reported in young adults. | 109 | Asherson’s Syndrome |
nord_109_4 | Related disorders of Asherson’s Syndrome | Symptoms of the following disorders can be similar to those of Asherson's syndrome. Comparisons may be useful for a differential diagnosis.Thrombotic thrombocytopenia purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). TTP appears to occur most often in females in the third or fourth decade of life. Findings may include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells (microangiopathic hemolytic anemia), and/or neurological abnormalities. Thrombocytopenia is associated with a variety of symptoms including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. In some cases, individuals with TTP may experience acute renal failure, which may result in diminished excretion of urine; blood appearing in the urine (hematuria); high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); and/or unusually low water content in the body (dehydration). In some cases, acute renal failure may lead to life-threatening complications. The exact cause of TTP is not known. (For more information on this disorder, choose “thrombotic thrombocytopenia purpura” as your search term in the Rare Disease Database.)Hemolytic-Uremic syndrome (HUS) is a very rare disorder that primarily affects young children between the ages of one and 10 years, particularly those under the age of four years. In many cases, the onset of HUS is preceded by a flu-like illness (gastroenteritis) characterized by vomiting, abdominal pain, fever, and diarrhea, which, in some cases, may be bloody. Symptoms of HUS usually become apparent three to 10 days after the development of gastroenteritis and may include sudden paleness (pallor), irritability, weakness, lack of energy (lethargy), and/or excretion of abnormally diminished amounts of urine (oliguria). The disease typically progresses to include inability of the kidneys to process waste products from the blood and excrete them into the urine (acute renal failure), a decrease in circulating red blood cells (microangiopathic hemolytic anemia); a decrease in circulating blood platelets, which assist in blood clotting functions (thrombocytopenia); and the abnormal accumulation of platelets within certain blood vessels (microthrombi), reducing the blood flow to several organs (e.g., kidneys, pancreas, brain) potentially leading to multiple organ dysfunction or failure. In some cases, neurological problems may be present at the onset of HUS or may occur at any time during the disorder's progression. Neurological symptoms may include dizziness, seizures (partial or generalized), disorientation or confusion, and/or loss of consciousness (coma). The onset of HUS is most frequently associated with infection by a particular strain (O157:H7) of Escherichia coli (E. coli) bacterium. (For more information on this disorder, choose “hemolytic uremic syndrome” as your search term in the Rare Disease Database.)HELLP is a rare syndrome that affects some pregnant women. The acronym HELLP stands for Hemolysis, the premature destruction of red blood cells, Elevated Liver enzymes, and Low Platelet counts. Platelets are small blood cells that clump together to form a plug (clot) at the site of injury to a blood vessel. HELLP syndrome may occur as an isolated condition or in women who have preeclampsia. Affected women may experience nausea and vomiting, headaches, fatigue, upper abdominal pain and vision problems. The severity of HELLP syndrome varies; it can be a mild condition or can cause life-threatening complications. The exact cause of HELLP syndrome is unknown. | Related disorders of Asherson’s Syndrome. Symptoms of the following disorders can be similar to those of Asherson's syndrome. Comparisons may be useful for a differential diagnosis.Thrombotic thrombocytopenia purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). TTP appears to occur most often in females in the third or fourth decade of life. Findings may include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells (microangiopathic hemolytic anemia), and/or neurological abnormalities. Thrombocytopenia is associated with a variety of symptoms including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. In some cases, individuals with TTP may experience acute renal failure, which may result in diminished excretion of urine; blood appearing in the urine (hematuria); high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); and/or unusually low water content in the body (dehydration). In some cases, acute renal failure may lead to life-threatening complications. The exact cause of TTP is not known. (For more information on this disorder, choose “thrombotic thrombocytopenia purpura” as your search term in the Rare Disease Database.)Hemolytic-Uremic syndrome (HUS) is a very rare disorder that primarily affects young children between the ages of one and 10 years, particularly those under the age of four years. In many cases, the onset of HUS is preceded by a flu-like illness (gastroenteritis) characterized by vomiting, abdominal pain, fever, and diarrhea, which, in some cases, may be bloody. Symptoms of HUS usually become apparent three to 10 days after the development of gastroenteritis and may include sudden paleness (pallor), irritability, weakness, lack of energy (lethargy), and/or excretion of abnormally diminished amounts of urine (oliguria). The disease typically progresses to include inability of the kidneys to process waste products from the blood and excrete them into the urine (acute renal failure), a decrease in circulating red blood cells (microangiopathic hemolytic anemia); a decrease in circulating blood platelets, which assist in blood clotting functions (thrombocytopenia); and the abnormal accumulation of platelets within certain blood vessels (microthrombi), reducing the blood flow to several organs (e.g., kidneys, pancreas, brain) potentially leading to multiple organ dysfunction or failure. In some cases, neurological problems may be present at the onset of HUS or may occur at any time during the disorder's progression. Neurological symptoms may include dizziness, seizures (partial or generalized), disorientation or confusion, and/or loss of consciousness (coma). The onset of HUS is most frequently associated with infection by a particular strain (O157:H7) of Escherichia coli (E. coli) bacterium. (For more information on this disorder, choose “hemolytic uremic syndrome” as your search term in the Rare Disease Database.)HELLP is a rare syndrome that affects some pregnant women. The acronym HELLP stands for Hemolysis, the premature destruction of red blood cells, Elevated Liver enzymes, and Low Platelet counts. Platelets are small blood cells that clump together to form a plug (clot) at the site of injury to a blood vessel. HELLP syndrome may occur as an isolated condition or in women who have preeclampsia. Affected women may experience nausea and vomiting, headaches, fatigue, upper abdominal pain and vision problems. The severity of HELLP syndrome varies; it can be a mild condition or can cause life-threatening complications. The exact cause of HELLP syndrome is unknown. | 109 | Asherson’s Syndrome |
nord_109_5 | Diagnosis of Asherson’s Syndrome | A diagnosis of Asherson's syndrome is made based upon a thorough clinical evaluation, identification of characteristic findings (e.g., multiple blood clots affecting at least three different organ systems that arise simultaneously within one week), and a variety of tests including simple blood tests that can detect antiphospholipid antibodies.A specialized blood test called a coagulation test is used to measure blood clotting and can indicate the presence of lupus anticoagulant in the blood. An Enzyme-Linked ImmunoSorbent Assay (ELISA) test can detect the presence of anticardiolipin antibodies in the blood. Positive tests may often need to be repeated because antiphospholipid antibodies can be present in short intervals (transiently) due to other reasons such as infection or drug use. Borderline negative tests may need to be repeated because individuals with APS have initially tested negative for the antiphospholipid antibodies. | Diagnosis of Asherson’s Syndrome. A diagnosis of Asherson's syndrome is made based upon a thorough clinical evaluation, identification of characteristic findings (e.g., multiple blood clots affecting at least three different organ systems that arise simultaneously within one week), and a variety of tests including simple blood tests that can detect antiphospholipid antibodies.A specialized blood test called a coagulation test is used to measure blood clotting and can indicate the presence of lupus anticoagulant in the blood. An Enzyme-Linked ImmunoSorbent Assay (ELISA) test can detect the presence of anticardiolipin antibodies in the blood. Positive tests may often need to be repeated because antiphospholipid antibodies can be present in short intervals (transiently) due to other reasons such as infection or drug use. Borderline negative tests may need to be repeated because individuals with APS have initially tested negative for the antiphospholipid antibodies. | 109 | Asherson’s Syndrome |
nord_109_6 | Therapies of Asherson’s Syndrome | TreatmentBecause of the recent identification and limited number of cases of Asherson's syndrome, no standard therapy has been approved. Researchers who have studied the disease recommend a combination of therapeutic regimens including drugs that prevent clotting (anticoagulants), corticosteroids, specialized proteins known as immunoglobulins, and repeated plasma exchanges using a procedure called plasmapheresis.Initial therapy for individuals is usually the anticoagulant, heparin, delivered intravenously. Corticosteroids may be given along with heparin. Steroids are given to minimize the effects of tissue loss (necrosis) that often accompanies Asherson's syndrome. Specialized proteins called immunoglobulins have also been used to treat affected individuals.Repeated plasma exchanges using fresh frozen plasma may be given using a procedure known as plasmapheresis. Plasmapheresis is a method for removing unwanted substances (e.g., antiphospholipid antibodies) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient's plasma is then replaced with other human plasma and the blood is transfused into the patient. This therapy is still under investigation to analyze side effects and effectiveness.Intensive antibiotic therapy may be used to treat infection.More research into the long-term effects of Asherson's syndrome is necessary, but researchers studying Asheron's have indicated that affected individuals who survive the initial onset of multiple blood clots have had an excellent prognosis so far. | Therapies of Asherson’s Syndrome. TreatmentBecause of the recent identification and limited number of cases of Asherson's syndrome, no standard therapy has been approved. Researchers who have studied the disease recommend a combination of therapeutic regimens including drugs that prevent clotting (anticoagulants), corticosteroids, specialized proteins known as immunoglobulins, and repeated plasma exchanges using a procedure called plasmapheresis.Initial therapy for individuals is usually the anticoagulant, heparin, delivered intravenously. Corticosteroids may be given along with heparin. Steroids are given to minimize the effects of tissue loss (necrosis) that often accompanies Asherson's syndrome. Specialized proteins called immunoglobulins have also been used to treat affected individuals.Repeated plasma exchanges using fresh frozen plasma may be given using a procedure known as plasmapheresis. Plasmapheresis is a method for removing unwanted substances (e.g., antiphospholipid antibodies) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient's plasma is then replaced with other human plasma and the blood is transfused into the patient. This therapy is still under investigation to analyze side effects and effectiveness.Intensive antibiotic therapy may be used to treat infection.More research into the long-term effects of Asherson's syndrome is necessary, but researchers studying Asheron's have indicated that affected individuals who survive the initial onset of multiple blood clots have had an excellent prognosis so far. | 109 | Asherson’s Syndrome |
nord_110_0 | Overview of Aspartylglycosaminuria | Aspartylglycosaminuria is a very rare genetic disorder that is concentrated among persons of Finnish decent, but is also found, even more rarely, in other populations around the world. It is an inborn error of metabolism, and one of the lysosomal storage diseases. It becomes apparent after the infant is a few months old. Major symptoms may include coarse facial features, spine and eye deformities, behavior problems and mental retardation. Aspartylglycosaminuria occurs as a result of deficient activity of a particular enzyme, leading to the accumulation of metabolic products in the body. | Overview of Aspartylglycosaminuria. Aspartylglycosaminuria is a very rare genetic disorder that is concentrated among persons of Finnish decent, but is also found, even more rarely, in other populations around the world. It is an inborn error of metabolism, and one of the lysosomal storage diseases. It becomes apparent after the infant is a few months old. Major symptoms may include coarse facial features, spine and eye deformities, behavior problems and mental retardation. Aspartylglycosaminuria occurs as a result of deficient activity of a particular enzyme, leading to the accumulation of metabolic products in the body. | 110 | Aspartylglycosaminuria |
nord_110_1 | Symptoms of Aspartylglycosaminuria | Aspartylglycosaminuria is a lysosomal storage disease characterized by normal development during the first months of life after which abnormal development begins to occur. Diarrhea and infections that keep reoccurring are noticed. After the first few years facial features begin to get coarse which continues during the following years. The skeleton may become deformed and the ocular lens may develop crystalline deposits. Mental deterioration may begin to occur after age five and behavior problems are common. Lung, heart and blood problems tend to occur in later years. The patient may show mental retardation uneven development of the head and face with sagging cheeks, a wide nose and broad face. The spine may be twisted (scoliosis) and the neck may be unusually short. Adult stature is usually below normal. | Symptoms of Aspartylglycosaminuria. Aspartylglycosaminuria is a lysosomal storage disease characterized by normal development during the first months of life after which abnormal development begins to occur. Diarrhea and infections that keep reoccurring are noticed. After the first few years facial features begin to get coarse which continues during the following years. The skeleton may become deformed and the ocular lens may develop crystalline deposits. Mental deterioration may begin to occur after age five and behavior problems are common. Lung, heart and blood problems tend to occur in later years. The patient may show mental retardation uneven development of the head and face with sagging cheeks, a wide nose and broad face. The spine may be twisted (scoliosis) and the neck may be unusually short. Adult stature is usually below normal. | 110 | Aspartylglycosaminuria |
nord_110_2 | Causes of Aspartylglycosaminuria | Aspartylglycosaminuria is a lysosomal storage disease. Lysosomes are cell particles containing enzymes that break down large molecules. A deficiency of the lysosomal enzyme, aspartylglycosamidase, causes the accumulation of a substance known as aspartylglucosamine in the body, resulting in disorders in the various body systems.This disorder is inherited as an autosomal recessive trait. The gene responsible for this disorder is located on the long arm of the fourth chromosome at 4q32-q33. Those affected by this disorder are most often of Finnish ancestry. However, aspartylglycosaminuria can occur in people of all heritages.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 subdivided into many bands that are numbered. For example, “chromosome 4q32-q33” refers to a region between bands 32 and 33 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Aspartylglycosaminuria. Aspartylglycosaminuria is a lysosomal storage disease. Lysosomes are cell particles containing enzymes that break down large molecules. A deficiency of the lysosomal enzyme, aspartylglycosamidase, causes the accumulation of a substance known as aspartylglucosamine in the body, resulting in disorders in the various body systems.This disorder is inherited as an autosomal recessive trait. The gene responsible for this disorder is located on the long arm of the fourth chromosome at 4q32-q33. Those affected by this disorder are most often of Finnish ancestry. However, aspartylglycosaminuria can occur in people of all heritages.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 subdivided into many bands that are numbered. For example, “chromosome 4q32-q33” refers to a region between bands 32 and 33 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 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. | 110 | Aspartylglycosaminuria |
nord_110_3 | Affects of Aspartylglycosaminuria | Aspartylglycosaminuria is a rare disorder that affects males and females in equal numbers. However, in Finland where the majority of cases are reported, there are an estimated 130 cases in 4.5 million persons. In the rest of the world, the condition is extremely rare and affects persons of various heritages. | Affects of Aspartylglycosaminuria. Aspartylglycosaminuria is a rare disorder that affects males and females in equal numbers. However, in Finland where the majority of cases are reported, there are an estimated 130 cases in 4.5 million persons. In the rest of the world, the condition is extremely rare and affects persons of various heritages. | 110 | Aspartylglycosaminuria |
nord_110_4 | Related disorders of Aspartylglycosaminuria | Symptoms of the following disorders can be similar to those of Aspartylglycosaminuria. Comparisons may be useful for a differential diagnosis:The Mucopolysaccharidoses (MPS) are a group of hereditary lysosomal storage diseases. They are characterized by abnormal accumulation of mucopolysaccharides, especially in the cartilage and bones. These deposits are also found in the arteries, skeleton, eyes, joints, ears, skin and teeth. In general these disorders are progressive. The child may appear normal at birth and around the age of one begin to show signs of both growth and mental retardation. (For more information on this disorder, choose “Mucopolysaccharidoses” as your search term in the Rare Disease Database.)Pseudo-Hurler Polydystrophy is an autosomal recessive inherited disorder characterized by onset in childhood, painless joint stiffness, decreased mobility, short stature, some coarseness of the facial features, mild mental retardation, evidence of multiple defective bone formations and aortic valve disease. (For more information on this disorder, choose “Pseudo-Hurler” as your search term in the Rare Disease Database.)I-Cell Disease begins very early in life. By the age of six months children have begun to show symptoms such as coarse facial features, a long and narrow head, excessive hair growth, and a low forehead. They may also show severe skeletal changes and mental and physical retardation is common. (For more information on this disorder, choose “I-Cell” as your search term in the Rare Disease Database.) | Related disorders of Aspartylglycosaminuria. Symptoms of the following disorders can be similar to those of Aspartylglycosaminuria. Comparisons may be useful for a differential diagnosis:The Mucopolysaccharidoses (MPS) are a group of hereditary lysosomal storage diseases. They are characterized by abnormal accumulation of mucopolysaccharides, especially in the cartilage and bones. These deposits are also found in the arteries, skeleton, eyes, joints, ears, skin and teeth. In general these disorders are progressive. The child may appear normal at birth and around the age of one begin to show signs of both growth and mental retardation. (For more information on this disorder, choose “Mucopolysaccharidoses” as your search term in the Rare Disease Database.)Pseudo-Hurler Polydystrophy is an autosomal recessive inherited disorder characterized by onset in childhood, painless joint stiffness, decreased mobility, short stature, some coarseness of the facial features, mild mental retardation, evidence of multiple defective bone formations and aortic valve disease. (For more information on this disorder, choose “Pseudo-Hurler” as your search term in the Rare Disease Database.)I-Cell Disease begins very early in life. By the age of six months children have begun to show symptoms such as coarse facial features, a long and narrow head, excessive hair growth, and a low forehead. They may also show severe skeletal changes and mental and physical retardation is common. (For more information on this disorder, choose “I-Cell” as your search term in the Rare Disease Database.) | 110 | Aspartylglycosaminuria |
nord_110_5 | Diagnosis of Aspartylglycosaminuria | Diagnosis of Aspartylglycosaminuria. | 110 | Aspartylglycosaminuria |
|
nord_110_6 | Therapies of Aspartylglycosaminuria | Treatment of Aspartylglycosaminuria is symptomatic and supportive. Genetic counseling may be of benefit for families. | Therapies of Aspartylglycosaminuria. Treatment of Aspartylglycosaminuria is symptomatic and supportive. Genetic counseling may be of benefit for families. | 110 | Aspartylglycosaminuria |
nord_111_0 | Overview of Aspergillosis | Aspergillosis is a fungal infection caused by Aspergillus, a species of mold that is found all over the world. More than 180 different types of Aspergillus have been identified and more are continuing to be identified. Most of these molds are harmless. However, some types can cause a variety of diseases in humans ranging from simple allergic reactions to life-threatening invasive disease. Collectively, this group of diseases is referred to as aspergillosis and is broadly broken down into three categories – allergic, chronic and invasive. There are several different forms including allergic bronchopulmonary aspergillosis, allergic Aspergillus sinusitis, invasive aspergillosis, cutaneous (skin) aspergillosis and chronic pulmonary aspergillosis, which also has several different presentations. Aspergillosis rarely develops in healthy individuals; most people breathe in these spores every day without any issues. An infection is much more likely to develop in individuals who have an underlying condition such as asthma, cystic fibrosis and previous lung disease, or who have taken corticosteroid drugs for a long period of time, or in individuals who have a weakened immune system, including people who have low levels of neutrophils, a type of white blood cell that helps the body fight off infection and heal itself (neutropenia), or who are taking drugs that suppress the immune system (immunosuppressive drugs) such as people who have had a bone marrow or organ transplant. In most instances, aspergillosis develops when susceptible individuals breathe in (inhale) Aspergillus spores. Aspergillosis is not contagious and cannot be transmitted from one person to another. | Overview of Aspergillosis. Aspergillosis is a fungal infection caused by Aspergillus, a species of mold that is found all over the world. More than 180 different types of Aspergillus have been identified and more are continuing to be identified. Most of these molds are harmless. However, some types can cause a variety of diseases in humans ranging from simple allergic reactions to life-threatening invasive disease. Collectively, this group of diseases is referred to as aspergillosis and is broadly broken down into three categories – allergic, chronic and invasive. There are several different forms including allergic bronchopulmonary aspergillosis, allergic Aspergillus sinusitis, invasive aspergillosis, cutaneous (skin) aspergillosis and chronic pulmonary aspergillosis, which also has several different presentations. Aspergillosis rarely develops in healthy individuals; most people breathe in these spores every day without any issues. An infection is much more likely to develop in individuals who have an underlying condition such as asthma, cystic fibrosis and previous lung disease, or who have taken corticosteroid drugs for a long period of time, or in individuals who have a weakened immune system, including people who have low levels of neutrophils, a type of white blood cell that helps the body fight off infection and heal itself (neutropenia), or who are taking drugs that suppress the immune system (immunosuppressive drugs) such as people who have had a bone marrow or organ transplant. In most instances, aspergillosis develops when susceptible individuals breathe in (inhale) Aspergillus spores. Aspergillosis is not contagious and cannot be transmitted from one person to another. | 111 | Aspergillosis |
nord_111_1 | Symptoms of Aspergillosis | The symptoms of aspergillosis vary depending upon the specific form of the disorder present. The lungs are usually affected. Aspergillosis can present as an allergic reaction, an isolated finding affecting a specific area of the body (e.g., the lungs, sinuses or ear canals), or as an invasive infection that spreads to affect various tissues or organs of the body.ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
This form of aspergillosis usually occurs in individuals with long-standing asthma or cystic fibrosis but has also been reported in patients with another chronic lung disease, chronic obstructive pulmonary disease (COPD). It is an allergic reaction to the breathing in (inhalation) of the fungi spores. These spores set off an improper response from an individual’s immune system. Initial symptoms resemble those associated with poorly controlled asthma and usually include chronic wheezing, shortness of breath (dyspnea), and a general feeling of poor health (malaise). Fever can occur but is not common. Allergic bronchopulmonary aspergillosis may also cause chest pain, a cough that brings up blood (hemoptysis) or brown-colored globs (plugs) of mucus and an excess of certain white blood cells in the blood (eosinophilia). The condition usually does not spread to other areas but can cause complications when diagnosis is delayed or it is undertreated including chronic widening (dilation) of the bronchial tubes (bronchiectasis) or severe, persistent asthma and loss of lung function.A related condition is called severe asthma with fungal sensitization [SAFS]. It is characterized by severe, poorly controlled asthma in the presence of allergy to Aspergillus or other molds, but without fulfilling the criteria for ABPA.CHRONIC PULMONARY ASPERGILLOSIS
Chronic pulmonary aspergillosis is characterized by scarring (fibrosis) within the lungs and the gradual loss of lung tissue which causes the formation of empty spaces (cavitation, or the widening and growth (expansion) of existing spaces. There is also thickening of the membranes around the lungs (pleural thickening). The term chronic pulmonary aspergillosis describes several distinct patterns of disease, including: aspergilloma, Aspergillus nodule, chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis and subacute invasive pulmonary aspergillosis. Chronic pulmonary aspergillosis can recur after treatment.Aspergilloma
The most distinctive form of aspergillosis is the development of a fungal ball known as an aspergilloma. These growths consist of a tangled mass of fungus fibers, mucus, tissue debris, inflammatory cells and blood clotting protein (fibrin). Aspergillomas form in air pockets or cavities found within the lungs that may have been formed from previous lung disease (e.g., tuberculosis or emphysema). Many affected individuals do not have any apparent symptoms (asymptomatic) for years. Symptoms that can develop include wheezing, shortness of breath, chest pain, a chronic cough, fatigue, a cough that brings up blood (hemoptysis) and unintended weight loss. Fever is rare unless individuals also have a bacterial infection. In some instances, hemoptysis can become severe, potentially causing suffocation (asphyxiation). An aspergilloma may remain the same size, can shrink or resolve without treatment. In some cases, an aspergilloma may gradually grow larger and damage nearby lung tissue; if that happens, the condition is called chronic cavitary pulmonary aspergillosis.Aspergillus Nodule
An Aspergillus nodule is a tiny mass of infected tissue. These nodules can form in individuals with fully functioning immune systems (immunocompetent hosts). Affected individuals can develop one nodule or multiple nodules, often without the formation of empty spaces (cavitation). Many individuals do not develop symptoms (asymptomatic), but some individuals will develop a cough, chest infection or worsening (exacerbation) of an existing lung condition such as asthma or chronic pulmonary obstructive disease.Chronic Cavitary Pulmonary Aspergillosis
Individuals with this form of aspergillosis develop cavities or empty spaces within the lungs (cavitation) or experience the widening or growth (expansion) of existing cavities. About half of these individuals have an aspergilloma on x-ray or CT scan. They can experience unintended weight loss, a chronic cough that produces mucus, the coughing up of blood, fatigue and shortness of breath. Less often, fever or night sweats can occur. Rarely, significant and extensive scarring (fibrosis) can occur. This is sometimes referred to as chronic fibrosing pulmonary aspergillosis.Subacute Invasive Pulmonary Aspergillosis (Chronic Necrotizing Aspergillosis)
This form of aspergillosis, also known as semi-invasive aspergillosis, has many similarities with chronic cavitary pulmonary aspergillosis, but progresses more quickly, usually over 1-3 months; the reason is that it affects individuals with some degree of immunosuppression (e.g., people taking high doses of steroids). Patients with more severe immunosuppression (e.g., undergoing chemotherapy or receiving a transplant) usually develop a more acute disease, invasive aspergillosis. Subacute invasive pulmonary aspergillosis shows a chronic, slowly progressive process that, unlike invasive aspergillosis, does not spread to other organ systems or the blood vessels (angioinvasion). In some affected individuals, an aspergilloma (fungal ball) may develop in a cavity created by the destruction of lung tissue by the original infection. General symptoms associated with this form of aspergillosis include fever, night sweats, a cough that brings up sputum, fatigue, a general feeling of poor health (malaise) and unintended weight loss. Affected individuals may also cough up blood or sputum; this can vary from mild to severe.INVASIVE ASPERGILLOSIS
Invasive aspergillosis is the most severe form of aspergillosis and usually affects individuals with weakened immune systems or those who have received bone marrow or solid organ transplant. It is characterized by infection that starts in the lungs and then rapidly travels through the bloodstream to affect various organs of the body potentially including the brain, kidneys, heart and skin. The specific symptoms associated with invasive aspergillosis vary based upon the organ system(s) involved. Affected individuals often develop fever, chills, headaches, a cough that brings up blood (mild hemoptysis) or sputum, shortness of breath (dyspnea) and chest pain. Severe life-threatening complications can develop including shock, delirium, massive bleeding from the lungs and inflammation of the trachea and bronchi (tracheobronchitis), which may cause airway obstruction. Organ failure (e.g., liver or kidney) can occur. If the infection spreads to the brain, seizures, intracranial bleeding or inflammation of the membranes surrounding the brain (meningitis) can occur. If the central nervous system is involved, it can present with a stroke.Invasive aspergillosis has been showed to affect about 10% of patients admitted to intensive care units with severe COVID-19 infection and can be a lethal infection.Additional Forms of Aspergillosis
Aspergillosis may occur as an isolated infection of individual areas such as the nail beds, eyes, skin, sinuses or ear canals. Infection of the ear canals can cause itchiness, pain and the drainage of fluid from the ears. Aspergillus can cause an allergic reaction or in the sinuses (allergic Aspergillus sinusitis) may cause a stuffy nose, runny nose, congestion, facial pain and headache. It can also cause invasive disease in the sinuses (invasive Aspergillus sinusitis) which can be more severe and may spread to other areas including the eye or the brain (central nervous system aspergillosis). Aspergillosis of the sinuses is sometimes associated with bone loss of the facial bones. An aspergilloma (fungus ball) may form in the sinuses.Infection with Aspergillus may cause inflammation of the thin membrane (endocardium) lining the heart, a condition called endocarditis. This condition occurs when heart tissue is directly infected by Aspergillus during cardiac surgery (post-operative aspergillosis). Individuals with aspergillosis affecting the site of surgery have also been reported following eye (ophthalmologic) and dental surgery.The skin can be affected, sometimes following trauma, through open surgical wounds or injury or if the infection starts somewhere else in the body and spreads to the skin. The gastrointestinal system can also be involved and can cause inflammation of the appendix (appendicitis), abdominal pain, ulcers and bleeding from the gastrointestinal tract.Aspergillus can also cause an infection within the eye called endophthalmitis. This most often occurs after trauma or surgery to the eye, or by the mold traveling to the eye through the blood during invasive aspergillosis (hematogenous seeding). Endophthalmitis can cause redness and pain in the eye. There may be a white or yellow discharge that comes out of the eye. Vision can be affected as well and there may be an increased sensitivity to bright light (photosensitivity). | Symptoms of Aspergillosis. The symptoms of aspergillosis vary depending upon the specific form of the disorder present. The lungs are usually affected. Aspergillosis can present as an allergic reaction, an isolated finding affecting a specific area of the body (e.g., the lungs, sinuses or ear canals), or as an invasive infection that spreads to affect various tissues or organs of the body.ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
This form of aspergillosis usually occurs in individuals with long-standing asthma or cystic fibrosis but has also been reported in patients with another chronic lung disease, chronic obstructive pulmonary disease (COPD). It is an allergic reaction to the breathing in (inhalation) of the fungi spores. These spores set off an improper response from an individual’s immune system. Initial symptoms resemble those associated with poorly controlled asthma and usually include chronic wheezing, shortness of breath (dyspnea), and a general feeling of poor health (malaise). Fever can occur but is not common. Allergic bronchopulmonary aspergillosis may also cause chest pain, a cough that brings up blood (hemoptysis) or brown-colored globs (plugs) of mucus and an excess of certain white blood cells in the blood (eosinophilia). The condition usually does not spread to other areas but can cause complications when diagnosis is delayed or it is undertreated including chronic widening (dilation) of the bronchial tubes (bronchiectasis) or severe, persistent asthma and loss of lung function.A related condition is called severe asthma with fungal sensitization [SAFS]. It is characterized by severe, poorly controlled asthma in the presence of allergy to Aspergillus or other molds, but without fulfilling the criteria for ABPA.CHRONIC PULMONARY ASPERGILLOSIS
Chronic pulmonary aspergillosis is characterized by scarring (fibrosis) within the lungs and the gradual loss of lung tissue which causes the formation of empty spaces (cavitation, or the widening and growth (expansion) of existing spaces. There is also thickening of the membranes around the lungs (pleural thickening). The term chronic pulmonary aspergillosis describes several distinct patterns of disease, including: aspergilloma, Aspergillus nodule, chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis and subacute invasive pulmonary aspergillosis. Chronic pulmonary aspergillosis can recur after treatment.Aspergilloma
The most distinctive form of aspergillosis is the development of a fungal ball known as an aspergilloma. These growths consist of a tangled mass of fungus fibers, mucus, tissue debris, inflammatory cells and blood clotting protein (fibrin). Aspergillomas form in air pockets or cavities found within the lungs that may have been formed from previous lung disease (e.g., tuberculosis or emphysema). Many affected individuals do not have any apparent symptoms (asymptomatic) for years. Symptoms that can develop include wheezing, shortness of breath, chest pain, a chronic cough, fatigue, a cough that brings up blood (hemoptysis) and unintended weight loss. Fever is rare unless individuals also have a bacterial infection. In some instances, hemoptysis can become severe, potentially causing suffocation (asphyxiation). An aspergilloma may remain the same size, can shrink or resolve without treatment. In some cases, an aspergilloma may gradually grow larger and damage nearby lung tissue; if that happens, the condition is called chronic cavitary pulmonary aspergillosis.Aspergillus Nodule
An Aspergillus nodule is a tiny mass of infected tissue. These nodules can form in individuals with fully functioning immune systems (immunocompetent hosts). Affected individuals can develop one nodule or multiple nodules, often without the formation of empty spaces (cavitation). Many individuals do not develop symptoms (asymptomatic), but some individuals will develop a cough, chest infection or worsening (exacerbation) of an existing lung condition such as asthma or chronic pulmonary obstructive disease.Chronic Cavitary Pulmonary Aspergillosis
Individuals with this form of aspergillosis develop cavities or empty spaces within the lungs (cavitation) or experience the widening or growth (expansion) of existing cavities. About half of these individuals have an aspergilloma on x-ray or CT scan. They can experience unintended weight loss, a chronic cough that produces mucus, the coughing up of blood, fatigue and shortness of breath. Less often, fever or night sweats can occur. Rarely, significant and extensive scarring (fibrosis) can occur. This is sometimes referred to as chronic fibrosing pulmonary aspergillosis.Subacute Invasive Pulmonary Aspergillosis (Chronic Necrotizing Aspergillosis)
This form of aspergillosis, also known as semi-invasive aspergillosis, has many similarities with chronic cavitary pulmonary aspergillosis, but progresses more quickly, usually over 1-3 months; the reason is that it affects individuals with some degree of immunosuppression (e.g., people taking high doses of steroids). Patients with more severe immunosuppression (e.g., undergoing chemotherapy or receiving a transplant) usually develop a more acute disease, invasive aspergillosis. Subacute invasive pulmonary aspergillosis shows a chronic, slowly progressive process that, unlike invasive aspergillosis, does not spread to other organ systems or the blood vessels (angioinvasion). In some affected individuals, an aspergilloma (fungal ball) may develop in a cavity created by the destruction of lung tissue by the original infection. General symptoms associated with this form of aspergillosis include fever, night sweats, a cough that brings up sputum, fatigue, a general feeling of poor health (malaise) and unintended weight loss. Affected individuals may also cough up blood or sputum; this can vary from mild to severe.INVASIVE ASPERGILLOSIS
Invasive aspergillosis is the most severe form of aspergillosis and usually affects individuals with weakened immune systems or those who have received bone marrow or solid organ transplant. It is characterized by infection that starts in the lungs and then rapidly travels through the bloodstream to affect various organs of the body potentially including the brain, kidneys, heart and skin. The specific symptoms associated with invasive aspergillosis vary based upon the organ system(s) involved. Affected individuals often develop fever, chills, headaches, a cough that brings up blood (mild hemoptysis) or sputum, shortness of breath (dyspnea) and chest pain. Severe life-threatening complications can develop including shock, delirium, massive bleeding from the lungs and inflammation of the trachea and bronchi (tracheobronchitis), which may cause airway obstruction. Organ failure (e.g., liver or kidney) can occur. If the infection spreads to the brain, seizures, intracranial bleeding or inflammation of the membranes surrounding the brain (meningitis) can occur. If the central nervous system is involved, it can present with a stroke.Invasive aspergillosis has been showed to affect about 10% of patients admitted to intensive care units with severe COVID-19 infection and can be a lethal infection.Additional Forms of Aspergillosis
Aspergillosis may occur as an isolated infection of individual areas such as the nail beds, eyes, skin, sinuses or ear canals. Infection of the ear canals can cause itchiness, pain and the drainage of fluid from the ears. Aspergillus can cause an allergic reaction or in the sinuses (allergic Aspergillus sinusitis) may cause a stuffy nose, runny nose, congestion, facial pain and headache. It can also cause invasive disease in the sinuses (invasive Aspergillus sinusitis) which can be more severe and may spread to other areas including the eye or the brain (central nervous system aspergillosis). Aspergillosis of the sinuses is sometimes associated with bone loss of the facial bones. An aspergilloma (fungus ball) may form in the sinuses.Infection with Aspergillus may cause inflammation of the thin membrane (endocardium) lining the heart, a condition called endocarditis. This condition occurs when heart tissue is directly infected by Aspergillus during cardiac surgery (post-operative aspergillosis). Individuals with aspergillosis affecting the site of surgery have also been reported following eye (ophthalmologic) and dental surgery.The skin can be affected, sometimes following trauma, through open surgical wounds or injury or if the infection starts somewhere else in the body and spreads to the skin. The gastrointestinal system can also be involved and can cause inflammation of the appendix (appendicitis), abdominal pain, ulcers and bleeding from the gastrointestinal tract.Aspergillus can also cause an infection within the eye called endophthalmitis. This most often occurs after trauma or surgery to the eye, or by the mold traveling to the eye through the blood during invasive aspergillosis (hematogenous seeding). Endophthalmitis can cause redness and pain in the eye. There may be a white or yellow discharge that comes out of the eye. Vision can be affected as well and there may be an increased sensitivity to bright light (photosensitivity). | 111 | Aspergillosis |
nord_111_2 | Causes of Aspergillosis | Aspergillosis is a fungal infection caused by certain types of molds. They are found throughout nature (ubiquitous) and can be found in the soil and decaying organic matter like decaying vegetation. They can be found indoors, especially in heating or cooling ducts or in insulation. There are about 180 species of Aspergillus, but only about 40 are known to be associated with disease in humans.Although they are found commonly throughout nature, these molds normally don’t cause problems. We all inhale the mold spores daily, but healthy individuals can promptly remove them from the lungs. However, in certain individuals such as people with a weakened or compromised immune system, they can cause severe, even life-threatening infection. Most people develop this infection by breathing in mold spores. Less often, infection can develop when spores enter the body through a cut or open wound.Allergic bronchopulmonary aspergillosis is more likely to occur in individuals who have asthma or cystic fibrosis. Forms of chronic pulmonary aspergillosis are more likely to occur in individuals who have had a previous lung disease including tuberculosis or chronic obstructive pulmonary disease (COPD) or a disorder that can affect the lungs like sarcoidosis. In addition, people who have had lung surgery in the past, e.g., for pneumothorax or lung cancer, can also develop chronic pulmonary aspergillosis.Invasive aspergillosis is more likely to occur in individuals who have a weakened immune system including people who have low levels of neutrophils (neutropenia), which are white blood cells that help to fight off infection. It can also occur in those receiving broad-spectrum antibiotics, individuals who are receiving chemotherapy or individuals who are receiving drugs that suppress the activity of the immune system (immunosuppressive drugs). Certain rare disorders like chronic granulomatous disease can also cause impaired function of the neutrophils and a susceptibility to Aspergillus.People who have recently undergone hematopoietic stem cell transplantation (HSCT) are at highest risk for invasive aspergillosis. Hematopoietic stem cells are found in the bone marrow and are cells that eventually grow into red blood cells, white blood cells and platelets. A transplant involves wiping out the existing bone marrow and replacing it with bone marrow from a healthy donor. Affected individuals must take immunosuppressive drugs to help fight off rejection, but this can leave them more susceptible to infection including infection with Aspergillus. People receiving immunosuppressive drugs for other reasons such as receiving an organ transplant can also be at risk of developing this infection.Other conditions can increase the risk of developing aspergillosis include people in the late stages of HIV/AIDS; the use of contaminated medical equipment near or in open wounds; long-term use of corticosteroids, which are very strong anti-inflammatory medications and traumatic injury including burns or other injury to the skin.Some researchers have noted that genetics can play a role in the development of aspergillosis. Researchers speculate that certain genes may make some individuals more likely to develop an infection with Aspergillus. This is called having a ‘genetic predisposition’ to developing a disease. Some research has indicated that genes that have a role in innate immune functions may be involved in the development of chronic pulmonary aspergillosis in some people. Genetic factors have also been explored for allergic bronchopulmonary aspergillosis, and this form of infection is believed to result from several factors (e.g., genetic, immunologic, environmental) occurring together. Research is underway to determine what role genetics play in the development of various forms of aspergillosis.Researchers have mapped the genome for a few specific types of Aspergillus. A genome is the complete genetic makeup of an organism and researchers hope that these genomes will lead them to novel treatment options and to a better understanding of the differences between the different species of Aspergillus. | Causes of Aspergillosis. Aspergillosis is a fungal infection caused by certain types of molds. They are found throughout nature (ubiquitous) and can be found in the soil and decaying organic matter like decaying vegetation. They can be found indoors, especially in heating or cooling ducts or in insulation. There are about 180 species of Aspergillus, but only about 40 are known to be associated with disease in humans.Although they are found commonly throughout nature, these molds normally don’t cause problems. We all inhale the mold spores daily, but healthy individuals can promptly remove them from the lungs. However, in certain individuals such as people with a weakened or compromised immune system, they can cause severe, even life-threatening infection. Most people develop this infection by breathing in mold spores. Less often, infection can develop when spores enter the body through a cut or open wound.Allergic bronchopulmonary aspergillosis is more likely to occur in individuals who have asthma or cystic fibrosis. Forms of chronic pulmonary aspergillosis are more likely to occur in individuals who have had a previous lung disease including tuberculosis or chronic obstructive pulmonary disease (COPD) or a disorder that can affect the lungs like sarcoidosis. In addition, people who have had lung surgery in the past, e.g., for pneumothorax or lung cancer, can also develop chronic pulmonary aspergillosis.Invasive aspergillosis is more likely to occur in individuals who have a weakened immune system including people who have low levels of neutrophils (neutropenia), which are white blood cells that help to fight off infection. It can also occur in those receiving broad-spectrum antibiotics, individuals who are receiving chemotherapy or individuals who are receiving drugs that suppress the activity of the immune system (immunosuppressive drugs). Certain rare disorders like chronic granulomatous disease can also cause impaired function of the neutrophils and a susceptibility to Aspergillus.People who have recently undergone hematopoietic stem cell transplantation (HSCT) are at highest risk for invasive aspergillosis. Hematopoietic stem cells are found in the bone marrow and are cells that eventually grow into red blood cells, white blood cells and platelets. A transplant involves wiping out the existing bone marrow and replacing it with bone marrow from a healthy donor. Affected individuals must take immunosuppressive drugs to help fight off rejection, but this can leave them more susceptible to infection including infection with Aspergillus. People receiving immunosuppressive drugs for other reasons such as receiving an organ transplant can also be at risk of developing this infection.Other conditions can increase the risk of developing aspergillosis include people in the late stages of HIV/AIDS; the use of contaminated medical equipment near or in open wounds; long-term use of corticosteroids, which are very strong anti-inflammatory medications and traumatic injury including burns or other injury to the skin.Some researchers have noted that genetics can play a role in the development of aspergillosis. Researchers speculate that certain genes may make some individuals more likely to develop an infection with Aspergillus. This is called having a ‘genetic predisposition’ to developing a disease. Some research has indicated that genes that have a role in innate immune functions may be involved in the development of chronic pulmonary aspergillosis in some people. Genetic factors have also been explored for allergic bronchopulmonary aspergillosis, and this form of infection is believed to result from several factors (e.g., genetic, immunologic, environmental) occurring together. Research is underway to determine what role genetics play in the development of various forms of aspergillosis.Researchers have mapped the genome for a few specific types of Aspergillus. A genome is the complete genetic makeup of an organism and researchers hope that these genomes will lead them to novel treatment options and to a better understanding of the differences between the different species of Aspergillus. | 111 | Aspergillosis |
nord_111_3 | Affects of Aspergillosis | Aspergillosis is a rare fungal infection. The exact number of people who develop this infection in the United States is not known because there is no national surveillance of this infection. Mild cases may go undiagnosed. According to the medical literature, the incidence of aspergillosis is increasing. Aspergillosis has been reported all over the world. Allergic bronchopulmonary aspergillosis has been estimated to affect about 1-4 million people worldwide. Chronic pulmonary aspergillosis is estimated to affect about 3 million people worldwide. Invasive aspergillosis is uncommon, as it affects specific patient populations. Many forms are rare. Aspergillosis can potentially affect individuals of any age. | Affects of Aspergillosis. Aspergillosis is a rare fungal infection. The exact number of people who develop this infection in the United States is not known because there is no national surveillance of this infection. Mild cases may go undiagnosed. According to the medical literature, the incidence of aspergillosis is increasing. Aspergillosis has been reported all over the world. Allergic bronchopulmonary aspergillosis has been estimated to affect about 1-4 million people worldwide. Chronic pulmonary aspergillosis is estimated to affect about 3 million people worldwide. Invasive aspergillosis is uncommon, as it affects specific patient populations. Many forms are rare. Aspergillosis can potentially affect individuals of any age. | 111 | Aspergillosis |
nord_111_4 | Related disorders of Aspergillosis | Symptoms of the following disorders can be similar to those of aspergillosis. Comparisons may be useful for a differential diagnosis.Mucormycosis is a general term for a group of uncommon infections cause by a fungus (fungal infection). Mucormycosis is caused by a group of related molds from the order Mucorales. An “order” is a scientific term for classifying similar organisms. These infections are usually acquired when spores from the molds are breathed in (inhaled) or less commonly, enter the body through a cut in the skin. Mucormycosis is an aggressive, life-threatening infection that occurs in people whose immune system doesn’t function well (immune-compromised) including people with uncontrolled diabetes mellitus, people who have low levels of neutrophils, a type of white blood cell that helps the body fight off infection and heal itself (neutropenia) or people whose immune system is being suppressed by medications (immunosuppression) as part of their treatment for blood cancer (hematological malignancy), hematopoietic stem cell transplantation or solid-organ transplant. The infection is not contagious; it cannot be spread from one person to another. Prompt diagnosis and early treatment are critical. Treatment usually consists of antifungal medications and surgery. (For more information on this disorder, choose “mucormycosis” as your search term in the Rare Disease Database.)There are many different disorders, infections or conditions that may have symptoms similar to those found with aspergillosis. These include nocardiosis; fusariosis; anthrax; pseudallescheriasis; cavernous sinus thrombosis; sinusitis; bacterial orbital cellulitis; Churg-Strauss syndrome; granulomatosis with polyangiitis (Wegener granulomatosis); pulmonary eosinophilia; acute respiratory distress syndrome; tuberculosis; lung cancer; or fungal, bacterial or viral pneumonia. For more information, choose the specific disorder or condition name as your search term in the Rare Disease Database. | Related disorders of Aspergillosis. Symptoms of the following disorders can be similar to those of aspergillosis. Comparisons may be useful for a differential diagnosis.Mucormycosis is a general term for a group of uncommon infections cause by a fungus (fungal infection). Mucormycosis is caused by a group of related molds from the order Mucorales. An “order” is a scientific term for classifying similar organisms. These infections are usually acquired when spores from the molds are breathed in (inhaled) or less commonly, enter the body through a cut in the skin. Mucormycosis is an aggressive, life-threatening infection that occurs in people whose immune system doesn’t function well (immune-compromised) including people with uncontrolled diabetes mellitus, people who have low levels of neutrophils, a type of white blood cell that helps the body fight off infection and heal itself (neutropenia) or people whose immune system is being suppressed by medications (immunosuppression) as part of their treatment for blood cancer (hematological malignancy), hematopoietic stem cell transplantation or solid-organ transplant. The infection is not contagious; it cannot be spread from one person to another. Prompt diagnosis and early treatment are critical. Treatment usually consists of antifungal medications and surgery. (For more information on this disorder, choose “mucormycosis” as your search term in the Rare Disease Database.)There are many different disorders, infections or conditions that may have symptoms similar to those found with aspergillosis. These include nocardiosis; fusariosis; anthrax; pseudallescheriasis; cavernous sinus thrombosis; sinusitis; bacterial orbital cellulitis; Churg-Strauss syndrome; granulomatosis with polyangiitis (Wegener granulomatosis); pulmonary eosinophilia; acute respiratory distress syndrome; tuberculosis; lung cancer; or fungal, bacterial or viral pneumonia. For more information, choose the specific disorder or condition name as your search term in the Rare Disease Database. | 111 | Aspergillosis |
nord_111_5 | Diagnosis of Aspergillosis | A diagnosis of aspergillosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as bronchoscopy with biopsy, x-rays, antigen skin tests, tissue culture or blood tests. Allergic bronchopulmonary aspergillosis should be suspected in individuals with difficult to control asthma or cystic fibrosis.Clinical Testing and Workup
When possible, doctors will take samples of affected tissue and a special doctor called a pathologist will study the tissue for changes caused by disease (histopathology). This can show the presence of mold. Samples can include fluid from the respiratory system or mucus coughed up from the lungs (sputum) if lung infection is suspected. Respiratory fluid can be obtained through a procedure called a bronchoalveolar lavage or BAL. During BAL, a narrow tube (bronchoscope) is slid down the windpipe into the lungs and a sterile solution is passed through the tube washing out (lavaging) cells. This fluid is collected and then the tube is removed, allowing the cells to be studied.Surgical removal (biopsy) of affected lung tissue can also be performed. In order to obtain a lung sample, physicians may recommend a bronchoscopy or percutaneous needle biopsy. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down an affected individual’s throat and obtains a sample of tissue to be analyzed (biopsy). During percutaneous needle biopsy, a needle is passed through the skin and inserted directly into the lungs to remove a tissue sample. A biopsy may not always be feasible due to the risk of complications such as bleeding.Along with histopathologic examination, a tissue sample can also be taken and used for a fungal culture. A fungal culture is a procedure in which a sample of affected tissue is taken and sent to a laboratory and any fungus or similar organism discovered in the tissue is given time to grow. This test can determine the presence and type of fungal infection. The advantage of this test is that it allows us to know which antifungal medications are active against the infection. However, sometimes fungal organisms fail to grow in a culture despite the presence of an infection. Thus, a negative result on a fungal culture does not rule out aspergillosis.An Aspergillus antigen skin test can be used to screen for allergic bronchopulmonary aspergillosis. During this test, a physician will inject a needle into a specific area of the skin. If the area becomes inflamed or irritated with 48-72 hours, the person has an allergic response to the Aspergillus fungus. Alternatively, a blood test (Aspergillus specific IgE) can be used if the skin test is not available. If the test is positive, then an additional test (total IgE) is required to make the diagnosis of allergic bronchopulmonary aspergillosis).A physician may also perform a blood test to determine whether any aspergillosis antibodies are present. Antibodies, also known as immunoglobulins, are specialized proteins produced by the body to combat invading microorganisms, toxins or other foreign substances. Blood tests can also reveal galactomannan or beta-d-glucan, which are substances found in the cell wall of Aspergillus. These tests, called assays, can be performed on certain people at risk of infection. The galactomannan assay test can also be performed on fluid obtained from the lungs (BAL fluid). When either of these tests is positive, this is indicative of invasive aspergillosis. These tests can also be positive for chronic pulmonary aspergillosis, although a blood galactomannan test is usually negative for this form of aspergillosis. The beta-d-glucan test is also often positive in other conditions, so it is not very specific for Aspergillosis.X-rays of the chest are taken to detect characteristic findings such as the presence of an aspergilloma in a lung cavity or the buildup of Aspergillus fungi in the lungs. More advanced imaging techniques such as computerized tomography (CT) scanning may be used to determine the exact location and extent of an infection. A CT scan can reveal an aspergilloma or findings that are suggestive of allergic bronchopulmonary aspergillosis or invasive aspergillosis. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan may be taken of the lungs, sinuses, or other areas of the body. | Diagnosis of Aspergillosis. A diagnosis of aspergillosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as bronchoscopy with biopsy, x-rays, antigen skin tests, tissue culture or blood tests. Allergic bronchopulmonary aspergillosis should be suspected in individuals with difficult to control asthma or cystic fibrosis.Clinical Testing and Workup
When possible, doctors will take samples of affected tissue and a special doctor called a pathologist will study the tissue for changes caused by disease (histopathology). This can show the presence of mold. Samples can include fluid from the respiratory system or mucus coughed up from the lungs (sputum) if lung infection is suspected. Respiratory fluid can be obtained through a procedure called a bronchoalveolar lavage or BAL. During BAL, a narrow tube (bronchoscope) is slid down the windpipe into the lungs and a sterile solution is passed through the tube washing out (lavaging) cells. This fluid is collected and then the tube is removed, allowing the cells to be studied.Surgical removal (biopsy) of affected lung tissue can also be performed. In order to obtain a lung sample, physicians may recommend a bronchoscopy or percutaneous needle biopsy. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down an affected individual’s throat and obtains a sample of tissue to be analyzed (biopsy). During percutaneous needle biopsy, a needle is passed through the skin and inserted directly into the lungs to remove a tissue sample. A biopsy may not always be feasible due to the risk of complications such as bleeding.Along with histopathologic examination, a tissue sample can also be taken and used for a fungal culture. A fungal culture is a procedure in which a sample of affected tissue is taken and sent to a laboratory and any fungus or similar organism discovered in the tissue is given time to grow. This test can determine the presence and type of fungal infection. The advantage of this test is that it allows us to know which antifungal medications are active against the infection. However, sometimes fungal organisms fail to grow in a culture despite the presence of an infection. Thus, a negative result on a fungal culture does not rule out aspergillosis.An Aspergillus antigen skin test can be used to screen for allergic bronchopulmonary aspergillosis. During this test, a physician will inject a needle into a specific area of the skin. If the area becomes inflamed or irritated with 48-72 hours, the person has an allergic response to the Aspergillus fungus. Alternatively, a blood test (Aspergillus specific IgE) can be used if the skin test is not available. If the test is positive, then an additional test (total IgE) is required to make the diagnosis of allergic bronchopulmonary aspergillosis).A physician may also perform a blood test to determine whether any aspergillosis antibodies are present. Antibodies, also known as immunoglobulins, are specialized proteins produced by the body to combat invading microorganisms, toxins or other foreign substances. Blood tests can also reveal galactomannan or beta-d-glucan, which are substances found in the cell wall of Aspergillus. These tests, called assays, can be performed on certain people at risk of infection. The galactomannan assay test can also be performed on fluid obtained from the lungs (BAL fluid). When either of these tests is positive, this is indicative of invasive aspergillosis. These tests can also be positive for chronic pulmonary aspergillosis, although a blood galactomannan test is usually negative for this form of aspergillosis. The beta-d-glucan test is also often positive in other conditions, so it is not very specific for Aspergillosis.X-rays of the chest are taken to detect characteristic findings such as the presence of an aspergilloma in a lung cavity or the buildup of Aspergillus fungi in the lungs. More advanced imaging techniques such as computerized tomography (CT) scanning may be used to determine the exact location and extent of an infection. A CT scan can reveal an aspergilloma or findings that are suggestive of allergic bronchopulmonary aspergillosis or invasive aspergillosis. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan may be taken of the lungs, sinuses, or other areas of the body. | 111 | Aspergillosis |
nord_111_6 | Therapies of Aspergillosis | Treatment
The treatment of aspergillosis varies depending upon the specific type of aspergillosis present, the extent of the infection, an individual’s overall health and other factors. Treatment options include watchful waiting, drug therapy, and surgery. The same treatments are used for children as for adults, however, there are differences including the dosage of medications. For some medications, the standard or most effective dosage for children is not known.In individuals with an aspergilloma who do not exhibit symptoms, no therapy may be necessary and watchful waiting may be recommended. Watchful waiting means that an asymptomatic person will be periodically monitored by physicians to detect if symptoms develop (e.g., coughing up of blood) or if the infection spreads or worsens.Treatment for aspergillosis will include antifungal medications. Antifungal medications inhibit the growth of and destroy fungal infections and are essential in controlling the spread of infection. The medication, voriconazole (Vfend) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of invasive aspergillosis. Voriconazole is a common antifungal medication. This medication can also be used to treat other forms of Aspergillus infection.The antifungal medication, isavuconazole (Cresemba) has also been approved by the FDA for the treatment of invasive aspergillosis. The antifungal medication, posaconazole (Noxafil) has been approved by the FDA as a preventive (prophylactic) treatment against fungal infections in individuals with low levels of white blood cells called neutrophils (neutropenia). Another antifungal medication that can be used to treat aspergillosis is amphotericin B. It comes in different formulations, including Amphotericin B deoxycholate and Liposomal Amphotericin B (Ambisome).A different type of antifungal medication called caspofungin has been approved the FDA for the treatment of invasive aspergillosis in individuals who have not responded to standard therapies, or who cannot tolerate standard therapy. This is called salvage therapy.Another antifungal medication called itraconazole has been used to treat certain affected individuals. This drug is not considered a frontline therapy for invasive aspergillosis but can be used in chronic and allergic forms. It is often used in individuals who do not have severe or non-life-threatening infection. It has also been used in individuals who have first been treated with amphotericin B. Most antifungal medications have not been effective in treating aspergillomas, although some individuals have responded to long-term treatment with oral itraconazole. This medication may not be as effective in immune-compromised individuals.Sometimes, doctors may recommend combination therapy in which more than one of these medications is used together; this is usually done when affected individuals are very unwell or do not respond to treatment with just one medication.Bronchial artery embolization is a procedure that can be used to treat chronic, significant coughing up of blood (hemoptysis). This procedure involves putting a catheter through the skin into a blood vessel, usually in the groin, advancing it to the bronchial arteries (arteries delivering oxygen via the blood to the lungs) and creating an artificial clot that restricts or completely stops the flow of blood. Unfortunately, this procedure is not always effective, and bleeding can recur.Surgery may be used to treat certain complications of invasive aspergillosis including massive hemoptysis that doesn’t resolve following bronchial artery embolization or localized infection that fails to respond to antifungal medications. A simple aspergilloma can also be removed surgically. Some affected individuals with underlying lung diseases may not be candidates for surgery or may be high-risk candidates. Surgery, often along with antifungal medications, can also be recommended when the sinuses, the gastrointestinal system or the heart are infected.Surgery may be necessary to remove infected or dead tissue, damaged skin and involved subcutaneous tissue. This is called surgical debridement and if the infection is significant, this can potentially lead to changes in the structure or shape of the affected area. Specific surgical recommendations will vary depending upon the exact location and extent of the infection.Infection of the ear canals may be treated by scraping out the infected tissue and ear drops containing antifungal medications.Individuals with allergic bronchopulmonary aspergillosis are treated with oral corticosteroids such as prednisone (inhaled steroids are ineffective). Corticosteroids are anti-inflammatory medications that suppress the immune system’s improper response to the Aspergillus infection. Some individuals may receive an antifungal medication along with corticosteroids such as itraconazole. Individuals who also have asthma require standard treatment for the asthma as well.Aspergillosis is a serious infection that can sometimes be life-threatening despite treatment. Many factors can influence treatment including the underlying condition associated with infection (e.g., hematologic cancer, neutropenia, etc.), the exact location and extent of infection, how long until the proper diagnosis was made and when treatment was started, an individual’s age and overall health and other factors. | Therapies of Aspergillosis. Treatment
The treatment of aspergillosis varies depending upon the specific type of aspergillosis present, the extent of the infection, an individual’s overall health and other factors. Treatment options include watchful waiting, drug therapy, and surgery. The same treatments are used for children as for adults, however, there are differences including the dosage of medications. For some medications, the standard or most effective dosage for children is not known.In individuals with an aspergilloma who do not exhibit symptoms, no therapy may be necessary and watchful waiting may be recommended. Watchful waiting means that an asymptomatic person will be periodically monitored by physicians to detect if symptoms develop (e.g., coughing up of blood) or if the infection spreads or worsens.Treatment for aspergillosis will include antifungal medications. Antifungal medications inhibit the growth of and destroy fungal infections and are essential in controlling the spread of infection. The medication, voriconazole (Vfend) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of invasive aspergillosis. Voriconazole is a common antifungal medication. This medication can also be used to treat other forms of Aspergillus infection.The antifungal medication, isavuconazole (Cresemba) has also been approved by the FDA for the treatment of invasive aspergillosis. The antifungal medication, posaconazole (Noxafil) has been approved by the FDA as a preventive (prophylactic) treatment against fungal infections in individuals with low levels of white blood cells called neutrophils (neutropenia). Another antifungal medication that can be used to treat aspergillosis is amphotericin B. It comes in different formulations, including Amphotericin B deoxycholate and Liposomal Amphotericin B (Ambisome).A different type of antifungal medication called caspofungin has been approved the FDA for the treatment of invasive aspergillosis in individuals who have not responded to standard therapies, or who cannot tolerate standard therapy. This is called salvage therapy.Another antifungal medication called itraconazole has been used to treat certain affected individuals. This drug is not considered a frontline therapy for invasive aspergillosis but can be used in chronic and allergic forms. It is often used in individuals who do not have severe or non-life-threatening infection. It has also been used in individuals who have first been treated with amphotericin B. Most antifungal medications have not been effective in treating aspergillomas, although some individuals have responded to long-term treatment with oral itraconazole. This medication may not be as effective in immune-compromised individuals.Sometimes, doctors may recommend combination therapy in which more than one of these medications is used together; this is usually done when affected individuals are very unwell or do not respond to treatment with just one medication.Bronchial artery embolization is a procedure that can be used to treat chronic, significant coughing up of blood (hemoptysis). This procedure involves putting a catheter through the skin into a blood vessel, usually in the groin, advancing it to the bronchial arteries (arteries delivering oxygen via the blood to the lungs) and creating an artificial clot that restricts or completely stops the flow of blood. Unfortunately, this procedure is not always effective, and bleeding can recur.Surgery may be used to treat certain complications of invasive aspergillosis including massive hemoptysis that doesn’t resolve following bronchial artery embolization or localized infection that fails to respond to antifungal medications. A simple aspergilloma can also be removed surgically. Some affected individuals with underlying lung diseases may not be candidates for surgery or may be high-risk candidates. Surgery, often along with antifungal medications, can also be recommended when the sinuses, the gastrointestinal system or the heart are infected.Surgery may be necessary to remove infected or dead tissue, damaged skin and involved subcutaneous tissue. This is called surgical debridement and if the infection is significant, this can potentially lead to changes in the structure or shape of the affected area. Specific surgical recommendations will vary depending upon the exact location and extent of the infection.Infection of the ear canals may be treated by scraping out the infected tissue and ear drops containing antifungal medications.Individuals with allergic bronchopulmonary aspergillosis are treated with oral corticosteroids such as prednisone (inhaled steroids are ineffective). Corticosteroids are anti-inflammatory medications that suppress the immune system’s improper response to the Aspergillus infection. Some individuals may receive an antifungal medication along with corticosteroids such as itraconazole. Individuals who also have asthma require standard treatment for the asthma as well.Aspergillosis is a serious infection that can sometimes be life-threatening despite treatment. Many factors can influence treatment including the underlying condition associated with infection (e.g., hematologic cancer, neutropenia, etc.), the exact location and extent of infection, how long until the proper diagnosis was made and when treatment was started, an individual’s age and overall health and other factors. | 111 | Aspergillosis |
nord_112_0 | Overview of Asphyxiating Thoracic Dystrophy | SummaryAsphyxiating thoracic dystrophy (ATD) is a very rare form of skeletal dysplasia that primarily affects development of the bone structure of the chest (thorax) resulting in a very narrow and bell-shaped chest. Other major characteristics include kidney problems (due to renal cyst development), shortened bones of the arms and legs, extra fingers and toes, and a shortened stature.ATD is inherited as an autosomal recessive genetic disorder. It is caused by changes (mutations) in at least 24 different genes that encode for ciliary transport protein: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586/0753.IntroductionATD is classified as a ciliopathy with major skeletal involvement or ciliary chondrodysplasia. Ciliopathies are conditions caused by mutations in genes involved in making proteins in the finger-like projections on the surface of cells (cilia). Abnormal cilia can lead to problems in the development of cartilage and bone. | Overview of Asphyxiating Thoracic Dystrophy. SummaryAsphyxiating thoracic dystrophy (ATD) is a very rare form of skeletal dysplasia that primarily affects development of the bone structure of the chest (thorax) resulting in a very narrow and bell-shaped chest. Other major characteristics include kidney problems (due to renal cyst development), shortened bones of the arms and legs, extra fingers and toes, and a shortened stature.ATD is inherited as an autosomal recessive genetic disorder. It is caused by changes (mutations) in at least 24 different genes that encode for ciliary transport protein: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586/0753.IntroductionATD is classified as a ciliopathy with major skeletal involvement or ciliary chondrodysplasia. Ciliopathies are conditions caused by mutations in genes involved in making proteins in the finger-like projections on the surface of cells (cilia). Abnormal cilia can lead to problems in the development of cartilage and bone. | 112 | Asphyxiating Thoracic Dystrophy |
nord_112_1 | Symptoms of Asphyxiating Thoracic Dystrophy | ATD is characterized by abnormal development of the rib cage (thorax) resulting in a small thoracic cavity. The characteristic “bell-shaped” chest cavity restricts the growth of the lungs and results in a variable degree of lung hypoplasia and breathing problems (respiratory distress) in the newborn period.Other clinical features that can be apparent at birth include too many fingers and/or toes (polydactyly), mild to moderate shortening of the long bones of the arms and legs (micromelia), insufficient growth of the pelvic bones, and cardiac defects.Patients typically present in the newborn period with variable degrees of respiratory distress and recurrent respiratory infections. These breathing problems are the most serious complications of ATD and are the main cause of mortality in these patients. Some reports indicate that 50-60% of children with ATD die in infancy or during the first few years after birth. For those patients that live into early childhood, the breathing problems tend to improve with age such that a subset of patients may live into adolescence or adulthood.Other complications of ATD can occur as the child grows including: high blood pressure, renal cysts, pancreatic cysts, and, less commonly liver diseases, dental abnormalities, and reduced or deteriorating vision (retinal dystrophy).Affected individuals may develop chronic nephritis (a kidney condition) that may lead to kidney failure or malfunctions. Heart abnormalities and narrowing of the airway may also occur. | Symptoms of Asphyxiating Thoracic Dystrophy. ATD is characterized by abnormal development of the rib cage (thorax) resulting in a small thoracic cavity. The characteristic “bell-shaped” chest cavity restricts the growth of the lungs and results in a variable degree of lung hypoplasia and breathing problems (respiratory distress) in the newborn period.Other clinical features that can be apparent at birth include too many fingers and/or toes (polydactyly), mild to moderate shortening of the long bones of the arms and legs (micromelia), insufficient growth of the pelvic bones, and cardiac defects.Patients typically present in the newborn period with variable degrees of respiratory distress and recurrent respiratory infections. These breathing problems are the most serious complications of ATD and are the main cause of mortality in these patients. Some reports indicate that 50-60% of children with ATD die in infancy or during the first few years after birth. For those patients that live into early childhood, the breathing problems tend to improve with age such that a subset of patients may live into adolescence or adulthood.Other complications of ATD can occur as the child grows including: high blood pressure, renal cysts, pancreatic cysts, and, less commonly liver diseases, dental abnormalities, and reduced or deteriorating vision (retinal dystrophy).Affected individuals may develop chronic nephritis (a kidney condition) that may lead to kidney failure or malfunctions. Heart abnormalities and narrowing of the airway may also occur. | 112 | Asphyxiating Thoracic Dystrophy |
nord_112_2 | Causes of Asphyxiating Thoracic Dystrophy | Mutations in 24 genes have been found to cause ATD to date. The genes are: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586/0753. It is estimated that 70 percent of affected individuals have mutations in one these genes. Mutations in these genes result in abnormal cilia proteins that affect bone development.ATD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Asphyxiating Thoracic Dystrophy. Mutations in 24 genes have been found to cause ATD to date. The genes are: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586/0753. It is estimated that 70 percent of affected individuals have mutations in one these genes. Mutations in these genes result in abnormal cilia proteins that affect bone development.ATD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 112 | Asphyxiating Thoracic Dystrophy |
nord_112_3 | Affects of Asphyxiating Thoracic Dystrophy | The incidence of ATD is about 1 in 100,000 to 150,000 live births. Males and females appear to be affected in equal numbers, as do persons of various ethnic or racial backgrounds. | Affects of Asphyxiating Thoracic Dystrophy. The incidence of ATD is about 1 in 100,000 to 150,000 live births. Males and females appear to be affected in equal numbers, as do persons of various ethnic or racial backgrounds. | 112 | Asphyxiating Thoracic Dystrophy |
nord_112_4 | Related disorders of Asphyxiating Thoracic Dystrophy | The following disorders have presentations that can be similar to those of ATD and should be considered for a differential diagnosis.Ellis-Van Creveld syndrome (also known as chondroectodermal dysplasia) is characterized by short stature with striking shortening of the proximal limbs (mesomelia) extremities. Extra fingers and toes, fused wrists, dystrophy of the fingernails, lip abnormalities, and heart defects also occur in this disorder. The disorder is inherited as autosomal recessive condition. (For more information on this condition, choose “Ellis Van Creveld syndrome” as your search term in the Rare Disease Database.)Metatrophic dysplasia is noticed in infancy, and is characterized by the development of a long narrow thorax, flattening of the vertebral bones and relatively short limbs. Progressive deformity (kyphoscoliosis) of the bones of the thorax and spine results in a short trunk as the child gets older. (For more information on this condition, choose “metatropic dysplasia” as your search term in the Rare Disease Database.)Diastrophic dysplasia is a relatively common form of short stature recognized art birth by the presence of short limbs, clubfeet, short hand with a hitchhiker thumb, cleft palate and cauliflower ear deformity. Although breathing problems may be present at birth and continue thereafter, life expectancy is normal. (For more information on this condition, choose “diastrophic dysplasia” as your search term in the Rare Disease Database.)Short rib-polydactyly syndromes (SRPs) are a heterogenous group of skeletal ciliopathies inherited as autosomal recessive disorders. SRPs I-IV are lethal SRPs characterized by an undersized (hypoplastic) thorax, short ribs, severe pulmonary hypoplasia, short limbs, multiple fingers and toes (polydactyly), and abdominal (visceral) abnormalities. All of the variants are thought to be inherited in an autosomal recessive pattern. SRPs belong to the short rib dysplasia with or without polydactyly family which also includes ATD, Ellis-Van Creveld syndrome, Sensenbrenner syndrome, and Weyer acrofacial dyostosis. Of note, the narrowing of the chest is much less severe in ATD than it is in SRPs I-IV. | Related disorders of Asphyxiating Thoracic Dystrophy. The following disorders have presentations that can be similar to those of ATD and should be considered for a differential diagnosis.Ellis-Van Creveld syndrome (also known as chondroectodermal dysplasia) is characterized by short stature with striking shortening of the proximal limbs (mesomelia) extremities. Extra fingers and toes, fused wrists, dystrophy of the fingernails, lip abnormalities, and heart defects also occur in this disorder. The disorder is inherited as autosomal recessive condition. (For more information on this condition, choose “Ellis Van Creveld syndrome” as your search term in the Rare Disease Database.)Metatrophic dysplasia is noticed in infancy, and is characterized by the development of a long narrow thorax, flattening of the vertebral bones and relatively short limbs. Progressive deformity (kyphoscoliosis) of the bones of the thorax and spine results in a short trunk as the child gets older. (For more information on this condition, choose “metatropic dysplasia” as your search term in the Rare Disease Database.)Diastrophic dysplasia is a relatively common form of short stature recognized art birth by the presence of short limbs, clubfeet, short hand with a hitchhiker thumb, cleft palate and cauliflower ear deformity. Although breathing problems may be present at birth and continue thereafter, life expectancy is normal. (For more information on this condition, choose “diastrophic dysplasia” as your search term in the Rare Disease Database.)Short rib-polydactyly syndromes (SRPs) are a heterogenous group of skeletal ciliopathies inherited as autosomal recessive disorders. SRPs I-IV are lethal SRPs characterized by an undersized (hypoplastic) thorax, short ribs, severe pulmonary hypoplasia, short limbs, multiple fingers and toes (polydactyly), and abdominal (visceral) abnormalities. All of the variants are thought to be inherited in an autosomal recessive pattern. SRPs belong to the short rib dysplasia with or without polydactyly family which also includes ATD, Ellis-Van Creveld syndrome, Sensenbrenner syndrome, and Weyer acrofacial dyostosis. Of note, the narrowing of the chest is much less severe in ATD than it is in SRPs I-IV. | 112 | Asphyxiating Thoracic Dystrophy |
nord_112_5 | Diagnosis of Asphyxiating Thoracic Dystrophy | ATD is diagnosed based on clinical presentation as well as radiologic findings of short ribs and abnormalities of the pelvis and limbs. A combination of breathing difficulties in the presence of a small, narrow chest, along with obvious shortened limb development is usually sufficient for a diagnosis. Molecular genetic testing is available to confirm the diagnosis.The presentation and severity of asphyxiating thoracic dystrophy varies considerably specifically with regard to the degree of breathing difficulties which may vary from life-threatening to the apparent absence of any distress.Prenatal diagnosis may be possible with ultrasound imaging. | Diagnosis of Asphyxiating Thoracic Dystrophy. ATD is diagnosed based on clinical presentation as well as radiologic findings of short ribs and abnormalities of the pelvis and limbs. A combination of breathing difficulties in the presence of a small, narrow chest, along with obvious shortened limb development is usually sufficient for a diagnosis. Molecular genetic testing is available to confirm the diagnosis.The presentation and severity of asphyxiating thoracic dystrophy varies considerably specifically with regard to the degree of breathing difficulties which may vary from life-threatening to the apparent absence of any distress.Prenatal diagnosis may be possible with ultrasound imaging. | 112 | Asphyxiating Thoracic Dystrophy |
nord_112_6 | Therapies of Asphyxiating Thoracic Dystrophy | Treatment
Treatment is based on managing respiratory infections and monitoring renal and hepatic function regularly. The risk of severe respiratory infections diminishes after age two.The vertical expandable prosthetic titanium rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. For treatment of spondylothoracic dysplasia, ribs are separated on each side of the chest and VEPTRs are placed on each side of the chest. | Therapies of Asphyxiating Thoracic Dystrophy. Treatment
Treatment is based on managing respiratory infections and monitoring renal and hepatic function regularly. The risk of severe respiratory infections diminishes after age two.The vertical expandable prosthetic titanium rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. For treatment of spondylothoracic dysplasia, ribs are separated on each side of the chest and VEPTRs are placed on each side of the chest. | 112 | Asphyxiating Thoracic Dystrophy |
nord_113_0 | Overview of Astrocytoma | An astrocytoma is a tumor that arises from the star-shaped cells (astrocytes) that form the supportive tissue of the brain. Other supportive cells of the brain include oligodendrocytes and ependymal cells. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from the glial tissue, including astrocytomas, are collectively referred to as gliomas.The World Health Organization (WHO) classifies astrocytomas into four grades depending on how fast they are growing and the likelihood that they will spread (infiltrate) to nearby brain tissue. Non-infiltrating astrocytomas usually grow more slowly than the infiltrating forms. Infiltrating, or diffuse astrocytomas are more common than non-infiltrating astrocytomas. They are generally more common in men and are most common in the cerebral hemispheres of adult patients. In children they occur both in the cerebral hemispheres as well as the brain stem. Tumors from oligodendrocytes (oligodendrogliomas) are also in the category of infiltrating gliomas and can occasionally be difficult to distinguish from astrocytomas. Some infiltrating gliomas are categorized as mixed oligodendroglioma-astrocytoma (oligoastrocytoma).Grade I astrocytoma is usually a non-infiltrating tumor. The most common type of grade I astrocytoma is pilocytic astrocytoma which is also known as juvenile pilocytic astrocytoma or JPA. This tumor grows slowly but can become very large. Pilocytic astrocytoma occurs most often in the cerebellum, cerebrum, optic nerve pathway and brainstem. This tumor occurs most often in children and teens and accounts for 2% of all brain tumors.Grade II astrocytoma is also called low-grade astrocytoma or diffuse astrocytoma and is usually an infiltrating tumor. This tumor grows relatively slowly and usually does not have well-defined borders. It occurs most often in adults between the ages of 20 and 40.Grade III astrocytoma is also called anaplastic (malignant) astrocytoma because this tumor grows more quickly than a grade II astrocytoma. Anaplastic astrocytoma occurs most often in adults between the ages of 30 and 50, and accounts for 4% of all brain tumors.Grade IV astrocytoma is also called glioblastoma or GBM and is the most aggressive type of nervous system tumor. It is also referred to as glioblastoma multiforme because of its wide variety of appearances under the microscope. Rarely, non-glial tissue elements can exist in a glioblastoma. The most common variant of GBM showing these additional tissue elements is called a mixed glioblastoma-sarcoma, or gliosarcoma. GBM occurs most often in adults between the ages of 50 and 80, is more common in men, and accounts for 23% of all primary brain tumors.Recently several markers have been identified in diffuse gliomas. Astrocytomas grades II and III often have acquired mutations in a gene called IDH1. These mutations ar acquired by the tumor and are not generally present in the normal cells of the patient. The presence of an IDH1 mutation in an astrocytoma is generally associated with an improved prognosis compared to an astrocytoma of similar grade that does not have an IDH1 mutation. A second marker, relevant to GBM, is MGMT methylation. When present, MGMT methylation may be associated with better response to chemotherapy (usually temozolomide) compared to GBMs without MGMT methylation. | Overview of Astrocytoma. An astrocytoma is a tumor that arises from the star-shaped cells (astrocytes) that form the supportive tissue of the brain. Other supportive cells of the brain include oligodendrocytes and ependymal cells. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from the glial tissue, including astrocytomas, are collectively referred to as gliomas.The World Health Organization (WHO) classifies astrocytomas into four grades depending on how fast they are growing and the likelihood that they will spread (infiltrate) to nearby brain tissue. Non-infiltrating astrocytomas usually grow more slowly than the infiltrating forms. Infiltrating, or diffuse astrocytomas are more common than non-infiltrating astrocytomas. They are generally more common in men and are most common in the cerebral hemispheres of adult patients. In children they occur both in the cerebral hemispheres as well as the brain stem. Tumors from oligodendrocytes (oligodendrogliomas) are also in the category of infiltrating gliomas and can occasionally be difficult to distinguish from astrocytomas. Some infiltrating gliomas are categorized as mixed oligodendroglioma-astrocytoma (oligoastrocytoma).Grade I astrocytoma is usually a non-infiltrating tumor. The most common type of grade I astrocytoma is pilocytic astrocytoma which is also known as juvenile pilocytic astrocytoma or JPA. This tumor grows slowly but can become very large. Pilocytic astrocytoma occurs most often in the cerebellum, cerebrum, optic nerve pathway and brainstem. This tumor occurs most often in children and teens and accounts for 2% of all brain tumors.Grade II astrocytoma is also called low-grade astrocytoma or diffuse astrocytoma and is usually an infiltrating tumor. This tumor grows relatively slowly and usually does not have well-defined borders. It occurs most often in adults between the ages of 20 and 40.Grade III astrocytoma is also called anaplastic (malignant) astrocytoma because this tumor grows more quickly than a grade II astrocytoma. Anaplastic astrocytoma occurs most often in adults between the ages of 30 and 50, and accounts for 4% of all brain tumors.Grade IV astrocytoma is also called glioblastoma or GBM and is the most aggressive type of nervous system tumor. It is also referred to as glioblastoma multiforme because of its wide variety of appearances under the microscope. Rarely, non-glial tissue elements can exist in a glioblastoma. The most common variant of GBM showing these additional tissue elements is called a mixed glioblastoma-sarcoma, or gliosarcoma. GBM occurs most often in adults between the ages of 50 and 80, is more common in men, and accounts for 23% of all primary brain tumors.Recently several markers have been identified in diffuse gliomas. Astrocytomas grades II and III often have acquired mutations in a gene called IDH1. These mutations ar acquired by the tumor and are not generally present in the normal cells of the patient. The presence of an IDH1 mutation in an astrocytoma is generally associated with an improved prognosis compared to an astrocytoma of similar grade that does not have an IDH1 mutation. A second marker, relevant to GBM, is MGMT methylation. When present, MGMT methylation may be associated with better response to chemotherapy (usually temozolomide) compared to GBMs without MGMT methylation. | 113 | Astrocytoma |
nord_113_1 | Symptoms of Astrocytoma | Symptoms of grade I and grade II astrocytomas are subtle because the brain is able to temporarily adapt to the presence of a slow-growing tumor. Symptoms of grade III and grade IV astrocytomas may be sudden and debilitating. Symptoms can result from increased pressure within the brain and may include headaches, vision changes and nausea or vomiting. Symptoms may also occur based on the location of the tumor due to interference with normal brain function and include focal seizures, difficulty with speaking, loss of balance and weakness, paralysis or loss of sensation of one side of the body. Fatigue and depression are common in individuals with an astrocytoma.Desmoplastic infantile astrocytoma (DIA) is a very rare grade I astrocytoma. This tumor tends to occur the cerebral hemispheres and is usually diagnosed in children less than two years of age. Symptoms may include an increased head size, bulging soft spots (fontanelles) in the skull, eyes that focus downward and seizures. A related tumor, desmoplastic infantile ganglioglioma, is a mixed astrocytic and neuronal tumor, but is otherwise similar to DIA.Subependymal giant cell astrocytoma occurs in the ventricles of the brain and is almost always associated with a genetic condition called tuberous sclerosis. Other rare neuroepithelial tumors include pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (a mixed glial-neuronal tumor). | Symptoms of Astrocytoma. Symptoms of grade I and grade II astrocytomas are subtle because the brain is able to temporarily adapt to the presence of a slow-growing tumor. Symptoms of grade III and grade IV astrocytomas may be sudden and debilitating. Symptoms can result from increased pressure within the brain and may include headaches, vision changes and nausea or vomiting. Symptoms may also occur based on the location of the tumor due to interference with normal brain function and include focal seizures, difficulty with speaking, loss of balance and weakness, paralysis or loss of sensation of one side of the body. Fatigue and depression are common in individuals with an astrocytoma.Desmoplastic infantile astrocytoma (DIA) is a very rare grade I astrocytoma. This tumor tends to occur the cerebral hemispheres and is usually diagnosed in children less than two years of age. Symptoms may include an increased head size, bulging soft spots (fontanelles) in the skull, eyes that focus downward and seizures. A related tumor, desmoplastic infantile ganglioglioma, is a mixed astrocytic and neuronal tumor, but is otherwise similar to DIA.Subependymal giant cell astrocytoma occurs in the ventricles of the brain and is almost always associated with a genetic condition called tuberous sclerosis. Other rare neuroepithelial tumors include pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (a mixed glial-neuronal tumor). | 113 | Astrocytoma |
nord_113_2 | Causes of Astrocytoma | The cause of most astrocytomas is not known. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.Astrocytomas occur with greater frequency with certain genetic disorders including Turcot syndrome, neurofibromatosis type-I tuberous sclerosis, Ollier's disease and Li-Fraumeni syndrome. | Causes of Astrocytoma. The cause of most astrocytomas is not known. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.Astrocytomas occur with greater frequency with certain genetic disorders including Turcot syndrome, neurofibromatosis type-I tuberous sclerosis, Ollier's disease and Li-Fraumeni syndrome. | 113 | Astrocytoma |
nord_113_3 | Affects of Astrocytoma | Grade I astrocytoma occurs most often in children and teens and account for 2% of all brain tumors. Grade II astrocytoma occurs most often in adults between the ages of 20 and 60. Grade III astrocytoma occurs most often in adults between the ages of 30 and 60, is more common in men and accounts for 4% of all brain tumors. Grade IV astrocytoma occurs most often in adults between the ages of 50 and 80, is more common in men and accounts for 23% of all primary brain tumors. | Affects of Astrocytoma. Grade I astrocytoma occurs most often in children and teens and account for 2% of all brain tumors. Grade II astrocytoma occurs most often in adults between the ages of 20 and 60. Grade III astrocytoma occurs most often in adults between the ages of 30 and 60, is more common in men and accounts for 4% of all brain tumors. Grade IV astrocytoma occurs most often in adults between the ages of 50 and 80, is more common in men and accounts for 23% of all primary brain tumors. | 113 | Astrocytoma |
nord_113_4 | Related disorders of Astrocytoma | Symptoms of the following disorders can be similar to those of astrocytomas. Comparisons may be useful for a differential diagnosis:Motor neuron disease is a group of neuromuscular disorders characterized by the progressive degeneration of motor neurons, the nerve cells that control movement and reflex. Symptoms of Motor Neuron Diseases may include muscle weakness, spasms and exaggerated reflexes.Multiple sclerosis (MS) is a chronic disease of the brain and spinal cord. MS is characterized by small lesions called plaques that may form randomly throughout the brain and spinal cord. These lesions consist of areas of dissolved myelin, the fatty material that forms a sheath around nerve cells (neurons) and conducts nerve impulses. Large, star-shaped nerve cells (astrocytes) overgrow and harden in the lesions, forming scars in the brain and spinal cord called scleroses. Destruction of the myelin sheath creates a variety of neurological symptoms that may include visual difficulties, impairment of speech, abnormal skin sensations or numbness, walking disturbances and difficulties with bladder and bowel function.There are many different types of brain tumors. The classification of brain tumors is based on the cells that the tumor originated from and the likelihood that it will spread to other tissues. | Related disorders of Astrocytoma. Symptoms of the following disorders can be similar to those of astrocytomas. Comparisons may be useful for a differential diagnosis:Motor neuron disease is a group of neuromuscular disorders characterized by the progressive degeneration of motor neurons, the nerve cells that control movement and reflex. Symptoms of Motor Neuron Diseases may include muscle weakness, spasms and exaggerated reflexes.Multiple sclerosis (MS) is a chronic disease of the brain and spinal cord. MS is characterized by small lesions called plaques that may form randomly throughout the brain and spinal cord. These lesions consist of areas of dissolved myelin, the fatty material that forms a sheath around nerve cells (neurons) and conducts nerve impulses. Large, star-shaped nerve cells (astrocytes) overgrow and harden in the lesions, forming scars in the brain and spinal cord called scleroses. Destruction of the myelin sheath creates a variety of neurological symptoms that may include visual difficulties, impairment of speech, abnormal skin sensations or numbness, walking disturbances and difficulties with bladder and bowel function.There are many different types of brain tumors. The classification of brain tumors is based on the cells that the tumor originated from and the likelihood that it will spread to other tissues. | 113 | Astrocytoma |
nord_113_5 | Diagnosis of Astrocytoma | The diagnosis of astrocytoma is based on a thorough clinical evaluation, characteristic physical findings, a careful patient history, and specialized tests, such as blood tests, neuroimaging techniques, and/or other diagnostic studies. Neuroimaging techniques, such as computed tomography (CT) scanning and magnetic resonance imaging (MRI) of the brain assist in evaluating tumor size, location, and other factors. During CT scanning, a computer and x-rays are used to create cross-sectional images of certain tissue structures. MRI uses a magnetic field to create cross-sectional images of particular organs and bodily tissues. Examination of a sample of the tumor (biopsy) and microscopic examination of tumor cells is used to determine the tumor type and grade. | Diagnosis of Astrocytoma. The diagnosis of astrocytoma is based on a thorough clinical evaluation, characteristic physical findings, a careful patient history, and specialized tests, such as blood tests, neuroimaging techniques, and/or other diagnostic studies. Neuroimaging techniques, such as computed tomography (CT) scanning and magnetic resonance imaging (MRI) of the brain assist in evaluating tumor size, location, and other factors. During CT scanning, a computer and x-rays are used to create cross-sectional images of certain tissue structures. MRI uses a magnetic field to create cross-sectional images of particular organs and bodily tissues. Examination of a sample of the tumor (biopsy) and microscopic examination of tumor cells is used to determine the tumor type and grade. | 113 | Astrocytoma |
nord_113_6 | Therapies of Astrocytoma | Grade I astrocytoma: Surgery is the standard treatment. Total surgical removal of accessible astrocytomas is often possible and successful. Accessible tumors are those that can be operated on without causing unacceptably severe damage to other parts of the brain. If surgery is performed, the surgeon will attempt to remove all identifiable parts of the astrocytoma when possible. When the astrocytoma involves a crucial part of the brain, partial removal of the growth usually reduces pressure, relieves symptoms and helps control seizures.Full or partial removal of the astrocytoma is sometimes followed by radiation therapy to destroy any remaining tumor cells. With the use of CT (computed tomography) and MRI (magnetic resonance imaging), radiation sometimes may be deferred for several months or years while the patient is scanned at regular intervals. Radiation as primary therapy is occasionally used on grade I astrocytomas.Chemotherapy may be administered after radiation in an attempt to destroy any cells that remain or may also be given during the course of radiation treatment. Chemotherapy may be used instead of radiation in very young children to avoid damage to the developing brain. The type of chemotherapeutic drug therapy selected is determined by a neuro-oncologist who examines the grade of tumor, previous treatment and current health status of the affected individual.Grade I astrocytoma can sometimes progress to a higher grade so follow-up scans at regular intervals are necessary to check for re-growth.Grade II astrocytoma: Treatment depends on the size and location of the tumor. Surgery may be used to remove accessible tumors. As with all infiltrating astrocytomas (grades II-IV) it cannot be completely removed with surgery because the tentacle-like projections of the tumor grow into the surrounding tissue. Radiation may be used if the tumor is not accessible or in addition to surgery. Grade II astrocytoma can also progress to a higher grade so follow-up is necessary to check for re-growth. A recurrent tumor may be treated with surgery, radiation or chemotherapy.Grade III astrocytoma: Treatment depends on the size and location of the tumor, what it looks like under the microscope and how far it has spread. The standard treatment is surgery and radiation therapy, accompanied or followed by chemotherapy. If surgery is not possible, radiation and chemotherapy may be recommended. Several different types of radiation therapy are available including conventional external beam radiation, focused radiation, stereotactic radiosurgery implanted radiation or conformal radiation. A radiation oncologist determines the most appropriate form of radiation for a particular tumor. Chemotherapeutic agents that are commonly used to treat grade III astrocytoma include carmustine (BCNU), lomustine (CCNU), procarbazine, cisplatin and temozolomide. Biodegradable wafers (called Gliadel Wafers) containing BCNU is sometimes inserted in the cavity that remains after a tumor is removed. Grade III astrocytoma tend to recur and treatment depends on the grade of tumor that recurs.The Food and Drug Administration (FDA) has approved temozolomide (Temodar) for the treatment of adults with anaplastic astrocytoma that has not responded to other forms of therapy (refractory anaplastic astrocytoma). For more information, contact:Merck Corporate Headquarters
2000 Galloping Hill Road
Kenilworth, N.J. 07033-0530Grade IV astrocytoma: The three main forms of treatment for GBM are surgery and radiation or chemotherapy. These treatments may be used alone or in combination with one another. The initial treatment in most cases is surgical excision and removal of as much as the tumor as possible (resection). Often, only a portion of the tumor can be safely removed because malignant cells may have spread to surrounding brain tissue. Because surgery cannot completely remove a tumor, radiation therapy and chemotherapy are used following surgery to continue treatment.The FDA has approved temozolomide (Temodar) for the treatment of adults with GBM. Temozolomide is used concurrently with radiation therapy, and also for a period of time after completion of radiotherapy. For more information, contact:Merck Corporate Headquarters
2000 Galloping Hill Road
Kenilworth, N.J. 07033-0530Gliadel Wafers have been approved by the FDA for the treatment of individuals with newly-diagnosed GBM as an adjunct to surgery and radiation. It has also been approved for individuals with recurrent GBM. Several of the wafers are placed in the cavity created by the surgical removal of a GBM. The wafers release the drugs into the surrounding tissue over a period of two or three weeks. For more information, contact:MGI Pharma, Inc.
5775 West Old Shakopee Road
Suite 100
Bloomington, MN 55437
Phone: (952) 346-4700
Fax: (352) 346-4800 | Therapies of Astrocytoma. Grade I astrocytoma: Surgery is the standard treatment. Total surgical removal of accessible astrocytomas is often possible and successful. Accessible tumors are those that can be operated on without causing unacceptably severe damage to other parts of the brain. If surgery is performed, the surgeon will attempt to remove all identifiable parts of the astrocytoma when possible. When the astrocytoma involves a crucial part of the brain, partial removal of the growth usually reduces pressure, relieves symptoms and helps control seizures.Full or partial removal of the astrocytoma is sometimes followed by radiation therapy to destroy any remaining tumor cells. With the use of CT (computed tomography) and MRI (magnetic resonance imaging), radiation sometimes may be deferred for several months or years while the patient is scanned at regular intervals. Radiation as primary therapy is occasionally used on grade I astrocytomas.Chemotherapy may be administered after radiation in an attempt to destroy any cells that remain or may also be given during the course of radiation treatment. Chemotherapy may be used instead of radiation in very young children to avoid damage to the developing brain. The type of chemotherapeutic drug therapy selected is determined by a neuro-oncologist who examines the grade of tumor, previous treatment and current health status of the affected individual.Grade I astrocytoma can sometimes progress to a higher grade so follow-up scans at regular intervals are necessary to check for re-growth.Grade II astrocytoma: Treatment depends on the size and location of the tumor. Surgery may be used to remove accessible tumors. As with all infiltrating astrocytomas (grades II-IV) it cannot be completely removed with surgery because the tentacle-like projections of the tumor grow into the surrounding tissue. Radiation may be used if the tumor is not accessible or in addition to surgery. Grade II astrocytoma can also progress to a higher grade so follow-up is necessary to check for re-growth. A recurrent tumor may be treated with surgery, radiation or chemotherapy.Grade III astrocytoma: Treatment depends on the size and location of the tumor, what it looks like under the microscope and how far it has spread. The standard treatment is surgery and radiation therapy, accompanied or followed by chemotherapy. If surgery is not possible, radiation and chemotherapy may be recommended. Several different types of radiation therapy are available including conventional external beam radiation, focused radiation, stereotactic radiosurgery implanted radiation or conformal radiation. A radiation oncologist determines the most appropriate form of radiation for a particular tumor. Chemotherapeutic agents that are commonly used to treat grade III astrocytoma include carmustine (BCNU), lomustine (CCNU), procarbazine, cisplatin and temozolomide. Biodegradable wafers (called Gliadel Wafers) containing BCNU is sometimes inserted in the cavity that remains after a tumor is removed. Grade III astrocytoma tend to recur and treatment depends on the grade of tumor that recurs.The Food and Drug Administration (FDA) has approved temozolomide (Temodar) for the treatment of adults with anaplastic astrocytoma that has not responded to other forms of therapy (refractory anaplastic astrocytoma). For more information, contact:Merck Corporate Headquarters
2000 Galloping Hill Road
Kenilworth, N.J. 07033-0530Grade IV astrocytoma: The three main forms of treatment for GBM are surgery and radiation or chemotherapy. These treatments may be used alone or in combination with one another. The initial treatment in most cases is surgical excision and removal of as much as the tumor as possible (resection). Often, only a portion of the tumor can be safely removed because malignant cells may have spread to surrounding brain tissue. Because surgery cannot completely remove a tumor, radiation therapy and chemotherapy are used following surgery to continue treatment.The FDA has approved temozolomide (Temodar) for the treatment of adults with GBM. Temozolomide is used concurrently with radiation therapy, and also for a period of time after completion of radiotherapy. For more information, contact:Merck Corporate Headquarters
2000 Galloping Hill Road
Kenilworth, N.J. 07033-0530Gliadel Wafers have been approved by the FDA for the treatment of individuals with newly-diagnosed GBM as an adjunct to surgery and radiation. It has also been approved for individuals with recurrent GBM. Several of the wafers are placed in the cavity created by the surgical removal of a GBM. The wafers release the drugs into the surrounding tissue over a period of two or three weeks. For more information, contact:MGI Pharma, Inc.
5775 West Old Shakopee Road
Suite 100
Bloomington, MN 55437
Phone: (952) 346-4700
Fax: (352) 346-4800 | 113 | Astrocytoma |
nord_114_0 | Overview of ASXL3-Related Disorder | ASXL3-related disorder, also known as Bainbridge-Ropers syndrome, is a neurodevelopmental disorder that was first described by Bainbridge et al. in 2013. It is associated with changes (pathogenic variants or mutations) in the ASXL3 gene. The initial description of this syndrome by Bainbridge et al. was based on four individuals with developmental delay, feeding difficulties, neurological abnormalities and difficulty gaining weight (failure to thrive). With the identification and publication of more patients, the spectrum of characteristics has expanded to include low muscle tone (hypotonia) (88%), characteristic facial features (92%), palate abnormalities (61%), musculoskeletal features (67%), behavioral issues (92%), crossed eyes (strabismus) (56%), sleep disturbance (50%) and autistic features (65%). Intellectual disability (or its precursor, global developmental delay) was noted in 95% of affected children. | Overview of ASXL3-Related Disorder. ASXL3-related disorder, also known as Bainbridge-Ropers syndrome, is a neurodevelopmental disorder that was first described by Bainbridge et al. in 2013. It is associated with changes (pathogenic variants or mutations) in the ASXL3 gene. The initial description of this syndrome by Bainbridge et al. was based on four individuals with developmental delay, feeding difficulties, neurological abnormalities and difficulty gaining weight (failure to thrive). With the identification and publication of more patients, the spectrum of characteristics has expanded to include low muscle tone (hypotonia) (88%), characteristic facial features (92%), palate abnormalities (61%), musculoskeletal features (67%), behavioral issues (92%), crossed eyes (strabismus) (56%), sleep disturbance (50%) and autistic features (65%). Intellectual disability (or its precursor, global developmental delay) was noted in 95% of affected children. | 114 | ASXL3-Related Disorder |
nord_114_1 | Symptoms of ASXL3-Related Disorder | Developmental delay and intellectual disability All patients described in the published literature, with sufficient clinical information to ascertain the level of delay in various developmental areas, had a speech and language delay. Some patients have been described with language regression as a child, and some patients have been described to communicate by alternate methods, such as Makaton signing. Developmental delay and intellectual disability ranged from mild to very severe. Autism spectrum disorder (ASD) and other behavioral concernsAutism diagnosis or autistic behaviors were described in 65% of individuals in the literature. Autistic traits included obsessions, inflexibility and incapacity for change, hand-flapping and rocking, and difficulties with sensory processing. Other behavioral difficulties described included self-injurious behaviors and aggression towards caregivers, emotional dysregulation with outbursts of either laughter, screaming, aggression and teeth grinding (bruxism).Feeding issuesFeeding difficulties were described in 74% of individuals in the literature. Several presented with failure to thrive in infancy. Feeding difficulties included poor neonatal suck or latch, vomiting, gastroesophageal reflux, food refusal behaviors and requirement for assistance-feeding. Some babies required nasogastric tube insertion. There were reports of ongoing requirement for tube feeding in childhood. Some feeding difficulties in infancy were reported to improve with time.Musculoskeletal featuresMusculoskeletal features were seen in 67% of individuals reported in the literature. Many individuals had hypotonia (88%), which could have explained the accounts of wide range of movement (hypermobility). Other musculoskeletal features were accounted for by spine and thoracic wall abnormalities (scoliosis, kyphosis, pectus excavatum), digit and joint abnormalities (contractures, arachnodactyly, ulnar deviation, camptodactyly, overlapping digits) and foot abnormalities (pes planus, narrow feet, varus deformity). A severe multi-joint condition of arthrogryposis multiplex congenita has been described in patients with pathogenic ASXL3 variants. There were reports of long slender hands and digits, and a long, thin body with long arms, legs, fingers and toes (Marfanoid body habitus). Palate abnormalities were described in 61% of individuals in the literature; these were most often a high and narrow palate, but there was also a description of a submucous cleft . Despite the Marfanoid habitus, there have been no reports of children with a dilated aorta, as is associated with Marfan syndrome and other connective tissue disorders. One child with ASXL3-related disorder was found to have a subclavian artery aneurysm.Facial featuresNon-specific abnormal facial features have been described in most affected children (92%). There are no specific or defining facial features, but typical features included abnormal head shape, prominent forehead, highly arched eyebrows, eyebrows that meet in the center of the face (synophrys), widely spaced and deep-set eyes, down-slanting palpebral fissures, long and tubular nose, low-hanging columella, prominent nasal bridge, wide mouth, high arched palate, everted vermilion of the lower lip, small lower jaw (micrognathia), and crowded teeth, but these may not be recognized until after diagnosis. Additional dental abnormalities have also been reported, including large teeth, missing teeth and lack of enamel development (enamel hypoplasia).SleepSleep disturbance was described in 50% of patients in the literature. This included reports of obstructive sleep apnea, poor sleep and easy waking. A report of rapid, deep breathing and slow, writhing movements (hyperventilation athetosis) was reportedly associated with the sleep-wake cycle, immediately prior to falling asleep. Structural brain abnormalitiesStructural brain abnormalities have been described, but are not as easily quantified, as MRI brain imaging is not routinely carried out unless there is a clinical indication. This may mean an under-reporting of brain abnormalities in the literature. Normal brain imaging was reported in most individuals, however there were some non-specific abnormalities such as white matter loss. One individual was reported to have normal early MRI scans but saw a clinical decline in correlation with subsequent cerebral and cerebellar atrophic changes. Cerebellar vermis hypoplasia has been described in some individuals. Seizures Seizures or epilepsy have been described in 32% of individuals. A variety of seizure types have been reported in the literature, including generalized (tonic-clonic and absence), focal and complex focal seizures. Variations of focal seizures have been described including atonic seizures (associated with other behaviors such as head-bobbing or spontaneous outbursts of laughter), myotonic seizures (with partial-body stiffness or shaking) and subclinical seizures. A typical epilepsy was described, consisting of generalised epilepsy that starts in childhood, with absence seizures and tonic-clonic seizures. However, there have been reports of later-onset epilepsy starting during adulthood. Seizure frequency has been variably reported, with some individuals having sporadic and self-limiting epilepsy, some that resolved with treatment, and some individuals having up to 140 seizures a day despite treatment. | Symptoms of ASXL3-Related Disorder. Developmental delay and intellectual disability All patients described in the published literature, with sufficient clinical information to ascertain the level of delay in various developmental areas, had a speech and language delay. Some patients have been described with language regression as a child, and some patients have been described to communicate by alternate methods, such as Makaton signing. Developmental delay and intellectual disability ranged from mild to very severe. Autism spectrum disorder (ASD) and other behavioral concernsAutism diagnosis or autistic behaviors were described in 65% of individuals in the literature. Autistic traits included obsessions, inflexibility and incapacity for change, hand-flapping and rocking, and difficulties with sensory processing. Other behavioral difficulties described included self-injurious behaviors and aggression towards caregivers, emotional dysregulation with outbursts of either laughter, screaming, aggression and teeth grinding (bruxism).Feeding issuesFeeding difficulties were described in 74% of individuals in the literature. Several presented with failure to thrive in infancy. Feeding difficulties included poor neonatal suck or latch, vomiting, gastroesophageal reflux, food refusal behaviors and requirement for assistance-feeding. Some babies required nasogastric tube insertion. There were reports of ongoing requirement for tube feeding in childhood. Some feeding difficulties in infancy were reported to improve with time.Musculoskeletal featuresMusculoskeletal features were seen in 67% of individuals reported in the literature. Many individuals had hypotonia (88%), which could have explained the accounts of wide range of movement (hypermobility). Other musculoskeletal features were accounted for by spine and thoracic wall abnormalities (scoliosis, kyphosis, pectus excavatum), digit and joint abnormalities (contractures, arachnodactyly, ulnar deviation, camptodactyly, overlapping digits) and foot abnormalities (pes planus, narrow feet, varus deformity). A severe multi-joint condition of arthrogryposis multiplex congenita has been described in patients with pathogenic ASXL3 variants. There were reports of long slender hands and digits, and a long, thin body with long arms, legs, fingers and toes (Marfanoid body habitus). Palate abnormalities were described in 61% of individuals in the literature; these were most often a high and narrow palate, but there was also a description of a submucous cleft . Despite the Marfanoid habitus, there have been no reports of children with a dilated aorta, as is associated with Marfan syndrome and other connective tissue disorders. One child with ASXL3-related disorder was found to have a subclavian artery aneurysm.Facial featuresNon-specific abnormal facial features have been described in most affected children (92%). There are no specific or defining facial features, but typical features included abnormal head shape, prominent forehead, highly arched eyebrows, eyebrows that meet in the center of the face (synophrys), widely spaced and deep-set eyes, down-slanting palpebral fissures, long and tubular nose, low-hanging columella, prominent nasal bridge, wide mouth, high arched palate, everted vermilion of the lower lip, small lower jaw (micrognathia), and crowded teeth, but these may not be recognized until after diagnosis. Additional dental abnormalities have also been reported, including large teeth, missing teeth and lack of enamel development (enamel hypoplasia).SleepSleep disturbance was described in 50% of patients in the literature. This included reports of obstructive sleep apnea, poor sleep and easy waking. A report of rapid, deep breathing and slow, writhing movements (hyperventilation athetosis) was reportedly associated with the sleep-wake cycle, immediately prior to falling asleep. Structural brain abnormalitiesStructural brain abnormalities have been described, but are not as easily quantified, as MRI brain imaging is not routinely carried out unless there is a clinical indication. This may mean an under-reporting of brain abnormalities in the literature. Normal brain imaging was reported in most individuals, however there were some non-specific abnormalities such as white matter loss. One individual was reported to have normal early MRI scans but saw a clinical decline in correlation with subsequent cerebral and cerebellar atrophic changes. Cerebellar vermis hypoplasia has been described in some individuals. Seizures Seizures or epilepsy have been described in 32% of individuals. A variety of seizure types have been reported in the literature, including generalized (tonic-clonic and absence), focal and complex focal seizures. Variations of focal seizures have been described including atonic seizures (associated with other behaviors such as head-bobbing or spontaneous outbursts of laughter), myotonic seizures (with partial-body stiffness or shaking) and subclinical seizures. A typical epilepsy was described, consisting of generalised epilepsy that starts in childhood, with absence seizures and tonic-clonic seizures. However, there have been reports of later-onset epilepsy starting during adulthood. Seizure frequency has been variably reported, with some individuals having sporadic and self-limiting epilepsy, some that resolved with treatment, and some individuals having up to 140 seizures a day despite treatment. | 114 | ASXL3-Related Disorder |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.