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_728_4
|
Related disorders of Lissencephaly
|
There is a related brain abnormality, lissencephaly type II, which is also known as cobblestone lissencephaly. It is characterized by severe brain malformations and associated obstructive hydrocephalus. Obstructive hydrocephalus is a condition in which there is obstructed flow of the fluid surrounding the brain and spinal cord (cerebrospinal fluid), resulting in increasing fluid pressure in the brain. Associated symptoms and findings may include abnormal enlargement of the ventricles of the brain, rapid enlargement of the head, and seizures. Lissencephaly type ll is a major manifestation of Walker-Warburg syndrome (see below).Walker-Warburg syndrome is characterized by lissencephaly type ll in association with abnormal development of the nerve-rich membrane at the back of the eyes (retinal dysplasia), obstructive hydrocephalus, and incomplete development or absence of the thick band of nerve fibers that join the brain’s two cerebral hemispheres. Affected infants also typically have severe growth failure, an unusually small head, seizures, and additional abnormalities of the eyes, including detachment of the retinas, corneal abnormality, small eyes (microphthalmia), and cataracts. In addition, in some affected infants, there may be abnormal protrusion of the brain through a defect at the back of the skull (occipital encephalocele). Walker-Warburg syndrome is inherited as an autosomal recessive trait. Walker-Warburg syndrome and its related disorders are now known collectively as muscular dystrophy-dystroglycanopathies. (For more information on this disorder, choose “Walker Warburg” as your search term in the Rare Disease Database.)
|
Related disorders of Lissencephaly. There is a related brain abnormality, lissencephaly type II, which is also known as cobblestone lissencephaly. It is characterized by severe brain malformations and associated obstructive hydrocephalus. Obstructive hydrocephalus is a condition in which there is obstructed flow of the fluid surrounding the brain and spinal cord (cerebrospinal fluid), resulting in increasing fluid pressure in the brain. Associated symptoms and findings may include abnormal enlargement of the ventricles of the brain, rapid enlargement of the head, and seizures. Lissencephaly type ll is a major manifestation of Walker-Warburg syndrome (see below).Walker-Warburg syndrome is characterized by lissencephaly type ll in association with abnormal development of the nerve-rich membrane at the back of the eyes (retinal dysplasia), obstructive hydrocephalus, and incomplete development or absence of the thick band of nerve fibers that join the brain’s two cerebral hemispheres. Affected infants also typically have severe growth failure, an unusually small head, seizures, and additional abnormalities of the eyes, including detachment of the retinas, corneal abnormality, small eyes (microphthalmia), and cataracts. In addition, in some affected infants, there may be abnormal protrusion of the brain through a defect at the back of the skull (occipital encephalocele). Walker-Warburg syndrome is inherited as an autosomal recessive trait. Walker-Warburg syndrome and its related disorders are now known collectively as muscular dystrophy-dystroglycanopathies. (For more information on this disorder, choose “Walker Warburg” as your search term in the Rare Disease Database.)
| 728 |
Lissencephaly
|
nord_728_5
|
Diagnosis of Lissencephaly
|
When the suspicion is high for lissencephaly type 1 because of family history and/or prenatal ultrasound screening, it is possible that the condition may be confirmed by specialized testing during pregnancy, such as cell-free fetal DNA, amniocentesis or chorionic villus sampling (CVS).Lissencephaly type 1 may be diagnosed thorough clinical evaluation, brain imaging studies, including computerized tomography (CT) scanning and/or magnetic resonance imaging (MRI) and genetic testing like chromosomal analysis and/or specific gene mutational analysis. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain's tissue structure. With MRI, a magnetic field and radio waves create cross-sectional images of the brain. Another test that can aid in the diagnosis is electroencephalogram (EEG). During an EEG, the brain's electrical impulses are recorded. Brain malformations, including lissencephaly, are often associated with abnormal brain electrical impulses and/or seizures. An abnormal EEG pattern may prompt further brain imaging and lead to the diagnosis of lissencephaly. Lastly, DNA analysis may detect certain deletions/mutations in genes linked to lissencephaly. Commercially available gene testing for known genetic causes of lissencephaly is now available. The number of genes included in these tests continues to expand with additional research.
|
Diagnosis of Lissencephaly. When the suspicion is high for lissencephaly type 1 because of family history and/or prenatal ultrasound screening, it is possible that the condition may be confirmed by specialized testing during pregnancy, such as cell-free fetal DNA, amniocentesis or chorionic villus sampling (CVS).Lissencephaly type 1 may be diagnosed thorough clinical evaluation, brain imaging studies, including computerized tomography (CT) scanning and/or magnetic resonance imaging (MRI) and genetic testing like chromosomal analysis and/or specific gene mutational analysis. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain's tissue structure. With MRI, a magnetic field and radio waves create cross-sectional images of the brain. Another test that can aid in the diagnosis is electroencephalogram (EEG). During an EEG, the brain's electrical impulses are recorded. Brain malformations, including lissencephaly, are often associated with abnormal brain electrical impulses and/or seizures. An abnormal EEG pattern may prompt further brain imaging and lead to the diagnosis of lissencephaly. Lastly, DNA analysis may detect certain deletions/mutations in genes linked to lissencephaly. Commercially available gene testing for known genetic causes of lissencephaly is now available. The number of genes included in these tests continues to expand with additional research.
| 728 |
Lissencephaly
|
nord_728_6
|
Therapies of Lissencephaly
|
Treatment
The treatment of lissencephaly type 1 is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Therapies for individuals with lissencephaly type 1 are symptomatic and supportive. Treatment may include measures to improve the intake of nutrients in infants with feeding difficulties; the administration of anticonvulsant drugs to help prevent, reduce, or control seizures; and/or other measures.Genetic counseling is recommended for families of affected children.
|
Therapies of Lissencephaly. Treatment
The treatment of lissencephaly type 1 is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Therapies for individuals with lissencephaly type 1 are symptomatic and supportive. Treatment may include measures to improve the intake of nutrients in infants with feeding difficulties; the administration of anticonvulsant drugs to help prevent, reduce, or control seizures; and/or other measures.Genetic counseling is recommended for families of affected children.
| 728 |
Lissencephaly
|
nord_729_0
|
Overview of Listeriosis
|
Listeriosis is a rare but serious infectious disease caused by the bacterium Listeria monocytogenes, which is predominantly transmitted to humans through the consumption of contaminated food. Clinical syndromes associated with listeriosis include febrile gastroenteritis, invasive disease (bacteremia, meningitis, meningoencephalitis) and pregnancy-associated infections causing spontaneous abortions, stillbirth, premature labor and neonatal disease. Approximately 20% of listeriosis cases are fatal. Listeriosis most often affects pregnant women and their newborns, adults aged 65 and older and individuals with weakened immune systems. Prompt recognition and treatment of the disease is necessary to avoid several serious complications.
|
Overview of Listeriosis. Listeriosis is a rare but serious infectious disease caused by the bacterium Listeria monocytogenes, which is predominantly transmitted to humans through the consumption of contaminated food. Clinical syndromes associated with listeriosis include febrile gastroenteritis, invasive disease (bacteremia, meningitis, meningoencephalitis) and pregnancy-associated infections causing spontaneous abortions, stillbirth, premature labor and neonatal disease. Approximately 20% of listeriosis cases are fatal. Listeriosis most often affects pregnant women and their newborns, adults aged 65 and older and individuals with weakened immune systems. Prompt recognition and treatment of the disease is necessary to avoid several serious complications.
| 729 |
Listeriosis
|
nord_729_1
|
Symptoms of Listeriosis
|
Symptoms associated with listeriosis may vary widely, ranging from mild febrile gastroenteritis to invasive disease (which occurs when the bacteria spread beyond the gastrointestinal tract) causing severe illness. People who are not pregnant most often present with bacteremia (bacteria in the blood), meningitis (infection of the meninges, the membrane surrounding the brain and spinal cord) or meningoencephalitis (infection of the meninges and brain). Common presenting symptoms in patients with bacteremia, meningitis, or meningoencephalitis include fever, muscle aches, headache, stiff neck, malaise, ataxia (loss of balance), convulsions and mental status changes, such as confusion. Less common clinical syndromes include endocarditis (infection of the lining of the heart), pneumonia, osteomyelitis (infection of the bone), septic arthritis (infection of the joint), abscesses of the brain or liver, peritonitis (infection of the membranes lining the abdominal cavity) and endophthalmitis (infection of structures within the eye). Symptoms secondary to these conditions depend on the anatomical site of infection and may include abdominal pain, bone pain, respiratory distress, pneumonia and heart failure. Outbreak investigations have demonstrated that listeriosis can cause febrile gastroenteritis, a noninvasive syndrome, in healthy individuals. Patients with febrile gastroenteritis typically experience diarrhea, fever/chills, fatigue, headache, abdominal pain and nausea.Listeriosis during pregnancy can result in fetal loss (spontaneous abortion and stillbirth), premature delivery and neonatal bacteremia or meningitis. Listeriosis may occur at any time during pregnancy; however, it is most often detected in the third trimester. Among pregnant women diagnosed with listeriosis, most reported only mild flu-like symptoms including fever, chills, myalgias (muscle aches), headaches, arthralgia (joint pain) and gastrointestinal symptoms. Some pregnant women do not recall having any symptoms before the diagnosis of listeriosis in their infant. In contrast to maternal illness, fetal and newborn infections are serious. Nearly one-quarter of pregnancy-associated cases result in fetal loss or death of the newborn. Infants with listeriosis (neonatal listeriosis) may present with fever, lethargy, irritability, diarrhea, poor feeding, vomiting, respiratory distress or a characteristic skin rash consisting of widely spread, small, pale nodules (granulomatosis infantiseptica). Neonatal listeriosis may be classified as early-onset or late-onset. Early-onset neonatal listeriosis, which occurs in the first 7 days of life, is most often associated with bacteremia or sepsis. Early-onset infections occur following maternal bacteremia with transplacental transmission before birth. Late-onset neonatal listeriosis is most often associated with meningitis. The mode of transmission is less clear in late-onset listeriosis; environmental sources may be involved in some cases, and outbreaks of hospital-acquired, neonatal listeriosis have been reported.
|
Symptoms of Listeriosis. Symptoms associated with listeriosis may vary widely, ranging from mild febrile gastroenteritis to invasive disease (which occurs when the bacteria spread beyond the gastrointestinal tract) causing severe illness. People who are not pregnant most often present with bacteremia (bacteria in the blood), meningitis (infection of the meninges, the membrane surrounding the brain and spinal cord) or meningoencephalitis (infection of the meninges and brain). Common presenting symptoms in patients with bacteremia, meningitis, or meningoencephalitis include fever, muscle aches, headache, stiff neck, malaise, ataxia (loss of balance), convulsions and mental status changes, such as confusion. Less common clinical syndromes include endocarditis (infection of the lining of the heart), pneumonia, osteomyelitis (infection of the bone), septic arthritis (infection of the joint), abscesses of the brain or liver, peritonitis (infection of the membranes lining the abdominal cavity) and endophthalmitis (infection of structures within the eye). Symptoms secondary to these conditions depend on the anatomical site of infection and may include abdominal pain, bone pain, respiratory distress, pneumonia and heart failure. Outbreak investigations have demonstrated that listeriosis can cause febrile gastroenteritis, a noninvasive syndrome, in healthy individuals. Patients with febrile gastroenteritis typically experience diarrhea, fever/chills, fatigue, headache, abdominal pain and nausea.Listeriosis during pregnancy can result in fetal loss (spontaneous abortion and stillbirth), premature delivery and neonatal bacteremia or meningitis. Listeriosis may occur at any time during pregnancy; however, it is most often detected in the third trimester. Among pregnant women diagnosed with listeriosis, most reported only mild flu-like symptoms including fever, chills, myalgias (muscle aches), headaches, arthralgia (joint pain) and gastrointestinal symptoms. Some pregnant women do not recall having any symptoms before the diagnosis of listeriosis in their infant. In contrast to maternal illness, fetal and newborn infections are serious. Nearly one-quarter of pregnancy-associated cases result in fetal loss or death of the newborn. Infants with listeriosis (neonatal listeriosis) may present with fever, lethargy, irritability, diarrhea, poor feeding, vomiting, respiratory distress or a characteristic skin rash consisting of widely spread, small, pale nodules (granulomatosis infantiseptica). Neonatal listeriosis may be classified as early-onset or late-onset. Early-onset neonatal listeriosis, which occurs in the first 7 days of life, is most often associated with bacteremia or sepsis. Early-onset infections occur following maternal bacteremia with transplacental transmission before birth. Late-onset neonatal listeriosis is most often associated with meningitis. The mode of transmission is less clear in late-onset listeriosis; environmental sources may be involved in some cases, and outbreaks of hospital-acquired, neonatal listeriosis have been reported.
| 729 |
Listeriosis
|
nord_729_2
|
Causes of Listeriosis
|
Listeriosis is caused by the bacterium Listeria monocytogenes. Nearly all cases of listeriosis (other than neonatal listeriosis) occur from eating contaminated food products, especially ready-to-eat, refrigerated foods. Unlike most foodborne bacterial pathogens, L. monocytogenes can grow at refrigeration temperatures. Listeria organisms are commonly found in the environment, including water, soil, mud and decaying vegetation. L. monocytogenes can be introduced into slaughterhouses and food manufacturing plants, which results in the contamination of food products such as meat or dairy products, raw produce and processed foods. Important sources of foodborne outbreaks include contaminated dairy products such as soft cheeses, unpasteurized or improperly pasteurized milk and ice cream, hot dogs and delicatessen meats and raw produce, including packaged salads, cantaloupe and sprouts.Although L. monocytogenes exposures are common, the interaction of several factors is thought to play a role in the development of invasive disease. These factors include the number of bacteria a person consumes (dose), the virulence of the bacterial strain and the functioning of the patient’s immune system.
|
Causes of Listeriosis. Listeriosis is caused by the bacterium Listeria monocytogenes. Nearly all cases of listeriosis (other than neonatal listeriosis) occur from eating contaminated food products, especially ready-to-eat, refrigerated foods. Unlike most foodborne bacterial pathogens, L. monocytogenes can grow at refrigeration temperatures. Listeria organisms are commonly found in the environment, including water, soil, mud and decaying vegetation. L. monocytogenes can be introduced into slaughterhouses and food manufacturing plants, which results in the contamination of food products such as meat or dairy products, raw produce and processed foods. Important sources of foodborne outbreaks include contaminated dairy products such as soft cheeses, unpasteurized or improperly pasteurized milk and ice cream, hot dogs and delicatessen meats and raw produce, including packaged salads, cantaloupe and sprouts.Although L. monocytogenes exposures are common, the interaction of several factors is thought to play a role in the development of invasive disease. These factors include the number of bacteria a person consumes (dose), the virulence of the bacterial strain and the functioning of the patient’s immune system.
| 729 |
Listeriosis
|
nord_729_3
|
Affects of Listeriosis
|
Invasive listeriosis usually affects pregnant women and their newborns, adults aged 65 and older and individuals with weakened immune systems (immunocompromised). Medical risk factors for invasive listeriosis include hematologic malignancy, organ transplantation, HIV infection or AIDS, alcoholism and liver and kidney disease. In the United States, L. monocytogenes accounts for ~5% of all cases of bacterial meningitis in infants <2 months of age and ~10% of all cases of bacterial meningitis in people ≥65 years of age. Invasive listeriosis occurs very infrequently in young, healthy adults. Overall rates of invasive listeriosis in the United States have remained relatively constant over the past decade (~3 cases per million population), as measured where active surveillance for listeriosis has been conducted.
|
Affects of Listeriosis. Invasive listeriosis usually affects pregnant women and their newborns, adults aged 65 and older and individuals with weakened immune systems (immunocompromised). Medical risk factors for invasive listeriosis include hematologic malignancy, organ transplantation, HIV infection or AIDS, alcoholism and liver and kidney disease. In the United States, L. monocytogenes accounts for ~5% of all cases of bacterial meningitis in infants <2 months of age and ~10% of all cases of bacterial meningitis in people ≥65 years of age. Invasive listeriosis occurs very infrequently in young, healthy adults. Overall rates of invasive listeriosis in the United States have remained relatively constant over the past decade (~3 cases per million population), as measured where active surveillance for listeriosis has been conducted.
| 729 |
Listeriosis
|
nord_729_4
|
Related disorders of Listeriosis
|
Symptoms of the following disorders can be similar to those of listeriosis. Comparisons may be useful for a differential diagnosis:The differential diagnosis of listeriosis includes all causes of meningitis or sepsis in newborn infants, such as group B streptococcus infection; all causes of meningitis and encephalitis in older adults and in individuals with weakened immune systems; and all causes of febrile illness during pregnancy, including viral syndromes.Group B streptococcus (group B strep) is a type of bacteria that causes infection among newborns, pregnant women, or women after childbirth, women after gynecologic surgery, and older men and women with other serious diseases. Group B strep remains the most common cause among newborns (neonates) of infection of the blood and of the brain. The responsible bacterium, usually Streptococcus agalactiae, may be found most often in the vagina and rectum of females and may be transmitted as the infant passes through the birth canal. Group B strep disease is said to be early onset if it is obvious within the first week of life. It is said to be late onset if the disease is evident after the first week of life and before the end of the first three months. Bacterial meningitis is a central nervous system infection caused by certain types of bacteria. Meningitis is characterized by inflammation of the membranes (meninges) around the brain or spinal cord. Inflammation can begin suddenly (acute) or develop gradually (subacute). Major symptoms may include fever, headache and a stiff neck, sometimes with aching muscles. Nausea, vomiting and other symptoms may occur. Five types of bacteria are responsible for most cases of bacterial meningitis: Haemophilus influenzae, Streptococcus pneumoniae (pneumococcus), Group B streptococcus, Neisseria meningitidis (meningococcus) and Listeria monocytogenes (Listeria). (For more information on this disorder, choose “meningitis” as your search term in the Rare Disease Database.)
|
Related disorders of Listeriosis. Symptoms of the following disorders can be similar to those of listeriosis. Comparisons may be useful for a differential diagnosis:The differential diagnosis of listeriosis includes all causes of meningitis or sepsis in newborn infants, such as group B streptococcus infection; all causes of meningitis and encephalitis in older adults and in individuals with weakened immune systems; and all causes of febrile illness during pregnancy, including viral syndromes.Group B streptococcus (group B strep) is a type of bacteria that causes infection among newborns, pregnant women, or women after childbirth, women after gynecologic surgery, and older men and women with other serious diseases. Group B strep remains the most common cause among newborns (neonates) of infection of the blood and of the brain. The responsible bacterium, usually Streptococcus agalactiae, may be found most often in the vagina and rectum of females and may be transmitted as the infant passes through the birth canal. Group B strep disease is said to be early onset if it is obvious within the first week of life. It is said to be late onset if the disease is evident after the first week of life and before the end of the first three months. Bacterial meningitis is a central nervous system infection caused by certain types of bacteria. Meningitis is characterized by inflammation of the membranes (meninges) around the brain or spinal cord. Inflammation can begin suddenly (acute) or develop gradually (subacute). Major symptoms may include fever, headache and a stiff neck, sometimes with aching muscles. Nausea, vomiting and other symptoms may occur. Five types of bacteria are responsible for most cases of bacterial meningitis: Haemophilus influenzae, Streptococcus pneumoniae (pneumococcus), Group B streptococcus, Neisseria meningitidis (meningococcus) and Listeria monocytogenes (Listeria). (For more information on this disorder, choose “meningitis” as your search term in the Rare Disease Database.)
| 729 |
Listeriosis
|
nord_729_5
|
Diagnosis of Listeriosis
|
A diagnosis of invasive listeriosis is confirmed through laboratory tests called cultures, which confirm the presence of L. monocytogenes in the body by isolating the bacteria from a clinical specimen. Cultures of blood, amniotic fluid, cerebrospinal fluid, placenta, or specimens from any affected organ systems may be performed to determine whether the bacterium L. monocytogenes is present. Certain x-ray tests such as computed tomography (CT) scan or magnetic resonance imaging (MRI) might be used to detect abscesses that may form on internal organs, especially the brain or liver.
|
Diagnosis of Listeriosis. A diagnosis of invasive listeriosis is confirmed through laboratory tests called cultures, which confirm the presence of L. monocytogenes in the body by isolating the bacteria from a clinical specimen. Cultures of blood, amniotic fluid, cerebrospinal fluid, placenta, or specimens from any affected organ systems may be performed to determine whether the bacterium L. monocytogenes is present. Certain x-ray tests such as computed tomography (CT) scan or magnetic resonance imaging (MRI) might be used to detect abscesses that may form on internal organs, especially the brain or liver.
| 729 |
Listeriosis
|
nord_729_6
|
Therapies of Listeriosis
|
Treatment
Listeriosis is treated with antibiotics. The most prescribed treatment is intravenous ampicillin. Many physicians also recommend treatment with the antibiotic gentamicin in combination with ampicillin. For affected individuals who cannot tolerate B-lactam antibiotics (such as ampicillin), trimethoprim-sulfamethoxazole is recommended. Other antibiotics are sometimes recommended. Antibiotic treatment of pregnant women with documented listeriosis may prevent infection of the fetus. L. monocytogenes is resistant to all third generation cephalosporins. Other treatment is symptomatic and supportive.Prevention
Knowing what foods to avoid and how to safely prepare and store foods is the best way to reduce the risk of listeriosis. This information is most important for those persons in groups at higher risk for invasive listeriosis, especially pregnant women, older adults and persons who have weakened immune systems.Recommendations for persons at higher risk for listeriosis: Do not eat or drink raw (unpasteurized) milk or other unpasteurized dairy products. Do not eat soft cheeses such as Brie, feta, and queso fresco, unless they are labeled as made from pasteurized milk. Additionally, be aware that soft cheeses, such as queso fresco, that were made from pasteurized milk but contaminated during cheese making have also caused listeriosis. Reheat leftovers, prepackaged foods, and deli meats until steaming hot. Do not eat refrigerated smoked seafood, unless it is contained in a cooked dish, such as a casserole or unless it is a canned or shelf-stable product.Recommendations for everyone to prevent listeriosis and other foodborne diseases: thoroughly cook all raw foods of animal origin, such as meat, because heat kills L. monocytogenes. Wash fruits and vegetables thoroughly if eating raw. Follow recommended “sell by” or “best if used by” labels on processed foods. Wash hands before preparing food and after handling raw meat, poultry and eggs; clean surfaces and utensils used to prepare uncooked foods; and keep unwashed and uncooked foods separate from foods that have been already prepared for eating.The following resource provides additional information:
https://www.cdc.gov/listeria/prevention.html
|
Therapies of Listeriosis. Treatment
Listeriosis is treated with antibiotics. The most prescribed treatment is intravenous ampicillin. Many physicians also recommend treatment with the antibiotic gentamicin in combination with ampicillin. For affected individuals who cannot tolerate B-lactam antibiotics (such as ampicillin), trimethoprim-sulfamethoxazole is recommended. Other antibiotics are sometimes recommended. Antibiotic treatment of pregnant women with documented listeriosis may prevent infection of the fetus. L. monocytogenes is resistant to all third generation cephalosporins. Other treatment is symptomatic and supportive.Prevention
Knowing what foods to avoid and how to safely prepare and store foods is the best way to reduce the risk of listeriosis. This information is most important for those persons in groups at higher risk for invasive listeriosis, especially pregnant women, older adults and persons who have weakened immune systems.Recommendations for persons at higher risk for listeriosis: Do not eat or drink raw (unpasteurized) milk or other unpasteurized dairy products. Do not eat soft cheeses such as Brie, feta, and queso fresco, unless they are labeled as made from pasteurized milk. Additionally, be aware that soft cheeses, such as queso fresco, that were made from pasteurized milk but contaminated during cheese making have also caused listeriosis. Reheat leftovers, prepackaged foods, and deli meats until steaming hot. Do not eat refrigerated smoked seafood, unless it is contained in a cooked dish, such as a casserole or unless it is a canned or shelf-stable product.Recommendations for everyone to prevent listeriosis and other foodborne diseases: thoroughly cook all raw foods of animal origin, such as meat, because heat kills L. monocytogenes. Wash fruits and vegetables thoroughly if eating raw. Follow recommended “sell by” or “best if used by” labels on processed foods. Wash hands before preparing food and after handling raw meat, poultry and eggs; clean surfaces and utensils used to prepare uncooked foods; and keep unwashed and uncooked foods separate from foods that have been already prepared for eating.The following resource provides additional information:
https://www.cdc.gov/listeria/prevention.html
| 729 |
Listeriosis
|
nord_730_0
|
Overview of Locked In Syndrome
|
SummaryLocked-in syndrome is a rare neurological disorder in which there is complete paralysis of all voluntary muscles except for the ones that control the movements of the eyes. Individuals with locked-in syndrome are conscious and awake, but have no ability to produce movements (outside of eye movement) or to speak (aphonia). Cognitive function is usually unaffected. Communication is possible through eye movements or blinking. Locked-in syndrome is caused by damaged to the pons, a part of the brainstem that contains nerve fibers that relay information to other areas of the brain.IntroductionThe first description of the locked-in syndrome can be found in The Count of Monte Cristo authored by Alexandre Dumas. To describe a patient with a locked-in syndrome, the author used the following words:‘Sight and hearing were the only senses remaining…. It was only, however, by means of one of these senses that he could reveal the thoughts and feelings that still occupied his mind, and the look by which he gave expression to his inner life was like the distant gleam of a candle which a traveler sees by night across some desert place, and knows that a living being dwells beyond the silence and obscurity. In his eyes, shaded by thick black lashes, was concentrated, as it often happens with an organ which is used to the exclusion of the others, all the activity, address, force, and intelligence which were formerly diffused over his whole body; and so although the movement of the arm, the sound of the voice, and the agility of the body, were wanting, the speaking eye sufficed for all’.In this way, he brilliantly highlighted the potential that these patients have to maintain a meaningful life despite their extreme disability.
|
Overview of Locked In Syndrome. SummaryLocked-in syndrome is a rare neurological disorder in which there is complete paralysis of all voluntary muscles except for the ones that control the movements of the eyes. Individuals with locked-in syndrome are conscious and awake, but have no ability to produce movements (outside of eye movement) or to speak (aphonia). Cognitive function is usually unaffected. Communication is possible through eye movements or blinking. Locked-in syndrome is caused by damaged to the pons, a part of the brainstem that contains nerve fibers that relay information to other areas of the brain.IntroductionThe first description of the locked-in syndrome can be found in The Count of Monte Cristo authored by Alexandre Dumas. To describe a patient with a locked-in syndrome, the author used the following words:‘Sight and hearing were the only senses remaining…. It was only, however, by means of one of these senses that he could reveal the thoughts and feelings that still occupied his mind, and the look by which he gave expression to his inner life was like the distant gleam of a candle which a traveler sees by night across some desert place, and knows that a living being dwells beyond the silence and obscurity. In his eyes, shaded by thick black lashes, was concentrated, as it often happens with an organ which is used to the exclusion of the others, all the activity, address, force, and intelligence which were formerly diffused over his whole body; and so although the movement of the arm, the sound of the voice, and the agility of the body, were wanting, the speaking eye sufficed for all’.In this way, he brilliantly highlighted the potential that these patients have to maintain a meaningful life despite their extreme disability.
| 730 |
Locked In Syndrome
|
nord_730_1
|
Symptoms of Locked In Syndrome
|
Individuals with locked-in syndrome classically cannot consciously or voluntarily chew, swallow, breathe, speak, or produce any movements other than those involving the eyes or eyelids. Some affected individuals can move their eyes up and down (vertically), but not side-to-side (horizontally). Affected individuals are bedridden and completely reliant on caregivers. Despite physical paralysis, cognitive function is unaffected.Individuals with locked-in syndrome are fully alert and aware of their environment. They can hear, see and have preserved sleep-wake cycles. Affected individuals can communicate through purposeful movements of their eyes or blinking or both. They can comprehend people talking or reading to them.Individuals with locked-in syndrome often initially are comatose before gradually regaining consciousness, but remain paralyzed and unable to speak.Clinical forms
The locked-in syndrome may be classified in three different clinical forms, according to the traditional classification of Bauer. This classification is based on the amount of motor outputs, which are preserved in the patients. It talks about a pure form when the patient loses the control of all body movements with the exception of blinking and vertical eye movements; an incomplete form when some voluntary movements other than eye movements are preserved and a total form when a complete loss of motor function occurs. The last condition is particularly dramatic as the patients are completely unable to interact with the environment and to express their needs and thoughts.Quality of life
Although the locked-in syndrome appears as the most dramatic form of motor disability one can imagine, some scientific reports indicate that the quality of life of patients is not so poor as expected. A recent survey investigated the self-reported quality of life of chronic patients with locked-in syndrome and concluded that many patients have a happy and meaningful life, especially when proper social services help patients to have a normal role at home as well as in the community. Additional symptoms under investigation
Patients with locked-in syndrome are traditionally considered cognitively intact as all the cerebral structures with the exception of the ventral portion of the pons of the brain are apparently preserved. However, recent evidence suggests that the patients can develop some non-motor symptoms including motor imagery defects, pathological laughter and crying, and difficulties in the recognition of some facial expressions. The interruption of the cortico-ponto-cerebellar pathways, by means of the the same lesion causing the locked-in syndrome, may be responsible for the appearance of these clinical manifestations. However, these symptoms are not detected in all affected individuals and are currently under further investigation. The recognition of motor imagery defects deserves special attention because these symptoms, whenever present, may interfere with the success of rehabilitation strategies.
|
Symptoms of Locked In Syndrome. Individuals with locked-in syndrome classically cannot consciously or voluntarily chew, swallow, breathe, speak, or produce any movements other than those involving the eyes or eyelids. Some affected individuals can move their eyes up and down (vertically), but not side-to-side (horizontally). Affected individuals are bedridden and completely reliant on caregivers. Despite physical paralysis, cognitive function is unaffected.Individuals with locked-in syndrome are fully alert and aware of their environment. They can hear, see and have preserved sleep-wake cycles. Affected individuals can communicate through purposeful movements of their eyes or blinking or both. They can comprehend people talking or reading to them.Individuals with locked-in syndrome often initially are comatose before gradually regaining consciousness, but remain paralyzed and unable to speak.Clinical forms
The locked-in syndrome may be classified in three different clinical forms, according to the traditional classification of Bauer. This classification is based on the amount of motor outputs, which are preserved in the patients. It talks about a pure form when the patient loses the control of all body movements with the exception of blinking and vertical eye movements; an incomplete form when some voluntary movements other than eye movements are preserved and a total form when a complete loss of motor function occurs. The last condition is particularly dramatic as the patients are completely unable to interact with the environment and to express their needs and thoughts.Quality of life
Although the locked-in syndrome appears as the most dramatic form of motor disability one can imagine, some scientific reports indicate that the quality of life of patients is not so poor as expected. A recent survey investigated the self-reported quality of life of chronic patients with locked-in syndrome and concluded that many patients have a happy and meaningful life, especially when proper social services help patients to have a normal role at home as well as in the community. Additional symptoms under investigation
Patients with locked-in syndrome are traditionally considered cognitively intact as all the cerebral structures with the exception of the ventral portion of the pons of the brain are apparently preserved. However, recent evidence suggests that the patients can develop some non-motor symptoms including motor imagery defects, pathological laughter and crying, and difficulties in the recognition of some facial expressions. The interruption of the cortico-ponto-cerebellar pathways, by means of the the same lesion causing the locked-in syndrome, may be responsible for the appearance of these clinical manifestations. However, these symptoms are not detected in all affected individuals and are currently under further investigation. The recognition of motor imagery defects deserves special attention because these symptoms, whenever present, may interfere with the success of rehabilitation strategies.
| 730 |
Locked In Syndrome
|
nord_730_2
|
Causes of Locked In Syndrome
|
Locked-in syndrome is most often caused by damage to a specific part of the brainstem known as the pons. The pons contains important neuronal pathways between the cerebrum, spinal cord and cerebellum. In locked-in syndrome there is an interruption of all the motor fibers running from grey matter in the brain via the spinal cord to the body’s muscles and also damage to the centers in the brainstem important for facial control and speaking.Damage to the pons most often results from tissue loss due to lack of blood flow (infarct) or bleeding (hemorrhage) – less frequently it can be caused by trauma. An infarct can be caused by several different conditions such as a blood clot (thrombosis) or stroke. Additional conditions that can cause locked-in syndrome include infection in certain portions of the brain, tumors, loss of the protective insulation (myelin) that surrounds nerve cells (myelinolysis), inflammation of the nerves (polymyositis), and certain disorders such as amyotrophic lateral sclerosis (ALS).
|
Causes of Locked In Syndrome. Locked-in syndrome is most often caused by damage to a specific part of the brainstem known as the pons. The pons contains important neuronal pathways between the cerebrum, spinal cord and cerebellum. In locked-in syndrome there is an interruption of all the motor fibers running from grey matter in the brain via the spinal cord to the body’s muscles and also damage to the centers in the brainstem important for facial control and speaking.Damage to the pons most often results from tissue loss due to lack of blood flow (infarct) or bleeding (hemorrhage) – less frequently it can be caused by trauma. An infarct can be caused by several different conditions such as a blood clot (thrombosis) or stroke. Additional conditions that can cause locked-in syndrome include infection in certain portions of the brain, tumors, loss of the protective insulation (myelin) that surrounds nerve cells (myelinolysis), inflammation of the nerves (polymyositis), and certain disorders such as amyotrophic lateral sclerosis (ALS).
| 730 |
Locked In Syndrome
|
nord_730_3
|
Affects of Locked In Syndrome
|
Locked-in syndrome is a rare neurological disorder that affects males and females in equal numbers. Locked-in syndrome can affect individuals of all ages including children, but most often is seen in adults who are more at risk for brain stroke and bleeding. Because cases of locked-in syndrome may go unrecognized or misdiagnosed, it is difficult to determine the actual number of individuals who have had the disorder in the general population.
|
Affects of Locked In Syndrome. Locked-in syndrome is a rare neurological disorder that affects males and females in equal numbers. Locked-in syndrome can affect individuals of all ages including children, but most often is seen in adults who are more at risk for brain stroke and bleeding. Because cases of locked-in syndrome may go unrecognized or misdiagnosed, it is difficult to determine the actual number of individuals who have had the disorder in the general population.
| 730 |
Locked In Syndrome
|
nord_730_4
|
Related disorders of Locked In Syndrome
|
Symptoms of the following disorders can be similar to those of locked-in syndrome. Comparisons may be useful for a differential diagnosis.Akinetic mutism is a rare neurological condition in which an affected individual does not move (akinetic) or talk (mute) despite being awake. Individuals with akinetic mutism have normal sleep/wake cycles, but (when awake) lie still and unresponsive, neither moving nor talking. Akinetic mutism is a form of minimally conscious state often due to vascular or traumatic damage in the midline frontal grey matter.A variety of conditions can cause symptoms or a clinical picture that is similar to locked-in syndrome. These disorders or conditions include Guillain-Barre syndrome, myasthenia gravis, poliomyelitis, polyneuritis or bilateral brainstem tumors. Locked-in syndrome can be mistaken for a vegetative state that may occur secondary to trauma or a variety of different conditions, especially if affected individuals have visual or hearing loss making the diagnosis more difficult.
|
Related disorders of Locked In Syndrome. Symptoms of the following disorders can be similar to those of locked-in syndrome. Comparisons may be useful for a differential diagnosis.Akinetic mutism is a rare neurological condition in which an affected individual does not move (akinetic) or talk (mute) despite being awake. Individuals with akinetic mutism have normal sleep/wake cycles, but (when awake) lie still and unresponsive, neither moving nor talking. Akinetic mutism is a form of minimally conscious state often due to vascular or traumatic damage in the midline frontal grey matter.A variety of conditions can cause symptoms or a clinical picture that is similar to locked-in syndrome. These disorders or conditions include Guillain-Barre syndrome, myasthenia gravis, poliomyelitis, polyneuritis or bilateral brainstem tumors. Locked-in syndrome can be mistaken for a vegetative state that may occur secondary to trauma or a variety of different conditions, especially if affected individuals have visual or hearing loss making the diagnosis more difficult.
| 730 |
Locked In Syndrome
|
nord_730_5
|
Diagnosis of Locked In Syndrome
|
A diagnosis of locked-in syndrome is usually made clinically. A variety of tests may be performed to rule out other conditions. Such tests include magnetic resonance imaging (MRI), which shows the damage to the pons, and magnetic resonance angiography, which can show the blood clot in the arteries of the brainstem. These tests can also rule out damage elsewhere in the brain.An electroencephalogram (EEG), a test that measures the electrical activity of the brain, may reveal normal brain activity and sleep-wake cycles in individuals with locked-in syndrome.Evoked potentials, tests that average the EEG signal in response to stimulation (pain or auditory or visual), permit a look at the damaged responses in the brainstem and the preserved responses in the brain.Electromyography and nerve conduction study can be used to rule out damage to the muscles and nerves.An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as the brain. MR angiography uses a magnetic field and radio waves to produce cross-sectional images of blood vessels inside the body.An electromyography is a test that records electrical activity in the skeletal (voluntary) muscles at rest and during muscle contraction.
Nerve conduction study determines the ability of specific nerves to relay nerve impulses to the muscles.
|
Diagnosis of Locked In Syndrome. A diagnosis of locked-in syndrome is usually made clinically. A variety of tests may be performed to rule out other conditions. Such tests include magnetic resonance imaging (MRI), which shows the damage to the pons, and magnetic resonance angiography, which can show the blood clot in the arteries of the brainstem. These tests can also rule out damage elsewhere in the brain.An electroencephalogram (EEG), a test that measures the electrical activity of the brain, may reveal normal brain activity and sleep-wake cycles in individuals with locked-in syndrome.Evoked potentials, tests that average the EEG signal in response to stimulation (pain or auditory or visual), permit a look at the damaged responses in the brainstem and the preserved responses in the brain.Electromyography and nerve conduction study can be used to rule out damage to the muscles and nerves.An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as the brain. MR angiography uses a magnetic field and radio waves to produce cross-sectional images of blood vessels inside the body.An electromyography is a test that records electrical activity in the skeletal (voluntary) muscles at rest and during muscle contraction.
Nerve conduction study determines the ability of specific nerves to relay nerve impulses to the muscles.
| 730 |
Locked In Syndrome
|
nord_730_6
|
Therapies of Locked In Syndrome
|
TreatmentTreatment should first be aimed at the underlying cause of the disorder. For example, reversal of a basilar artery blood clot (thrombosis) with intraarterial thrombolytic therapy may be attempted up to six hours after symptoms onset. Tumors may be treated with intravenous steroids or radiation.Affected individuals often need an artificial aid for breathing and will have a tracheotomy (a tube going in the airway via a small hole in the throat) in the beginning.Feeding and drinking will not be possible via the mouth (it may cause respiratory infection by running into the lungs rather than stomach) and hence will need to be assured via a small tube inserted in the stomach called gastrostomy.It is important to establish an eye-coded communication as soon as possible. Healthcare providers and family and friends should try to find out what is the easiest code for the affected individual and consequently all use the same code. This can be ‘look up' for ‘yes' and ‘look down' for no or whatever is the easiest movement for the specific case. Communication is then limited to closed yes-no questions and can next be replaced by eye-coded letter spellers such as saying the alphabet and having the affected individual look down to choose her or his letter. There are many variations on this way of communication presenting the letters in frequency of use in the English language (. . . . . . . . . . . . . . . . . . . . . . . . . Z) or using letter boards with different columns and lines for vowels and consonants for example.Next, treatment should be aimed at the early rehabilitation of the small voluntary movements that remain or recover (often in a finger or foot or swallowing and sound production). Rehabilitation and various supportive therapies are very beneficial and should be started as early as possible even if it needs to be stressed that recovery of near-normal motor control, speaking, swallowing and walking are extremely unusual.Devices to aid in communication and other assistive technologies have proven beneficial as well as allowing individuals to become active members of society. Infrared eye tracking devices now permit affected individuals to use a computer with artificial voice, control their environment, surf on the internet and send email. In rare cases, some individuals have recovered limited motor abilities, however, in most people such recovery does not occur. Those who recover some motor control in hand or head (as will over half of the patients) can use this to communicate with a computer and sometimes control their wheelchair.Recent studies and articles in the medical literature have noted that despite significant motor disability affected individuals can retain a good quality of life. In addition, quality of life is unrelated to the degree of physical impairment. With advances in care and assistive technologies, individuals with locked-in syndrome can become productive members of society.
|
Therapies of Locked In Syndrome. TreatmentTreatment should first be aimed at the underlying cause of the disorder. For example, reversal of a basilar artery blood clot (thrombosis) with intraarterial thrombolytic therapy may be attempted up to six hours after symptoms onset. Tumors may be treated with intravenous steroids or radiation.Affected individuals often need an artificial aid for breathing and will have a tracheotomy (a tube going in the airway via a small hole in the throat) in the beginning.Feeding and drinking will not be possible via the mouth (it may cause respiratory infection by running into the lungs rather than stomach) and hence will need to be assured via a small tube inserted in the stomach called gastrostomy.It is important to establish an eye-coded communication as soon as possible. Healthcare providers and family and friends should try to find out what is the easiest code for the affected individual and consequently all use the same code. This can be ‘look up' for ‘yes' and ‘look down' for no or whatever is the easiest movement for the specific case. Communication is then limited to closed yes-no questions and can next be replaced by eye-coded letter spellers such as saying the alphabet and having the affected individual look down to choose her or his letter. There are many variations on this way of communication presenting the letters in frequency of use in the English language (. . . . . . . . . . . . . . . . . . . . . . . . . Z) or using letter boards with different columns and lines for vowels and consonants for example.Next, treatment should be aimed at the early rehabilitation of the small voluntary movements that remain or recover (often in a finger or foot or swallowing and sound production). Rehabilitation and various supportive therapies are very beneficial and should be started as early as possible even if it needs to be stressed that recovery of near-normal motor control, speaking, swallowing and walking are extremely unusual.Devices to aid in communication and other assistive technologies have proven beneficial as well as allowing individuals to become active members of society. Infrared eye tracking devices now permit affected individuals to use a computer with artificial voice, control their environment, surf on the internet and send email. In rare cases, some individuals have recovered limited motor abilities, however, in most people such recovery does not occur. Those who recover some motor control in hand or head (as will over half of the patients) can use this to communicate with a computer and sometimes control their wheelchair.Recent studies and articles in the medical literature have noted that despite significant motor disability affected individuals can retain a good quality of life. In addition, quality of life is unrelated to the degree of physical impairment. With advances in care and assistive technologies, individuals with locked-in syndrome can become productive members of society.
| 730 |
Locked In Syndrome
|
nord_731_0
|
Overview of Loeys-Dietz Syndrome
|
SummaryLoeys-Dietz syndrome (LDS) is a genetic condition affecting the connective tissue and involving multiple organ systems including the blood vessels, skeleton, eyes and skin. It was first described in 2005 and has many shared characteristics with Marfan syndrome. While not all individuals have characteristic craniofacial features, individuals with this disorder often have widely spaced eyes, tortuous blood vessels, a uvula that splits in two (bifid uvula) and/or cleft palate.LDS is an autosomal dominant genetic condition that can be inherited from a parent or occur for the first time in an individual as a result of a new pathogenic variant in one of several genes: GFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3.IntroductionPeople with LDS are at risk for blood vessel aneurysms, particularly at the root of the aorta, but also in other locations of the arterial tree, that can be life-threatening. Therefore, it is extremely important to screen, diagnose, and prevent complications early.
|
Overview of Loeys-Dietz Syndrome. SummaryLoeys-Dietz syndrome (LDS) is a genetic condition affecting the connective tissue and involving multiple organ systems including the blood vessels, skeleton, eyes and skin. It was first described in 2005 and has many shared characteristics with Marfan syndrome. While not all individuals have characteristic craniofacial features, individuals with this disorder often have widely spaced eyes, tortuous blood vessels, a uvula that splits in two (bifid uvula) and/or cleft palate.LDS is an autosomal dominant genetic condition that can be inherited from a parent or occur for the first time in an individual as a result of a new pathogenic variant in one of several genes: GFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3.IntroductionPeople with LDS are at risk for blood vessel aneurysms, particularly at the root of the aorta, but also in other locations of the arterial tree, that can be life-threatening. Therefore, it is extremely important to screen, diagnose, and prevent complications early.
| 731 |
Loeys-Dietz Syndrome
|
nord_731_1
|
Symptoms of Loeys-Dietz Syndrome
|
LDS is a disorder of connective tissue, so it affects the bones, ligaments, arterial walls, and skin most significantly. A patient may not have all of the findings listed here, or maybe just one or two of the findings and still have the disease.Widely spaced eyes (hypertelorism)
Bifid uvula/cleft palate
Aortic root aneurysm
Arterial tortuosity
Scoliosis
Long, thin fingers (arachnodactyly)
Protruded or caved in chest (pectus carinatum or pectus excavatum)
Flat feet (Pes planus)
Joint hypermobility
Thin, translucent skin
Club feet
Early fused skull (craniosynostosis) During development in the womb and during childhood the eyes may be more noticeable widely set apart than normal, the hard palate may not close completely and/or the skull sutures to close too quickly causing a misshapen head and possibly elevated pressure inside of the skull. In other parts of the body, the chest may be either caved-in (pectus excavatum) or protruded out (pectus carinatum), the joints may be flexible, the fingers/toes may be abnormally long and the spine may be curved. Sometimes the joints can also become too tight. The eyes and skin are affected as well in some patients, resulting in thin skin. It can be easy to see the veins through the skin as well as excessive bruising. The artery walls also are prone to expanding/dilating more than they should and once this reaches a certain threshold it is called an aneurysm. These blood vessels may grow abnormally long and twisted or tortuous, making them more likely to split or dissect. Arteries in the head/neck, where the aorta exits the heart and, in the abdomen, as low as the popliteal area behind the knee have been reported to have aneurysms. These malformed and weakened arteries tend to balloon outwards with high risk of bursting. A ruptured aneurysm is an emergency and can be life-threatening if left untreated. Approximately 2/3 of people with LDS will have an aortic aneurysm at diagnosis and nearly all will have some aortic ballooning.
|
Symptoms of Loeys-Dietz Syndrome. LDS is a disorder of connective tissue, so it affects the bones, ligaments, arterial walls, and skin most significantly. A patient may not have all of the findings listed here, or maybe just one or two of the findings and still have the disease.Widely spaced eyes (hypertelorism)
Bifid uvula/cleft palate
Aortic root aneurysm
Arterial tortuosity
Scoliosis
Long, thin fingers (arachnodactyly)
Protruded or caved in chest (pectus carinatum or pectus excavatum)
Flat feet (Pes planus)
Joint hypermobility
Thin, translucent skin
Club feet
Early fused skull (craniosynostosis) During development in the womb and during childhood the eyes may be more noticeable widely set apart than normal, the hard palate may not close completely and/or the skull sutures to close too quickly causing a misshapen head and possibly elevated pressure inside of the skull. In other parts of the body, the chest may be either caved-in (pectus excavatum) or protruded out (pectus carinatum), the joints may be flexible, the fingers/toes may be abnormally long and the spine may be curved. Sometimes the joints can also become too tight. The eyes and skin are affected as well in some patients, resulting in thin skin. It can be easy to see the veins through the skin as well as excessive bruising. The artery walls also are prone to expanding/dilating more than they should and once this reaches a certain threshold it is called an aneurysm. These blood vessels may grow abnormally long and twisted or tortuous, making them more likely to split or dissect. Arteries in the head/neck, where the aorta exits the heart and, in the abdomen, as low as the popliteal area behind the knee have been reported to have aneurysms. These malformed and weakened arteries tend to balloon outwards with high risk of bursting. A ruptured aneurysm is an emergency and can be life-threatening if left untreated. Approximately 2/3 of people with LDS will have an aortic aneurysm at diagnosis and nearly all will have some aortic ballooning.
| 731 |
Loeys-Dietz Syndrome
|
nord_731_2
|
Causes of Loeys-Dietz Syndrome
|
About 1/3 of individuals with LDS have an affected parent, while 2/3 of cases are caused by new or de novo pathogenic gene variants (mutations). These variants may then be passed down to children in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The non-working abnormal gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. Since it was first described relatively recently (2005) and is a rare disease, more research is needed to fully understand the pathogenesis of LDS. Currently, researchers have identified several genes in the transforming growth factor beta (TGFβ) pathway which may be mutated in the disease including: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, and TGFB3. The genes in this pathway are important for gene expression, cell growth, differentiation and controlled cell death (apoptosis). Notably, the gene SMAD3 has been associated with a condition known as aneurysm-osteoarthritis syndrome (AOS), which shares some of the characteristics of LDS. Disease causing variants in all of these genes cause them to lose their normal function, resulting in many of the symptoms of LDS.
|
Causes of Loeys-Dietz Syndrome. About 1/3 of individuals with LDS have an affected parent, while 2/3 of cases are caused by new or de novo pathogenic gene variants (mutations). These variants may then be passed down to children in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The non-working abnormal gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. Since it was first described relatively recently (2005) and is a rare disease, more research is needed to fully understand the pathogenesis of LDS. Currently, researchers have identified several genes in the transforming growth factor beta (TGFβ) pathway which may be mutated in the disease including: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, and TGFB3. The genes in this pathway are important for gene expression, cell growth, differentiation and controlled cell death (apoptosis). Notably, the gene SMAD3 has been associated with a condition known as aneurysm-osteoarthritis syndrome (AOS), which shares some of the characteristics of LDS. Disease causing variants in all of these genes cause them to lose their normal function, resulting in many of the symptoms of LDS.
| 731 |
Loeys-Dietz Syndrome
|
nord_731_3
|
Affects of Loeys-Dietz Syndrome
|
LDS is a rare disorder that affects males and females in equal numbers. The prevalence of LDS is unknown though with more availability of genetic testing the number of patients diagnosed has increased significantly in recent years. The condition occurs in all ethnic groups.
|
Affects of Loeys-Dietz Syndrome. LDS is a rare disorder that affects males and females in equal numbers. The prevalence of LDS is unknown though with more availability of genetic testing the number of patients diagnosed has increased significantly in recent years. The condition occurs in all ethnic groups.
| 731 |
Loeys-Dietz Syndrome
|
nord_731_4
|
Related disorders of Loeys-Dietz Syndrome
|
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with significant clinical overlap with LDS including aortic root aneurysm, pectus (chest wall) deformities, scoliosis and arachnodactyly. However, individuals with LDS more often have widely spaced eyes, cleft palate/bifid uvula, craniosynostosis and/or club feet. Individuals with LDS also have aneurysms more throughout the arterial tree, where those with MFS are most often at the root of the aorta. Individuals with MFS are more likely to have eye lens dislocations and heart valve problems. MFS is caused by pathogenic variants in the FBN1 gene. (For more information on this disorder, choose “Marfan syndrome” as your search term on the Rare Disease Database.Shprintzen-Goldberg syndrome (SGS) is caused by autosomal dominant pathogenic variants in the SKI gene, which also interrupts TGFβ activity, similar to LDS. Symptoms included skeletal and heart abnormalities along with intellectual disability. Intellectual disability is less often seen in LDS and the skeletal anomalies are usually more profound in SGS. (For more information on this disorder, choose “Shprintzen-Goldberg syndrome” as your search term on the Rare Disease Database.)Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant connective tissue disorder that is also associated with thin skin, aggressive arterial aneurysms, and an increased rate of pregnancy complications such as ruptured uterus. Pathogenic mutations in the COL3A1 gene cause vEDS. (For more information on this disorder, choose “Ehlers-Danlos syndrome” as your search term on the Rare Disease Database.)Arterial tortuosity syndrome (ATS) is an extremely rare autosomal recessive connective tissue disorder caused by a mutation of the SLC2A10 gene. Arteries are fragile, twisting, and prone to tearing or narrowing. (For more information on this disorder, choose “arterial tortuosity syndrome” as your search term on the Rare Disease Database.)Autosomal recessive cutis laxa type 1 (EFEMP2-related cutis laxa) is an autosomal recessive connective tissue disorder characterized by widely spaced eyes, a high arched palate, arterial aneurysms and heart malformations. It is caused by different gene mutations than LDS and does not tend to cause a bifid uvula or skeletal malformations. (For more information on this disorder, choose “cutis laxa” as your search term on the Rare Disease Database.)
|
Related disorders of Loeys-Dietz Syndrome. Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with significant clinical overlap with LDS including aortic root aneurysm, pectus (chest wall) deformities, scoliosis and arachnodactyly. However, individuals with LDS more often have widely spaced eyes, cleft palate/bifid uvula, craniosynostosis and/or club feet. Individuals with LDS also have aneurysms more throughout the arterial tree, where those with MFS are most often at the root of the aorta. Individuals with MFS are more likely to have eye lens dislocations and heart valve problems. MFS is caused by pathogenic variants in the FBN1 gene. (For more information on this disorder, choose “Marfan syndrome” as your search term on the Rare Disease Database.Shprintzen-Goldberg syndrome (SGS) is caused by autosomal dominant pathogenic variants in the SKI gene, which also interrupts TGFβ activity, similar to LDS. Symptoms included skeletal and heart abnormalities along with intellectual disability. Intellectual disability is less often seen in LDS and the skeletal anomalies are usually more profound in SGS. (For more information on this disorder, choose “Shprintzen-Goldberg syndrome” as your search term on the Rare Disease Database.)Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant connective tissue disorder that is also associated with thin skin, aggressive arterial aneurysms, and an increased rate of pregnancy complications such as ruptured uterus. Pathogenic mutations in the COL3A1 gene cause vEDS. (For more information on this disorder, choose “Ehlers-Danlos syndrome” as your search term on the Rare Disease Database.)Arterial tortuosity syndrome (ATS) is an extremely rare autosomal recessive connective tissue disorder caused by a mutation of the SLC2A10 gene. Arteries are fragile, twisting, and prone to tearing or narrowing. (For more information on this disorder, choose “arterial tortuosity syndrome” as your search term on the Rare Disease Database.)Autosomal recessive cutis laxa type 1 (EFEMP2-related cutis laxa) is an autosomal recessive connective tissue disorder characterized by widely spaced eyes, a high arched palate, arterial aneurysms and heart malformations. It is caused by different gene mutations than LDS and does not tend to cause a bifid uvula or skeletal malformations. (For more information on this disorder, choose “cutis laxa” as your search term on the Rare Disease Database.)
| 731 |
Loeys-Dietz Syndrome
|
nord_731_5
|
Diagnosis of Loeys-Dietz Syndrome
|
The diagnosis of LDS is based on clinical suspicion and molecular confirmation through genetic testing to look for pathogenic variants in the causal genes: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB, and TGFB3. Genetic testing should be considered in patients with typical signs/symptoms described previously and in families with known histories of thoracic aortic aneurysms. Cleft palate/bifid uvula, widely spaced eyes, translucent skin, arthritis and/or arterial tortuosity or aneurysm should prompt a physician to consider testing for LDS. Prenatal diagnosis by genetic testing is possible for pregnancies at increased risk for LDS if the disease-causing variant in the family is already known.
|
Diagnosis of Loeys-Dietz Syndrome. The diagnosis of LDS is based on clinical suspicion and molecular confirmation through genetic testing to look for pathogenic variants in the causal genes: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB, and TGFB3. Genetic testing should be considered in patients with typical signs/symptoms described previously and in families with known histories of thoracic aortic aneurysms. Cleft palate/bifid uvula, widely spaced eyes, translucent skin, arthritis and/or arterial tortuosity or aneurysm should prompt a physician to consider testing for LDS. Prenatal diagnosis by genetic testing is possible for pregnancies at increased risk for LDS if the disease-causing variant in the family is already known.
| 731 |
Loeys-Dietz Syndrome
|
nord_731_6
|
Therapies of Loeys-Dietz Syndrome
|
There is no known cure for LDS, but there are treatments directed at specific symptoms. These treatments typically require a team of specialists including a geneticist, cardiologist, heart (cardiothoracic) and bone (orthopedic) surgeons, rheumatologist, among others.Most importantly, the goal of treatment is to screen and correct blood vessel weaknesses before they tear. The physician may prescribe a beta- or angiotensin receptor blocker such as losartan to slow down the ballooning/stretching of the aortic root. Every 6 months to 1 year, the individual should be screened for aneurysms of the entire arterial tree (from head to hips). This screening includes blood vessel imaging by CT angiography or MR angiography and heart imaging by echocardiography. If repeated imaging does not show any changes or concern for aneurysms, it may be acceptable to image less frequently. The doctors will be looking to see whether the aortic root balloons to larger than 4 cm (1.5 inches), at which point they may recommend a surgery to replace the ballooning section of the aorta and sometimes the aortic valve of the heart. This surgery is typically safe and effective in fixing the problem.To treat some of the musculoskeletal abnormalities associated with LDS, the care team may recommend nonsurgical management of the symptoms such as bracing or surgical correction of the abnormalities. These abnormalities include an abnormally curved spine (scoliosis), an indented or protruding chest, and issues with the bones of the neck. Doctors will recommend X-rays and CT scans to determine whether surgery should be performed. These surgeries can be complicated and require close attention for complications afterwards. Staying active and conditioned is recommended for individuals with LDS. Athletic goals and limits should be discussed with the cardiologist and the care team to determine an individualized health plan.
|
Therapies of Loeys-Dietz Syndrome. There is no known cure for LDS, but there are treatments directed at specific symptoms. These treatments typically require a team of specialists including a geneticist, cardiologist, heart (cardiothoracic) and bone (orthopedic) surgeons, rheumatologist, among others.Most importantly, the goal of treatment is to screen and correct blood vessel weaknesses before they tear. The physician may prescribe a beta- or angiotensin receptor blocker such as losartan to slow down the ballooning/stretching of the aortic root. Every 6 months to 1 year, the individual should be screened for aneurysms of the entire arterial tree (from head to hips). This screening includes blood vessel imaging by CT angiography or MR angiography and heart imaging by echocardiography. If repeated imaging does not show any changes or concern for aneurysms, it may be acceptable to image less frequently. The doctors will be looking to see whether the aortic root balloons to larger than 4 cm (1.5 inches), at which point they may recommend a surgery to replace the ballooning section of the aorta and sometimes the aortic valve of the heart. This surgery is typically safe and effective in fixing the problem.To treat some of the musculoskeletal abnormalities associated with LDS, the care team may recommend nonsurgical management of the symptoms such as bracing or surgical correction of the abnormalities. These abnormalities include an abnormally curved spine (scoliosis), an indented or protruding chest, and issues with the bones of the neck. Doctors will recommend X-rays and CT scans to determine whether surgery should be performed. These surgeries can be complicated and require close attention for complications afterwards. Staying active and conditioned is recommended for individuals with LDS. Athletic goals and limits should be discussed with the cardiologist and the care team to determine an individualized health plan.
| 731 |
Loeys-Dietz Syndrome
|
nord_732_0
|
Overview of Long QT Syndrome
|
Long QT syndrome (LQTS) is an autosomal dominant disorder, caused by abnormalities of the heart’s electrical conduction system, and is characterized on the electrocardiogram (a test that records the electrical activity of the heart) by prolongation of the QT interval that corresponds to prolongation of the recovery phase or repolarization of the heart muscle (ventricular myocardium) after each heartbeat. QT prolongation predisposes those affected to an increased risk of life threatening sudden alterations in the cardiac rhythm, (termed arrhythmias), specifically torsade de pointes (TdP) or ventricular fibrillation (VF). These arrhythmias can lead to sudden loss of consciousness (syncope), cardiac arrest and potentially cause sudden cardiac death. The severity of cardiac symptoms varies greatly from one person to another, even among family members who carry the same rare genetic variant. Some individuals may have no apparent symptoms (asymptomatic) for their entire lives, whilst others develop arrhythmias resulting in episodes of syncope, and cardiac arrest, at a young age. Several different factors are known to trigger the onset of symptoms including physical activity, excitement and fright, although cardiac events may occur while asleep or at rest.Long QT syndrome is caused by a disease-causing change (mutation) in one of at least 15 different genes that encode specific ion channels within the cardiomyocyte (heart muscle cell) membranes. These mutations are typically inherited in an autosomal dominant manner, although compound heterozygous (two mutations within one gene), digenic (mutations within two different genes) and homozygous (the same mutation in both copies of a single gene) alleles are all well recognized causes of Long QT syndrome. Individuals with more than one mutation typically have more severe symptoms than those with a single mutation.IntroductionIn 1957, Jervell and Lange-Nielsen described a Norwegian family with 4 of 6 siblings affected by sensorineural deafness, significant QT prolongation and recurrent syncope starting in early childhood, resulting in the sudden death of 3 of the children (1). Subsequent descriptions of an almost identical condition aside from normal hearing were made in 1963 by Romano (2) and 1964 by Ward (3), who described multiple individuals from two distinct families affected by recurrent ventricular fibrillation, a condition in which the heart’s normal electrical activity becomes disordered resulting in uncoordinated heartbeats and malfunction of the main pumping chambers of the heart (ventricles). Ventricular fibrillation can lead to loss of consciousness during exertion (exertional syncope) and sudden death. All cases were typified by marked QT prolongation of the surface ECG. These two previously eponymous syndromes (the dominantly inherited Romano Ward and the recessive Jervell Lange-Nielsen) are now recognized as a single clinical entity, long QT syndrome (LQTS)There are three major types of LTQS; namely LQTS 1, 2 and 3 which correspond to the first three genes and associated proteins (cardiac potassium and sodium channels) identified in the 1990s. Since then a number of other genes have been implicated, perhaps most notably those associated with calcium handling, although the three initial types remain the most prevalent and best characterized. Two syndromic LQT variants with varying extracardiac features, previously referred to as long QT 7 and long QT 8, are now referred to as Andersen-Tawil and Timothy syndromes respectively. NORD has individuals reports on these two disorders.
|
Overview of Long QT Syndrome. Long QT syndrome (LQTS) is an autosomal dominant disorder, caused by abnormalities of the heart’s electrical conduction system, and is characterized on the electrocardiogram (a test that records the electrical activity of the heart) by prolongation of the QT interval that corresponds to prolongation of the recovery phase or repolarization of the heart muscle (ventricular myocardium) after each heartbeat. QT prolongation predisposes those affected to an increased risk of life threatening sudden alterations in the cardiac rhythm, (termed arrhythmias), specifically torsade de pointes (TdP) or ventricular fibrillation (VF). These arrhythmias can lead to sudden loss of consciousness (syncope), cardiac arrest and potentially cause sudden cardiac death. The severity of cardiac symptoms varies greatly from one person to another, even among family members who carry the same rare genetic variant. Some individuals may have no apparent symptoms (asymptomatic) for their entire lives, whilst others develop arrhythmias resulting in episodes of syncope, and cardiac arrest, at a young age. Several different factors are known to trigger the onset of symptoms including physical activity, excitement and fright, although cardiac events may occur while asleep or at rest.Long QT syndrome is caused by a disease-causing change (mutation) in one of at least 15 different genes that encode specific ion channels within the cardiomyocyte (heart muscle cell) membranes. These mutations are typically inherited in an autosomal dominant manner, although compound heterozygous (two mutations within one gene), digenic (mutations within two different genes) and homozygous (the same mutation in both copies of a single gene) alleles are all well recognized causes of Long QT syndrome. Individuals with more than one mutation typically have more severe symptoms than those with a single mutation.IntroductionIn 1957, Jervell and Lange-Nielsen described a Norwegian family with 4 of 6 siblings affected by sensorineural deafness, significant QT prolongation and recurrent syncope starting in early childhood, resulting in the sudden death of 3 of the children (1). Subsequent descriptions of an almost identical condition aside from normal hearing were made in 1963 by Romano (2) and 1964 by Ward (3), who described multiple individuals from two distinct families affected by recurrent ventricular fibrillation, a condition in which the heart’s normal electrical activity becomes disordered resulting in uncoordinated heartbeats and malfunction of the main pumping chambers of the heart (ventricles). Ventricular fibrillation can lead to loss of consciousness during exertion (exertional syncope) and sudden death. All cases were typified by marked QT prolongation of the surface ECG. These two previously eponymous syndromes (the dominantly inherited Romano Ward and the recessive Jervell Lange-Nielsen) are now recognized as a single clinical entity, long QT syndrome (LQTS)There are three major types of LTQS; namely LQTS 1, 2 and 3 which correspond to the first three genes and associated proteins (cardiac potassium and sodium channels) identified in the 1990s. Since then a number of other genes have been implicated, perhaps most notably those associated with calcium handling, although the three initial types remain the most prevalent and best characterized. Two syndromic LQT variants with varying extracardiac features, previously referred to as long QT 7 and long QT 8, are now referred to as Andersen-Tawil and Timothy syndromes respectively. NORD has individuals reports on these two disorders.
| 732 |
Long QT Syndrome
|
nord_732_1
|
Symptoms of Long QT Syndrome
|
Symptoms, including syncope, can occur at any age from the newborn period to middle age, but most often appear during the pre-teen years through the 20s. Generally, the severity and frequency of episodes decreases during middle age and symptoms are less common after the age of 40 years. Approximately 50% of individuals, who have a mutation in one of the 15 genes that predispose to the disorder, ultimately develop symptoms; the others remain asymptomatic. Symptoms include palpitations, presyncope and syncope, all of which relate to the onset of a specific ventricular arrhythmia (tachycardia), torsade de pointes. This is usually self-limiting and will self-terminate in approximately 80% of cases, which explains the recurrent nature of symptoms. However, this may persist leading to ventricular fibrillation with associated cardiac arrest that is fatal unless the patient is treated with a defibrillator to restore normal sinus rhythm. Tragically the first manifestation of LQTS can be fatal. Symptoms, such as syncope, may occur without warning and recur unexpectedly. Exertion, excitement or stress may trigger these recurrent symptoms, although they often begin without any precipitating factors. Specific triggers are well recognized and are classically associated with specific subtypes. For example, exercise, especially swimming in LQTS1; exercise, emotional situations, and surprise or sudden noises, particularly when at rest (e.g. alarm clock or phone ringing), in LQTS2; and rest or sleep in LQTS3.Another important trigger for cardiac events is medication. A significant number of prescribed agents which can be found at (www.crediblemeds.org) can affect potassium channel function and thereby further prolong the QT interval. It is important to differentiate between medications unmasking LQTS and true drug-induced QT prolongation, although the latter may also have a genetic basis. Due to cerebral anoxia (i.e. lack of oxygen delivered to the brain during LQT associated arrhythmia), cardiac events may be mistaken for seizures. The misdiagnosis of LQTS as epilepsy is very well recognized. Therefore, patients with recurrent ‘seizures’ with normal neurological investigations and no response to anti-epileptic medication should have a comprehensive cardiac evaluation. Interestingly an overlap between LQTS and true epileptic seizures is recognized in a small proportion of patients with long QT2. The severity and frequency of cardiac events varies depending on numerous individual factors, but specifically the QT interval, age, sex and LQT type. Ultimately, the QT interval is the best assessment of risk, and patients with severe QT prolongation often present in early childhood with symptomatic arrhythmias. The risk of cardiac events differs between males and females. Males appear to be at greater risk during childhood through puberty, often associated with long QT1. Females with long QT2 have an increased risk relative to males after puberty, after childbirth (postpartum) and after the menopause. The hormonal influences on the QT interval and therefore effective risk are well described; testosterone is typically protective so the QT interval in males shortens post-puberty by 20 milliseconds, whereas in females the balance between estrogen and progesterone is important and thought to underlie the increased rate of events at specific times as detailed above.
|
Symptoms of Long QT Syndrome. Symptoms, including syncope, can occur at any age from the newborn period to middle age, but most often appear during the pre-teen years through the 20s. Generally, the severity and frequency of episodes decreases during middle age and symptoms are less common after the age of 40 years. Approximately 50% of individuals, who have a mutation in one of the 15 genes that predispose to the disorder, ultimately develop symptoms; the others remain asymptomatic. Symptoms include palpitations, presyncope and syncope, all of which relate to the onset of a specific ventricular arrhythmia (tachycardia), torsade de pointes. This is usually self-limiting and will self-terminate in approximately 80% of cases, which explains the recurrent nature of symptoms. However, this may persist leading to ventricular fibrillation with associated cardiac arrest that is fatal unless the patient is treated with a defibrillator to restore normal sinus rhythm. Tragically the first manifestation of LQTS can be fatal. Symptoms, such as syncope, may occur without warning and recur unexpectedly. Exertion, excitement or stress may trigger these recurrent symptoms, although they often begin without any precipitating factors. Specific triggers are well recognized and are classically associated with specific subtypes. For example, exercise, especially swimming in LQTS1; exercise, emotional situations, and surprise or sudden noises, particularly when at rest (e.g. alarm clock or phone ringing), in LQTS2; and rest or sleep in LQTS3.Another important trigger for cardiac events is medication. A significant number of prescribed agents which can be found at (www.crediblemeds.org) can affect potassium channel function and thereby further prolong the QT interval. It is important to differentiate between medications unmasking LQTS and true drug-induced QT prolongation, although the latter may also have a genetic basis. Due to cerebral anoxia (i.e. lack of oxygen delivered to the brain during LQT associated arrhythmia), cardiac events may be mistaken for seizures. The misdiagnosis of LQTS as epilepsy is very well recognized. Therefore, patients with recurrent ‘seizures’ with normal neurological investigations and no response to anti-epileptic medication should have a comprehensive cardiac evaluation. Interestingly an overlap between LQTS and true epileptic seizures is recognized in a small proportion of patients with long QT2. The severity and frequency of cardiac events varies depending on numerous individual factors, but specifically the QT interval, age, sex and LQT type. Ultimately, the QT interval is the best assessment of risk, and patients with severe QT prolongation often present in early childhood with symptomatic arrhythmias. The risk of cardiac events differs between males and females. Males appear to be at greater risk during childhood through puberty, often associated with long QT1. Females with long QT2 have an increased risk relative to males after puberty, after childbirth (postpartum) and after the menopause. The hormonal influences on the QT interval and therefore effective risk are well described; testosterone is typically protective so the QT interval in males shortens post-puberty by 20 milliseconds, whereas in females the balance between estrogen and progesterone is important and thought to underlie the increased rate of events at specific times as detailed above.
| 732 |
Long QT Syndrome
|
nord_732_2
|
Causes of Long QT Syndrome
|
Genetics of LQTS
Long QT syndrome is caused by a disease-causing change (mutation) in the coding sequence in one of several different genes known to be associated with the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the encoded protein product may be faulty, inefficient, absent, or overactive. Depending upon the functions of the particular protein, this can affect many organ systems of the body.Long QT syndrome has been shown to be caused by mutations in one of at least 15 different ion-channel genes: the KCNQ1 gene causing LQTS1; KCNH2 causing LQT2; SCN5A causing LQT3; ANK2 causing LQTS4; KCNE1 causing LQTS5; KCNE2 causing LQT6; KCNJ2 causing LQTS7; CACNA1c causing LQTS8; CAV3 causing LQTS9; SCN4B causing LQTS10; AKAB9 causing LQTS11; SNTA1 causing LQTS12; KCNJ5 causing LQTS13; CALM1 causing LQTS14; and CALM2 causing LQTS15. Mutations in KCNQ1, KCNH2, and SCN5A correlate to Long QT types 1-3 and account for the majority (60-75%) of genetically identifiable cases. Humans inherit two copies of every gene, one from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the presentation of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo) in the affected individual. The chance of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy regardless of the sex of the child.Rarely, the mutations that cause Long QT syndrome may occur sporadically (de novo), which means that in those specific cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Typically, the mutation is inherited from or “carried” by a parent. Long QT syndrome also shows variable expressivity and incomplete penetrance. In autosomal dominant disorders this means that manifestations of the disorder may not be present in all those who inherit the same altered gene for the disease. In those who develop symptoms, the specific characteristics that develop may vary greatly in range and severity from one person to another. Several different factors may account for this variability including multiple environmental and genetic factors (e.g. modifier genes). Other factors that have been speculated to impact disease severity and expression include hormonal aspects, behavioral components, and normal variation with the nerves that serve the heart (the heart’s innervation), the autonomic nervous system. This system controls the involuntary actions of the body including regulating the heartbeat. Approximately 20%-40% of families with a diagnosis of Long QT syndrome do not have a mutation in one of the above 15 genes, suggesting that additional as-yet-unidentified genes can also cause the disorder. More research is necessary to identify the specific genes involved in these cases. In those with an identifiable genetic variant, the first two types of Long QT syndrome, LQTS1 (KCNQ1) and LQTS2 (KCNH2), account for approximately 75%-80% of cases, whereas LQTS3 (SCN5A) accounts for approximately 10% of cases. The remaining known genes account for less than 5% of cases and some of these variants have only been described in a few individuals. Molecular biology of LQTS
The genes associated with Long QT syndrome produce (encode) proteins, which are major components of the cardiac ion channels of the heart, specifically potassium, sodium and calcium, but also scaffolding proteins that ensure normal channel function (e.g. ankyrin-B). Ion channels, which are pores in cell membranes, regulate the movement of electrically-charged particles called ions (e.g. potassium and sodium) through the membrane and these are ultimately responsible for cardiac activation (depolarization) and relaxation (repolarization). Mutations in these genes result in abnormal functioning of the ion channels and, in turn, affect the proper function of the heart’s electrical system leading to either continued depolarization or delayed repolarization, the net effect of which is to prolong the cardiac cell action potential and QT interval on the ECG.
|
Causes of Long QT Syndrome. Genetics of LQTS
Long QT syndrome is caused by a disease-causing change (mutation) in the coding sequence in one of several different genes known to be associated with the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the encoded protein product may be faulty, inefficient, absent, or overactive. Depending upon the functions of the particular protein, this can affect many organ systems of the body.Long QT syndrome has been shown to be caused by mutations in one of at least 15 different ion-channel genes: the KCNQ1 gene causing LQTS1; KCNH2 causing LQT2; SCN5A causing LQT3; ANK2 causing LQTS4; KCNE1 causing LQTS5; KCNE2 causing LQT6; KCNJ2 causing LQTS7; CACNA1c causing LQTS8; CAV3 causing LQTS9; SCN4B causing LQTS10; AKAB9 causing LQTS11; SNTA1 causing LQTS12; KCNJ5 causing LQTS13; CALM1 causing LQTS14; and CALM2 causing LQTS15. Mutations in KCNQ1, KCNH2, and SCN5A correlate to Long QT types 1-3 and account for the majority (60-75%) of genetically identifiable cases. Humans inherit two copies of every gene, one from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the presentation of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo) in the affected individual. The chance of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy regardless of the sex of the child.Rarely, the mutations that cause Long QT syndrome may occur sporadically (de novo), which means that in those specific cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Typically, the mutation is inherited from or “carried” by a parent. Long QT syndrome also shows variable expressivity and incomplete penetrance. In autosomal dominant disorders this means that manifestations of the disorder may not be present in all those who inherit the same altered gene for the disease. In those who develop symptoms, the specific characteristics that develop may vary greatly in range and severity from one person to another. Several different factors may account for this variability including multiple environmental and genetic factors (e.g. modifier genes). Other factors that have been speculated to impact disease severity and expression include hormonal aspects, behavioral components, and normal variation with the nerves that serve the heart (the heart’s innervation), the autonomic nervous system. This system controls the involuntary actions of the body including regulating the heartbeat. Approximately 20%-40% of families with a diagnosis of Long QT syndrome do not have a mutation in one of the above 15 genes, suggesting that additional as-yet-unidentified genes can also cause the disorder. More research is necessary to identify the specific genes involved in these cases. In those with an identifiable genetic variant, the first two types of Long QT syndrome, LQTS1 (KCNQ1) and LQTS2 (KCNH2), account for approximately 75%-80% of cases, whereas LQTS3 (SCN5A) accounts for approximately 10% of cases. The remaining known genes account for less than 5% of cases and some of these variants have only been described in a few individuals. Molecular biology of LQTS
The genes associated with Long QT syndrome produce (encode) proteins, which are major components of the cardiac ion channels of the heart, specifically potassium, sodium and calcium, but also scaffolding proteins that ensure normal channel function (e.g. ankyrin-B). Ion channels, which are pores in cell membranes, regulate the movement of electrically-charged particles called ions (e.g. potassium and sodium) through the membrane and these are ultimately responsible for cardiac activation (depolarization) and relaxation (repolarization). Mutations in these genes result in abnormal functioning of the ion channels and, in turn, affect the proper function of the heart’s electrical system leading to either continued depolarization or delayed repolarization, the net effect of which is to prolong the cardiac cell action potential and QT interval on the ECG.
| 732 |
Long QT Syndrome
|
nord_732_3
|
Affects of Long QT Syndrome
|
Long QT syndrome affects males and females in equal numbers and has been identified in all ethnic groups. The exact incidence and prevalence of the disorder is not known. It is estimated to occur in approximately 1 in 2,000 live births from a clinical and genetic study of 44,500 newborns (neonates).
|
Affects of Long QT Syndrome. Long QT syndrome affects males and females in equal numbers and has been identified in all ethnic groups. The exact incidence and prevalence of the disorder is not known. It is estimated to occur in approximately 1 in 2,000 live births from a clinical and genetic study of 44,500 newborns (neonates).
| 732 |
Long QT Syndrome
|
nord_732_4
|
Related disorders of Long QT Syndrome
|
The symptoms of LQTS can overlap with many other conditions. As mentioned already, many cases of Long QT syndrome are still misdiagnosed as epilepsy. Vasovagal (neurocardiogenic) syncope is very common in teenage life and patients may have transient changes in the QT interval. Other conditions that may lead to syncope are hypertrophic and arrhythmogenic cardiomyopathies, and importantly structural heart disease can lead to abnormal repolarization and QT prolongation. Perhaps most important in cases of exertional syncope is exclusion of catecholaminergic polymorphic ventricular tachycardia (CPVT) a malignant disorder associated with ventricular arrhythmias during exercise and emotion (i.e. catecholaminergic states) in the setting of a normal resting ECG and structurally normal heart. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Brugada syndrome is a rare inherited heart disorder characterized by abnormalities of the heart’s electrical system. The symptoms vary greatly from case to case. Some affected individuals will experience no apparent symptoms (asymptomatic); others may develop irregular heartbeats leading to episodes of unconsciousness (syncope), cardiac arrest, and, potentially, sudden death often during sleep. Brugada syndrome is inherited as an autosomal dominant trait and is caused by mutations in the SCN5A gene, the same gene that causes LQTS3 (allelic disorders). (For more information, choose “Brugada” as your search term in the Rare Disease Database.)
|
Related disorders of Long QT Syndrome. The symptoms of LQTS can overlap with many other conditions. As mentioned already, many cases of Long QT syndrome are still misdiagnosed as epilepsy. Vasovagal (neurocardiogenic) syncope is very common in teenage life and patients may have transient changes in the QT interval. Other conditions that may lead to syncope are hypertrophic and arrhythmogenic cardiomyopathies, and importantly structural heart disease can lead to abnormal repolarization and QT prolongation. Perhaps most important in cases of exertional syncope is exclusion of catecholaminergic polymorphic ventricular tachycardia (CPVT) a malignant disorder associated with ventricular arrhythmias during exercise and emotion (i.e. catecholaminergic states) in the setting of a normal resting ECG and structurally normal heart. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Brugada syndrome is a rare inherited heart disorder characterized by abnormalities of the heart’s electrical system. The symptoms vary greatly from case to case. Some affected individuals will experience no apparent symptoms (asymptomatic); others may develop irregular heartbeats leading to episodes of unconsciousness (syncope), cardiac arrest, and, potentially, sudden death often during sleep. Brugada syndrome is inherited as an autosomal dominant trait and is caused by mutations in the SCN5A gene, the same gene that causes LQTS3 (allelic disorders). (For more information, choose “Brugada” as your search term in the Rare Disease Database.)
| 732 |
Long QT Syndrome
|
nord_732_5
|
Diagnosis of Long QT Syndrome
|
The diagnosis of long QT syndrome is a clinical one, based upon a thorough evaluation, a detailed patient and family history and a specialized test called an electrocardiogram (ECG or EKG). Individuals with unexplained history of fainting, syncope, atypical epilepsy or sudden cardiac arrest should be evaluated for Long QT syndrome. An ECG records electrical activity of the heart and may reveal abnormal electrical patterns. The ECG may be abnormal at rest, both in terms of QT interval prolongation and T-wave morphology (shape). As the penetrance of LQTS is low, many patients may have a relatively normal ECG at rest but the QT interval and morphological changes can be brought out either by standing or during the recovery period from exercise. Molecular genetic testing can support a diagnosis of Long QT syndrome in many cases, although genetic testing is a probabilistic not deterministic outcome (it can indicate a predisposition of long QT syndrome, not whether a person will develop the condition and associated symptoms) and any identified genetic variant needs to be carefully interpreted in the context of a wider familial evaluation and correlated with clinical findings.
|
Diagnosis of Long QT Syndrome. The diagnosis of long QT syndrome is a clinical one, based upon a thorough evaluation, a detailed patient and family history and a specialized test called an electrocardiogram (ECG or EKG). Individuals with unexplained history of fainting, syncope, atypical epilepsy or sudden cardiac arrest should be evaluated for Long QT syndrome. An ECG records electrical activity of the heart and may reveal abnormal electrical patterns. The ECG may be abnormal at rest, both in terms of QT interval prolongation and T-wave morphology (shape). As the penetrance of LQTS is low, many patients may have a relatively normal ECG at rest but the QT interval and morphological changes can be brought out either by standing or during the recovery period from exercise. Molecular genetic testing can support a diagnosis of Long QT syndrome in many cases, although genetic testing is a probabilistic not deterministic outcome (it can indicate a predisposition of long QT syndrome, not whether a person will develop the condition and associated symptoms) and any identified genetic variant needs to be carefully interpreted in the context of a wider familial evaluation and correlated with clinical findings.
| 732 |
Long QT Syndrome
|
nord_732_6
|
Therapies of Long QT Syndrome
|
Treatment is aimed at preventing symptoms such as syncope or cardiac arrest. Specific medications, avoidance of triggering events and QT prolonging medication, and certain medical devices may all be used to treat individuals with Long QT syndrome. Genetic counseling is of great benefit for affected individuals and their families to understand implications for family members, recurrence risk, family planning options, and psychological adjustment to disease and/or carrier status. The treatment of choice for most affected individuals is drug therapy with beta-adrenergic blocking agents (beta blockers). Beta blockers prevent adrenergic stimulation of the heart via the beta-receptors and can be highly effective in treating long QT syndrome. Nadolol and propranolol are longer acting beta-blockers and the agents of choice in managing the condition. Even though many patients now diagnosed are asymptomatic due to better awareness of the condition and more effective family cascade testing (i.e. identifying family members who are at risk of also having long QT syndrome), beta-blockers are still recommended if any evidence of the condition can be elicited either at rest or with provocation such as exercise stress tests. Beta blockers need to be taken daily and the failure to do so (noncompliance) by affected individuals can lead to the development of symptoms including sudden death. Individuals for whom beta blockers are unsuccessful or contraindicated may be treated by a surgical procedure in which the autonomic nerves supplying the heart are interrupted (left cardiac sympathetic denervation or sympathectomy). The autonomic nerves release catecholamines which stimulate the heart via the beta-receptors, so this can be considered another form of anti-adrenergic therapy. The heart rhythm is controlled by the sympathetic nervous system, which controls many of the involuntary actions of the body. These nerves work to regulate the heart rhythm and this procedure can significantly reduce the frequency of arrhythmic events. During the procedure, a small cut (incision) is made in the chest wall and specific autonomic nerves supplying the heart are cut. Left cardiac sympathetic denervation is usually reserved for individuals who are considered high risk, develop symptoms despite beta blocker therapy, or are contraindicated to or cannot tolerate beta blocker therapy. For affected individuals who have been resuscitated from cardiac arrest (whether on or off beta blockers), treatment with an implantable automatic cardioverter-defibrillator or ICD should be considered. These small devices are implanted under the skin of the chest, and wires are passed down into the heart to monitor the heart rhythm on a beat by beat basis. The device detects episodes of torsades de pointes automatically and delivers an electrical shock to restore normal cardiac rhythm. ICDs are also considered for individuals who experience recurrent syncopal events despite therapy with beta blockers. ICDs do not prevent the occurrence of torsade de pointes and, therefore, are used in conjunction with beta blockers and/or cardiac sympathectomy. An ICD is a therapy that carries significant medical and psychological complications, especially in younger individuals, and should be undertaken only after detailed consultation with appropriate medical personnel experienced in the management of LQTS and a careful consideration of the risks and benefits. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as specific subtype; effectiveness of medications; an individual’s previous history, age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the healthcare team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Some individuals with long QT syndrome are encouraged to avoid potential triggering events such as jumping into cold water or amusement park rides. Individuals with Long QT syndrome who wish to participate in competitive sports should be referred to a clinical expert for evaluation of risk. Affected individuals need to avoid drugs that prolong the QT interval, a full list of such drugs can be found at www.crediblemeds.org.
|
Therapies of Long QT Syndrome. Treatment is aimed at preventing symptoms such as syncope or cardiac arrest. Specific medications, avoidance of triggering events and QT prolonging medication, and certain medical devices may all be used to treat individuals with Long QT syndrome. Genetic counseling is of great benefit for affected individuals and their families to understand implications for family members, recurrence risk, family planning options, and psychological adjustment to disease and/or carrier status. The treatment of choice for most affected individuals is drug therapy with beta-adrenergic blocking agents (beta blockers). Beta blockers prevent adrenergic stimulation of the heart via the beta-receptors and can be highly effective in treating long QT syndrome. Nadolol and propranolol are longer acting beta-blockers and the agents of choice in managing the condition. Even though many patients now diagnosed are asymptomatic due to better awareness of the condition and more effective family cascade testing (i.e. identifying family members who are at risk of also having long QT syndrome), beta-blockers are still recommended if any evidence of the condition can be elicited either at rest or with provocation such as exercise stress tests. Beta blockers need to be taken daily and the failure to do so (noncompliance) by affected individuals can lead to the development of symptoms including sudden death. Individuals for whom beta blockers are unsuccessful or contraindicated may be treated by a surgical procedure in which the autonomic nerves supplying the heart are interrupted (left cardiac sympathetic denervation or sympathectomy). The autonomic nerves release catecholamines which stimulate the heart via the beta-receptors, so this can be considered another form of anti-adrenergic therapy. The heart rhythm is controlled by the sympathetic nervous system, which controls many of the involuntary actions of the body. These nerves work to regulate the heart rhythm and this procedure can significantly reduce the frequency of arrhythmic events. During the procedure, a small cut (incision) is made in the chest wall and specific autonomic nerves supplying the heart are cut. Left cardiac sympathetic denervation is usually reserved for individuals who are considered high risk, develop symptoms despite beta blocker therapy, or are contraindicated to or cannot tolerate beta blocker therapy. For affected individuals who have been resuscitated from cardiac arrest (whether on or off beta blockers), treatment with an implantable automatic cardioverter-defibrillator or ICD should be considered. These small devices are implanted under the skin of the chest, and wires are passed down into the heart to monitor the heart rhythm on a beat by beat basis. The device detects episodes of torsades de pointes automatically and delivers an electrical shock to restore normal cardiac rhythm. ICDs are also considered for individuals who experience recurrent syncopal events despite therapy with beta blockers. ICDs do not prevent the occurrence of torsade de pointes and, therefore, are used in conjunction with beta blockers and/or cardiac sympathectomy. An ICD is a therapy that carries significant medical and psychological complications, especially in younger individuals, and should be undertaken only after detailed consultation with appropriate medical personnel experienced in the management of LQTS and a careful consideration of the risks and benefits. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as specific subtype; effectiveness of medications; an individual’s previous history, age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the healthcare team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Some individuals with long QT syndrome are encouraged to avoid potential triggering events such as jumping into cold water or amusement park rides. Individuals with Long QT syndrome who wish to participate in competitive sports should be referred to a clinical expert for evaluation of risk. Affected individuals need to avoid drugs that prolong the QT interval, a full list of such drugs can be found at www.crediblemeds.org.
| 732 |
Long QT Syndrome
|
nord_733_0
|
Overview of Low Gamma-GT Familial Intrahepatic Cholestasis
|
Low gamma-GT (GGT) familial intrahepatic cholestasis refers to a spectrum of disease, ranging from mild to severe cases. This spectrum of disease predominantly affects the liver. Advancements in understanding of bile transport physiology have led to the discovery of a variety of protein defects whose dysfunction leads to low GGT familial intrahepatic cholestasis. Children with defects in bile acid synthesis or conjugation, children with abnormalities of cell organization manifest as arthrogryposis-renal dysfunction-cholestasis syndrome, and children with “neonatal hemochromatosis” all may have low GGT familial intrahepatic cholestasis. These disorders are not covered in this report.This report primarily covers the two severe forms of low GGT familial intrahepatic cholestasis that have been classically described (PFIC1 aka FIC1 deficiency; and PFIC2 aka BSEP deficiency). Two milder forms, known as benign recurrent intrahepatic cholestasis (BRIC) 1 and 2 are also described. These less severe diseases result from defects in the same proteins which cause PFIC 1 and 2. Thus PFIC and BRIC lie at different ends of a spectrum of disease with common genetic basis. Newer forms of genetic based disorders which manifest as low GGT cholestasis (PFIC 4-6) will be presented in less detail given the relatively few patients known to be affected by these disorders. Some persons with low GGT familial intrahepatic cholestasis cannot be shown to have any of the disorders mentioned in this report. The search continues for causes for these persons' illness or illnesses.The main symptom of this spectrum of disease is interruption or suppression of the flow of bile from the liver (cholestasis). Cholestasis in these disorders occurs due to defects within the liver (intrahepatic) rather than within the bile ducts outside the liver (extrahepatic). Features of cholestasis may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, easy bleeding, rickets, and persistent, severe itchiness (pruritus). In many cases, symptoms or signs are present at birth or during the newborn period. The more severe forms of these disorders eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure.PFIC1 and BRIC1 are caused by mutations in a gene named ATP8B1. ATP8B1 encodes a protein named familial intrahepatic cholestasis 1 (FIC1). PFIC2 and BRIC2 are caused by mutations in a gene named ABCB11. ABCB11 encodes a protein named bile salt export pump (BSEP). Recently, additional proteins have been identified in whom mutations result in a phenotypic pattern that is similar to PFIC 1 and 2, mainly cholestasis presenting in the neonatal period. PFIC4 stems from loss of function mutations in TJP2 encoding the tight junction protein TJP2. PFIC5 results from mutations in NR1H4, which encodes the farnesoid X receptor (FXR), the nuclear receptor transcription factor which regulates BSEP expression. PFIC6 results in defects in MYO5B, on which BSEP depends to localize to the appropriate location within the cell. All forms of PFIC are inherited in an autosomal recessive pattern. Some affected individuals do not have mutations in any of these genes, suggesting that additional, as of yet unidentified, forms of these disorders may exist.These disorders have normal or low serum levels of an enzyme known as gamma-glutamyl transferase (GGT) and, therefore, may be collectively known as low GGT familial intrahepatic cholestasis. Most children with severe cholestasis have elevated levels of this enzyme, enabling physicians to distinguish these disorders from other causes of cholestasis.Researchers have also identified a disorder known as PFIC type 3 or multidrug resistance protein 3 (MDR3) deficiency. Although this disorder is often grouped with PFIC disorders, it is associated with high levels of GGT enzyme activity and the underlying defects causing this disorder are different. MDR3 deficiency is not covered in this report.The classification of these disorders is complicated and has continually changed as more about these disorders has become known. Various names have been used for these disorders such as FIC1 deficiency and Byler’s Syndrome for PFIC1; and BSEP deficiency and Byler’s disease for PFIC2, adding to the confusion. The classification and grouping of these disorders may undergo further changes in the future as more becomes known about the genetic underpinnings driving disease development.
|
Overview of Low Gamma-GT Familial Intrahepatic Cholestasis. Low gamma-GT (GGT) familial intrahepatic cholestasis refers to a spectrum of disease, ranging from mild to severe cases. This spectrum of disease predominantly affects the liver. Advancements in understanding of bile transport physiology have led to the discovery of a variety of protein defects whose dysfunction leads to low GGT familial intrahepatic cholestasis. Children with defects in bile acid synthesis or conjugation, children with abnormalities of cell organization manifest as arthrogryposis-renal dysfunction-cholestasis syndrome, and children with “neonatal hemochromatosis” all may have low GGT familial intrahepatic cholestasis. These disorders are not covered in this report.This report primarily covers the two severe forms of low GGT familial intrahepatic cholestasis that have been classically described (PFIC1 aka FIC1 deficiency; and PFIC2 aka BSEP deficiency). Two milder forms, known as benign recurrent intrahepatic cholestasis (BRIC) 1 and 2 are also described. These less severe diseases result from defects in the same proteins which cause PFIC 1 and 2. Thus PFIC and BRIC lie at different ends of a spectrum of disease with common genetic basis. Newer forms of genetic based disorders which manifest as low GGT cholestasis (PFIC 4-6) will be presented in less detail given the relatively few patients known to be affected by these disorders. Some persons with low GGT familial intrahepatic cholestasis cannot be shown to have any of the disorders mentioned in this report. The search continues for causes for these persons' illness or illnesses.The main symptom of this spectrum of disease is interruption or suppression of the flow of bile from the liver (cholestasis). Cholestasis in these disorders occurs due to defects within the liver (intrahepatic) rather than within the bile ducts outside the liver (extrahepatic). Features of cholestasis may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, easy bleeding, rickets, and persistent, severe itchiness (pruritus). In many cases, symptoms or signs are present at birth or during the newborn period. The more severe forms of these disorders eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure.PFIC1 and BRIC1 are caused by mutations in a gene named ATP8B1. ATP8B1 encodes a protein named familial intrahepatic cholestasis 1 (FIC1). PFIC2 and BRIC2 are caused by mutations in a gene named ABCB11. ABCB11 encodes a protein named bile salt export pump (BSEP). Recently, additional proteins have been identified in whom mutations result in a phenotypic pattern that is similar to PFIC 1 and 2, mainly cholestasis presenting in the neonatal period. PFIC4 stems from loss of function mutations in TJP2 encoding the tight junction protein TJP2. PFIC5 results from mutations in NR1H4, which encodes the farnesoid X receptor (FXR), the nuclear receptor transcription factor which regulates BSEP expression. PFIC6 results in defects in MYO5B, on which BSEP depends to localize to the appropriate location within the cell. All forms of PFIC are inherited in an autosomal recessive pattern. Some affected individuals do not have mutations in any of these genes, suggesting that additional, as of yet unidentified, forms of these disorders may exist.These disorders have normal or low serum levels of an enzyme known as gamma-glutamyl transferase (GGT) and, therefore, may be collectively known as low GGT familial intrahepatic cholestasis. Most children with severe cholestasis have elevated levels of this enzyme, enabling physicians to distinguish these disorders from other causes of cholestasis.Researchers have also identified a disorder known as PFIC type 3 or multidrug resistance protein 3 (MDR3) deficiency. Although this disorder is often grouped with PFIC disorders, it is associated with high levels of GGT enzyme activity and the underlying defects causing this disorder are different. MDR3 deficiency is not covered in this report.The classification of these disorders is complicated and has continually changed as more about these disorders has become known. Various names have been used for these disorders such as FIC1 deficiency and Byler’s Syndrome for PFIC1; and BSEP deficiency and Byler’s disease for PFIC2, adding to the confusion. The classification and grouping of these disorders may undergo further changes in the future as more becomes known about the genetic underpinnings driving disease development.
| 733 |
Low Gamma-GT Familial Intrahepatic Cholestasis
|
nord_733_1
|
Symptoms of Low Gamma-GT Familial Intrahepatic Cholestasis
|
The age of onset, severity and specific symptoms of low GGT familial intrahepatic cholestasis may vary from one individual to another, even among members of the same family. Although these disorders are generally described as being either mild or severe, cases have been identified that appear to fall in between these extremes (intermediate types), leading researchers to classify these disorders as a spectrum of disease. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS
The symptoms of PFIC types 1 and 2 are extremely similar. Symptoms are often present at birth or during the first few months of life (congenital). Progression may vary dramatically. Some individuals may develop severe symptoms early during infancy; others may not develop symptoms until later in childhood.The major finding associated with all forms of PFIC is interruption or suppression of the flow of bile from the liver (cholestasis). This interruption or suppression usually begins during the first few months of life. Affected infants have episodes of cholestasis followed by disease-free periods. However, eventually cholestasis progresses to become a persistent condition.The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.The initial symptoms associated with PFIC may be foul smelling, greasy stools or watery diarrhea, which are often present at birth (congenital). Affected infants may also experience intense, often persistent, itching (pruritus). Itching can cause irritability and skin abrasions due to constant scratching. Itching can be resistant to treatment and have tremendously adverse effects on children and their families. Itching may occur with or without excessive bilirubin in the body (hyperbilirubinemia), resulting in yellowing of the skin, mucous membranes and whites of the eyes (jaundice). Initially, jaundice may come and go, but eventually it may continually persist. Additional symptoms common to liver disease such as an abnormally large liver and spleen (hepatosplenomegaly) may also occur.Another common finding associated with PFIC is impairment of the ability of the digestive system properly to absorb fat, vitamins and other nutrients (malabsorption). Malabsorption leads to vitamin deficiency and eventually results in failure to thrive, growth deficiency, bleeding episodes such as repeated nosebleeds, an abnormal susceptibility to bruising, and rickets. Rickets is a bone disorder with characteristic growth plate abnormalities and progressive softening of the bone structure. As a result, many children may be small for their age (short stature).PFIC types 1 and 2 eventually progress to cause serious life-threatening complications including the formation of fibrous tissue (fibrosis) and liver regeneration with scarring (cirrhosis) in the liver, eventually resulting in liver failure. Without intervention, these complications may develop by the end of the first decade of life.Additional symptoms have been reported in some cases including repeated infections, hearing impairment due to abnormalities of the inner ear (sensorineural deafness), profound diarrhea, and pancreatitis. These extrahepatic, or outside the liver, manifestations of disease are more commonly reported in individuals with PFIC1 as the FIC1 protein is expressed in many tissues throughout the body. This is in contrast to BSEP protein which is exclusive to the liver cell. Notably, the extrahepatic manifestations of PFIC1 can persist, or even worsen after liver transplant. In addition, PFIC1 after liver transplant may be associated with abnormal fat accumulation and associated inflammation within the liver (steatohepatitis). PFIC2 after liver transplant sometimes returns; this has been traced to formation of antibodies against BSEP that block BSEP function.BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS
The milder forms of low GGT familial intrahepatic cholestasis are known as benign recurrent intrahepatic cholestasis (BRIC) types 1 and 2. Onset of BRIC can be at any age, but in most cases occurs during the first decade.
Affected individuals have prolonged recurrent attacks of cholestasis lasting from a few weeks to several months. The stimulus that brings on an attack is usually unclear. Generally, cholestasis associated with BRIC types 1 and 2 is self-limiting and not progressive. Chronic liver damage does not develop. Months or years may separate attacks of cholestasis. Symptoms usually begin in childhood or adolescence and may occur with regularity. Attacks typically begin with tiredness, weakness, and loss of appetite. Intense itchiness and yellowing of the skin, mucous membranes and whites of the eye may follow. The liver may be enlarged. Excessive fat in the feces and unintended weight loss may also occur. Affected individuals may experience impaired absorption of essential vitamins and nutrients in the digestive system (malabsorption). Hearing loss may occur in patients with BRIC1. In some cases, individuals with mild symptoms during childhood (BRIC) may develop more serious complications as an adult, with their condition being better classified as PFIC.INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Some females with mutations in the genes that cause low GGT familial intrahepatic cholestasis may develop a condition known as intrahepatic cholestasis of pregnancy (ICP). This condition is characterized by cholestasis, itching and, in some cases, jaundice that develops during pregnancy, usually during the third trimester. The symptoms resolve without treatment (spontaneously) after the pregnancy (postpartum). Generally, females who develop ICP do not exhibit symptoms before pregnancy and do not develop chronic liver damage. Some females with ICP also are sensitive to hormonal contraceptive agents. Contraceptive-associated intrahepatic cholestasis and ICP can be viewed as forms of BRIC in which the stimulus to an attack is known.
|
Symptoms of Low Gamma-GT Familial Intrahepatic Cholestasis. The age of onset, severity and specific symptoms of low GGT familial intrahepatic cholestasis may vary from one individual to another, even among members of the same family. Although these disorders are generally described as being either mild or severe, cases have been identified that appear to fall in between these extremes (intermediate types), leading researchers to classify these disorders as a spectrum of disease. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS
The symptoms of PFIC types 1 and 2 are extremely similar. Symptoms are often present at birth or during the first few months of life (congenital). Progression may vary dramatically. Some individuals may develop severe symptoms early during infancy; others may not develop symptoms until later in childhood.The major finding associated with all forms of PFIC is interruption or suppression of the flow of bile from the liver (cholestasis). This interruption or suppression usually begins during the first few months of life. Affected infants have episodes of cholestasis followed by disease-free periods. However, eventually cholestasis progresses to become a persistent condition.The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.The initial symptoms associated with PFIC may be foul smelling, greasy stools or watery diarrhea, which are often present at birth (congenital). Affected infants may also experience intense, often persistent, itching (pruritus). Itching can cause irritability and skin abrasions due to constant scratching. Itching can be resistant to treatment and have tremendously adverse effects on children and their families. Itching may occur with or without excessive bilirubin in the body (hyperbilirubinemia), resulting in yellowing of the skin, mucous membranes and whites of the eyes (jaundice). Initially, jaundice may come and go, but eventually it may continually persist. Additional symptoms common to liver disease such as an abnormally large liver and spleen (hepatosplenomegaly) may also occur.Another common finding associated with PFIC is impairment of the ability of the digestive system properly to absorb fat, vitamins and other nutrients (malabsorption). Malabsorption leads to vitamin deficiency and eventually results in failure to thrive, growth deficiency, bleeding episodes such as repeated nosebleeds, an abnormal susceptibility to bruising, and rickets. Rickets is a bone disorder with characteristic growth plate abnormalities and progressive softening of the bone structure. As a result, many children may be small for their age (short stature).PFIC types 1 and 2 eventually progress to cause serious life-threatening complications including the formation of fibrous tissue (fibrosis) and liver regeneration with scarring (cirrhosis) in the liver, eventually resulting in liver failure. Without intervention, these complications may develop by the end of the first decade of life.Additional symptoms have been reported in some cases including repeated infections, hearing impairment due to abnormalities of the inner ear (sensorineural deafness), profound diarrhea, and pancreatitis. These extrahepatic, or outside the liver, manifestations of disease are more commonly reported in individuals with PFIC1 as the FIC1 protein is expressed in many tissues throughout the body. This is in contrast to BSEP protein which is exclusive to the liver cell. Notably, the extrahepatic manifestations of PFIC1 can persist, or even worsen after liver transplant. In addition, PFIC1 after liver transplant may be associated with abnormal fat accumulation and associated inflammation within the liver (steatohepatitis). PFIC2 after liver transplant sometimes returns; this has been traced to formation of antibodies against BSEP that block BSEP function.BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS
The milder forms of low GGT familial intrahepatic cholestasis are known as benign recurrent intrahepatic cholestasis (BRIC) types 1 and 2. Onset of BRIC can be at any age, but in most cases occurs during the first decade.
Affected individuals have prolonged recurrent attacks of cholestasis lasting from a few weeks to several months. The stimulus that brings on an attack is usually unclear. Generally, cholestasis associated with BRIC types 1 and 2 is self-limiting and not progressive. Chronic liver damage does not develop. Months or years may separate attacks of cholestasis. Symptoms usually begin in childhood or adolescence and may occur with regularity. Attacks typically begin with tiredness, weakness, and loss of appetite. Intense itchiness and yellowing of the skin, mucous membranes and whites of the eye may follow. The liver may be enlarged. Excessive fat in the feces and unintended weight loss may also occur. Affected individuals may experience impaired absorption of essential vitamins and nutrients in the digestive system (malabsorption). Hearing loss may occur in patients with BRIC1. In some cases, individuals with mild symptoms during childhood (BRIC) may develop more serious complications as an adult, with their condition being better classified as PFIC.INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Some females with mutations in the genes that cause low GGT familial intrahepatic cholestasis may develop a condition known as intrahepatic cholestasis of pregnancy (ICP). This condition is characterized by cholestasis, itching and, in some cases, jaundice that develops during pregnancy, usually during the third trimester. The symptoms resolve without treatment (spontaneously) after the pregnancy (postpartum). Generally, females who develop ICP do not exhibit symptoms before pregnancy and do not develop chronic liver damage. Some females with ICP also are sensitive to hormonal contraceptive agents. Contraceptive-associated intrahepatic cholestasis and ICP can be viewed as forms of BRIC in which the stimulus to an attack is known.
| 733 |
Low Gamma-GT Familial Intrahepatic Cholestasis
|
nord_733_2
|
Causes of Low Gamma-GT Familial Intrahepatic Cholestasis
|
PFIC1 (FIC1 deficiency) occurs due to disruptions or changes (mutations) in ATP8B1, a gene that encodes a protein that is thought to be involved in maintaining differences in composition among different portions of cell membranes. Its function has been proposed to permit the secretion and transport of bile acids from the liver to the digestive tract. It is expressed not only in the liver, but other areas of the body as well, where its function permits other transporter proteins to work correctly. Its absence or dysfunction thus leads to problems like pancreatic inflammation and loss of hearing.PFIC2 (BSEP deficiency) occurs due to disruptions mutations in the ABCB11 gene. It encodes a protein known as bile salt export pump (BSEP), which is involved in transporting bile salts from the liver to the digestive tract. BSEP is only expressed in the liver.BRIC1 is caused by mutations in ATP8B1 and BRIC2 is caused by mutations in ABCB11. Researchers believe individuals with mild forms of low GGT familial intrahepatic cholestasis have more residual protein activity than individuals with severe or intermediate forms.Mutations in TJP2 result in abnormalities in the tight junction protein 2, one of the intracellular anchors for tight junctions that bind liver cells together and protects them from damage from dangerous detergent bile salts which are meant to be excreted from the liver.PFIC 5 and 6 result from mutations in NR1H4 and MYO5B respectively. The protein products from these genes assist in the proper localization of the BSEP protein. Therefore, when these genes are defective, BSEP is not able to properly situate within the cell, resulting in the inability to transport bile salts out of the liver cell and the ‘BSEP-like’ physical manifestations of low GGT cholestasis.Low GGT familial intrahepatic cholestasis 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.Some affected individuals have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents of both carrying the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
|
Causes of Low Gamma-GT Familial Intrahepatic Cholestasis. PFIC1 (FIC1 deficiency) occurs due to disruptions or changes (mutations) in ATP8B1, a gene that encodes a protein that is thought to be involved in maintaining differences in composition among different portions of cell membranes. Its function has been proposed to permit the secretion and transport of bile acids from the liver to the digestive tract. It is expressed not only in the liver, but other areas of the body as well, where its function permits other transporter proteins to work correctly. Its absence or dysfunction thus leads to problems like pancreatic inflammation and loss of hearing.PFIC2 (BSEP deficiency) occurs due to disruptions mutations in the ABCB11 gene. It encodes a protein known as bile salt export pump (BSEP), which is involved in transporting bile salts from the liver to the digestive tract. BSEP is only expressed in the liver.BRIC1 is caused by mutations in ATP8B1 and BRIC2 is caused by mutations in ABCB11. Researchers believe individuals with mild forms of low GGT familial intrahepatic cholestasis have more residual protein activity than individuals with severe or intermediate forms.Mutations in TJP2 result in abnormalities in the tight junction protein 2, one of the intracellular anchors for tight junctions that bind liver cells together and protects them from damage from dangerous detergent bile salts which are meant to be excreted from the liver.PFIC 5 and 6 result from mutations in NR1H4 and MYO5B respectively. The protein products from these genes assist in the proper localization of the BSEP protein. Therefore, when these genes are defective, BSEP is not able to properly situate within the cell, resulting in the inability to transport bile salts out of the liver cell and the ‘BSEP-like’ physical manifestations of low GGT cholestasis.Low GGT familial intrahepatic cholestasis 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.Some affected individuals have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents of both carrying the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
| 733 |
Low Gamma-GT Familial Intrahepatic Cholestasis
|
nord_733_3
|
Affects of Low Gamma-GT Familial Intrahepatic Cholestasis
|
Low GGT familial intrahepatic cholestasis affects males and females in equal numbers. The exact incidence is unknown, but these disorders are extremely rare. However, because particularly in their milder forms these disorders often go unrecognized or misdiagnosed, they may be under-diagnosed, making it difficult to determine their true frequency in the general population.PFIC1 was first described in a large kindred in the Amish community and was referred to as Byler syndrome after the family in which the disorder was observed. A second cluster of individuals with PFIC1 was identified among the Greenland Inuit people and has been referred to as Greenland familial cholestasis. Since its original description PFIC has been described in individuals of every race and various ethnicities.
|
Affects of Low Gamma-GT Familial Intrahepatic Cholestasis. Low GGT familial intrahepatic cholestasis affects males and females in equal numbers. The exact incidence is unknown, but these disorders are extremely rare. However, because particularly in their milder forms these disorders often go unrecognized or misdiagnosed, they may be under-diagnosed, making it difficult to determine their true frequency in the general population.PFIC1 was first described in a large kindred in the Amish community and was referred to as Byler syndrome after the family in which the disorder was observed. A second cluster of individuals with PFIC1 was identified among the Greenland Inuit people and has been referred to as Greenland familial cholestasis. Since its original description PFIC has been described in individuals of every race and various ethnicities.
| 733 |
Low Gamma-GT Familial Intrahepatic Cholestasis
|
nord_733_4
|
Related disorders of Low Gamma-GT Familial Intrahepatic Cholestasis
|
Symptoms of the following disorders can be similar to those of low GGT familial intrahepatic cholestasis. Comparisons may be useful for a differential diagnosis:Neonatal cholestasis refers to impaired flow of bile at any point from the liver cells into the intestine of a newborn. Neonatal cholestasis may be caused by viruses, metabolic disease or genetic disorders, as well as other rare diseases that affect or impair the function of the liver. In a small percent of patients, the cause of liver injury is unknown – these cases are referred to as idiopathic neonatal hepatitis (INH). The incidence of neonatal cholestasis is estimated to be ~1:2500 live births worldwide, and 25% to 50% are now known to be associated with changes (mutations) in specific genes. (For more information on this disorder, choose “neonatal cholestasis” as your search term in the Rare Disease Database.)Biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and promoting absorption of fats and vitamins by the intestines. In biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (fibrosis). In some cases, additional abnormalities may be present, including heart defects and intestinal, spleen and kidney malformations. The exact cause of biliary atresia is unknown. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.)MDR3 deficiency is a rare genetic disorder that predominantly affects the liver. The disorder is also known as progressive familial intrahepatic cholestasis type 3. MDR3 deficiency shares many of the symptoms of PFIC. Affected individuals may be prone to forming gallstones. Because the disorder is so rare, the full spectrum of symptoms associated with MDR3 deficiency is unknown. Mild forms of this disorder may be manifest as gallstones, as intrahepatic cholestasis of pregnancy, or as cirrhosis and jaundice in middle age. MDR3 deficiency is inherited in an autosomal recessive pattern. It is high GGT.Metabolic disorders are a group of disorders in which certain enzymes required to “metabolize” or breakdown various substances in the body (e.g., carbohydrates, proteins, fats) are missing or reduced. Many of these enzymes are crucial in the production of energy. Absence or deficiency of critical enzymes causes substances to build up in the body potentially damaging various organs. Various metabolic diseases are associated with liver dysfunction similar to that found in PFIC and BRIC. These disorders include alpha-1-antitrypsin deficiency, cystic fibrosis, fatty acid oxidation disorders, galactosemia, tyrosinemia, Zellweger syndrome, hereditary fructose intolerance, and bile acid synthesis defects. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Several rare disorders may involve the liver, causing signs and symptoms that are similar to those found in low GGT familial intrahepatic cholestasis. These disorders include familial hypercholanemia, arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, Alagille syndrome, and Smith-Lemli-Opitz syndrome. These disorders are low GGT, except for Alagille syndrome, which is high GGT. They generally have additional signs and symptoms that can distinguish them from low GGT familial intrahepatic cholestasis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
|
Related disorders of Low Gamma-GT Familial Intrahepatic Cholestasis. Symptoms of the following disorders can be similar to those of low GGT familial intrahepatic cholestasis. Comparisons may be useful for a differential diagnosis:Neonatal cholestasis refers to impaired flow of bile at any point from the liver cells into the intestine of a newborn. Neonatal cholestasis may be caused by viruses, metabolic disease or genetic disorders, as well as other rare diseases that affect or impair the function of the liver. In a small percent of patients, the cause of liver injury is unknown – these cases are referred to as idiopathic neonatal hepatitis (INH). The incidence of neonatal cholestasis is estimated to be ~1:2500 live births worldwide, and 25% to 50% are now known to be associated with changes (mutations) in specific genes. (For more information on this disorder, choose “neonatal cholestasis” as your search term in the Rare Disease Database.)Biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and promoting absorption of fats and vitamins by the intestines. In biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (fibrosis). In some cases, additional abnormalities may be present, including heart defects and intestinal, spleen and kidney malformations. The exact cause of biliary atresia is unknown. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.)MDR3 deficiency is a rare genetic disorder that predominantly affects the liver. The disorder is also known as progressive familial intrahepatic cholestasis type 3. MDR3 deficiency shares many of the symptoms of PFIC. Affected individuals may be prone to forming gallstones. Because the disorder is so rare, the full spectrum of symptoms associated with MDR3 deficiency is unknown. Mild forms of this disorder may be manifest as gallstones, as intrahepatic cholestasis of pregnancy, or as cirrhosis and jaundice in middle age. MDR3 deficiency is inherited in an autosomal recessive pattern. It is high GGT.Metabolic disorders are a group of disorders in which certain enzymes required to “metabolize” or breakdown various substances in the body (e.g., carbohydrates, proteins, fats) are missing or reduced. Many of these enzymes are crucial in the production of energy. Absence or deficiency of critical enzymes causes substances to build up in the body potentially damaging various organs. Various metabolic diseases are associated with liver dysfunction similar to that found in PFIC and BRIC. These disorders include alpha-1-antitrypsin deficiency, cystic fibrosis, fatty acid oxidation disorders, galactosemia, tyrosinemia, Zellweger syndrome, hereditary fructose intolerance, and bile acid synthesis defects. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Several rare disorders may involve the liver, causing signs and symptoms that are similar to those found in low GGT familial intrahepatic cholestasis. These disorders include familial hypercholanemia, arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, Alagille syndrome, and Smith-Lemli-Opitz syndrome. These disorders are low GGT, except for Alagille syndrome, which is high GGT. They generally have additional signs and symptoms that can distinguish them from low GGT familial intrahepatic cholestasis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
| 733 |
Low Gamma-GT Familial Intrahepatic Cholestasis
|
nord_733_5
|
Diagnosis of Low Gamma-GT Familial Intrahepatic Cholestasis
|
A diagnosis of low GGT familial intrahepatic cholestasis should be suspected in infants and children with evidence of cholestasis. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history, a comprehensive family history, and a variety of tests. These tests include measuring serum levels of bilirubin, bile salts, and gamma-glutamyltransferase. Surgical excision and microscopic examination of liver tissue (biopsy) may be performed to aid in diagnosis and to detect the presence of cirrhosis. Increasingly, molecular genetic testing is available on a clinical basis and has emerged as a more prominent diagnostic tool. All children identified with low GGT cholestasis should undergo confirmatory genetic testing to identify the causative gene where applicable.
|
Diagnosis of Low Gamma-GT Familial Intrahepatic Cholestasis. A diagnosis of low GGT familial intrahepatic cholestasis should be suspected in infants and children with evidence of cholestasis. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history, a comprehensive family history, and a variety of tests. These tests include measuring serum levels of bilirubin, bile salts, and gamma-glutamyltransferase. Surgical excision and microscopic examination of liver tissue (biopsy) may be performed to aid in diagnosis and to detect the presence of cirrhosis. Increasingly, molecular genetic testing is available on a clinical basis and has emerged as a more prominent diagnostic tool. All children identified with low GGT cholestasis should undergo confirmatory genetic testing to identify the causative gene where applicable.
| 733 |
Low Gamma-GT Familial Intrahepatic Cholestasis
|
nord_733_6
|
Therapies of Low Gamma-GT Familial Intrahepatic Cholestasis
|
Treatment
No specific therapy exists for individuals with low GGT familial intrahepatic cholestasis. Supportive measures are focused on improving nutritional deficiencies and managing complications of end stage liver disease. Additional treatment is directed toward the specific symptoms that are apparent in each individual. Treatment options include drug therapy, various surgical procedures, and in severe cases liver transplantation. Restoring vitamins and nutrients lost through malabsorption is necessary in many cases. Various drug therapies have been tried in individuals with PFIC, with moderate success. Ursodeoxycholic acid is often the initial treatment option for affected individuals and may be effective in some cases. Additional drug therapies that have been used to treat individuals with PFIC include phenobarbital, rifampin, cholestyramine, antihistamines, opiate antagonists (Naltrexone), and selective serotonin reuptake inhibitors (sertraline). These therapies can alleviate or improve some of the clinical symptoms such as intense itching. However, they are not effective in all cases and there is no conclusive evidence that demonstrates that they stop the progression of liver disease.When medical therapy is insufficient, surgical intervention may be considered with the goal of bypassing the enterohepatic circulation and/or decreasing reabsorption of bile salts. Researchers believe that these acids abnormally accumulate within the liver in individuals with PFIC. Procedures including partial external biliary diversion, partial internal biliary diversion, and ileal exclusion have generally, though not uniformly, resulted in sustained clinical improvement in PFIC patients. Notably, no single procedure has demonstrated definitive superiority with center-experience likely driving center-specific approaches. Reports of the value of various forms surgical intervention are, with rare exceptions, flawed because they do not classify results in terms of underlying genetic defect. Newer therapeutics including inhibitors of the ileal apical-sodium dependent bile acid transporter (ASBT) which effectively act as a ‘chemical’ biliary diversion are currently under investigation.In certain cases, a procedure called nasobiliary drainage has been used to treat individuals with mild disease due to mutations in ATP8B1 (BRIC1). During this procedure, a thin, flexible tube (catheter) is run from the nose to the common bile duct, allowing for the drainage of excess bile acids via the catheter. This lowers body levels of bile acids and of other substances in bile. In the cases reported, individuals demonstrated rapid and long-lasting remission of cholestatic episodes and relief from associated itching. In severe cases (i.e., cases that have progressed to cirrhosis or liver failure or in which biliary diversion or ileal exclusion was unsuccessful), liver transplantation may be required. Some affected individuals who have undergone liver transplantation have demonstrated dramatic improvement of symptoms. In some cases of PFIC1, certain symptoms (e.g., malabsorption and diarrhea) may persist. In some cases of PFIC2, low GGT cholestasis may recur.Supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E, and K. Calcium, phosphate, and zinc supplementation may also be required. Young children may be given formula with medium chain triglycerides because this form of fat is better absorbed by individuals with PFIC (i.e., independent of bile flow).Genetic counseling is recommended for affected individuals and their families. Affected individuals should receive regular follow-up examinations, especially screening for individuals with severe disease because of the increased risk of hepatobiliary carcinoma.
|
Therapies of Low Gamma-GT Familial Intrahepatic Cholestasis. Treatment
No specific therapy exists for individuals with low GGT familial intrahepatic cholestasis. Supportive measures are focused on improving nutritional deficiencies and managing complications of end stage liver disease. Additional treatment is directed toward the specific symptoms that are apparent in each individual. Treatment options include drug therapy, various surgical procedures, and in severe cases liver transplantation. Restoring vitamins and nutrients lost through malabsorption is necessary in many cases. Various drug therapies have been tried in individuals with PFIC, with moderate success. Ursodeoxycholic acid is often the initial treatment option for affected individuals and may be effective in some cases. Additional drug therapies that have been used to treat individuals with PFIC include phenobarbital, rifampin, cholestyramine, antihistamines, opiate antagonists (Naltrexone), and selective serotonin reuptake inhibitors (sertraline). These therapies can alleviate or improve some of the clinical symptoms such as intense itching. However, they are not effective in all cases and there is no conclusive evidence that demonstrates that they stop the progression of liver disease.When medical therapy is insufficient, surgical intervention may be considered with the goal of bypassing the enterohepatic circulation and/or decreasing reabsorption of bile salts. Researchers believe that these acids abnormally accumulate within the liver in individuals with PFIC. Procedures including partial external biliary diversion, partial internal biliary diversion, and ileal exclusion have generally, though not uniformly, resulted in sustained clinical improvement in PFIC patients. Notably, no single procedure has demonstrated definitive superiority with center-experience likely driving center-specific approaches. Reports of the value of various forms surgical intervention are, with rare exceptions, flawed because they do not classify results in terms of underlying genetic defect. Newer therapeutics including inhibitors of the ileal apical-sodium dependent bile acid transporter (ASBT) which effectively act as a ‘chemical’ biliary diversion are currently under investigation.In certain cases, a procedure called nasobiliary drainage has been used to treat individuals with mild disease due to mutations in ATP8B1 (BRIC1). During this procedure, a thin, flexible tube (catheter) is run from the nose to the common bile duct, allowing for the drainage of excess bile acids via the catheter. This lowers body levels of bile acids and of other substances in bile. In the cases reported, individuals demonstrated rapid and long-lasting remission of cholestatic episodes and relief from associated itching. In severe cases (i.e., cases that have progressed to cirrhosis or liver failure or in which biliary diversion or ileal exclusion was unsuccessful), liver transplantation may be required. Some affected individuals who have undergone liver transplantation have demonstrated dramatic improvement of symptoms. In some cases of PFIC1, certain symptoms (e.g., malabsorption and diarrhea) may persist. In some cases of PFIC2, low GGT cholestasis may recur.Supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E, and K. Calcium, phosphate, and zinc supplementation may also be required. Young children may be given formula with medium chain triglycerides because this form of fat is better absorbed by individuals with PFIC (i.e., independent of bile flow).Genetic counseling is recommended for affected individuals and their families. Affected individuals should receive regular follow-up examinations, especially screening for individuals with severe disease because of the increased risk of hepatobiliary carcinoma.
| 733 |
Low Gamma-GT Familial Intrahepatic Cholestasis
|
nord_734_0
|
Overview of Lowe syndrome
|
Lowe syndrome is characterized by vision problems including clouding of the lenses of the eyes (cataracts) that are present at birth, kidney problems that usually develop in the first year of life, and brain abnormalities that are associated with intellectual disabilities. Lowe syndrome is inherited as an X-linked genetic condition.
|
Overview of Lowe syndrome. Lowe syndrome is characterized by vision problems including clouding of the lenses of the eyes (cataracts) that are present at birth, kidney problems that usually develop in the first year of life, and brain abnormalities that are associated with intellectual disabilities. Lowe syndrome is inherited as an X-linked genetic condition.
| 734 |
Lowe syndrome
|
nord_734_1
|
Symptoms of Lowe syndrome
|
Boys with Lowe syndrome have cataracts that are present at birth in each eye (and detectable by high resolution ultrasound prenatally in suspect cases). With only extremely rare exceptions, these require surgery early in life, as soon as health allows for anesthesia to perform it. But even in optimal circumstances, corrected visual acuities when recordable are rarely better than 20/100. Approximately half of eyes will develop high pressure in the eye (glaucoma) that can damage the optic nerve and lead to blindness if not controlled. Infants with Lowe syndrome have poor muscle tone (hypotonia) at birth and experience delayed motor development. Almost all boys with Lowe syndrome have developmental and intellectual disability that can range from mild (~10%-25%) to severe (~50%-65%). Seizures occur in approximately half of those by six years of age, and behavioral problems are present in some boys with Lowe syndrome. A fraction of affected males develop growths on the corneas of one or both eyes called keloids during late childhood and adolescence. These growths are progressive and can lead to blindness.The kidney problem associated with Lowe syndrome is called proximal tubular dysfunction of the Fanconi type. This abnormality results in the loss of certain substances (amino acids, bicarbonates, and phosphates) into the urine that are normally filtered prior to excretion into the urine or reabsorbed by the body. However, as mentioned, the spilling or leakage of amino acids into the urine seldom begins until the end of the first year of life, sometimes delaying and confounding the diagnosis. The filters in the kidney (glomeruli) usually begin to fail in boys with Lowe syndrome after 10 years of age. Kidney failure is slow and progressive and results in a reduced life expectancy of approximately 30-40 years.Other signs frequent in boys with Lowe syndrome include short stature, dental cysts and abnormal dentin formation of the teeth, skin cysts, and vitamin D deficiency that can lead to soft bones, skeletal changes (rickets), bone fractures, scoliosis, and non-inflammatory degenerative joint disease. Some patients have shown a delayed bleeding diathesis following surgery characterized by normal hemostasis and clot formation, only to be followed a few hours later by sudden recurrence of bleeding. This may be an important consideration with any surgery but especially both cataract surgery and glaucoma surgery in which bleeding inside the eye may have considerable consequences.
|
Symptoms of Lowe syndrome. Boys with Lowe syndrome have cataracts that are present at birth in each eye (and detectable by high resolution ultrasound prenatally in suspect cases). With only extremely rare exceptions, these require surgery early in life, as soon as health allows for anesthesia to perform it. But even in optimal circumstances, corrected visual acuities when recordable are rarely better than 20/100. Approximately half of eyes will develop high pressure in the eye (glaucoma) that can damage the optic nerve and lead to blindness if not controlled. Infants with Lowe syndrome have poor muscle tone (hypotonia) at birth and experience delayed motor development. Almost all boys with Lowe syndrome have developmental and intellectual disability that can range from mild (~10%-25%) to severe (~50%-65%). Seizures occur in approximately half of those by six years of age, and behavioral problems are present in some boys with Lowe syndrome. A fraction of affected males develop growths on the corneas of one or both eyes called keloids during late childhood and adolescence. These growths are progressive and can lead to blindness.The kidney problem associated with Lowe syndrome is called proximal tubular dysfunction of the Fanconi type. This abnormality results in the loss of certain substances (amino acids, bicarbonates, and phosphates) into the urine that are normally filtered prior to excretion into the urine or reabsorbed by the body. However, as mentioned, the spilling or leakage of amino acids into the urine seldom begins until the end of the first year of life, sometimes delaying and confounding the diagnosis. The filters in the kidney (glomeruli) usually begin to fail in boys with Lowe syndrome after 10 years of age. Kidney failure is slow and progressive and results in a reduced life expectancy of approximately 30-40 years.Other signs frequent in boys with Lowe syndrome include short stature, dental cysts and abnormal dentin formation of the teeth, skin cysts, and vitamin D deficiency that can lead to soft bones, skeletal changes (rickets), bone fractures, scoliosis, and non-inflammatory degenerative joint disease. Some patients have shown a delayed bleeding diathesis following surgery characterized by normal hemostasis and clot formation, only to be followed a few hours later by sudden recurrence of bleeding. This may be an important consideration with any surgery but especially both cataract surgery and glaucoma surgery in which bleeding inside the eye may have considerable consequences.
| 734 |
Lowe syndrome
|
nord_734_2
|
Causes of Lowe syndrome
|
Lowe syndrome is an X-linked genetic disorder caused by a mutation in the OCRL gene that results in reduced activity of the phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme. About a third of affected males have a new mutation in the gene; in most of the rest, the disorder is inherited from a mother who is a genetic carrier of the condition.X-linked genetic disorders are conditions caused by an abnormal gene on the X-chromosome and occur mostly in males. Females who have a disease gene present on one of their X-chromosomes are carriers for that disorder. As in other X-linked disorders, carrier females have two X chromosomes, and one is inactivated so that the genes on that chromosome are nonfunctioning. Although in many X-linked disorders, carrier females usually do not display features because the activity of the product of the normal gene is sufficient to prevent abnormalities, such is not true for Lowe syndrome. Essentially every female carrier for Lowe syndrome over the age of 10 years will show characteristic changes in the lenses of her eyes, different from any other metabolic cataract. Some carriers will develop visually significant cataracts even in their early 30’s, sufficient to require cataract surgery, and may be missed by the operating surgeon. However, these highly informative and distinctive changes in the lenses of a carrier female should lead the ophthalmologist suspecting this diagnosis in an infant male to dilate the pupils and to reflexively examine the mother of the child under consideration. A male has only one X-chromosome that he inherits from his mother; if a male inherits an X-chromosome that contains a disease gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. Each pregnancy, of course, is independent of the last and does not influence the outcome of the next pregnancy.No males with Lowe syndrome have been reported to have children.
|
Causes of Lowe syndrome. Lowe syndrome is an X-linked genetic disorder caused by a mutation in the OCRL gene that results in reduced activity of the phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme. About a third of affected males have a new mutation in the gene; in most of the rest, the disorder is inherited from a mother who is a genetic carrier of the condition.X-linked genetic disorders are conditions caused by an abnormal gene on the X-chromosome and occur mostly in males. Females who have a disease gene present on one of their X-chromosomes are carriers for that disorder. As in other X-linked disorders, carrier females have two X chromosomes, and one is inactivated so that the genes on that chromosome are nonfunctioning. Although in many X-linked disorders, carrier females usually do not display features because the activity of the product of the normal gene is sufficient to prevent abnormalities, such is not true for Lowe syndrome. Essentially every female carrier for Lowe syndrome over the age of 10 years will show characteristic changes in the lenses of her eyes, different from any other metabolic cataract. Some carriers will develop visually significant cataracts even in their early 30’s, sufficient to require cataract surgery, and may be missed by the operating surgeon. However, these highly informative and distinctive changes in the lenses of a carrier female should lead the ophthalmologist suspecting this diagnosis in an infant male to dilate the pupils and to reflexively examine the mother of the child under consideration. A male has only one X-chromosome that he inherits from his mother; if a male inherits an X-chromosome that contains a disease gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. Each pregnancy, of course, is independent of the last and does not influence the outcome of the next pregnancy.No males with Lowe syndrome have been reported to have children.
| 734 |
Lowe syndrome
|
nord_734_3
|
Affects of Lowe syndrome
|
Lowe syndrome is a rare genetic disorder that occurs almost exclusively in males. The prevalence is estimated to be between 1 and 10 males per 1,000,000 people. This condition has been reported in North and South America, Europe, Japan, and India.
|
Affects of Lowe syndrome. Lowe syndrome is a rare genetic disorder that occurs almost exclusively in males. The prevalence is estimated to be between 1 and 10 males per 1,000,000 people. This condition has been reported in North and South America, Europe, Japan, and India.
| 734 |
Lowe syndrome
|
nord_734_4
|
Related disorders of Lowe syndrome
|
Signs of the following disorders can be similar to those of Lowe syndrome. Comparisons may useful for a differential diagnosis:Congenital rubella (German measles) is a syndrome that occurs when a fetus has been infected with the rubella virus while in the uterus. It is primarily characterized by abnormalities of the heart and nervous system, the eyes, and the ears. The fetus is most vulnerable to the virus during the first three months of pregnancy, although pregnant women are advised to avoid exposure to rubella virus at all times. Women who contract rubella during pregnancy have a high risk of having a baby with congenital rubella. (For more information on this disorder, choose “rubella, congenital” as your search term in the Rare Disease Database.)Zellweger spectrum disorders are a group of genetic disorders of variable severity characterized by low muscle tone (hypotonia), feeding difficulty, and abnormal facial features. Other symptoms may include vision and hearing deficits, seizures, and liver dysfunction. Mutations in several different genes have been found to be associated with the reduction or elimination of cell structures called peroxisomes that are required to breakdown a certain class of fatty acids called very-long-chain fatty acids.. However, congenital cataracts are not a feature. (For more information on this disorder, choose “Zellweger” as your search term in the Rare Disease Database.)Cataract-dental syndrome (Nance-Horan syndrome) is an extremely rare genetic disorder that may be evident at birth (congenital) due the cataracts. It is primarily characterized by abnormalities of the teeth and clouding of the lens of the eyes (congenital cataracts), resulting in poor vision. Additional eye abnormalities are also often present, such as unusual smallness of the front, clear portion of the eye through which light passes (microcornea) and involuntary, rapid, rhythmic eye movements (nystagmus). In some cases, the disorder may also be associated with additional physical abnormalities (simple ears turned forward, short fourth and fifth fingers and toes, and highly abnormal teeth that are barrel-shaped and widely spaced, and possibly intellectual disability. The range and severity may vary greatly from person to person, even among affected members of the same family. Importantly, women and mothers who are carriers for this condition, which is also X-linked, also have highly distinctive cataracts, usually involving the Y-sutures of the lens which are occasionally visually impairing. Most carrier females also have corneas that are modestly smaller in diameter than normal but may escape notice unless the ophthalmologist takes the initiative to measure them. (For more information on this disorder, choose “cataract-dental syndrome” or “Nance-Horan” as your search term in the Rare Disease Database.)Smith-Lemli-Opitz syndrome (SLOS) is a highly variable genetic disorder that is characterized by slow growth before and after birth, small head (microcephaly), mild to moderate developmental disability, and multiple birth defects including particular facial features, occasional cataracts at birth, cleft palate, heart defects, fused second and third toes, extra fingers and toes and underdeveloped external genitals in males. The severity of SLOS varies greatly in affected individuals, even in the same family, and some have normal development and only minor birth defects. SLOS is caused by a deficiency in the enzyme 7-dehydrocholesterol reductase that results in an abnormality in cholesterol synthesis. SLOS is inherited as an autosomal recessive genetic disorder. Aminoaciduria and rickets and other features are not present, even though hypotonia is. (For more information on this disorder, choose “Smith-Lemli-Opitz” as your search term in the Rare Disease Database.)Dent disease is an X-linked disorder with overlapping features of kidney stones (nephrolithiasis), hypophosphatemic rickets, and excessive calcium, phosphate, protein, and amino acids in the urine. Many males with Dent disease also have mild developmental delay. About two-thirds of males with Dent disease have mutations in a chloride channel gene called CLCN5, but most of the others have mild mutations in OCRL, interestingly without the typical face, the behavioral features, the metabolic acidosis, and without the congenital cataracts of classical Lowe syndrome. . (For more information on this disorder, choose “Dent” as your search term in the Rare Disease Database.)
|
Related disorders of Lowe syndrome. Signs of the following disorders can be similar to those of Lowe syndrome. Comparisons may useful for a differential diagnosis:Congenital rubella (German measles) is a syndrome that occurs when a fetus has been infected with the rubella virus while in the uterus. It is primarily characterized by abnormalities of the heart and nervous system, the eyes, and the ears. The fetus is most vulnerable to the virus during the first three months of pregnancy, although pregnant women are advised to avoid exposure to rubella virus at all times. Women who contract rubella during pregnancy have a high risk of having a baby with congenital rubella. (For more information on this disorder, choose “rubella, congenital” as your search term in the Rare Disease Database.)Zellweger spectrum disorders are a group of genetic disorders of variable severity characterized by low muscle tone (hypotonia), feeding difficulty, and abnormal facial features. Other symptoms may include vision and hearing deficits, seizures, and liver dysfunction. Mutations in several different genes have been found to be associated with the reduction or elimination of cell structures called peroxisomes that are required to breakdown a certain class of fatty acids called very-long-chain fatty acids.. However, congenital cataracts are not a feature. (For more information on this disorder, choose “Zellweger” as your search term in the Rare Disease Database.)Cataract-dental syndrome (Nance-Horan syndrome) is an extremely rare genetic disorder that may be evident at birth (congenital) due the cataracts. It is primarily characterized by abnormalities of the teeth and clouding of the lens of the eyes (congenital cataracts), resulting in poor vision. Additional eye abnormalities are also often present, such as unusual smallness of the front, clear portion of the eye through which light passes (microcornea) and involuntary, rapid, rhythmic eye movements (nystagmus). In some cases, the disorder may also be associated with additional physical abnormalities (simple ears turned forward, short fourth and fifth fingers and toes, and highly abnormal teeth that are barrel-shaped and widely spaced, and possibly intellectual disability. The range and severity may vary greatly from person to person, even among affected members of the same family. Importantly, women and mothers who are carriers for this condition, which is also X-linked, also have highly distinctive cataracts, usually involving the Y-sutures of the lens which are occasionally visually impairing. Most carrier females also have corneas that are modestly smaller in diameter than normal but may escape notice unless the ophthalmologist takes the initiative to measure them. (For more information on this disorder, choose “cataract-dental syndrome” or “Nance-Horan” as your search term in the Rare Disease Database.)Smith-Lemli-Opitz syndrome (SLOS) is a highly variable genetic disorder that is characterized by slow growth before and after birth, small head (microcephaly), mild to moderate developmental disability, and multiple birth defects including particular facial features, occasional cataracts at birth, cleft palate, heart defects, fused second and third toes, extra fingers and toes and underdeveloped external genitals in males. The severity of SLOS varies greatly in affected individuals, even in the same family, and some have normal development and only minor birth defects. SLOS is caused by a deficiency in the enzyme 7-dehydrocholesterol reductase that results in an abnormality in cholesterol synthesis. SLOS is inherited as an autosomal recessive genetic disorder. Aminoaciduria and rickets and other features are not present, even though hypotonia is. (For more information on this disorder, choose “Smith-Lemli-Opitz” as your search term in the Rare Disease Database.)Dent disease is an X-linked disorder with overlapping features of kidney stones (nephrolithiasis), hypophosphatemic rickets, and excessive calcium, phosphate, protein, and amino acids in the urine. Many males with Dent disease also have mild developmental delay. About two-thirds of males with Dent disease have mutations in a chloride channel gene called CLCN5, but most of the others have mild mutations in OCRL, interestingly without the typical face, the behavioral features, the metabolic acidosis, and without the congenital cataracts of classical Lowe syndrome. . (For more information on this disorder, choose “Dent” as your search term in the Rare Disease Database.)
| 734 |
Lowe syndrome
|
nord_734_5
|
Diagnosis of Lowe syndrome
|
Lowe syndrome is diagnosed when a reduced activity of the phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme is demonstrated in cultured skin cells (fibroblasts). Molecular genetic testing for OCRL gene mutations is also available and accurately detects more than 95% of affected males.Carrier testing for female relatives is available. Approximately 95% of carrier females older than 10 years of age have specific and distinctive abnormalities of the lens of the eye that can be diagnosed by an experienced ophthalmologist. Molecular genetic testing for carrier status is available if a specific OCRL gene mutation has been identified in a male relative. Biochemical testing for phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme activity is not reliable for carrier testing for Lowe syndrome because the range of enzyme activity spreads over the normal range.Prenatal diagnosis is available with biochemical testing (enzyme assay) or molecular genetic testing if the OCRL gene mutation has been determined in an affected male relative or carrier mother.
|
Diagnosis of Lowe syndrome. Lowe syndrome is diagnosed when a reduced activity of the phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme is demonstrated in cultured skin cells (fibroblasts). Molecular genetic testing for OCRL gene mutations is also available and accurately detects more than 95% of affected males.Carrier testing for female relatives is available. Approximately 95% of carrier females older than 10 years of age have specific and distinctive abnormalities of the lens of the eye that can be diagnosed by an experienced ophthalmologist. Molecular genetic testing for carrier status is available if a specific OCRL gene mutation has been identified in a male relative. Biochemical testing for phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme activity is not reliable for carrier testing for Lowe syndrome because the range of enzyme activity spreads over the normal range.Prenatal diagnosis is available with biochemical testing (enzyme assay) or molecular genetic testing if the OCRL gene mutation has been determined in an affected male relative or carrier mother.
| 734 |
Lowe syndrome
|
nord_734_6
|
Therapies of Lowe syndrome
|
TreatmentTreatment of Lowe syndrome usually requires a team of medical professionals including a pediatric ophthalmologist, nephrologist, geneticist, nutritionist, endocrinologist, neurologist, child development specialist, general surgeon, orthopedist, and dentist.Low muscle tone (hypotonia) can sometimes result in feeding problems and may require tube feeding and standard measures for gastroesophageal reflux.Early removal of cataracts is recommended to promote optimum development of vision. Eyeglasses and contact lenses help to improve vision. Glaucoma occurring in half of males sometimes may be treated with medication (eyedrops) but usually requires surgery, which is not always successful with a single operation. If they occur, corneal keloids can sometimes be removed surgically but often recur more aggressive than before. There is no consistent proven therapy to eradicate corneal keloids.Proximal tubular dysfunction of the Fanconi type is treated with oral supplements of sodium and potassium bicarbonate or citrate. Doses must be determined on an individual basis.Oral phosphate and oral calcitriol are used to treat (or prevent) rickets. Bone density should be monitored periodically. Seizure disorders are treated with anticonvulsant medications. Behavior problems are treated with behavior modification and medications.Early intervention programs that include physical therapy, occupational therapy, speech and language therapy, special education services, and services for visually impaired are recommended and should begin in early infancy.Boys with Lowe syndrome should be monitored regularly for vision problems (especially later onset glaucoma), kidney function, growth, developmental progress, scoliosis, and joint problems, and dental problems.End-stage renal disease has been treated successfully with dialysis and kidney transplantation in some late-adolescent adult men.
|
Therapies of Lowe syndrome. TreatmentTreatment of Lowe syndrome usually requires a team of medical professionals including a pediatric ophthalmologist, nephrologist, geneticist, nutritionist, endocrinologist, neurologist, child development specialist, general surgeon, orthopedist, and dentist.Low muscle tone (hypotonia) can sometimes result in feeding problems and may require tube feeding and standard measures for gastroesophageal reflux.Early removal of cataracts is recommended to promote optimum development of vision. Eyeglasses and contact lenses help to improve vision. Glaucoma occurring in half of males sometimes may be treated with medication (eyedrops) but usually requires surgery, which is not always successful with a single operation. If they occur, corneal keloids can sometimes be removed surgically but often recur more aggressive than before. There is no consistent proven therapy to eradicate corneal keloids.Proximal tubular dysfunction of the Fanconi type is treated with oral supplements of sodium and potassium bicarbonate or citrate. Doses must be determined on an individual basis.Oral phosphate and oral calcitriol are used to treat (or prevent) rickets. Bone density should be monitored periodically. Seizure disorders are treated with anticonvulsant medications. Behavior problems are treated with behavior modification and medications.Early intervention programs that include physical therapy, occupational therapy, speech and language therapy, special education services, and services for visually impaired are recommended and should begin in early infancy.Boys with Lowe syndrome should be monitored regularly for vision problems (especially later onset glaucoma), kidney function, growth, developmental progress, scoliosis, and joint problems, and dental problems.End-stage renal disease has been treated successfully with dialysis and kidney transplantation in some late-adolescent adult men.
| 734 |
Lowe syndrome
|
nord_735_0
|
Overview of Lymphangioleiomyomatosis
|
SummaryLymphangioleiomyomatosis (LAM) is a rare progressive multisystem disorder that predominantly impacts women of reproductive age. It is estimated to affect 3.4-7.8/1,000,000 women worldwide. There are two main types of LAM: sporadic LAM (that occurs spontaneously) and LAM associated with tuberous sclerosis complex (TSC), an inheritable genetic condition. LAM is characterized by the spread and uncontrolled growth (proliferation) of specialized cells (smooth muscle-like LAM cells) in certain organs of the body, especially the lungs, kidneys and lymphatics. The most common symptom associated with LAM is difficulty breathing (dyspnea), especially on exertion. Affected individuals may also experience complications including lung collapse (pneumothorax) or fluid accumulation around the lungs (pleural effusion) and in the abdomen, and benign kidney tumors called angiomyolipomas. The disorder is progressive and, in some patients, may result in chronic respiratory failure. Fortunately, treatment with sirolimus allows for a slower progression of disease and better management of complications. Further research leading to better understanding of this rare disease promises improved therapeutic options in the future.
|
Overview of Lymphangioleiomyomatosis. SummaryLymphangioleiomyomatosis (LAM) is a rare progressive multisystem disorder that predominantly impacts women of reproductive age. It is estimated to affect 3.4-7.8/1,000,000 women worldwide. There are two main types of LAM: sporadic LAM (that occurs spontaneously) and LAM associated with tuberous sclerosis complex (TSC), an inheritable genetic condition. LAM is characterized by the spread and uncontrolled growth (proliferation) of specialized cells (smooth muscle-like LAM cells) in certain organs of the body, especially the lungs, kidneys and lymphatics. The most common symptom associated with LAM is difficulty breathing (dyspnea), especially on exertion. Affected individuals may also experience complications including lung collapse (pneumothorax) or fluid accumulation around the lungs (pleural effusion) and in the abdomen, and benign kidney tumors called angiomyolipomas. The disorder is progressive and, in some patients, may result in chronic respiratory failure. Fortunately, treatment with sirolimus allows for a slower progression of disease and better management of complications. Further research leading to better understanding of this rare disease promises improved therapeutic options in the future.
| 735 |
Lymphangioleiomyomatosis
|
nord_735_1
|
Symptoms of Lymphangioleiomyomatosis
|
The symptoms of LAM vary depending on the organs affected. The abnormal LAM cells infiltrate tissues, form cysts and obstruct the affected airways (breathing tubes), blood vessels and lymphatic vessels. Consequently, pulmonary LAM can present with shortness of breath upon exertion, cough, wheezing and chest pain. Sometimes, individuals may cough up small amounts of blood (hemoptysis) and have bleeding in their lungs (pulmonary hemorrhage) due to obstructed blood vessels. Infiltration of the lung with LAM cells results in progressive breathing difficulties, lung collapse and interference with the lung’s ability to deliver oxygen to the rest of the body. About 50-60% of individuals with LAM experience a lung collapse (pneumothorax) at some point in their life. In about one third of these patients, the pneumothorax may be the first manifestation that brings the diagnosis of LAM to light. The symptoms of a collapsed lung may include sudden, sharp chest pain, difficult, rapid breathing (tachypnea), rapid heartbeat (tachycardia), low blood pressure (hypotension), profuse sweating (diaphoresis), dizziness and/or lack of normal chest movement on the affected side of the chest. This complication tends to recur in LAM, therefore management with a medicine or surgical technique that adheres lungs to the chest wall (pleurodesis) is recommended.About 10 to 30% of people with LAM experience fluid (e.g. chyle) accumulation in the chest cavity around the lungs (pleural effusion). Chyle is a fat-laden cloudy fluid that is absorbed during digestion by the lymphatic vessels located around the intestine. Chyle normally flows through lymphatic vessels into the upper chest (thoracic duct) and is then deposited into veins, where it mixes with blood. In some people with LAM, the lymphatic vessels may rupture or become blocked (obstructed) due to the infiltration of LAM cells, causing chyle to accumulate in the chest cavity (chylothorax). In some patients, chyle may accumulate in the abdomen causing an increase in girth, a condition called chylous ascites. Involvement of the axial lymphatics may also lead to formation of chyle-filled lymphatic cysts called lymphangioleiomyomas within the chest and abdomen.Approximately 30% of individuals with sporadic LAM and up to 80% of individuals with TSC-LAM develop angiomyolipomas, which are benign tumors made up of fat, blood vessels and smooth muscle-like cells. These tumors most commonly affect the kidneys and often do not cause symptoms. In some patients, they may cause flank pain, blood in the urine (hematuria) or bleeding into the abdomen.Symptoms of LAM may become progressively worse as LAM cell proliferation continues and may result in chronic life-threatening respiratory failure.
|
Symptoms of Lymphangioleiomyomatosis. The symptoms of LAM vary depending on the organs affected. The abnormal LAM cells infiltrate tissues, form cysts and obstruct the affected airways (breathing tubes), blood vessels and lymphatic vessels. Consequently, pulmonary LAM can present with shortness of breath upon exertion, cough, wheezing and chest pain. Sometimes, individuals may cough up small amounts of blood (hemoptysis) and have bleeding in their lungs (pulmonary hemorrhage) due to obstructed blood vessels. Infiltration of the lung with LAM cells results in progressive breathing difficulties, lung collapse and interference with the lung’s ability to deliver oxygen to the rest of the body. About 50-60% of individuals with LAM experience a lung collapse (pneumothorax) at some point in their life. In about one third of these patients, the pneumothorax may be the first manifestation that brings the diagnosis of LAM to light. The symptoms of a collapsed lung may include sudden, sharp chest pain, difficult, rapid breathing (tachypnea), rapid heartbeat (tachycardia), low blood pressure (hypotension), profuse sweating (diaphoresis), dizziness and/or lack of normal chest movement on the affected side of the chest. This complication tends to recur in LAM, therefore management with a medicine or surgical technique that adheres lungs to the chest wall (pleurodesis) is recommended.About 10 to 30% of people with LAM experience fluid (e.g. chyle) accumulation in the chest cavity around the lungs (pleural effusion). Chyle is a fat-laden cloudy fluid that is absorbed during digestion by the lymphatic vessels located around the intestine. Chyle normally flows through lymphatic vessels into the upper chest (thoracic duct) and is then deposited into veins, where it mixes with blood. In some people with LAM, the lymphatic vessels may rupture or become blocked (obstructed) due to the infiltration of LAM cells, causing chyle to accumulate in the chest cavity (chylothorax). In some patients, chyle may accumulate in the abdomen causing an increase in girth, a condition called chylous ascites. Involvement of the axial lymphatics may also lead to formation of chyle-filled lymphatic cysts called lymphangioleiomyomas within the chest and abdomen.Approximately 30% of individuals with sporadic LAM and up to 80% of individuals with TSC-LAM develop angiomyolipomas, which are benign tumors made up of fat, blood vessels and smooth muscle-like cells. These tumors most commonly affect the kidneys and often do not cause symptoms. In some patients, they may cause flank pain, blood in the urine (hematuria) or bleeding into the abdomen.Symptoms of LAM may become progressively worse as LAM cell proliferation continues and may result in chronic life-threatening respiratory failure.
| 735 |
Lymphangioleiomyomatosis
|
nord_735_2
|
Causes of Lymphangioleiomyomatosis
|
LAM is associated with the rare genetic disorder known as tuberous sclerosis complex (TSC) as both diseases are caused by changes (mutations) in one of two genes known as the TSC1 gene or TSC2 gene. There are two main types of LAM: sporadic LAM (called S-LAM that may occur without TSC) and LAM associated with TSC (called TSC-LAM). In both cases, abnormal LAM cells circulate in blood and lymphatic vessels and deposit in the lungs, causing cysts and lung damage. In S-LAM, mutations are thought to be somatic mutations (e.g., mutations that occur in peripheral tissues after conception and are not inherited). These mutations are not found in the blood or the normal lung or normal kidney cells of affected individuals. On the contrary, in TSC-LAM, these mutations may occur spontaneously (sporadically) for unknown reasons or be inherited in an autosomal dominant pattern. Most cases represent new (sporadic) gene mutations, with no family history of the disease. Approximately one-third of women with TSC show evidence of pulmonary LAM; however, the prevalence of LAM in women with TSC increases with age and by the age of 40 years almost 80% of women with TSC have cystic changes consistent with LAM. Consequently, the TSC Guidelines recommend that females with TSC be screened for LAM at least once on reaching adulthood.Other factors affect the disease process in LAM but are not completely understood. For example, researchers have observed that estrogen and progesterone receptors are commonly expressed on LAM cells. In addition, LAM symptoms flare up during surges of female hormones, such as during pregnancy, with hormonal contraception, or during menstruation, and then symptoms stabilize post-menopause. The mechanism of action of female hormones in LAM on a molecular level is still not fully understood.
|
Causes of Lymphangioleiomyomatosis. LAM is associated with the rare genetic disorder known as tuberous sclerosis complex (TSC) as both diseases are caused by changes (mutations) in one of two genes known as the TSC1 gene or TSC2 gene. There are two main types of LAM: sporadic LAM (called S-LAM that may occur without TSC) and LAM associated with TSC (called TSC-LAM). In both cases, abnormal LAM cells circulate in blood and lymphatic vessels and deposit in the lungs, causing cysts and lung damage. In S-LAM, mutations are thought to be somatic mutations (e.g., mutations that occur in peripheral tissues after conception and are not inherited). These mutations are not found in the blood or the normal lung or normal kidney cells of affected individuals. On the contrary, in TSC-LAM, these mutations may occur spontaneously (sporadically) for unknown reasons or be inherited in an autosomal dominant pattern. Most cases represent new (sporadic) gene mutations, with no family history of the disease. Approximately one-third of women with TSC show evidence of pulmonary LAM; however, the prevalence of LAM in women with TSC increases with age and by the age of 40 years almost 80% of women with TSC have cystic changes consistent with LAM. Consequently, the TSC Guidelines recommend that females with TSC be screened for LAM at least once on reaching adulthood.Other factors affect the disease process in LAM but are not completely understood. For example, researchers have observed that estrogen and progesterone receptors are commonly expressed on LAM cells. In addition, LAM symptoms flare up during surges of female hormones, such as during pregnancy, with hormonal contraception, or during menstruation, and then symptoms stabilize post-menopause. The mechanism of action of female hormones in LAM on a molecular level is still not fully understood.
| 735 |
Lymphangioleiomyomatosis
|
nord_735_3
|
Affects of Lymphangioleiomyomatosis
|
LAM is a rare disorder that is estimated to affect approximately 3.4-7.8/1,000,000 women worldwide. The US LAM clinic network follows ~1,500 patients with LAM and there are ~3,000 patients with LAM registered with The LAM Foundation. Current estimates suggest that there are roughly 8,000–21,000 patients with sporadic LAM and 80,000–160,000 patients with TSC-LAM worldwide. However, many researchers believe that the disorder is under-diagnosed making it difficult to determine the true frequency in the general population. LAM predominantly affects women of reproductive age, with an average age at symptom onset of 33 years of age. Two thirds of people who first present with symptoms of LAM are in their thirties or forties, but the age range can extend from pre-adolescent to elderly.
|
Affects of Lymphangioleiomyomatosis. LAM is a rare disorder that is estimated to affect approximately 3.4-7.8/1,000,000 women worldwide. The US LAM clinic network follows ~1,500 patients with LAM and there are ~3,000 patients with LAM registered with The LAM Foundation. Current estimates suggest that there are roughly 8,000–21,000 patients with sporadic LAM and 80,000–160,000 patients with TSC-LAM worldwide. However, many researchers believe that the disorder is under-diagnosed making it difficult to determine the true frequency in the general population. LAM predominantly affects women of reproductive age, with an average age at symptom onset of 33 years of age. Two thirds of people who first present with symptoms of LAM are in their thirties or forties, but the age range can extend from pre-adolescent to elderly.
| 735 |
Lymphangioleiomyomatosis
|
nord_735_4
|
Related disorders of Lymphangioleiomyomatosis
|
Symptoms of the following disorders can be similar to those of LAM. Comparisons may be useful for a differential diagnosis:There are several obstructive lung diseases that can cause symptoms that are similar to LAM, such as emphysema, asthma and chronic obstructive pulmonary disease (COPD). In addition, one third of women with LAM have shortness of breath that is relieved by bronchodilators, just like in asthma, which often causes diagnostic delay. Fortunately, these other obstructive lung diseases can be ruled out with laboratory tests and radiographic (x-ray) studies.As discussed previously, TSC is a rare genetic multisystem disorder that overlaps with LAM; 30 to 50 percent of women with TSC develop pulmonary LAM. TSC is characterized by episodes of uncontrolled electrical activity in the brain (seizures), intellectual disability, distinctive skin abnormalities and benign (noncancerous) tumor-like nodules (hamartomas) of the brain, certain regions of the eyes (e.g., retinas), the heart, the kidneys, the lungs, or other tissues or organs. In addition, many affected individuals may have cyst-like areas within certain skeletal regions, particularly bones of the fingers and toes (phalanges). Characteristic skin lesions include sharply defined areas of decreased skin coloration (hypopigmentation) that may develop during infancy and relatively small reddish nodules that may appear on the cheeks and nose beginning at approximately age four. These reddish lesions eventually enlarge, blend together (coalesce), and develop a wart-like appearance (sebaceous adenomas). Additional skin lesions may also develop, including flat, “coffee-colored” areas of increased skin pigmentation (café-au-lait spots); benign, fibrous nodules (fibromas) arising around or beneath the nails; or rough, elevated, “knobby” lesions (shagreen patches) on the lower back. (For more information on this disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)Langerhans cell histiocytosis (LCH) is a rare spectrum of disorders characterized by overproduction (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the various tissues and organs of the body (lesions). The appearance of LCH in the lungs may have similarities to LAM on CT scans. (For more information on this disorder, choose “Langerhans cell histiocytosis” as your search term in the Rare Disease Database.)Birt-Hogg-Dubé syndrome (BHD) is a rare genetic skin disorder characterized by the development of skin papules on the head, face and upper torso. BHD syndrome also predisposes individuals to the development of benign cysts in the lungs and repeated episodes of a collapsed lung (pneumothorax), which are both signs and symptoms of LAM. (For more information on this disorder, choose “Birt-Hogg-Dubé syndrome” as your search term in the Rare Disease Database.)Finally, other diagnoses to consider include follicular bronchiolitis, lymphoid interstitial pneumonia, light chain deposition disease and advanced interstitial lung disease.
|
Related disorders of Lymphangioleiomyomatosis. Symptoms of the following disorders can be similar to those of LAM. Comparisons may be useful for a differential diagnosis:There are several obstructive lung diseases that can cause symptoms that are similar to LAM, such as emphysema, asthma and chronic obstructive pulmonary disease (COPD). In addition, one third of women with LAM have shortness of breath that is relieved by bronchodilators, just like in asthma, which often causes diagnostic delay. Fortunately, these other obstructive lung diseases can be ruled out with laboratory tests and radiographic (x-ray) studies.As discussed previously, TSC is a rare genetic multisystem disorder that overlaps with LAM; 30 to 50 percent of women with TSC develop pulmonary LAM. TSC is characterized by episodes of uncontrolled electrical activity in the brain (seizures), intellectual disability, distinctive skin abnormalities and benign (noncancerous) tumor-like nodules (hamartomas) of the brain, certain regions of the eyes (e.g., retinas), the heart, the kidneys, the lungs, or other tissues or organs. In addition, many affected individuals may have cyst-like areas within certain skeletal regions, particularly bones of the fingers and toes (phalanges). Characteristic skin lesions include sharply defined areas of decreased skin coloration (hypopigmentation) that may develop during infancy and relatively small reddish nodules that may appear on the cheeks and nose beginning at approximately age four. These reddish lesions eventually enlarge, blend together (coalesce), and develop a wart-like appearance (sebaceous adenomas). Additional skin lesions may also develop, including flat, “coffee-colored” areas of increased skin pigmentation (café-au-lait spots); benign, fibrous nodules (fibromas) arising around or beneath the nails; or rough, elevated, “knobby” lesions (shagreen patches) on the lower back. (For more information on this disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)Langerhans cell histiocytosis (LCH) is a rare spectrum of disorders characterized by overproduction (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the various tissues and organs of the body (lesions). The appearance of LCH in the lungs may have similarities to LAM on CT scans. (For more information on this disorder, choose “Langerhans cell histiocytosis” as your search term in the Rare Disease Database.)Birt-Hogg-Dubé syndrome (BHD) is a rare genetic skin disorder characterized by the development of skin papules on the head, face and upper torso. BHD syndrome also predisposes individuals to the development of benign cysts in the lungs and repeated episodes of a collapsed lung (pneumothorax), which are both signs and symptoms of LAM. (For more information on this disorder, choose “Birt-Hogg-Dubé syndrome” as your search term in the Rare Disease Database.)Finally, other diagnoses to consider include follicular bronchiolitis, lymphoid interstitial pneumonia, light chain deposition disease and advanced interstitial lung disease.
| 735 |
Lymphangioleiomyomatosis
|
nord_735_5
|
Diagnosis of Lymphangioleiomyomatosis
|
The diagnosis of LAM may be confirmed by a thorough clinical evaluation that includes a detailed patient history and a variety of specialized tests.High resolution CT scan (HRCT) shows characteristic thin-walled cysts in the lungs consistent with LAM and can help rule out other pulmonary conditions. HRCT may also reveal angiomyolipomas or lymphangioleiomyomas in the abdomen that support a diagnosis of LAM. Chest x-rays are not diagnostic for LAM and are often normal early in the disease course. VEGF-D blood test is elevated in ~60-70% of individuals with LAM. In combination with a characteristic CT scan, the finding of elevated VEGF-D can establish the diagnosis of LAM without the need of a surgical lung biopsy, which is the gold standard for diagnosis but comes with its risks and complications. Lung function tests are useful to obtain a baseline of the individual’s lung function and facilitate monitoring over time. Currently, no test can accurately predict the course of the disease (prognosis) and progression seems to vary greatly from one person to another, though there has been a significant improvement in our understanding of LAM in the past decade. Patients with LAM have a favorable life expectancy with a transplant-free survival of more than 20 years from the time of diagnosis.
|
Diagnosis of Lymphangioleiomyomatosis. The diagnosis of LAM may be confirmed by a thorough clinical evaluation that includes a detailed patient history and a variety of specialized tests.High resolution CT scan (HRCT) shows characteristic thin-walled cysts in the lungs consistent with LAM and can help rule out other pulmonary conditions. HRCT may also reveal angiomyolipomas or lymphangioleiomyomas in the abdomen that support a diagnosis of LAM. Chest x-rays are not diagnostic for LAM and are often normal early in the disease course. VEGF-D blood test is elevated in ~60-70% of individuals with LAM. In combination with a characteristic CT scan, the finding of elevated VEGF-D can establish the diagnosis of LAM without the need of a surgical lung biopsy, which is the gold standard for diagnosis but comes with its risks and complications. Lung function tests are useful to obtain a baseline of the individual’s lung function and facilitate monitoring over time. Currently, no test can accurately predict the course of the disease (prognosis) and progression seems to vary greatly from one person to another, though there has been a significant improvement in our understanding of LAM in the past decade. Patients with LAM have a favorable life expectancy with a transplant-free survival of more than 20 years from the time of diagnosis.
| 735 |
Lymphangioleiomyomatosis
|
nord_735_6
|
Therapies of Lymphangioleiomyomatosis
|
Treatment
Individuals with LAM are encouraged to lead a normal life with a healthy lifestyle as LAM is generally a chronic disease with slow progression over decades. LAM is a progressive disease with no cure but, in recent years, a medication called sirolimus has been shown to slow the decline in lung function in LAM. Sirolimus has been shown to slow the disease process, resolve fluid accumulation in the lungs (chylous effusions) and regress renal masses (angiomyolipomas). Sirolimus is approved by the U.S. Food and Drug Administration (FDA) as well as by the regulatory agencies in the European Union and 15 other countries across the world to treat LAM. Fluid accumulation in the lungs (pleural effusion) should be first managed with a trial of sirolimus, and invasive procedures such as drainage should only be employed in patients where sirolimus doesn’t have a satisfactory response. It is worth noting that it can sometimes take a few months for sirolimus to take full effect in the resolution of chylous fluids. Lung collapse (pneumothorax) may require the placement of a chest tube. Due to the high risk of recurrence, it is recommended that patients with LAM undergo a procedure called pleurodesis (a technique that adheres lungs to the chest wall) early in order to reduce the number of future pneumothoraces. Drugs that temporarily widen the bronchial tubes (bronchodilators) may help to alleviate breathing difficulties (asthma-like symptoms) in some patients. Influenza and pneumococcal vaccination are recommended due to the pulmonary vulnerability of individuals with LAM. Supplemental oxygen should be administered to qualifying patients as needed. As with other respiratory conditions, patients with LAM may benefit from pulmonary rehabilitation. In individuals with severe cases of LAM, lung transplantation may be considered. Renal angiomyolipomas pose a risk for internal bleeding especially as they increase in size. Interventional radiology procedures such as embolization or treatment with sirolimus may be needed to reduce the risk of bleeding. Surgical resection is rarely needed and should be reserved as a last resort. Because of the association between surges in female hormones and worsening of symptoms of LAM, estrogen-containing contraceptives are contraindicated. Postmenopausal patients and patients with reduced mobility should be tested for osteoporosis. Any loss of bone mineral density should be treated with vitamin D and calcium supplementation and/or bisphosphonates according to treatment guidelines for osteoporosis.
|
Therapies of Lymphangioleiomyomatosis. Treatment
Individuals with LAM are encouraged to lead a normal life with a healthy lifestyle as LAM is generally a chronic disease with slow progression over decades. LAM is a progressive disease with no cure but, in recent years, a medication called sirolimus has been shown to slow the decline in lung function in LAM. Sirolimus has been shown to slow the disease process, resolve fluid accumulation in the lungs (chylous effusions) and regress renal masses (angiomyolipomas). Sirolimus is approved by the U.S. Food and Drug Administration (FDA) as well as by the regulatory agencies in the European Union and 15 other countries across the world to treat LAM. Fluid accumulation in the lungs (pleural effusion) should be first managed with a trial of sirolimus, and invasive procedures such as drainage should only be employed in patients where sirolimus doesn’t have a satisfactory response. It is worth noting that it can sometimes take a few months for sirolimus to take full effect in the resolution of chylous fluids. Lung collapse (pneumothorax) may require the placement of a chest tube. Due to the high risk of recurrence, it is recommended that patients with LAM undergo a procedure called pleurodesis (a technique that adheres lungs to the chest wall) early in order to reduce the number of future pneumothoraces. Drugs that temporarily widen the bronchial tubes (bronchodilators) may help to alleviate breathing difficulties (asthma-like symptoms) in some patients. Influenza and pneumococcal vaccination are recommended due to the pulmonary vulnerability of individuals with LAM. Supplemental oxygen should be administered to qualifying patients as needed. As with other respiratory conditions, patients with LAM may benefit from pulmonary rehabilitation. In individuals with severe cases of LAM, lung transplantation may be considered. Renal angiomyolipomas pose a risk for internal bleeding especially as they increase in size. Interventional radiology procedures such as embolization or treatment with sirolimus may be needed to reduce the risk of bleeding. Surgical resection is rarely needed and should be reserved as a last resort. Because of the association between surges in female hormones and worsening of symptoms of LAM, estrogen-containing contraceptives are contraindicated. Postmenopausal patients and patients with reduced mobility should be tested for osteoporosis. Any loss of bone mineral density should be treated with vitamin D and calcium supplementation and/or bisphosphonates according to treatment guidelines for osteoporosis.
| 735 |
Lymphangioleiomyomatosis
|
nord_736_0
|
Overview of Lymphatic Malformations
|
SummaryLymphatic malformations are rare, non-malignant masses consisting of fluid-filled channels or spaces thought to be caused by the abnormal development of the lymphatic system. These malformations are usually apparent at birth or by two years of age. Lymphatic malformations can affect any area of the body (except the brain), but most commonly affect the head and neck. When evident at birth (congenital), lymphatic malformations tend to be soft, spongy, non-tender masses. The specific symptoms and severity of lymphatic malformations varies based upon the size and specific location of the malformation. Some lymphatic malformations can be massive. Lymphatic malformations, regardless of size, can potentially cause functional impairment of nearby structures or organs and disfigurement of affected areas.IntroductionThe lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that transport a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates between tissue cells and contains proteins, fats and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it passes through a network of lymph nodes that help the body remove sources of infection (e.g., viruses, bacteria, etc.) and inflammation (e.g. antigens). Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows and in the chest, abdomen and groin. The lymphatic system also includes the spleen, which filters worn-out red blood cells and produces lymphocytes and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells.Several different terms were once used to describe conditions now grouped under the umbrella term “lymphatic malformations.” Such terms include cystic hygroma, lymphangioma, cavernous lymphangioma, cystic lymphangioma and lymphangioma circumscriptum. These terms have been abandoned because some of the outdated terms imply a relationship to cancer. Lymphatic malformations are not cancerous and there is no known risk of malignant transformation.
|
Overview of Lymphatic Malformations. SummaryLymphatic malformations are rare, non-malignant masses consisting of fluid-filled channels or spaces thought to be caused by the abnormal development of the lymphatic system. These malformations are usually apparent at birth or by two years of age. Lymphatic malformations can affect any area of the body (except the brain), but most commonly affect the head and neck. When evident at birth (congenital), lymphatic malformations tend to be soft, spongy, non-tender masses. The specific symptoms and severity of lymphatic malformations varies based upon the size and specific location of the malformation. Some lymphatic malformations can be massive. Lymphatic malformations, regardless of size, can potentially cause functional impairment of nearby structures or organs and disfigurement of affected areas.IntroductionThe lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that transport a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates between tissue cells and contains proteins, fats and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it passes through a network of lymph nodes that help the body remove sources of infection (e.g., viruses, bacteria, etc.) and inflammation (e.g. antigens). Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows and in the chest, abdomen and groin. The lymphatic system also includes the spleen, which filters worn-out red blood cells and produces lymphocytes and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells.Several different terms were once used to describe conditions now grouped under the umbrella term “lymphatic malformations.” Such terms include cystic hygroma, lymphangioma, cavernous lymphangioma, cystic lymphangioma and lymphangioma circumscriptum. These terms have been abandoned because some of the outdated terms imply a relationship to cancer. Lymphatic malformations are not cancerous and there is no known risk of malignant transformation.
| 736 |
Lymphatic Malformations
|
nord_736_1
|
Symptoms of Lymphatic Malformations
|
Generally, symptoms from lymphatic malformations arise from compression or obstruction of nearby structures. Lymphatic malformations can involve any tissue. Usually they are found in only one area of the body (localized), but occasionally can be widespread (diffuse). When lymphatic malformations are widespread in bone and soft tissue, the condition may be referred to as lymphangiomatosis. Lymphatic malformations usually slowly grow larger as the patient grows, but sometimes get smaller spontaneously. Certain events such as puberty, infection, trauma or bleeding into a lymphatic malformation can cause them to grow rapidly.It is important to note that affected individuals may not have all of the symptoms discussed below and that one child’s experience can vary dramatically from another child’s experience. Parents of affected children should talk to their physician and medical team about their child’s specific case, associated symptoms and overall prognosis. The specific symptoms that develop depend upon the size and exact location of a lymphatic malformation.Lymphatic malformations are associated with overgrowth (hypertrophy) and swelling of any affected area including the lips, tongue, jaws, cheeks, arms, legs, fingers or toes. Malformations affecting the tongue, windpipe (trachea) or mouth can cause difficulty breathing (dyspnea), difficulties with speech and difficulty swallowing (dysphagia) and feeding problems. If the eye socket (orbit) is involved, double vision (diplopia) or displacement of the eyeball can occur (proptosis). Lymphatic malformations affecting the chest can cause wheezing, chest pain, chest pressure, shortness of breath, difficulty breathing and potentially airway compromise. Lymphatic malformations affecting the gastrointestinal tract or pelvis can cause constipation, bladder obstruction, recurrent infection or protein loss. Lesions in bone can be associated with bone overgrowth or bone loss.Certain complications can occur with lymphatic malformations including recurrent inflammation or bleeding (hemorrhaging) into the malformation. When lymphatic malformations become inflamed, they swell, and the skin in the involved area becomes red and warm. This is known as cellulitis. Recurrent cellulitis can cause pain and disfigurement of the affected area. Some patients with lymphatic malformation have abnormally low numbers of lymphocytes which make them prone to cellulitis. Bleeding into a lymphatic malformation can cause rapid pain, hardening, and swelling or enlargement of the malformation in the affected area.Radiographically lymphatic malformations have been categorized into three subtypes – macrocystic, microcystic or mixed (a combination of the other two). Macrocystic and microcystic lymphatic malformations are differentiated by the size of the fluid-containing portion of the malformation. The macrocystic type is made up of large cysts, more than 2 centimeters in diameter; the microcystic type is made up of smaller cysts or soft tissue enlargement without cyst formation. Most lymphatic malformations have both macrocystic and microcystic portions and histologically there is no difference between these categories. Macrocystic lymphatic malformations are characterized by a single or multiple fluid-filled pockets or cysts that occur most commonly in the nape of the neck. Macrocystic lymphatic malformations generally form soft, large translucent masses that can involve any area of the neck or chest. Overlying skin may have a bluish tinge. Although macrocystic lymphatic malformations typically appear on the back of the neck, they can, less frequently, originate near the armpits (axilla), in the groin, in the rear of the abdominal cavity, in the chest wall or in the hip or tailbone region. Macrocystic lymphatic malformations can potentially be extremely large, even large enough to obstruct the airway at delivery.Microcystic lymphatic malformations may appear as several small, raised sacs (vesicles) on the skin that contain clear or bloody (hemorrhagic) fluid. They generally grow slowly usually in proportion with a growing child. Microcystic lymphatic malformations can thicken or swell causing enlargement of surrounding soft tissue and bones. They can be found on any area of skin or mucous membrane.
|
Symptoms of Lymphatic Malformations. Generally, symptoms from lymphatic malformations arise from compression or obstruction of nearby structures. Lymphatic malformations can involve any tissue. Usually they are found in only one area of the body (localized), but occasionally can be widespread (diffuse). When lymphatic malformations are widespread in bone and soft tissue, the condition may be referred to as lymphangiomatosis. Lymphatic malformations usually slowly grow larger as the patient grows, but sometimes get smaller spontaneously. Certain events such as puberty, infection, trauma or bleeding into a lymphatic malformation can cause them to grow rapidly.It is important to note that affected individuals may not have all of the symptoms discussed below and that one child’s experience can vary dramatically from another child’s experience. Parents of affected children should talk to their physician and medical team about their child’s specific case, associated symptoms and overall prognosis. The specific symptoms that develop depend upon the size and exact location of a lymphatic malformation.Lymphatic malformations are associated with overgrowth (hypertrophy) and swelling of any affected area including the lips, tongue, jaws, cheeks, arms, legs, fingers or toes. Malformations affecting the tongue, windpipe (trachea) or mouth can cause difficulty breathing (dyspnea), difficulties with speech and difficulty swallowing (dysphagia) and feeding problems. If the eye socket (orbit) is involved, double vision (diplopia) or displacement of the eyeball can occur (proptosis). Lymphatic malformations affecting the chest can cause wheezing, chest pain, chest pressure, shortness of breath, difficulty breathing and potentially airway compromise. Lymphatic malformations affecting the gastrointestinal tract or pelvis can cause constipation, bladder obstruction, recurrent infection or protein loss. Lesions in bone can be associated with bone overgrowth or bone loss.Certain complications can occur with lymphatic malformations including recurrent inflammation or bleeding (hemorrhaging) into the malformation. When lymphatic malformations become inflamed, they swell, and the skin in the involved area becomes red and warm. This is known as cellulitis. Recurrent cellulitis can cause pain and disfigurement of the affected area. Some patients with lymphatic malformation have abnormally low numbers of lymphocytes which make them prone to cellulitis. Bleeding into a lymphatic malformation can cause rapid pain, hardening, and swelling or enlargement of the malformation in the affected area.Radiographically lymphatic malformations have been categorized into three subtypes – macrocystic, microcystic or mixed (a combination of the other two). Macrocystic and microcystic lymphatic malformations are differentiated by the size of the fluid-containing portion of the malformation. The macrocystic type is made up of large cysts, more than 2 centimeters in diameter; the microcystic type is made up of smaller cysts or soft tissue enlargement without cyst formation. Most lymphatic malformations have both macrocystic and microcystic portions and histologically there is no difference between these categories. Macrocystic lymphatic malformations are characterized by a single or multiple fluid-filled pockets or cysts that occur most commonly in the nape of the neck. Macrocystic lymphatic malformations generally form soft, large translucent masses that can involve any area of the neck or chest. Overlying skin may have a bluish tinge. Although macrocystic lymphatic malformations typically appear on the back of the neck, they can, less frequently, originate near the armpits (axilla), in the groin, in the rear of the abdominal cavity, in the chest wall or in the hip or tailbone region. Macrocystic lymphatic malformations can potentially be extremely large, even large enough to obstruct the airway at delivery.Microcystic lymphatic malformations may appear as several small, raised sacs (vesicles) on the skin that contain clear or bloody (hemorrhagic) fluid. They generally grow slowly usually in proportion with a growing child. Microcystic lymphatic malformations can thicken or swell causing enlargement of surrounding soft tissue and bones. They can be found on any area of skin or mucous membrane.
| 736 |
Lymphatic Malformations
|
nord_736_2
|
Causes of Lymphatic Malformations
|
The exact cause of lymphatic malformations is unknown. Lymphatic malformations result from abnormalities in the development of the lymphatic vascular system during embryonic growth. In a large number of patients, the lymphatic malformations have an activating mutation in the PIK3CA gene. This is a somatic (non-inherited) mutation isolated to the lymphatic endothelial cells lining the fluid filled channels. PIK3CA is known to play a role in regulating cell growth by signaling through the PI3K/mTOR pathway. Five different point mutations in DNA from lymphatic malformation tissue have been identified. It is unclear, however, if mutations in the PIK3CA gene alone cause lymphatic malformations. Sometimes the term “PROS” (PIK3CA-related overgrowth syndrome) is used to describe instances when both a PIK3CA mutation has been detected and overgrowth of the affected area is present.Lymphatic malformations may occur in-utero as a part of a larger syndrome. These include: Noonan syndrome, Turner syndrome and Down syndrome. Usually, lymphatic malformations detected prenatally regress and are absent at birth. Lymphatic malformations are also a feature of CLOVES syndrome and Klippel-Trenaunay syndrome (KTS). (For more information these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
|
Causes of Lymphatic Malformations. The exact cause of lymphatic malformations is unknown. Lymphatic malformations result from abnormalities in the development of the lymphatic vascular system during embryonic growth. In a large number of patients, the lymphatic malformations have an activating mutation in the PIK3CA gene. This is a somatic (non-inherited) mutation isolated to the lymphatic endothelial cells lining the fluid filled channels. PIK3CA is known to play a role in regulating cell growth by signaling through the PI3K/mTOR pathway. Five different point mutations in DNA from lymphatic malformation tissue have been identified. It is unclear, however, if mutations in the PIK3CA gene alone cause lymphatic malformations. Sometimes the term “PROS” (PIK3CA-related overgrowth syndrome) is used to describe instances when both a PIK3CA mutation has been detected and overgrowth of the affected area is present.Lymphatic malformations may occur in-utero as a part of a larger syndrome. These include: Noonan syndrome, Turner syndrome and Down syndrome. Usually, lymphatic malformations detected prenatally regress and are absent at birth. Lymphatic malformations are also a feature of CLOVES syndrome and Klippel-Trenaunay syndrome (KTS). (For more information these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
| 736 |
Lymphatic Malformations
|
nord_736_3
|
Affects of Lymphatic Malformations
|
Lymphatic malformations affect males and females in equal numbers. Most lymphatic malformations are evident at birth or within two years of age. However, in some patients, lymphatic malformations may not become apparent until adulthood. The exact prevalence of lymphatic malformations in the general population is unknown, but is thought to be approximately 1:4000 live births.
|
Affects of Lymphatic Malformations. Lymphatic malformations affect males and females in equal numbers. Most lymphatic malformations are evident at birth or within two years of age. However, in some patients, lymphatic malformations may not become apparent until adulthood. The exact prevalence of lymphatic malformations in the general population is unknown, but is thought to be approximately 1:4000 live births.
| 736 |
Lymphatic Malformations
|
nord_736_4
|
Related disorders of Lymphatic Malformations
|
Symptoms of the following disorders can be similar to those of lymphatic malformations. Comparisons may be useful for a differential diagnosis.Despite having a similar sounding name, complex lymphatic anomalies (including generalized lymphatic anomaly, Gorham-Stout disease, and kaposiform lymphangiomatosis) are a distinct group of conditions that are different from lymphatic malformations. Treatment options for complex lymphatic anomalies sometimes overlap with lymphatic malformations, but the underlying genetic cause has yet to be determined.Gorham-Stout disease, which is also known as vanishing bone disease, is a rare bone disorder characterized by bone loss (osteolysis) associated with overgrowth (proliferation) of small blood (vascular) or lymphatic vessels. Affected individuals experience progression destruction and resorption of bone. Multiple bones may become involved. Areas commonly affected include the pelvis, shoulder, spine, ribs, jaw and skull. Pain and swelling in the affected area may occur. Bones affected by Gorham-Stout disease are prone to fracture. Severity can vary from one individual to another and can potentially cause disfigurement and functional disability. The exact cause of Gorham-Stout disease is unknown. (For more information on this disorder, choose “Gorham” as your search term in the Rare Disease Database.)There are a variety of conditions or similar lesions that can be mistaken for a lymphatic malformation including Langerhans cell histiocytosis, lymphangioleiomyomatosis (LAM), and congenital pulmonary lymphangiectasia. Some benign and malignant tumors including hemangiomas, lipomas and gliomas need to be differentiated from lymphatic malformations. A variety of skin conditions can be mistaken for a lymphatic malformation that is limited to the skin. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
|
Related disorders of Lymphatic Malformations. Symptoms of the following disorders can be similar to those of lymphatic malformations. Comparisons may be useful for a differential diagnosis.Despite having a similar sounding name, complex lymphatic anomalies (including generalized lymphatic anomaly, Gorham-Stout disease, and kaposiform lymphangiomatosis) are a distinct group of conditions that are different from lymphatic malformations. Treatment options for complex lymphatic anomalies sometimes overlap with lymphatic malformations, but the underlying genetic cause has yet to be determined.Gorham-Stout disease, which is also known as vanishing bone disease, is a rare bone disorder characterized by bone loss (osteolysis) associated with overgrowth (proliferation) of small blood (vascular) or lymphatic vessels. Affected individuals experience progression destruction and resorption of bone. Multiple bones may become involved. Areas commonly affected include the pelvis, shoulder, spine, ribs, jaw and skull. Pain and swelling in the affected area may occur. Bones affected by Gorham-Stout disease are prone to fracture. Severity can vary from one individual to another and can potentially cause disfigurement and functional disability. The exact cause of Gorham-Stout disease is unknown. (For more information on this disorder, choose “Gorham” as your search term in the Rare Disease Database.)There are a variety of conditions or similar lesions that can be mistaken for a lymphatic malformation including Langerhans cell histiocytosis, lymphangioleiomyomatosis (LAM), and congenital pulmonary lymphangiectasia. Some benign and malignant tumors including hemangiomas, lipomas and gliomas need to be differentiated from lymphatic malformations. A variety of skin conditions can be mistaken for a lymphatic malformation that is limited to the skin. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
| 736 |
Lymphatic Malformations
|
nord_736_5
|
Diagnosis of Lymphatic Malformations
|
A diagnosis of lymphatic malformation can often be made before birth (prenatally) using ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. After birth, a diagnosis of a lymphatic malformation is made based upon a physical examination along with a detailed patient history.Advanced imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT) scanning and ultrasound may be used to evaluate the extent of a lymphatic malformation after birth. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.Genetic testing of malformation tissue for PIK3CA or other gene variants is available and can be used direct treatment planning (https://www.ncbi.nlm.nih.gov/gtr/tests/570484/).
|
Diagnosis of Lymphatic Malformations. A diagnosis of lymphatic malformation can often be made before birth (prenatally) using ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. After birth, a diagnosis of a lymphatic malformation is made based upon a physical examination along with a detailed patient history.Advanced imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT) scanning and ultrasound may be used to evaluate the extent of a lymphatic malformation after birth. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.Genetic testing of malformation tissue for PIK3CA or other gene variants is available and can be used direct treatment planning (https://www.ncbi.nlm.nih.gov/gtr/tests/570484/).
| 736 |
Lymphatic Malformations
|
nord_736_6
|
Therapies of Lymphatic Malformations
|
TreatmentThe treatment of lymphatic malformations is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric surgeons, neurosurgeons, ear-nose-throat specialists (otolaryngologists), speech pathologists, eye specialists (ophthalmologists) and other healthcare professionals may need to systematically and comprehensively plan a child’s treatment.Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as the exact size and location of a lymphatic malformation; the presence or absence of certain symptoms; the child’s age and overall health; the child’s tolerance of certain medications or treatments; personal preference and/or other elements. Decisions concerning the use of particular drugs and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient and/or parents based upon the specifics of the case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. For lymphatic malformations of the head and neck, staging systems have been developed that help guide treatment planning and predict treatment outcome.The main therapeutic options for treating a lymphatic malformation are active observation, percutaneous drainage, surgery, sclerotherapy, laser therapy, radiofrequency ablation or medical therapy. These different treatment options may be used in various combinations. Some lymphatic malformations have gone away without any therapy (spontaneous resolution), so observation is a viable treatment option in some cases.Percutaneous drainage is a procedure during which an incision is made into a lymphatic malformation and the fluid is drained, usually through a catheter or similar device. Percutaneous drainage is often performed along with surgery or sclerotherapy, as the drained cyst fluid can re-accumulate.Generally, macrocystic lymphatic malformations can be treated effectively and usually do not recur. Mixed and microcystic lymphatic malformations are often more difficult to treat as they do not respond as well to conventional therapies. There is a risk of recurrence of lymphatic malformations regardless of the treatment choice. Mixed and microcystic lymphatic malformations are more likely to recur and may require repeated therapies. In some cases, lymphatic malformations require lifelong therapy.Sclerotherapy is a procedure in which a solution called a sclerosant or sclerosing agent, is injected directly into the macrocystic lymphatic malformation. This solution causes scarring within the lymphatic malformation, which eventually causes it to shrink or collapse. Most moderately sized macrocystic lymphatic malformations can be easily treated with sclerotherapy. Although the popularity of sclerotherapy for lymphatic malformations is increasing, there is no specifically favored or agreed upon sclerosing agent used. Agents that have been used include alcohol, bleomycin, picinabil (OK-432), doxycycline, acetic acid and hypertonic saline. Sclerotherapy may require multiple sessions to be effective, especially in extensive malformations.Some lymphatic malformations, especially those that are localized to one area of the body, may be surgically removed (excised). The aim of surgery to remove a lymphatic malformation is to regain function of an affected area and prevent disfiguring complications. The exact location of a lymphatic malformation, such as proximity to a vital organ, may dictate only partial removal of the malformation. However, partial removal of a malformation may be sufficient to prevent complications. In some cases, the involvement of vital organs or structures makes surgical removal of a lymphatic malformation impossible.Laser therapy is sometimes used to treat individuals with lymphatic malformations that involve the skin or mucous membranes. Multiple treatments spaced out over time may be required, and laser therapy is usually used in combination with other treatment options.Radiofrequency ablation has been used to treat individuals with superficial skin or mucosal lymphatic malformations. During this procedure, a small needle is inserted into a lymphatic malformation. The needle is used to deliver a high-frequency alternating current (radiofrequency waves) that destroys (ablates) affected lymphatic vessel tissue. Initial reports show marked improvement or complete resolution of individuals treated with radiofrequency ablation. More research is necessary to determine the long-term safety and effectiveness of this potential therapy and other therapies for individuals with lymphatic malformations.Medical therapy with the drugs sirolimus or sildenafil can be used to treat both localized and diffuse lymphatic malformations. Sirolimus is most commonly used to treat cancer and is only recently prescribed to treat lymphatic malformations. This drug is taken orally, and it works by inhibiting cell growth by targeting the PI3K/mTOR pathway. How long an individual should take sirolimus remains to be determined. Sildenafil is also taken orally. It has been shown, in a small number of patients, to shrink lymphatic malformations. This drug allows blood and lymphatic vessel walls to relax, and this leads to decreased fluid collection. Clinical trials are underway to establish dosing guidelines and to compare these drugs to other treatment options. In the future it may be possible to use targeted medical therapies to inhibit PIK3CA gene variant activity in lymphatic malformations. Additional treatment for individuals with lymphatic malformations may be necessary based on the extent to which the malformation impairs normal breathing, eating and speaking. For example, airway compromise and difficulty breathing may ultimately require treatment with a tracheotomy, a procedure by which a tube is inserted into the throat through an incision in the windpipe, in order to achieve airway stabilization. If eating is impaired, a modified diet and/or gastrostomy tube may be necessary. Some children may require reconstructive surgery for the jaw bones because of overgrowth caused by the penetration of a lymphatic malformation. Infections may require antibiotics. Pain medication and anti-inflammatory medications may also be used in some cases.
|
Therapies of Lymphatic Malformations. TreatmentThe treatment of lymphatic malformations is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric surgeons, neurosurgeons, ear-nose-throat specialists (otolaryngologists), speech pathologists, eye specialists (ophthalmologists) and other healthcare professionals may need to systematically and comprehensively plan a child’s treatment.Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as the exact size and location of a lymphatic malformation; the presence or absence of certain symptoms; the child’s age and overall health; the child’s tolerance of certain medications or treatments; personal preference and/or other elements. Decisions concerning the use of particular drugs and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient and/or parents based upon the specifics of the case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. For lymphatic malformations of the head and neck, staging systems have been developed that help guide treatment planning and predict treatment outcome.The main therapeutic options for treating a lymphatic malformation are active observation, percutaneous drainage, surgery, sclerotherapy, laser therapy, radiofrequency ablation or medical therapy. These different treatment options may be used in various combinations. Some lymphatic malformations have gone away without any therapy (spontaneous resolution), so observation is a viable treatment option in some cases.Percutaneous drainage is a procedure during which an incision is made into a lymphatic malformation and the fluid is drained, usually through a catheter or similar device. Percutaneous drainage is often performed along with surgery or sclerotherapy, as the drained cyst fluid can re-accumulate.Generally, macrocystic lymphatic malformations can be treated effectively and usually do not recur. Mixed and microcystic lymphatic malformations are often more difficult to treat as they do not respond as well to conventional therapies. There is a risk of recurrence of lymphatic malformations regardless of the treatment choice. Mixed and microcystic lymphatic malformations are more likely to recur and may require repeated therapies. In some cases, lymphatic malformations require lifelong therapy.Sclerotherapy is a procedure in which a solution called a sclerosant or sclerosing agent, is injected directly into the macrocystic lymphatic malformation. This solution causes scarring within the lymphatic malformation, which eventually causes it to shrink or collapse. Most moderately sized macrocystic lymphatic malformations can be easily treated with sclerotherapy. Although the popularity of sclerotherapy for lymphatic malformations is increasing, there is no specifically favored or agreed upon sclerosing agent used. Agents that have been used include alcohol, bleomycin, picinabil (OK-432), doxycycline, acetic acid and hypertonic saline. Sclerotherapy may require multiple sessions to be effective, especially in extensive malformations.Some lymphatic malformations, especially those that are localized to one area of the body, may be surgically removed (excised). The aim of surgery to remove a lymphatic malformation is to regain function of an affected area and prevent disfiguring complications. The exact location of a lymphatic malformation, such as proximity to a vital organ, may dictate only partial removal of the malformation. However, partial removal of a malformation may be sufficient to prevent complications. In some cases, the involvement of vital organs or structures makes surgical removal of a lymphatic malformation impossible.Laser therapy is sometimes used to treat individuals with lymphatic malformations that involve the skin or mucous membranes. Multiple treatments spaced out over time may be required, and laser therapy is usually used in combination with other treatment options.Radiofrequency ablation has been used to treat individuals with superficial skin or mucosal lymphatic malformations. During this procedure, a small needle is inserted into a lymphatic malformation. The needle is used to deliver a high-frequency alternating current (radiofrequency waves) that destroys (ablates) affected lymphatic vessel tissue. Initial reports show marked improvement or complete resolution of individuals treated with radiofrequency ablation. More research is necessary to determine the long-term safety and effectiveness of this potential therapy and other therapies for individuals with lymphatic malformations.Medical therapy with the drugs sirolimus or sildenafil can be used to treat both localized and diffuse lymphatic malformations. Sirolimus is most commonly used to treat cancer and is only recently prescribed to treat lymphatic malformations. This drug is taken orally, and it works by inhibiting cell growth by targeting the PI3K/mTOR pathway. How long an individual should take sirolimus remains to be determined. Sildenafil is also taken orally. It has been shown, in a small number of patients, to shrink lymphatic malformations. This drug allows blood and lymphatic vessel walls to relax, and this leads to decreased fluid collection. Clinical trials are underway to establish dosing guidelines and to compare these drugs to other treatment options. In the future it may be possible to use targeted medical therapies to inhibit PIK3CA gene variant activity in lymphatic malformations. Additional treatment for individuals with lymphatic malformations may be necessary based on the extent to which the malformation impairs normal breathing, eating and speaking. For example, airway compromise and difficulty breathing may ultimately require treatment with a tracheotomy, a procedure by which a tube is inserted into the throat through an incision in the windpipe, in order to achieve airway stabilization. If eating is impaired, a modified diet and/or gastrostomy tube may be necessary. Some children may require reconstructive surgery for the jaw bones because of overgrowth caused by the penetration of a lymphatic malformation. Infections may require antibiotics. Pain medication and anti-inflammatory medications may also be used in some cases.
| 736 |
Lymphatic Malformations
|
nord_737_0
|
Overview of Lymphedema-Distichiasis Syndrome
|
Lymphedema-distichiasis syndrome is a rare genetic multisystem disorder characterized by swelling of the legs because of fluid accumulation and the development of extra eyelashes (distichiasis). Distichiasis may range from a few extra lashes to a full set of extra eyelashes. Swelling most often affects both legs (bilateral) and usually occurs around puberty. Additional anomalies sometimes associated with this disorder include early onset varicose veins, droopy eyelids (ptosis), heart defects, cleft palate, abnormal heart rhythm and abnormal curvature of the spine (scoliosis). Lymphedema-distichiasis syndrome is caused by changes (pathogenic variants) of the FOXC2 gene and is inherited in an autosomal dominant pattern.
|
Overview of Lymphedema-Distichiasis Syndrome. Lymphedema-distichiasis syndrome is a rare genetic multisystem disorder characterized by swelling of the legs because of fluid accumulation and the development of extra eyelashes (distichiasis). Distichiasis may range from a few extra lashes to a full set of extra eyelashes. Swelling most often affects both legs (bilateral) and usually occurs around puberty. Additional anomalies sometimes associated with this disorder include early onset varicose veins, droopy eyelids (ptosis), heart defects, cleft palate, abnormal heart rhythm and abnormal curvature of the spine (scoliosis). Lymphedema-distichiasis syndrome is caused by changes (pathogenic variants) of the FOXC2 gene and is inherited in an autosomal dominant pattern.
| 737 |
Lymphedema-Distichiasis Syndrome
|
nord_737_1
|
Symptoms of Lymphedema-Distichiasis Syndrome
|
The symptoms of lymphedema-distichiasis vary greatly from person to person even among members of the same family. The most common finding is the extra row of eyelashes (distichiasis). Most patients also develop swelling (edema) or puffiness of the legs because of the accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the skin.The severity of lymphedema (swelling due to the accumulation of lymph fluid) varies, but usually involves only the legs. In most people, both legs are affected (bilateral). In some people, swelling may cause tightness, discomfort and unusual tingling sensations (paresthesias) in the affected areas. Typically, lymphedema develops around puberty, although it can develop as early as before the person is born or in adulthood.Males develop lymphedema at an earlier age than females and are more likely to develop cellulitis. Cellulitis is an infection that is often associated with lymphedema. Cellulitis is characterized by swollen, reddened skin that may feel warm and tender.Distichiasis may range from a few extra lashes to a full set of extra eyelashes. This can be very hard to see and is often missed by routine examination. Associated eye abnormalities may occur including an abnormal sensitivity to light (photophobia), inflammation of the delicate membrane that lines the inside of the eyelids (conjunctivitis), irritation of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea) and the development of a small tender bump on the eyelid (stye). Drooping or sagging of the eyelids (ptosis) may also occur.Many individuals with lymphedema-distichiasis syndrome develop varicose veins, a condition marked by twisted, widened and enlarged veins just below the surface of the skin. In some people, varicose veins may precede the development of lymphedema. In individuals with lymphedema-distichiasis syndrome, varicose veins develop at a much younger age and with greater frequency than in the general population.Congenital heart disease has been reported in some individuals with lymphedema-distichiasis syndrome, especially a condition known as tetralogy of Fallot. Tetralogy of Fallot consists of a combination of four different heart defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles; and the abnormal enlargement of the right ventricle. This combination of abnormalities typically leads to poor blood flow to the lungs and poor blood oxygenation. The symptoms tend to worsen with time if this remains untreated and can be life-threatening.In some patients, irregular heartbeats (arrhythmias) may develop.Rarely, additional abnormalities have been reported to occur in association with lymphedema-distichiasis syndrome including crossed eyes (strabismus), incomplete closure of the roof of the mouth (cleft palate), side-to-side curvature of the spine (scoliosis), webbing of the neck, and cysts on the outermost layer of the membranes (meninges) that cover the spinal cord (spinal extradural cysts). Very rarely, patients may have total body swelling prior to birth (hydrops fetalis). Also very rarely, patients may have breathing problems due to abnormal lymph flow in their lungs.
|
Symptoms of Lymphedema-Distichiasis Syndrome. The symptoms of lymphedema-distichiasis vary greatly from person to person even among members of the same family. The most common finding is the extra row of eyelashes (distichiasis). Most patients also develop swelling (edema) or puffiness of the legs because of the accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the skin.The severity of lymphedema (swelling due to the accumulation of lymph fluid) varies, but usually involves only the legs. In most people, both legs are affected (bilateral). In some people, swelling may cause tightness, discomfort and unusual tingling sensations (paresthesias) in the affected areas. Typically, lymphedema develops around puberty, although it can develop as early as before the person is born or in adulthood.Males develop lymphedema at an earlier age than females and are more likely to develop cellulitis. Cellulitis is an infection that is often associated with lymphedema. Cellulitis is characterized by swollen, reddened skin that may feel warm and tender.Distichiasis may range from a few extra lashes to a full set of extra eyelashes. This can be very hard to see and is often missed by routine examination. Associated eye abnormalities may occur including an abnormal sensitivity to light (photophobia), inflammation of the delicate membrane that lines the inside of the eyelids (conjunctivitis), irritation of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea) and the development of a small tender bump on the eyelid (stye). Drooping or sagging of the eyelids (ptosis) may also occur.Many individuals with lymphedema-distichiasis syndrome develop varicose veins, a condition marked by twisted, widened and enlarged veins just below the surface of the skin. In some people, varicose veins may precede the development of lymphedema. In individuals with lymphedema-distichiasis syndrome, varicose veins develop at a much younger age and with greater frequency than in the general population.Congenital heart disease has been reported in some individuals with lymphedema-distichiasis syndrome, especially a condition known as tetralogy of Fallot. Tetralogy of Fallot consists of a combination of four different heart defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles; and the abnormal enlargement of the right ventricle. This combination of abnormalities typically leads to poor blood flow to the lungs and poor blood oxygenation. The symptoms tend to worsen with time if this remains untreated and can be life-threatening.In some patients, irregular heartbeats (arrhythmias) may develop.Rarely, additional abnormalities have been reported to occur in association with lymphedema-distichiasis syndrome including crossed eyes (strabismus), incomplete closure of the roof of the mouth (cleft palate), side-to-side curvature of the spine (scoliosis), webbing of the neck, and cysts on the outermost layer of the membranes (meninges) that cover the spinal cord (spinal extradural cysts). Very rarely, patients may have total body swelling prior to birth (hydrops fetalis). Also very rarely, patients may have breathing problems due to abnormal lymph flow in their lungs.
| 737 |
Lymphedema-Distichiasis Syndrome
|
nord_737_2
|
Causes of Lymphedema-Distichiasis Syndrome
|
Lymphedema-distichiasis syndrome occurs due to variants that disrupt/change the forkhead family transcription factor (FOXC2) gene. It is currently unknown exactly how variants in this gene lead to the symptoms of lymphedema-distichiasis syndrome, but the variants are thought to result in loss-of-function.Lymphedema is caused by the accumulation of protein-rich fluid (lymph) in areas of the body, typically due to dysfunction or abnormality of the lymphatic system. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute lymph and blood cells throughout the body. In lymphedema-distichiasis syndrome it is possible that the lymphedema develops due to obstruction, malformation, underdevelopment (hypoplasia) or improper function of various lymphatic vessels. One group of researchers, Mellor et al., showed that the venous valves failed in both the superficial and deep veins in the lower limbs of individuals with FOXC2 variants suggesting that the FOXC2 gene is important for the normal development and maintenance of venous and lymphatic valves. Their group also showed that lymph vessel function in people with lymphedema distichiasis syndrome was negatively affected by gravity, possibly explaining why the legs are primarily affected when the variant is present in every cell in the body.Lymphedema-distichiasis syndrome is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
|
Causes of Lymphedema-Distichiasis Syndrome. Lymphedema-distichiasis syndrome occurs due to variants that disrupt/change the forkhead family transcription factor (FOXC2) gene. It is currently unknown exactly how variants in this gene lead to the symptoms of lymphedema-distichiasis syndrome, but the variants are thought to result in loss-of-function.Lymphedema is caused by the accumulation of protein-rich fluid (lymph) in areas of the body, typically due to dysfunction or abnormality of the lymphatic system. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute lymph and blood cells throughout the body. In lymphedema-distichiasis syndrome it is possible that the lymphedema develops due to obstruction, malformation, underdevelopment (hypoplasia) or improper function of various lymphatic vessels. One group of researchers, Mellor et al., showed that the venous valves failed in both the superficial and deep veins in the lower limbs of individuals with FOXC2 variants suggesting that the FOXC2 gene is important for the normal development and maintenance of venous and lymphatic valves. Their group also showed that lymph vessel function in people with lymphedema distichiasis syndrome was negatively affected by gravity, possibly explaining why the legs are primarily affected when the variant is present in every cell in the body.Lymphedema-distichiasis syndrome is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
| 737 |
Lymphedema-Distichiasis Syndrome
|
nord_737_3
|
Affects of Lymphedema-Distichiasis Syndrome
|
Lymphedema-distichiasis affects males and females in equal numbers. Lymphedema develops in males at an earlier age than females. The prevalence of this disorder in the general population is unknown. Lymphedema-distichiasis syndrome may go undiagnosed making it difficult to determine its true frequency in the general population.
|
Affects of Lymphedema-Distichiasis Syndrome. Lymphedema-distichiasis affects males and females in equal numbers. Lymphedema develops in males at an earlier age than females. The prevalence of this disorder in the general population is unknown. Lymphedema-distichiasis syndrome may go undiagnosed making it difficult to determine its true frequency in the general population.
| 737 |
Lymphedema-Distichiasis Syndrome
|
nord_737_4
|
Related disorders of Lymphedema-Distichiasis Syndrome
|
Symptoms of the following disorders can be similar to those of lymphedema-distichiasis. Comparisons may be useful for a differential diagnosis.The hereditary lymphedemas are the disorders most commonly confused with lymphedema-distichiasis syndrome. The disorder which is most similar is hereditary lymphedema type II or Meige syndrome. Persons with Meige syndrome have pubertal onset of lymphedema (swelling due to accumulation of tissue fluid) this is not typically associated with other symptoms or malformations. This disorder is autosomal dominant, but the gene is not known.Hereditary lymphedema type IA, also known as Milroy disease, typically presents much earlier than lymphedema-distichiasis or Meige. Most patients have lower limb lymphedema at birth or in the first year of life. This disorder is also autosomal dominant and is caused by variants in the FLT4 or VEGFR3 gene.Hypotrichosis-lymphedema-telangiectasia syndrome is another disorder associated with lower limb lymphedema. The lymphedema typically occurs in childhood. This is associated with loss of hair and telangiectasias which are most commonly seen on the palms of the hands. It is caused by variants in SOX18 and can be either autosomal dominant or autosomal recessive.Yellow nail syndrome typically presents much later in life than lymphedema-distichiasis, Milroy, Meige, or hypotrichosis-lymphedema-telangiectasia. It is a rare disorder characterized by yellow, thickened, and curved nails with almost complete stoppage of nail growth. Loss of the strip of hardened skin at the base and sides of a fingernail (cuticles) may also occur. Separation of the nails from the nail bed (onycholysis) may cause the nails to fall out. Yellow nail syndrome is usually associated with the presence of fluid in the lungs (plural effusion) and swelling of the arms and legs (lymphedema). Other respiratory problems may occur such as chronic inflammation of the bronchi and bronchioles (bronchiectasis), chronic bronchitis, and/or ongoing inflammation of the membranes that line the sinus cavities (sinusitis). Lymphedema usually occurs around puberty. The genetic etiology of yellow nail syndrome is unknown although it has been associated in some patients with variants in the FOXC2 gene and is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Yellow Nail” as your search term in the Rare Disease Database.)None of the above disorders have distichiasis.
|
Related disorders of Lymphedema-Distichiasis Syndrome. Symptoms of the following disorders can be similar to those of lymphedema-distichiasis. Comparisons may be useful for a differential diagnosis.The hereditary lymphedemas are the disorders most commonly confused with lymphedema-distichiasis syndrome. The disorder which is most similar is hereditary lymphedema type II or Meige syndrome. Persons with Meige syndrome have pubertal onset of lymphedema (swelling due to accumulation of tissue fluid) this is not typically associated with other symptoms or malformations. This disorder is autosomal dominant, but the gene is not known.Hereditary lymphedema type IA, also known as Milroy disease, typically presents much earlier than lymphedema-distichiasis or Meige. Most patients have lower limb lymphedema at birth or in the first year of life. This disorder is also autosomal dominant and is caused by variants in the FLT4 or VEGFR3 gene.Hypotrichosis-lymphedema-telangiectasia syndrome is another disorder associated with lower limb lymphedema. The lymphedema typically occurs in childhood. This is associated with loss of hair and telangiectasias which are most commonly seen on the palms of the hands. It is caused by variants in SOX18 and can be either autosomal dominant or autosomal recessive.Yellow nail syndrome typically presents much later in life than lymphedema-distichiasis, Milroy, Meige, or hypotrichosis-lymphedema-telangiectasia. It is a rare disorder characterized by yellow, thickened, and curved nails with almost complete stoppage of nail growth. Loss of the strip of hardened skin at the base and sides of a fingernail (cuticles) may also occur. Separation of the nails from the nail bed (onycholysis) may cause the nails to fall out. Yellow nail syndrome is usually associated with the presence of fluid in the lungs (plural effusion) and swelling of the arms and legs (lymphedema). Other respiratory problems may occur such as chronic inflammation of the bronchi and bronchioles (bronchiectasis), chronic bronchitis, and/or ongoing inflammation of the membranes that line the sinus cavities (sinusitis). Lymphedema usually occurs around puberty. The genetic etiology of yellow nail syndrome is unknown although it has been associated in some patients with variants in the FOXC2 gene and is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Yellow Nail” as your search term in the Rare Disease Database.)None of the above disorders have distichiasis.
| 737 |
Lymphedema-Distichiasis Syndrome
|
nord_737_5
|
Diagnosis of Lymphedema-Distichiasis Syndrome
|
A diagnosis of lymphedema-distichiasis syndrome is primarily made based upon a thorough clinical evaluation, a detailed patient history and the identification of characteristic findings (i.e., primary lymphedema, distichiasis). FOXC2 molecular testing is available clinically to help confirm a diagnosis. A variety of specialized tests may be performed to determine the extent of the disorder. Such tests include lymphoscintigraphy or an echocardiogram. During lymphoscintigraphy, a substance known as a contrast medium is injected into a lymphatic vessel (usually in a hand or foot). A series of x-rays are taken that show the medium as it moves through the lymphatic vessels giving physicians a picture of the health and structure of the lymphatic vessels. During an echocardiogram, reflected sounds waves are used to create an image of the heart, which can reveal congenital heart defects potentially associated with lymphedema-distichiasis syndrome.
|
Diagnosis of Lymphedema-Distichiasis Syndrome. A diagnosis of lymphedema-distichiasis syndrome is primarily made based upon a thorough clinical evaluation, a detailed patient history and the identification of characteristic findings (i.e., primary lymphedema, distichiasis). FOXC2 molecular testing is available clinically to help confirm a diagnosis. A variety of specialized tests may be performed to determine the extent of the disorder. Such tests include lymphoscintigraphy or an echocardiogram. During lymphoscintigraphy, a substance known as a contrast medium is injected into a lymphatic vessel (usually in a hand or foot). A series of x-rays are taken that show the medium as it moves through the lymphatic vessels giving physicians a picture of the health and structure of the lymphatic vessels. During an echocardiogram, reflected sounds waves are used to create an image of the heart, which can reveal congenital heart defects potentially associated with lymphedema-distichiasis syndrome.
| 737 |
Lymphedema-Distichiasis Syndrome
|
nord_737_6
|
Therapies of Lymphedema-Distichiasis Syndrome
|
Treatment
The treatment of lymphedema-distichiasis syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment is aimed at reducing swelling and preventing infection. Complete decongestive therapy (CDT) is a form of treatment in which specialized massage techniques are coupled with therapeutic bandaging, meticulous skin care, exercise and the use of well-fitted compression garments such as fitted stockings. Antibiotics may be used to treat recurrent infections such as cellulitis or as a preventive (prophylactic) measure in individuals with recurrent infections.Distichiasis may be managed with lubrication or plucking (epilation). More definitive treatments for distichiasis include cryotherapy, electrolysis or lid splitting. Cryotherapy is the application of extreme cold to destroy diseased tissue. Electrolysis uses a short-wave radio frequency to destroy the extra eyelashes. Lip splitting is a surgical procedure in which the eyelid is split open to expose the root (follicle) of the eyelashes. Each extra eyelash is then removed (excised). In some cases, cryotherapy or electrolysis is used in conjunction with lid splitting.In some patients, surgery may be performed to treat other abnormalities such as ptosis or cleft palate. Individuals with heart abnormalities may be monitored regularly.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
|
Therapies of Lymphedema-Distichiasis Syndrome. Treatment
The treatment of lymphedema-distichiasis syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment is aimed at reducing swelling and preventing infection. Complete decongestive therapy (CDT) is a form of treatment in which specialized massage techniques are coupled with therapeutic bandaging, meticulous skin care, exercise and the use of well-fitted compression garments such as fitted stockings. Antibiotics may be used to treat recurrent infections such as cellulitis or as a preventive (prophylactic) measure in individuals with recurrent infections.Distichiasis may be managed with lubrication or plucking (epilation). More definitive treatments for distichiasis include cryotherapy, electrolysis or lid splitting. Cryotherapy is the application of extreme cold to destroy diseased tissue. Electrolysis uses a short-wave radio frequency to destroy the extra eyelashes. Lip splitting is a surgical procedure in which the eyelid is split open to expose the root (follicle) of the eyelashes. Each extra eyelash is then removed (excised). In some cases, cryotherapy or electrolysis is used in conjunction with lid splitting.In some patients, surgery may be performed to treat other abnormalities such as ptosis or cleft palate. Individuals with heart abnormalities may be monitored regularly.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
| 737 |
Lymphedema-Distichiasis Syndrome
|
nord_738_0
|
Overview of Lymphocytic Infiltrate of Jessner
|
SummaryLymphocytic infiltrate of Jessner is a rare skin condition that may be characterized by non-cancerous (benign) buildup of white blood cells, which present as lesions or lumps on the skin. These lesions may be seen on areas including the face, neck, upper extremities, shoulders, and upper back (skin most exposed to sunlight). They may be described as small, non-scaly in nature, and pink/red in color. Although the lesions are typically not painful, patients with lymphocytic infiltrate of Jessner may experience itchiness and redness. Presentation can vary, for example, the lesions may remain unchanged for several years and resolve. Other patients may go through worsening of symptoms for years.IntroductionLymphocytic infiltrate of Jessner has been thought to fall in the same spectrum as the autoimmune disease known as lupus tumidus or discoid lupus erythematosus. However, other scientists believe that lymphocytic infiltrate of Jessner should be designated its own category.
|
Overview of Lymphocytic Infiltrate of Jessner. SummaryLymphocytic infiltrate of Jessner is a rare skin condition that may be characterized by non-cancerous (benign) buildup of white blood cells, which present as lesions or lumps on the skin. These lesions may be seen on areas including the face, neck, upper extremities, shoulders, and upper back (skin most exposed to sunlight). They may be described as small, non-scaly in nature, and pink/red in color. Although the lesions are typically not painful, patients with lymphocytic infiltrate of Jessner may experience itchiness and redness. Presentation can vary, for example, the lesions may remain unchanged for several years and resolve. Other patients may go through worsening of symptoms for years.IntroductionLymphocytic infiltrate of Jessner has been thought to fall in the same spectrum as the autoimmune disease known as lupus tumidus or discoid lupus erythematosus. However, other scientists believe that lymphocytic infiltrate of Jessner should be designated its own category.
| 738 |
Lymphocytic Infiltrate of Jessner
|
nord_738_1
|
Symptoms of Lymphocytic Infiltrate of Jessner
|
Patients living with lymphocytic infiltrate of Jessner may experience symptoms including itchiness (pruritus), redness of the skin (erythema), and pimple-like eruptions (papules), most commonly on areas exposed to sunlight. These pimple-like lesions may last up to several months. As they extend from the perimeter, these lesions form well-defined, smooth, red patches (plaques) whose diameter may go as far as up to one inch. Occasionally, clear centers will form on the plaques. The skin surrounding the lesions may be reddened or itching. Those affected may also experience a burning sensation surrounding the skin lesions. An additional symptom that people with Jessner disease frequently report is sensitivity of the skin to sunlight exposure cutaneous photosensitivity. The course of lymphocytic Infiltrate of Jessner varies from person to person. It is important to note that the symptoms typically disappear after several years but it is also possible that they may reappear later. The course or progression of the disease may alternate between periods of worsening and relieving of symptoms. These periods may last up to months or even years in some individuals.
|
Symptoms of Lymphocytic Infiltrate of Jessner. Patients living with lymphocytic infiltrate of Jessner may experience symptoms including itchiness (pruritus), redness of the skin (erythema), and pimple-like eruptions (papules), most commonly on areas exposed to sunlight. These pimple-like lesions may last up to several months. As they extend from the perimeter, these lesions form well-defined, smooth, red patches (plaques) whose diameter may go as far as up to one inch. Occasionally, clear centers will form on the plaques. The skin surrounding the lesions may be reddened or itching. Those affected may also experience a burning sensation surrounding the skin lesions. An additional symptom that people with Jessner disease frequently report is sensitivity of the skin to sunlight exposure cutaneous photosensitivity. The course of lymphocytic Infiltrate of Jessner varies from person to person. It is important to note that the symptoms typically disappear after several years but it is also possible that they may reappear later. The course or progression of the disease may alternate between periods of worsening and relieving of symptoms. These periods may last up to months or even years in some individuals.
| 738 |
Lymphocytic Infiltrate of Jessner
|
nord_738_2
|
Causes of Lymphocytic Infiltrate of Jessner
|
Lymphocytic Infiltrate of Jessner is a rare inflammatory disease with an unknown cause. What is known however is that this condition involves the inappropriate accumulation of T helper cells (subtype of white blood cells) in the skin. Some clinical scientists argue that this condition is possibly a subtype of the autoimmune condition known as lupus erythematosus, while others believe that it may have its own class. Jessner disease may have a genetic/hereditary component. In addition, affected individuals may also have a prior history of photosensitivity.
|
Causes of Lymphocytic Infiltrate of Jessner. Lymphocytic Infiltrate of Jessner is a rare inflammatory disease with an unknown cause. What is known however is that this condition involves the inappropriate accumulation of T helper cells (subtype of white blood cells) in the skin. Some clinical scientists argue that this condition is possibly a subtype of the autoimmune condition known as lupus erythematosus, while others believe that it may have its own class. Jessner disease may have a genetic/hereditary component. In addition, affected individuals may also have a prior history of photosensitivity.
| 738 |
Lymphocytic Infiltrate of Jessner
|
nord_738_3
|
Affects of Lymphocytic Infiltrate of Jessner
|
While its prevalence in the United States or Europe is not clearly understood as of yet, some scientists believe that lymphocytic Infiltrate of Jessner occurs predominantly in males. In addition, its onset usually occurs between the ages of thirty and fifty and rarely affects children.
|
Affects of Lymphocytic Infiltrate of Jessner. While its prevalence in the United States or Europe is not clearly understood as of yet, some scientists believe that lymphocytic Infiltrate of Jessner occurs predominantly in males. In addition, its onset usually occurs between the ages of thirty and fifty and rarely affects children.
| 738 |
Lymphocytic Infiltrate of Jessner
|
nord_738_4
|
Related disorders of Lymphocytic Infiltrate of Jessner
|
Symptoms common in those living with Jessner’s lymphocytic infiltrate of the skin may also be found in other skin-related disorders. These include lymphocytoma cutis, mycosis fungoides, discoid lupus erythematosus; lupus erythematosus tumidus (LET), leprosy, polymorphous light eruption (PMLE), cutaneous lymphoid hyperplasia, granuloma annulare, and granuloma faciale. In some patients, it may be difficult to differentiate between Jessner’s lymphocytic infiltrate of the skin and the others mentioned above. Lymphocytoma cutis is a skin disorder developed from the accumulation of white blood cells lymphatic cells as well as cells found in connective tissue (histiocytes). The accumulation of these cells form lesions that appear purple or yellow-brown in color, shiny and spherical in form, and may either be confined to a small area or widespread.Mycosis fungoides (MF) is a chronic disorder of the lymph that progresses over time. MF is one of the most common types of cutaneous T cell lymphoma (CTCL). It is also known as a mature T cell non-Hodgkin lymphoma. MF’s clinical presentation involves the skin, with potential to spread to lymph nodes, the blood, and internal organs (viscera). At first, this condition mirrors the appearance of eczema and other inflammatory skin disorders. With time, however, the disease progresses into lesions varying from localized to widespread, mushroom-like tumors, or intense widespread reddening of the skin (erythroderma). Discoid lupus erythematosus (DLE) is a subtype of lupus erythematosus, which only presents with lesions on the skin. These lesions that form on the skin often appear on the face and lead to redness, roughness (hyperkeratosis), and dilation of blood vessels (telangiectasia). This condition may also eventually lead to systemic lupus, which causes the immune system to attack its own tissues. Leprosy also known as Hansen’s disease is both contagious and progressive in nature. It is thought to be spread through the respiratory route. This disorder is caused by airborne bacteria called Hansen’s bacillus or Mycobacterium leprae. Additionally, it is more prevalent in regions of warmer climate and affects the skin and peripheral nerves. In Leprosy, abnormal cells (granulomatous) are formed primarily around the nerves located in the skin. Clinical findings may include reddened patches on the skin, diminished sensation in affected areas, burning sensation usually in the lower extremities (paresthesias), wounds or burns without pain, and enlarged peripheral nerves. Polymorphous light eruption (PMLE) is also referred to as sun poisoning or sun allergy. Those affected with PMLE often experience rashes accompanied with itching. Skin lesions can occur up to days after sun-exposure and can last up to several days or even weeks.Cutaneous lymphoid hyperplasia is also known as cutaneous B cell pseudo lymphoma or borrelial lymphocytoma cutis. It is a rare disorder in which there is a large increase in the number of B cells. Its clinical presentation includes skin-colored or red plaques on the chest or face. In contrast with Jessner’s lymphocytic infiltrate, this disorder often presents with infiltrates throughout the skin. Lastly, granuloma annulare (GA) and granuloma faciale (GF) may also appear similar to Jessner’s lymphocytic infiltrate. GA is common and often self-limited. It may affect both children as well as adults. While there are various forms of GA, the most common is localized GA. This form of GA presents with non-scaly reddened plaques on lower extremities. Some cases of GA may resolve spontaneously within only a few years. On the other hand, granuloma faciale (GF) is a chronic and benign form of inflammatory skin disorder. Its presentation includes single or multiple lesions on the face that appear reddish brown in color and its size may range. Some people who live with this disorder may not experience any symptoms, while others may experience itching.
|
Related disorders of Lymphocytic Infiltrate of Jessner. Symptoms common in those living with Jessner’s lymphocytic infiltrate of the skin may also be found in other skin-related disorders. These include lymphocytoma cutis, mycosis fungoides, discoid lupus erythematosus; lupus erythematosus tumidus (LET), leprosy, polymorphous light eruption (PMLE), cutaneous lymphoid hyperplasia, granuloma annulare, and granuloma faciale. In some patients, it may be difficult to differentiate between Jessner’s lymphocytic infiltrate of the skin and the others mentioned above. Lymphocytoma cutis is a skin disorder developed from the accumulation of white blood cells lymphatic cells as well as cells found in connective tissue (histiocytes). The accumulation of these cells form lesions that appear purple or yellow-brown in color, shiny and spherical in form, and may either be confined to a small area or widespread.Mycosis fungoides (MF) is a chronic disorder of the lymph that progresses over time. MF is one of the most common types of cutaneous T cell lymphoma (CTCL). It is also known as a mature T cell non-Hodgkin lymphoma. MF’s clinical presentation involves the skin, with potential to spread to lymph nodes, the blood, and internal organs (viscera). At first, this condition mirrors the appearance of eczema and other inflammatory skin disorders. With time, however, the disease progresses into lesions varying from localized to widespread, mushroom-like tumors, or intense widespread reddening of the skin (erythroderma). Discoid lupus erythematosus (DLE) is a subtype of lupus erythematosus, which only presents with lesions on the skin. These lesions that form on the skin often appear on the face and lead to redness, roughness (hyperkeratosis), and dilation of blood vessels (telangiectasia). This condition may also eventually lead to systemic lupus, which causes the immune system to attack its own tissues. Leprosy also known as Hansen’s disease is both contagious and progressive in nature. It is thought to be spread through the respiratory route. This disorder is caused by airborne bacteria called Hansen’s bacillus or Mycobacterium leprae. Additionally, it is more prevalent in regions of warmer climate and affects the skin and peripheral nerves. In Leprosy, abnormal cells (granulomatous) are formed primarily around the nerves located in the skin. Clinical findings may include reddened patches on the skin, diminished sensation in affected areas, burning sensation usually in the lower extremities (paresthesias), wounds or burns without pain, and enlarged peripheral nerves. Polymorphous light eruption (PMLE) is also referred to as sun poisoning or sun allergy. Those affected with PMLE often experience rashes accompanied with itching. Skin lesions can occur up to days after sun-exposure and can last up to several days or even weeks.Cutaneous lymphoid hyperplasia is also known as cutaneous B cell pseudo lymphoma or borrelial lymphocytoma cutis. It is a rare disorder in which there is a large increase in the number of B cells. Its clinical presentation includes skin-colored or red plaques on the chest or face. In contrast with Jessner’s lymphocytic infiltrate, this disorder often presents with infiltrates throughout the skin. Lastly, granuloma annulare (GA) and granuloma faciale (GF) may also appear similar to Jessner’s lymphocytic infiltrate. GA is common and often self-limited. It may affect both children as well as adults. While there are various forms of GA, the most common is localized GA. This form of GA presents with non-scaly reddened plaques on lower extremities. Some cases of GA may resolve spontaneously within only a few years. On the other hand, granuloma faciale (GF) is a chronic and benign form of inflammatory skin disorder. Its presentation includes single or multiple lesions on the face that appear reddish brown in color and its size may range. Some people who live with this disorder may not experience any symptoms, while others may experience itching.
| 738 |
Lymphocytic Infiltrate of Jessner
|
nord_738_5
|
Diagnosis of Lymphocytic Infiltrate of Jessner
|
First, a thorough medical history and physical examination should be completed to assess for all potential risk factors including genetics and photosensitivity. In addition, a skin biopsy from a newly formed lesion should be tested in order to rule out other similar conditions including discoid lupus erythematosus (DLE) and polymorphous light eruption (PLE). Additional labs may also be beneficial in confirming the diagnosis and ruling out other conditions, which may include lymphocytoma cutis (blood cell cancer of the skin). Such assessments include a complete blood count (CBC), presence of antibodies using the antinuclear antibody panel (ANA test), and presence of inflammation or autoimmune disease with the erythrocyte sedimentation rate (ESR).
|
Diagnosis of Lymphocytic Infiltrate of Jessner. First, a thorough medical history and physical examination should be completed to assess for all potential risk factors including genetics and photosensitivity. In addition, a skin biopsy from a newly formed lesion should be tested in order to rule out other similar conditions including discoid lupus erythematosus (DLE) and polymorphous light eruption (PLE). Additional labs may also be beneficial in confirming the diagnosis and ruling out other conditions, which may include lymphocytoma cutis (blood cell cancer of the skin). Such assessments include a complete blood count (CBC), presence of antibodies using the antinuclear antibody panel (ANA test), and presence of inflammation or autoimmune disease with the erythrocyte sedimentation rate (ESR).
| 738 |
Lymphocytic Infiltrate of Jessner
|
nord_738_6
|
Therapies of Lymphocytic Infiltrate of Jessner
|
Treatment
Since lymphocytic Infiltrate of Jessner may sometimes resolve on its own, initial recommendation usually includes watchful waiting. In this case, treatment may not be necessary. Others who may need to seek treatment might be advised to use cosmetics to improve appearance, protect from sunlight, removal of the lesions via surgery, radiotherapy, steroids including topical medium-potency formulations, freezing of the lesions (cryotherapy), the use of select oral medications, or appropriate chemotherapy drugs (cyclophosphamide, methotrexate). It is important to note that the use of steroids, whether they be topical or systemic, must be monitored very closely. In addition, routine follow-up visits to the dermatologist are essential to monitor overall progress and treatment. Those seeking treatment must also remember to protect from sunlight to prevent progression of existing lesions or formation of new lesions.
|
Therapies of Lymphocytic Infiltrate of Jessner. Treatment
Since lymphocytic Infiltrate of Jessner may sometimes resolve on its own, initial recommendation usually includes watchful waiting. In this case, treatment may not be necessary. Others who may need to seek treatment might be advised to use cosmetics to improve appearance, protect from sunlight, removal of the lesions via surgery, radiotherapy, steroids including topical medium-potency formulations, freezing of the lesions (cryotherapy), the use of select oral medications, or appropriate chemotherapy drugs (cyclophosphamide, methotrexate). It is important to note that the use of steroids, whether they be topical or systemic, must be monitored very closely. In addition, routine follow-up visits to the dermatologist are essential to monitor overall progress and treatment. Those seeking treatment must also remember to protect from sunlight to prevent progression of existing lesions or formation of new lesions.
| 738 |
Lymphocytic Infiltrate of Jessner
|
nord_739_0
|
Overview of Lymphomatoid Granulomatosis
|
Lymphomatoid granulomatosis is a rare disorder characterized by overproduction (proliferation) of white blood cells called lymphocytes (lymphoproliferative disorder). The abnormal cells infiltrate and accumulate (form lesions or nodules) within tissues. The lesions or nodules damage or destroy the blood vessels within these tissues. The lungs are most commonly affected in lymphomatoid granulomatosis. Symptoms often include cough, shortness of breath (dyspnea) and chest tightness. Other areas of the body such as the skin, central nervous system, kidneys and liver are also frequently affected.The abnormal cells in lymphomatoid granulomatosis are B-cells (B lymphocytes) containing the Epstein-Barr virus. There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes. Because lymphomatoid granulomatosis is caused by the growth of abnormal B-cells, affected individuals may eventually develop B-cell lymphoma, a form of non-Hodgkin lymphoma. Lymphoma is a general term for cancer of the lymphatic system.
|
Overview of Lymphomatoid Granulomatosis. Lymphomatoid granulomatosis is a rare disorder characterized by overproduction (proliferation) of white blood cells called lymphocytes (lymphoproliferative disorder). The abnormal cells infiltrate and accumulate (form lesions or nodules) within tissues. The lesions or nodules damage or destroy the blood vessels within these tissues. The lungs are most commonly affected in lymphomatoid granulomatosis. Symptoms often include cough, shortness of breath (dyspnea) and chest tightness. Other areas of the body such as the skin, central nervous system, kidneys and liver are also frequently affected.The abnormal cells in lymphomatoid granulomatosis are B-cells (B lymphocytes) containing the Epstein-Barr virus. There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes. Because lymphomatoid granulomatosis is caused by the growth of abnormal B-cells, affected individuals may eventually develop B-cell lymphoma, a form of non-Hodgkin lymphoma. Lymphoma is a general term for cancer of the lymphatic system.
| 739 |
Lymphomatoid Granulomatosis
|
nord_739_1
|
Symptoms of Lymphomatoid Granulomatosis
|
The symptoms and progression of lymphomatoid granulomatosis vary greatly from person to person. The disorder may occasionally resolve without treatment (spontaneous remission) in some affected individuals or more commonly it will progress and cause life-threatening complications. Occasionally, it is an incidental and asymptomatic finding on chest radiographs.In almost all affected individuals, lymphomatoid granulomatosis affects the lungs and often causes a cough, shortness of breath (dyspnea) and/or chest tightness. In most patients, the cough is non-productive and is rarely associated with blood (hemoptysis). Systemic symptoms are not uncommon and may include fever, a general feeling of poor health (malaise), weight loss, and fatigue. Approximately one-third of affect individuals will develop skin lesions such as a patchy reddish (erythematous) rash consisting of flat discolored lesions (macules), small, elevated bumps (papules) or, more rarely, solid, raised, flat-topped lesions (plaques). Small bumps or growths (nodules) just below the surface of the skin (subcutaneous) may also develop. Larger nodules may become open sores (ulcerated).In approximately one-third of patients, the central nervous may be involved potentially resulting in mental status changes, headaches, seizures, paralysis of one side of the body (hemiparesis), or loss of the ability to coordinate voluntary movements (ataxia).Less commonly, the kidneys or liver may be involved, although this rarely leads to the development of symptoms. In some cases the liver may become enlarged (hepatomegaly). In some extremely rare cases, lymphomatoid granulomatosis may only affect the skin or only the central nervous system (isolated lymphomatoid granulomatosis).Lymphomatoid granulomatosis may eventually progress to a form of large B-cell lymphoma.
|
Symptoms of Lymphomatoid Granulomatosis. The symptoms and progression of lymphomatoid granulomatosis vary greatly from person to person. The disorder may occasionally resolve without treatment (spontaneous remission) in some affected individuals or more commonly it will progress and cause life-threatening complications. Occasionally, it is an incidental and asymptomatic finding on chest radiographs.In almost all affected individuals, lymphomatoid granulomatosis affects the lungs and often causes a cough, shortness of breath (dyspnea) and/or chest tightness. In most patients, the cough is non-productive and is rarely associated with blood (hemoptysis). Systemic symptoms are not uncommon and may include fever, a general feeling of poor health (malaise), weight loss, and fatigue. Approximately one-third of affect individuals will develop skin lesions such as a patchy reddish (erythematous) rash consisting of flat discolored lesions (macules), small, elevated bumps (papules) or, more rarely, solid, raised, flat-topped lesions (plaques). Small bumps or growths (nodules) just below the surface of the skin (subcutaneous) may also develop. Larger nodules may become open sores (ulcerated).In approximately one-third of patients, the central nervous may be involved potentially resulting in mental status changes, headaches, seizures, paralysis of one side of the body (hemiparesis), or loss of the ability to coordinate voluntary movements (ataxia).Less commonly, the kidneys or liver may be involved, although this rarely leads to the development of symptoms. In some cases the liver may become enlarged (hepatomegaly). In some extremely rare cases, lymphomatoid granulomatosis may only affect the skin or only the central nervous system (isolated lymphomatoid granulomatosis).Lymphomatoid granulomatosis may eventually progress to a form of large B-cell lymphoma.
| 739 |
Lymphomatoid Granulomatosis
|
nord_739_2
|
Causes of Lymphomatoid Granulomatosis
|
The exact cause of lymphomatoid granulomatosis is unknown. Lymphomatoid granulomatosis occurs with greater frequency in individuals with some form of immune system dysfunction including individuals with human immunodeficiency virus (HIV) infection and Wiskott-Aldrich syndrome. In most patients the cause of the immune dysfunction is unknown.It is likely that some combination of immunodeficiency, genetic and familial factors all play a role in the development of lymphomatoid granulomatosis. The therapy used varies, but is generally directed against eliminating the EBV-infected B-cells or boosting the immune system.The classification of lymphomatoid granulomatosis has been difficult. Originally, the disorder was viewed as a benign process with the potential to progress to malignant lymphoma. Researchers believed that defective cells were T-cells. Scientific advances in technology have allowed researchers to determine that the abnormal cells in lymphomatoid granulomatosis are B-cells infected by the Epstein-Barr virus. However, most of the cells within the tissues are T-cells, reacting against the abnormal EBV-infected B-cells. The Epstein-Barr virus is common among the general population and is relatively well-known because it is the cause of infectious mononucleosis (IM), usually with no long-lasting effects.
|
Causes of Lymphomatoid Granulomatosis. The exact cause of lymphomatoid granulomatosis is unknown. Lymphomatoid granulomatosis occurs with greater frequency in individuals with some form of immune system dysfunction including individuals with human immunodeficiency virus (HIV) infection and Wiskott-Aldrich syndrome. In most patients the cause of the immune dysfunction is unknown.It is likely that some combination of immunodeficiency, genetic and familial factors all play a role in the development of lymphomatoid granulomatosis. The therapy used varies, but is generally directed against eliminating the EBV-infected B-cells or boosting the immune system.The classification of lymphomatoid granulomatosis has been difficult. Originally, the disorder was viewed as a benign process with the potential to progress to malignant lymphoma. Researchers believed that defective cells were T-cells. Scientific advances in technology have allowed researchers to determine that the abnormal cells in lymphomatoid granulomatosis are B-cells infected by the Epstein-Barr virus. However, most of the cells within the tissues are T-cells, reacting against the abnormal EBV-infected B-cells. The Epstein-Barr virus is common among the general population and is relatively well-known because it is the cause of infectious mononucleosis (IM), usually with no long-lasting effects.
| 739 |
Lymphomatoid Granulomatosis
|
nord_739_3
|
Affects of Lymphomatoid Granulomatosis
|
Lymphomatoid granulomatosis affects males twice as often as females. It is most common in middle-age adults in the fourth to sixth decade of life, but can occur at any age and has been reported in children. The prevalence of lymphomatoid granulomatosis is unknown.The disorder was first described in the medical literature in 1972.
|
Affects of Lymphomatoid Granulomatosis. Lymphomatoid granulomatosis affects males twice as often as females. It is most common in middle-age adults in the fourth to sixth decade of life, but can occur at any age and has been reported in children. The prevalence of lymphomatoid granulomatosis is unknown.The disorder was first described in the medical literature in 1972.
| 739 |
Lymphomatoid Granulomatosis
|
nord_739_4
|
Related disorders of Lymphomatoid Granulomatosis
|
Churg-Strauss syndrome is a rare disorder that may affect multiple organ systems, especially the lungs. The disorder is characterized by the abnormal clustering of certain white blood cells (hypereosinophilia) in the blood and tissues, inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions called granulomas (granulomatosis). Most affected individuals have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities (i.e., pulmonary infiltrates) often precede the development of the generalized (systemic) symptoms and findings seen in Churg-Strauss syndrome by as little as six months or as much as two decades. Asthma, a chronic respiratory disorder, is characterized by inflammation and narrowing of the lungs’ airways, causing difficulties breathing (dyspnea), coughing, the production of a high-pitched whistling sound while breathing (wheezing), and/or other symptoms and findings. Nonspecific findings associated with Churg-Strauss syndrome typically include flu-like symptoms, such as fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia), weight loss, and muscle pain (myalgia). Additional symptoms and findings may vary depending upon the specific organ systems involved. The nerves outside the central nervous system (peripheral nerves), kidneys, or gastrointestinal tract are often involved. Without appropriate treatment, serious organ damage and potentially life-threatening complications may result. Although the exact cause of Churg-Strauss syndrome is unknown, many researchers indicate that abnormal functioning of the immune system plays an important role. (For more information, choose “Churg Strauss” as a search term in the Rare Disease Database.)Granulomatosis with polyangiitis is an uncommon disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some patients, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of this condition is not known. (For more information on this disorder, choose “granulomatosis with polyangiitis ” as your search term in the Rare Disease Database.)Lymphoma is a general term for other cancers of the lymphatic system. Lymphomas result from errors in the production of a white blood cell (lymphocyte) or transformation of a lymphocyte into a malignant cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant lymphocytes may lead to enlargement of a specific lymph node region or regions; involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from patient to patient, depending upon the extent and region(s) of involvement and other factors.Sarcoidosis is a multisystem disorder that most often affects individuals between 20 and 40 years of age. Females appear to be affected more frequently than males. Sarcoidosis is characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of certain granular white blood cells (modified macrophages or epithelioid cells) in certain organs of the body. The granulomas that are formed are thought to alter the normal structure of and, potentially, the normal functions of, the affected organ(s), causing symptoms associated with the particular body system(s) in question. In individuals with sarcoidosis, such granuloma formation most commonly affects the lungs. However, in many patients, the upper respiratory system, lymph nodes, skin, and/or eyes may be involved. In some patients, other organs may be affected, including the liver, bone marrow, spleen, musculoskeletal system, heart, salivary glands, and/or nervous system (i.e., central or peripheral nervous system). The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organ(s) involved and the degree of such involvement. The exact cause of sarcoidosis is not known. However, possible infectious, environmental, genetic, and immunological factors are under investigation as potential causes of the disorder. (For more information on this disorder, choose “sarcoidosis” as your search term in the Rare Disease Database.)
|
Related disorders of Lymphomatoid Granulomatosis. Churg-Strauss syndrome is a rare disorder that may affect multiple organ systems, especially the lungs. The disorder is characterized by the abnormal clustering of certain white blood cells (hypereosinophilia) in the blood and tissues, inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions called granulomas (granulomatosis). Most affected individuals have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities (i.e., pulmonary infiltrates) often precede the development of the generalized (systemic) symptoms and findings seen in Churg-Strauss syndrome by as little as six months or as much as two decades. Asthma, a chronic respiratory disorder, is characterized by inflammation and narrowing of the lungs’ airways, causing difficulties breathing (dyspnea), coughing, the production of a high-pitched whistling sound while breathing (wheezing), and/or other symptoms and findings. Nonspecific findings associated with Churg-Strauss syndrome typically include flu-like symptoms, such as fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia), weight loss, and muscle pain (myalgia). Additional symptoms and findings may vary depending upon the specific organ systems involved. The nerves outside the central nervous system (peripheral nerves), kidneys, or gastrointestinal tract are often involved. Without appropriate treatment, serious organ damage and potentially life-threatening complications may result. Although the exact cause of Churg-Strauss syndrome is unknown, many researchers indicate that abnormal functioning of the immune system plays an important role. (For more information, choose “Churg Strauss” as a search term in the Rare Disease Database.)Granulomatosis with polyangiitis is an uncommon disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some patients, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of this condition is not known. (For more information on this disorder, choose “granulomatosis with polyangiitis ” as your search term in the Rare Disease Database.)Lymphoma is a general term for other cancers of the lymphatic system. Lymphomas result from errors in the production of a white blood cell (lymphocyte) or transformation of a lymphocyte into a malignant cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant lymphocytes may lead to enlargement of a specific lymph node region or regions; involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from patient to patient, depending upon the extent and region(s) of involvement and other factors.Sarcoidosis is a multisystem disorder that most often affects individuals between 20 and 40 years of age. Females appear to be affected more frequently than males. Sarcoidosis is characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of certain granular white blood cells (modified macrophages or epithelioid cells) in certain organs of the body. The granulomas that are formed are thought to alter the normal structure of and, potentially, the normal functions of, the affected organ(s), causing symptoms associated with the particular body system(s) in question. In individuals with sarcoidosis, such granuloma formation most commonly affects the lungs. However, in many patients, the upper respiratory system, lymph nodes, skin, and/or eyes may be involved. In some patients, other organs may be affected, including the liver, bone marrow, spleen, musculoskeletal system, heart, salivary glands, and/or nervous system (i.e., central or peripheral nervous system). The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organ(s) involved and the degree of such involvement. The exact cause of sarcoidosis is not known. However, possible infectious, environmental, genetic, and immunological factors are under investigation as potential causes of the disorder. (For more information on this disorder, choose “sarcoidosis” as your search term in the Rare Disease Database.)
| 739 |
Lymphomatoid Granulomatosis
|
nord_739_5
|
Diagnosis of Lymphomatoid Granulomatosis
|
A diagnosis of lymphomatoid granulomatosis is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests such as the surgical removal and microscopic examination (biopsy) of tissue samples taken from an affected organ such as the lungs. A skin biopsy is not reliable because the characteristic abnormal cells may be missing.Certain x-ray studies (e.g., CT scans) may be able to aid in diagnosis. A CT scan of the lungs or another affected organ can help determine the extent of lymphomatoid granulomatosis. Magnetic resonance imaging (MRI) of the brain and lumbar puncture (LP) should be performed to rule out involvement of the central nervous system.
|
Diagnosis of Lymphomatoid Granulomatosis. A diagnosis of lymphomatoid granulomatosis is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests such as the surgical removal and microscopic examination (biopsy) of tissue samples taken from an affected organ such as the lungs. A skin biopsy is not reliable because the characteristic abnormal cells may be missing.Certain x-ray studies (e.g., CT scans) may be able to aid in diagnosis. A CT scan of the lungs or another affected organ can help determine the extent of lymphomatoid granulomatosis. Magnetic resonance imaging (MRI) of the brain and lumbar puncture (LP) should be performed to rule out involvement of the central nervous system.
| 739 |
Lymphomatoid Granulomatosis
|
nord_739_6
|
Therapies of Lymphomatoid Granulomatosis
|
TreatmentThe most effective therapy for individuals with lymphomatoid granulomatosis is unknown. For individuals with minimal disease, observation may be recommended since long-term survival without treatment has occurred as well as spontaneous remission. In most cases, however, treatment is recommended. Treatment recommendations are based on the grade of disease. Lymphomatoid granulomatosis is pathologically divided into three grades (I, II, III), which are determined by the number of EBV+ B-cells and the extent of necrosis. In most patients with low-grade (grade I/II) disease, immune-modulation with interferon alfa-2b has been shown to be highly effective and leads to long-term remission in a subset of patients. Patients who relapse after treatment with interferon alfa-2b and still have low-grade disease can be retreated with interferon alfa-2b. In patients with high-grade (grade III) disease, interferon alfa-2b is not effective, and combination chemotherapy with rituximab should be used. However, there is a frequent rate of recurrence with low-grade disease following chemotherapy+rituximab in high-grade disease and this frequently responds to treatment with interferon alfa-2b.Corticosteroids alone are only recommended as a temporizing measure and should not be used for long term control of lymphomatoid granulomatosis. Similarly, rituximab alone is seldom effective for long term disease control. Neither of these agents effectively eradicates the abnormal EBV clones and corticosteroids can further increase immunosuppression and ultimately accelerate disease progression.If patients develop lymphomatoid granulomatosis on immunosuppressive agents, they should have these agents discontinued if at all possible since this may lead to clinical remission. If the disease is progressive or advanced, then treatment as outlined above should be instituted.
|
Therapies of Lymphomatoid Granulomatosis. TreatmentThe most effective therapy for individuals with lymphomatoid granulomatosis is unknown. For individuals with minimal disease, observation may be recommended since long-term survival without treatment has occurred as well as spontaneous remission. In most cases, however, treatment is recommended. Treatment recommendations are based on the grade of disease. Lymphomatoid granulomatosis is pathologically divided into three grades (I, II, III), which are determined by the number of EBV+ B-cells and the extent of necrosis. In most patients with low-grade (grade I/II) disease, immune-modulation with interferon alfa-2b has been shown to be highly effective and leads to long-term remission in a subset of patients. Patients who relapse after treatment with interferon alfa-2b and still have low-grade disease can be retreated with interferon alfa-2b. In patients with high-grade (grade III) disease, interferon alfa-2b is not effective, and combination chemotherapy with rituximab should be used. However, there is a frequent rate of recurrence with low-grade disease following chemotherapy+rituximab in high-grade disease and this frequently responds to treatment with interferon alfa-2b.Corticosteroids alone are only recommended as a temporizing measure and should not be used for long term control of lymphomatoid granulomatosis. Similarly, rituximab alone is seldom effective for long term disease control. Neither of these agents effectively eradicates the abnormal EBV clones and corticosteroids can further increase immunosuppression and ultimately accelerate disease progression.If patients develop lymphomatoid granulomatosis on immunosuppressive agents, they should have these agents discontinued if at all possible since this may lead to clinical remission. If the disease is progressive or advanced, then treatment as outlined above should be instituted.
| 739 |
Lymphomatoid Granulomatosis
|
nord_740_0
|
Overview of Lysosomal Free Sialic Acid Storage Disorders
|
Summary
Free sialic acid storage disorder (FSASD) is a rare neurodegenerative, multisystem disorder characterized by abnormal accumulation of free sialic acid (a sugar molecule) in various tissues and organs of the body. FSASD occurs because of changes (variants) in the SLC17A5 gene and is inherited in an autosomal recessive pattern meaning each parent passes down one variant to the affected child. FSASD comprises a spectrum of disease severity, historically divided into three subtypes, ranging from the most severe form (also called infantile free sialic acid storage disorder (ISSD)), often lethal in utero or in early childhood, to an intermediate severe form, to the mildest, slowly progressive form (also called Salla disease) with patients living into adulthood. The specific symptoms associated with these subtypes can vary greatly. All subtypes are associated with some degree of degeneration of nerve cells (neurodegeneration) and cognitive impairment. Introduction
FSASD belongs to a larger group of diseases known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks.The protein SLC17A5, also called sialin, transports sialic acid out of lysosomes. Low levels or inactivity of SLC17A5 leads to abnormal accumulation (storage) of free sialic acid inside the lysosomes of tissues and organs of individuals affected with FSASD. Sialic acid is a charged sugar involved in various biological processes, including cellular recognition, cell-cell attachment and cell signaling. Abnormal sialic acid levels in tissues and organs likely contribute to the symptoms of individuals with FSASD. Like some other lysosomal storage diseases, the spectrum of FSASD disease severity correlates with the severity of the genetic variants (e.g., variants in the SLC17A5 gene in FSASD) and the amount of stored material (e.g., free sialic acid in FSASD) in lysosomes.
|
Overview of Lysosomal Free Sialic Acid Storage Disorders. Summary
Free sialic acid storage disorder (FSASD) is a rare neurodegenerative, multisystem disorder characterized by abnormal accumulation of free sialic acid (a sugar molecule) in various tissues and organs of the body. FSASD occurs because of changes (variants) in the SLC17A5 gene and is inherited in an autosomal recessive pattern meaning each parent passes down one variant to the affected child. FSASD comprises a spectrum of disease severity, historically divided into three subtypes, ranging from the most severe form (also called infantile free sialic acid storage disorder (ISSD)), often lethal in utero or in early childhood, to an intermediate severe form, to the mildest, slowly progressive form (also called Salla disease) with patients living into adulthood. The specific symptoms associated with these subtypes can vary greatly. All subtypes are associated with some degree of degeneration of nerve cells (neurodegeneration) and cognitive impairment. Introduction
FSASD belongs to a larger group of diseases known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks.The protein SLC17A5, also called sialin, transports sialic acid out of lysosomes. Low levels or inactivity of SLC17A5 leads to abnormal accumulation (storage) of free sialic acid inside the lysosomes of tissues and organs of individuals affected with FSASD. Sialic acid is a charged sugar involved in various biological processes, including cellular recognition, cell-cell attachment and cell signaling. Abnormal sialic acid levels in tissues and organs likely contribute to the symptoms of individuals with FSASD. Like some other lysosomal storage diseases, the spectrum of FSASD disease severity correlates with the severity of the genetic variants (e.g., variants in the SLC17A5 gene in FSASD) and the amount of stored material (e.g., free sialic acid in FSASD) in lysosomes.
| 740 |
Lysosomal Free Sialic Acid Storage Disorders
|
nord_740_1
|
Symptoms of Lysosomal Free Sialic Acid Storage Disorders
|
The symptoms and severity of FSASD are highly variable. Some individuals will develop severe, life-threatening complications; others will have milder findings. The more severely affected patients usually exhibit symptoms within six months of birth or even before birth; milder cases may become apparent later during infancy or childhood. Affected individuals may not have all the symptoms discussed below.Severe FSASD
Symptoms of severe FSASD (also called infantile sialic acid storage disorder, ISSD) are usually apparent at birth or early in infancy; some infants may be born prematurely or die in the womb. Affected infants may have fluid accumulation in the abdominal cavity (ascites), abnormal enlargement of the liver and spleen (hepatosplenomegaly) and coarse facial features. Some infants have diminished muscle tone (hypotonia) and may be referred to as “floppy babies”.Affected infants may also fail to gain weight and grow at the normal rate for age and sex (failure to thrive), may experience significant delays in attaining developmental milestones (developmental delays) or may lose milestones that have been previously acquired. Cognitive deficits and seizures may occur.Skeletal abnormalities in infants with severe FSASD can include malformation (dysplasia) near the ends of the long bones (metaphyses), clubbed feet, abnormally short thigh bones (femurs), malformation (dysplasia) of the hip and underdevelopment of certain bones of the fingers and toes (phalanges).Severe FSASD eventually progresses to cause life-threatening complications such as serious respiratory infections and abnormal enlargement of the heart (cardiomegaly). Some infants develop nephrotic syndrome, in which damage to the kidneys causes them to leak large quantities of protein into the urine. Nephrotic syndrome can cause swelling in the arms and legs, around the eyes or in other areas due to fluid accumulation (edema). Additional symptoms may include a swollen abdomen, unintended weight gain and high blood pressure. Most individuals with severe FSASD die in early childhood.Mild FSASD
Mild FSASD (also called Salla disease) is the least severe form of the disorder. The specific symptoms and severity can vary from one individual to another. Although Salla disease can cause life-threatening complications, some individuals have lived into their 70s. Affected infants appear normal at birth but may develop symptoms during the first year of life. Such symptoms include diminished muscle tone (hypotonia), rapid, involuntary eye movements (nystagmus) and difficulty coordinating voluntary movements (ataxia). Affected infants often exhibit delays in reaching developmental milestones (developmental delays) such as sitting, walking or talking.Approximately two-thirds of children with mild FSASD eventually learn to walk. Some degree of speech impairment is usually present. Affected infants may learn single words or small sentences, but this ability may be lost as they age. The ability to speak is affected more severely than the ability to understand speech. Affected children exhibit some degree of cognitive impairment as well.Some individuals with mild FSASD may not develop symptoms until later in childhood when a variety of neurological findings become apparent. These include seizures, involuntary muscles spasms that result in slow, stiff movements of the legs (spasticity) and repetitive, involuntary, writhing movements of the arms and legs (athetosis). Some individuals who previously developed the ability to walk or talk may lose these skills (regression). Some individuals may experience a gradual coarsening of facial features.Intermediate FSASD
The severity of intermediate FSASD can vary greatly from one individual to another. Only a handful of people with intermediate lysosomal free sialic acid storage disease have been reported in the medical literature. The symptoms are similar to those of the mild and severe forms of the disease, but less severe than severe FSASD and more severe than mild FSASD.
|
Symptoms of Lysosomal Free Sialic Acid Storage Disorders. The symptoms and severity of FSASD are highly variable. Some individuals will develop severe, life-threatening complications; others will have milder findings. The more severely affected patients usually exhibit symptoms within six months of birth or even before birth; milder cases may become apparent later during infancy or childhood. Affected individuals may not have all the symptoms discussed below.Severe FSASD
Symptoms of severe FSASD (also called infantile sialic acid storage disorder, ISSD) are usually apparent at birth or early in infancy; some infants may be born prematurely or die in the womb. Affected infants may have fluid accumulation in the abdominal cavity (ascites), abnormal enlargement of the liver and spleen (hepatosplenomegaly) and coarse facial features. Some infants have diminished muscle tone (hypotonia) and may be referred to as “floppy babies”.Affected infants may also fail to gain weight and grow at the normal rate for age and sex (failure to thrive), may experience significant delays in attaining developmental milestones (developmental delays) or may lose milestones that have been previously acquired. Cognitive deficits and seizures may occur.Skeletal abnormalities in infants with severe FSASD can include malformation (dysplasia) near the ends of the long bones (metaphyses), clubbed feet, abnormally short thigh bones (femurs), malformation (dysplasia) of the hip and underdevelopment of certain bones of the fingers and toes (phalanges).Severe FSASD eventually progresses to cause life-threatening complications such as serious respiratory infections and abnormal enlargement of the heart (cardiomegaly). Some infants develop nephrotic syndrome, in which damage to the kidneys causes them to leak large quantities of protein into the urine. Nephrotic syndrome can cause swelling in the arms and legs, around the eyes or in other areas due to fluid accumulation (edema). Additional symptoms may include a swollen abdomen, unintended weight gain and high blood pressure. Most individuals with severe FSASD die in early childhood.Mild FSASD
Mild FSASD (also called Salla disease) is the least severe form of the disorder. The specific symptoms and severity can vary from one individual to another. Although Salla disease can cause life-threatening complications, some individuals have lived into their 70s. Affected infants appear normal at birth but may develop symptoms during the first year of life. Such symptoms include diminished muscle tone (hypotonia), rapid, involuntary eye movements (nystagmus) and difficulty coordinating voluntary movements (ataxia). Affected infants often exhibit delays in reaching developmental milestones (developmental delays) such as sitting, walking or talking.Approximately two-thirds of children with mild FSASD eventually learn to walk. Some degree of speech impairment is usually present. Affected infants may learn single words or small sentences, but this ability may be lost as they age. The ability to speak is affected more severely than the ability to understand speech. Affected children exhibit some degree of cognitive impairment as well.Some individuals with mild FSASD may not develop symptoms until later in childhood when a variety of neurological findings become apparent. These include seizures, involuntary muscles spasms that result in slow, stiff movements of the legs (spasticity) and repetitive, involuntary, writhing movements of the arms and legs (athetosis). Some individuals who previously developed the ability to walk or talk may lose these skills (regression). Some individuals may experience a gradual coarsening of facial features.Intermediate FSASD
The severity of intermediate FSASD can vary greatly from one individual to another. Only a handful of people with intermediate lysosomal free sialic acid storage disease have been reported in the medical literature. The symptoms are similar to those of the mild and severe forms of the disease, but less severe than severe FSASD and more severe than mild FSASD.
| 740 |
Lysosomal Free Sialic Acid Storage Disorders
|
nord_740_2
|
Causes of Lysosomal Free Sialic Acid Storage Disorders
|
FSASD is caused by changes (variants) in the SLC17A5 gene. The SLC17A5 gene contains instructions for producing (encoding) a protein called sialin that is required to transport free sialic acid out of lysosomes and into the cytosol of cells. Sialic acid is a charged sugar produced when lysosomes break down certain sugar-containing proteins (glycoproteins), carbohydrates or fats (glycolipids). In sialic acid storage disorders, deficient levels of functioning sialin result in the accumulation (storage) of free sialic acid in lysosomes.FSASD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a changed gene from each parent. If an individual receives one normal gene and one changed 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 changed 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 Lysosomal Free Sialic Acid Storage Disorders. FSASD is caused by changes (variants) in the SLC17A5 gene. The SLC17A5 gene contains instructions for producing (encoding) a protein called sialin that is required to transport free sialic acid out of lysosomes and into the cytosol of cells. Sialic acid is a charged sugar produced when lysosomes break down certain sugar-containing proteins (glycoproteins), carbohydrates or fats (glycolipids). In sialic acid storage disorders, deficient levels of functioning sialin result in the accumulation (storage) of free sialic acid in lysosomes.FSASD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a changed gene from each parent. If an individual receives one normal gene and one changed 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 changed 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.
| 740 |
Lysosomal Free Sialic Acid Storage Disorders
|
nord_740_3
|
Affects of Lysosomal Free Sialic Acid Storage Disorders
|
FSASD affect males and females in equal numbers. The worldwide prevalence of FSASD is estimated at less than 1 per 1,000,000 individuals. Higher estimated prevalence rates occur in the Salla region of Finland and in other Scandinavian countries. Approximately 250 individuals with FSASD have been reported in the literature, of which the majority (> 160 cases) are of Finnish or Swedish ancestry. Individuals with FSASD may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of the disease in the general population.
|
Affects of Lysosomal Free Sialic Acid Storage Disorders. FSASD affect males and females in equal numbers. The worldwide prevalence of FSASD is estimated at less than 1 per 1,000,000 individuals. Higher estimated prevalence rates occur in the Salla region of Finland and in other Scandinavian countries. Approximately 250 individuals with FSASD have been reported in the literature, of which the majority (> 160 cases) are of Finnish or Swedish ancestry. Individuals with FSASD may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of the disease in the general population.
| 740 |
Lysosomal Free Sialic Acid Storage Disorders
|
nord_740_4
|
Related disorders of Lysosomal Free Sialic Acid Storage Disorders
|
Signs and symptoms of the disorders mentioned below can be similar to those of FSASD. Comparisons may be useful for a differential diagnosis.Sialuria is a rare disorder characterized by elevated levels of free sialic acid. Unlike FSASD, accumulation of sialic acid in sialuria occurs in the gel-like fluid within cells (cytoplasm) and not in the lysosomes. Individuals with sialuria may have an enlarged liver (hepatomegaly), coarse facial features and seizures, and may experience delays in reaching developmental milestones. Sialuria is due to variants in the GNE gene and is inherited in a dominant pattern (only one variant the GNE gene is needed for the disease to occur).There are several types of metabolic disorders in which there is secondary accumulation of certain substances like fats and sugars, which are associated with clinical manifestations of coarse facial features and developmental delays similar to those of FSASD. These disorders include galactosemia, sialidosis, Gaucher disease, galactosialidosis, Wolman disease, cholesteryl ester storage deficiency, the mucopolysaccharidoses and other lysosomal storage disorders (for more information on these disorders, choose the specific lysosomal storage disorder name as your search term in the Rare Disease Database).
|
Related disorders of Lysosomal Free Sialic Acid Storage Disorders. Signs and symptoms of the disorders mentioned below can be similar to those of FSASD. Comparisons may be useful for a differential diagnosis.Sialuria is a rare disorder characterized by elevated levels of free sialic acid. Unlike FSASD, accumulation of sialic acid in sialuria occurs in the gel-like fluid within cells (cytoplasm) and not in the lysosomes. Individuals with sialuria may have an enlarged liver (hepatomegaly), coarse facial features and seizures, and may experience delays in reaching developmental milestones. Sialuria is due to variants in the GNE gene and is inherited in a dominant pattern (only one variant the GNE gene is needed for the disease to occur).There are several types of metabolic disorders in which there is secondary accumulation of certain substances like fats and sugars, which are associated with clinical manifestations of coarse facial features and developmental delays similar to those of FSASD. These disorders include galactosemia, sialidosis, Gaucher disease, galactosialidosis, Wolman disease, cholesteryl ester storage deficiency, the mucopolysaccharidoses and other lysosomal storage disorders (for more information on these disorders, choose the specific lysosomal storage disorder name as your search term in the Rare Disease Database).
| 740 |
Lysosomal Free Sialic Acid Storage Disorders
|
nord_740_5
|
Diagnosis of Lysosomal Free Sialic Acid Storage Disorders
|
A diagnosis of a FSASD may be suspected based upon identification of characteristic signs and symptoms and by performing a thorough clinical evaluation, a detailed patient history (including family history) and specialized tests that detect elevated levels of free sialic acid in certain cells and tissues or in urine.A suspected diagnosis before birth (prenatally) is possible through chorionic villus sampling (CVS). During CVS, fetal tissue samples are removed, and tests (assays) are performed on cultured tissue cells and/or white blood cells (leukocytes) to detect elevated levels of free sialic acid. The diagnosis of FSASD is ultimately confirmed by identifying disease-causing genetic variant(s) in the SLC17A5 gene by molecular genetic testing. This testing is available on a clinical basis.
|
Diagnosis of Lysosomal Free Sialic Acid Storage Disorders. A diagnosis of a FSASD may be suspected based upon identification of characteristic signs and symptoms and by performing a thorough clinical evaluation, a detailed patient history (including family history) and specialized tests that detect elevated levels of free sialic acid in certain cells and tissues or in urine.A suspected diagnosis before birth (prenatally) is possible through chorionic villus sampling (CVS). During CVS, fetal tissue samples are removed, and tests (assays) are performed on cultured tissue cells and/or white blood cells (leukocytes) to detect elevated levels of free sialic acid. The diagnosis of FSASD is ultimately confirmed by identifying disease-causing genetic variant(s) in the SLC17A5 gene by molecular genetic testing. This testing is available on a clinical basis.
| 740 |
Lysosomal Free Sialic Acid Storage Disorders
|
nord_740_6
|
Therapies of Lysosomal Free Sialic Acid Storage Disorders
|
Treatment
There is no disease-modifying treatment specific for FSASD. Treatment is directed toward the specific symptoms that are apparent in each individual. Seizures are treated by generally accepted standards including the use of anticonvulsants.Early intervention is important in ensuring that children with FSASD reach their highest potential. Services that may be beneficial include special education, physical therapy to improve strength and coordination, speech therapy and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families.
|
Therapies of Lysosomal Free Sialic Acid Storage Disorders. Treatment
There is no disease-modifying treatment specific for FSASD. Treatment is directed toward the specific symptoms that are apparent in each individual. Seizures are treated by generally accepted standards including the use of anticonvulsants.Early intervention is important in ensuring that children with FSASD reach their highest potential. Services that may be beneficial include special education, physical therapy to improve strength and coordination, speech therapy and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families.
| 740 |
Lysosomal Free Sialic Acid Storage Disorders
|
nord_741_0
|
Overview of Lysosomal Storage Disorders
|
Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases.
|
Overview of Lysosomal Storage Disorders. Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases.
| 741 |
Lysosomal Storage Disorders
|
nord_741_1
|
Symptoms of Lysosomal Storage Disorders
|
Although the signs and symptoms vary from disease to disease in this group, symptoms occur in each case because of an enzyme deficiency that inhibits the ability of the lysosomes present in each of the body's cells to perform their normal function. The lysosomes function as the primary digestive units within cells. Their function is to break down complex components into simpler ones. Each cell has hundreds of lysosomes that degrade complex cellular components such as proteins (substrates) into simpler components. When this process does not take place, the substrate begins to accumulate in the cells. That is why these diseases are called “storage diseases”. The symptoms of lysosomal storage disorders are generally progressive over a period of time.This report gives an overview of lysosomal storage diseases as a group. For more specific information on any particular disease in this group, consult the NORD report on that topic.Some lysosomal storage diseases and a few of their characteristic signs and symptoms are as follows:Aspartylglucosaminuria: Patients appear normal for several months after birth and then present with recurrent infections, diarrhea, and hernias. Later, there may be a gradual coarsening of facial features, an enlarged tongue (macroglossia) and enlargement of the liver (hepatomegaly).Batten Disease: Batten disease is the juvenile form of a group of progressive neurological disorders known as neuronal ceroid lipofuscinoses (NCL). It is characterized by the accumulation of a fatty substance (lipopigment) in the brain, as well as in tissue that does not contain nerve cells. Batten disease is marked by rapidly progressive vision failure (optic atrophy) and neurological disturbances, which may begin before eight years of age. Occurring mostly in families of Northern European Scandinavian ancestry, the disorder affects the brain and may cause deterioration of both intellect and neurological functions.Cystinosis: The early signs of this disorder typically involve the kidneys and the eyes. Excessive storage of the amino acid cystine in all cells of the body results in impaired kidney function, increased sensitivity to light, and marked growth retardation. There are infantile (the most common and most severe), juvenile, and adult forms, each with associated symptoms.Fabry Disease: The symptoms of Fabry disease usually begin during early childhood or adolescence but may not become apparent until the second or third decade of life. Early symptoms include episodes of severe burning pain in the hands and feet. Other early signs may include a decrease in sweat production, discomfort in warm temperatures, and the appearance of a reddish to dark blue skin rash, especially in the area between the hips and knees. These skin lesions may be flat or raised, and some people may not have them at all.Gaucher Disease Types I, II, and III: Gaucher disease is the most common type of lysosomal storage disorder. Researchers have identified three distinct types of Gaucher disease based upon the absence (type I) or presence and extent of (types II and III) neurological complications. Most affected individuals have type I, and they may experience easy bruising, chronic fatigue, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). Gaucher disease type II occurs in newborns and infants, and is characterized by neurological complications that may include involuntary muscle spasms, difficulty swallowing and the loss of previously acquired motor skills. Gaucher disease type III appears during the first decade of life. Neurological complications may include mental deterioration, an inability to coordinate voluntary movements, and muscle spasms of the arms, legs, or entire body.Glycogen Storage Disease II (Pompe Disease): Pompe disease has an infantile form and a delayed onset form. The delayed onset form may be further broken down into a childhood form and a juvenile/adult form. Patients with the infantile form are the most severely affected. Although these infants usually appear normal at birth, the disease presents within the first two to three months with rapidly progressive muscle weakness, diminished muscle tone (hypotonia) and a type of heart disease known as hypertrophic cardiomyopathy. Feeding problems and respiratory difficulties are common. The childhood form presents during infancy or early childhood. Motor milestones may be delayed and some symptoms may resemble muscular dystrophy. The cardiac enlargement that is often present in the infantile form is seldom seen in the childhood form. The juvenile/adult form presents between the first and seventh decades as a slowly progressive muscle weakness or with symptoms of respiratory insufficiency. There is no cardiac involvement with this form.GM2-Gangliosidosis Type I (Tay Sachs Disease): Two main forms of Tay Sachs disease exist: the classic or infantile form and the late-onset form. In individuals with infantile Tay Sachs disease, symptoms typically first appear between three and five months of age. These may include feeding problems, general weakness (lethargy), and an exaggerated startle reflex in response to sudden loud noises. Motor delays and mental deterioration are progressive. In individuals with the late-onset form, symptoms may become apparent anytime from adolescence through the mid-30s. The infantile form often progresses rapidly, resulting in significant mental and physical deterioration. A characteristic symptom of Tay Sachs disease, which occurs in 90 percent of cases, is the development of cherry red spots in the backs of the eyes. Symptoms of late-onset Tay Sachs disease vary widely from case to case. This disorder progresses much more slowly than the infantile form.GM2-Gangliosidosis Type II (Sandhoff Disease): The first symptoms of Sandhoff disease typically begin between the ages of three and six months. The disease is clinically indistinguishable from GM2-Gangliosidosis Type I.Metachromatic Leukodystrophy: Early signs and symptoms may be vague and gradual, making this disorder difficult to diagnose. Unsteadiness when walking is often the first symptom observed. Occasionally, the earliest symptom is developmental delay or deteriorating school performance. Over time, symptoms may include marked spasticity, seizures, and profound mental retardation.Mucolipidosis Types I, II/III and IV: Mucolipidosis I, also known as sialidosis, has juvenile and infantile forms (sialidosis type I and sialidosis type II). Sialidosis type I usually becomes apparent during the second decade of life with the advent of sudden involuntary muscle contactions, the appearance of red sopts (cherry-red macules) in the eyes, and/or other neurological findings. Sialidosis type II may begin during infancy or later and is characterized by the same visual characteristics as sialidosis type I, as well as other symptoms such as mildly coarse facial features, skeletal malformations, and/or mild mental retardation. Symptoms of ML II, also known as I-cell disease, typically become apparent during infancy and include abnormalities of the skull and face, growth failure, and/or mental retardation. Type III, also known as pseudo-Hurler disease, is characterized by stiffness of the hands and shoulders with later development of carpal tunnel syndrome, deterioration of hip joints, scoliosis, and short stature. ML IV is characterized by mental retardation, greatly reduced ability in the acquisition of skills requiring the coordination of muscular and mental activities, corneal clouding, retinal degeneration, and diminished muscle tone. Mucopolysaccharide Storage Diseases (Hurler Disease and variants, Hunter, Sanfilippo Types A,B,C,D, Morquio Types A and B, Maroteaux-Lamy and Sly diseases): The MPS diseases are caused by disturbances in the normal breakdown of complex carbohydrates known as mucopolysaccharides. All of the MPS diseases have certain characteristics in common, which include deformities of the bones and joints that interfere with mobility and often cause osteoarthritis, especially of the large, weight-bearing joints. All of the MPS diseases except Sanfilippo disease interfere with growth, causing short stature.Niemann-Pick Disease Types A/B, C1 and C2: Niemann-Pick disease is a group of inherited disorders related to fat metabolism. Certain characteristics common to all types include enlargement of the liver and spleen. Children with Niemann-Pick disease, types A or C, also experience progressive loss of motor skills, feeding difficulties, progressive learning disabilities, and seizures. Schindler Disease Types I and II: Type I, the classical form, first appears during infancy. Affected individuals appear to develop normally until approximately one year of age, when they begin to lose previously acquired skills that require the coordination of physical and mental activities. Type II is the adult-onset form. Symptoms may include the development of clusters of wart-like discolorations on the skin, permanent widening of groups of blood vessels causing redness of the skin in affected areas, relative coarsening of facial features, and mild intellectual impairment.
|
Symptoms of Lysosomal Storage Disorders. Although the signs and symptoms vary from disease to disease in this group, symptoms occur in each case because of an enzyme deficiency that inhibits the ability of the lysosomes present in each of the body's cells to perform their normal function. The lysosomes function as the primary digestive units within cells. Their function is to break down complex components into simpler ones. Each cell has hundreds of lysosomes that degrade complex cellular components such as proteins (substrates) into simpler components. When this process does not take place, the substrate begins to accumulate in the cells. That is why these diseases are called “storage diseases”. The symptoms of lysosomal storage disorders are generally progressive over a period of time.This report gives an overview of lysosomal storage diseases as a group. For more specific information on any particular disease in this group, consult the NORD report on that topic.Some lysosomal storage diseases and a few of their characteristic signs and symptoms are as follows:Aspartylglucosaminuria: Patients appear normal for several months after birth and then present with recurrent infections, diarrhea, and hernias. Later, there may be a gradual coarsening of facial features, an enlarged tongue (macroglossia) and enlargement of the liver (hepatomegaly).Batten Disease: Batten disease is the juvenile form of a group of progressive neurological disorders known as neuronal ceroid lipofuscinoses (NCL). It is characterized by the accumulation of a fatty substance (lipopigment) in the brain, as well as in tissue that does not contain nerve cells. Batten disease is marked by rapidly progressive vision failure (optic atrophy) and neurological disturbances, which may begin before eight years of age. Occurring mostly in families of Northern European Scandinavian ancestry, the disorder affects the brain and may cause deterioration of both intellect and neurological functions.Cystinosis: The early signs of this disorder typically involve the kidneys and the eyes. Excessive storage of the amino acid cystine in all cells of the body results in impaired kidney function, increased sensitivity to light, and marked growth retardation. There are infantile (the most common and most severe), juvenile, and adult forms, each with associated symptoms.Fabry Disease: The symptoms of Fabry disease usually begin during early childhood or adolescence but may not become apparent until the second or third decade of life. Early symptoms include episodes of severe burning pain in the hands and feet. Other early signs may include a decrease in sweat production, discomfort in warm temperatures, and the appearance of a reddish to dark blue skin rash, especially in the area between the hips and knees. These skin lesions may be flat or raised, and some people may not have them at all.Gaucher Disease Types I, II, and III: Gaucher disease is the most common type of lysosomal storage disorder. Researchers have identified three distinct types of Gaucher disease based upon the absence (type I) or presence and extent of (types II and III) neurological complications. Most affected individuals have type I, and they may experience easy bruising, chronic fatigue, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). Gaucher disease type II occurs in newborns and infants, and is characterized by neurological complications that may include involuntary muscle spasms, difficulty swallowing and the loss of previously acquired motor skills. Gaucher disease type III appears during the first decade of life. Neurological complications may include mental deterioration, an inability to coordinate voluntary movements, and muscle spasms of the arms, legs, or entire body.Glycogen Storage Disease II (Pompe Disease): Pompe disease has an infantile form and a delayed onset form. The delayed onset form may be further broken down into a childhood form and a juvenile/adult form. Patients with the infantile form are the most severely affected. Although these infants usually appear normal at birth, the disease presents within the first two to three months with rapidly progressive muscle weakness, diminished muscle tone (hypotonia) and a type of heart disease known as hypertrophic cardiomyopathy. Feeding problems and respiratory difficulties are common. The childhood form presents during infancy or early childhood. Motor milestones may be delayed and some symptoms may resemble muscular dystrophy. The cardiac enlargement that is often present in the infantile form is seldom seen in the childhood form. The juvenile/adult form presents between the first and seventh decades as a slowly progressive muscle weakness or with symptoms of respiratory insufficiency. There is no cardiac involvement with this form.GM2-Gangliosidosis Type I (Tay Sachs Disease): Two main forms of Tay Sachs disease exist: the classic or infantile form and the late-onset form. In individuals with infantile Tay Sachs disease, symptoms typically first appear between three and five months of age. These may include feeding problems, general weakness (lethargy), and an exaggerated startle reflex in response to sudden loud noises. Motor delays and mental deterioration are progressive. In individuals with the late-onset form, symptoms may become apparent anytime from adolescence through the mid-30s. The infantile form often progresses rapidly, resulting in significant mental and physical deterioration. A characteristic symptom of Tay Sachs disease, which occurs in 90 percent of cases, is the development of cherry red spots in the backs of the eyes. Symptoms of late-onset Tay Sachs disease vary widely from case to case. This disorder progresses much more slowly than the infantile form.GM2-Gangliosidosis Type II (Sandhoff Disease): The first symptoms of Sandhoff disease typically begin between the ages of three and six months. The disease is clinically indistinguishable from GM2-Gangliosidosis Type I.Metachromatic Leukodystrophy: Early signs and symptoms may be vague and gradual, making this disorder difficult to diagnose. Unsteadiness when walking is often the first symptom observed. Occasionally, the earliest symptom is developmental delay or deteriorating school performance. Over time, symptoms may include marked spasticity, seizures, and profound mental retardation.Mucolipidosis Types I, II/III and IV: Mucolipidosis I, also known as sialidosis, has juvenile and infantile forms (sialidosis type I and sialidosis type II). Sialidosis type I usually becomes apparent during the second decade of life with the advent of sudden involuntary muscle contactions, the appearance of red sopts (cherry-red macules) in the eyes, and/or other neurological findings. Sialidosis type II may begin during infancy or later and is characterized by the same visual characteristics as sialidosis type I, as well as other symptoms such as mildly coarse facial features, skeletal malformations, and/or mild mental retardation. Symptoms of ML II, also known as I-cell disease, typically become apparent during infancy and include abnormalities of the skull and face, growth failure, and/or mental retardation. Type III, also known as pseudo-Hurler disease, is characterized by stiffness of the hands and shoulders with later development of carpal tunnel syndrome, deterioration of hip joints, scoliosis, and short stature. ML IV is characterized by mental retardation, greatly reduced ability in the acquisition of skills requiring the coordination of muscular and mental activities, corneal clouding, retinal degeneration, and diminished muscle tone. Mucopolysaccharide Storage Diseases (Hurler Disease and variants, Hunter, Sanfilippo Types A,B,C,D, Morquio Types A and B, Maroteaux-Lamy and Sly diseases): The MPS diseases are caused by disturbances in the normal breakdown of complex carbohydrates known as mucopolysaccharides. All of the MPS diseases have certain characteristics in common, which include deformities of the bones and joints that interfere with mobility and often cause osteoarthritis, especially of the large, weight-bearing joints. All of the MPS diseases except Sanfilippo disease interfere with growth, causing short stature.Niemann-Pick Disease Types A/B, C1 and C2: Niemann-Pick disease is a group of inherited disorders related to fat metabolism. Certain characteristics common to all types include enlargement of the liver and spleen. Children with Niemann-Pick disease, types A or C, also experience progressive loss of motor skills, feeding difficulties, progressive learning disabilities, and seizures. Schindler Disease Types I and II: Type I, the classical form, first appears during infancy. Affected individuals appear to develop normally until approximately one year of age, when they begin to lose previously acquired skills that require the coordination of physical and mental activities. Type II is the adult-onset form. Symptoms may include the development of clusters of wart-like discolorations on the skin, permanent widening of groups of blood vessels causing redness of the skin in affected areas, relative coarsening of facial features, and mild intellectual impairment.
| 741 |
Lysosomal Storage Disorders
|
nord_741_2
|
Causes of Lysosomal Storage Disorders
|
In each case, lysosomal storage diseases are caused by an inborn error of metabolism that results in the absence or deficiency of an enzyme, leading to the inappropriate storage of material in various cells of the body. Most lysosomal storage disorders are inherited in an autosomal recessive manner.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 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 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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 four or five 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.Although most lysosomal storage disorders follow an autosomal recessive inheritance pattern, there are exceptions. Fabry disease and Hunter syndrome follow an X-linked recessive inheritance pattern. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. (However, it has been noted that some carriers of Fabry disease do experience significant clinical problems.) Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. The genes associated with many, but not all, lysosomal storage disorders have been identified. To learn more about the genetic locations associated with specific diseases, search the Rare Disease Database for reports on those topics.
|
Causes of Lysosomal Storage Disorders. In each case, lysosomal storage diseases are caused by an inborn error of metabolism that results in the absence or deficiency of an enzyme, leading to the inappropriate storage of material in various cells of the body. Most lysosomal storage disorders are inherited in an autosomal recessive manner.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 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 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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 four or five 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.Although most lysosomal storage disorders follow an autosomal recessive inheritance pattern, there are exceptions. Fabry disease and Hunter syndrome follow an X-linked recessive inheritance pattern. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. (However, it has been noted that some carriers of Fabry disease do experience significant clinical problems.) Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. The genes associated with many, but not all, lysosomal storage disorders have been identified. To learn more about the genetic locations associated with specific diseases, search the Rare Disease Database for reports on those topics.
| 741 |
Lysosomal Storage Disorders
|
nord_741_3
|
Affects of Lysosomal Storage Disorders
|
As a group, lysosomal storage diseases are believed to have an estimated frequency of about one in every 5,000 live births. Although the individual diseases are rare, the group together affects many people around the world. Some of the diseases have a higher incidence in certain populations. For instance, Gaucher and Tay-Sachs diseases are more prevalent among the Ashkenazi Jewish population. A mutation associated with Hurler syndrome is known to occur more frequently among Scandinavian and Russian peoples.
|
Affects of Lysosomal Storage Disorders. As a group, lysosomal storage diseases are believed to have an estimated frequency of about one in every 5,000 live births. Although the individual diseases are rare, the group together affects many people around the world. Some of the diseases have a higher incidence in certain populations. For instance, Gaucher and Tay-Sachs diseases are more prevalent among the Ashkenazi Jewish population. A mutation associated with Hurler syndrome is known to occur more frequently among Scandinavian and Russian peoples.
| 741 |
Lysosomal Storage Disorders
|
nord_741_4
|
Related disorders of Lysosomal Storage Disorders
|
Related disorders of Lysosomal Storage Disorders.
| 741 |
Lysosomal Storage Disorders
|
|
nord_741_5
|
Diagnosis of Lysosomal Storage Disorders
|
Prenatal diagnosis is possible for all lysosomal storage disorders. Early detection of lysosomal storage diseases, whether before birth or as soon as possible afterward, is important because when therapies are available, either for the disease itself or for associated symptoms, they may significantly limit the long-term course and impact of the disease.
|
Diagnosis of Lysosomal Storage Disorders. Prenatal diagnosis is possible for all lysosomal storage disorders. Early detection of lysosomal storage diseases, whether before birth or as soon as possible afterward, is important because when therapies are available, either for the disease itself or for associated symptoms, they may significantly limit the long-term course and impact of the disease.
| 741 |
Lysosomal Storage Disorders
|
nord_741_6
|
Therapies of Lysosomal Storage Disorders
|
TreatmentThere is no cure for lysosomal storage disorders, and there are not yet specific treatments for many of these diseases. However, progress is being made in the search for therapies, and there are treatments available for some lysosomal storage disorders that greatly improve the quality of life for those affected.Bone marrow transplantation (BMT) is effective in preventing the progressive mental retardation in children with MPS IH (Hurler disease) if it is done before two years of age. It is less effective in correcting or preventing the bone and joint complications of the disease. BMT is considered standard treatment for infants with MPS IH if a suitable matched bone marrow donor can be found and the procedure done before the child reaches the age of two years. The principle of BMT is to replace the bone marrow, and therefore the whole blood system, of an individual affected by a particular disease with marrow from another person who is healthy. BMT is under investigation for the treatment of other lysosomal storage diseases. So far, none has shown as much benefit as patients with MPS IH (Hurler disease).Enzyme replacement therapy (ERT) has proven effective for individuals with Gaucher disease type I. Anemia and low platelet counts have improved, enlargement of the liver and spleen have been greatly reduced, and skeletal findings have improved. These systemic manifestations also improve in individuals with Gaucher disease types II and III who receive ERT. However, ERT has not been effective in reducing or reversing neurological symptoms associated with Gaucher disease types II and III.The orphan drug alglucerase injection (Ceredase), which is a placenta-derived enzyme, was approved by the U.S. Food and Drug Administration (FDA) in April 1991 for the treatment of Gaucher disease type I. It was the first ERT proven effective for the treatment of Gaucher disease type I, and it continues to be studied for the treatment of types II and III.The synthetic form of this drug, imiglucerase (Cerezyme), was approved by the FDA in 1994. Recombinant DNA technology, or genetic engineering, is used to produce Cerezyme. This was an important step in overcoming limitations of the availability of Ceredase, which is derived from human tissue sources. Ceredase and Cerezyme are manufactured by the Genzyme Corporation of Cambridge, MA. They replace, glucocerebrosidase, the enzyme that individuals with Gaucher lack.In 2003, the FDA approved the use of miglustat (Zavesca) tablets as the first oral treatment option for individuals with Gaucher disease type I. Zavesca is the first of a new class of drugs known as substrate reduction therapy. Zavesca is used for individuals with mild to moderate Gaucher disease type I who do not respond to enzyme replacement therapy. For information on Zavesca, contact:Actelion Pharmaceuticals Ltd.Gewerbestrasse 164123 Allschwil, SwitzerlandTel: +41 61 487 45 45Fax: +41 61 487 45 00www.actelion.comEnzyme replacement therapies for Fabry disease and MPS I, earlier designated as orphan drugs, were approved by the FDA in the spring of 2003.The FDA approved Fabrazyme for Fabry disease making it the first specific treatment approved for that disease. Fabry results from a deficiency of the enzyme alpha-galactosidase A, and Fabrazyme is a version of the human form of this natural enzyme produced by recombinant DNA technology. It is given intravenously. The replacement of this missing enzyme reduces lipid accumulation in many types of cells, including blood vessels in the kidney and other organs. Fabrazyme was approved under an accelerated or early approval mechanism that expedites the approval of therapies that treat serious or life-threatening illnesses when studies indicate early favorable outcomes that are likely to predict clinical benefit. Fabrazyme is manufactured by the Genzyme Corporation of Cambridge, MA.The FDA also granted marketing approval for Aldurazyme, the first specific treatment for MPS I, during the spring of 2003. Aldurazyme is indicated for patients with the Hurler and Hurler-Scheie forms of MPS I, and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established.MPS I is caused by a deficiency of the enzyme alpha L-iduronidase, leading to the accumulation of a carbohydrate called glycosaminoglycan (GAG) in tissues and organ systems.Hurler is the most severe form of MPS I, Scheie is a milder form, and Hurler-Scheie is an intermediate form. Until the approval of Aldurazyme, it was possible to treat only the neurological symptoms of MPS I by bone marrow transplantation. Treatment with Aldurazyme is the first specific treatment for the non-neurological complications of this disease.Enzyme replacement therapies have also been approved by FDA for Pompe disease and Hunter syndrome.Aside from these therapies for specific disorders, much of the treatment that is currently available for lysosomal storage diseases involves treating symptoms rather than treating the underlying disease.
|
Therapies of Lysosomal Storage Disorders. TreatmentThere is no cure for lysosomal storage disorders, and there are not yet specific treatments for many of these diseases. However, progress is being made in the search for therapies, and there are treatments available for some lysosomal storage disorders that greatly improve the quality of life for those affected.Bone marrow transplantation (BMT) is effective in preventing the progressive mental retardation in children with MPS IH (Hurler disease) if it is done before two years of age. It is less effective in correcting or preventing the bone and joint complications of the disease. BMT is considered standard treatment for infants with MPS IH if a suitable matched bone marrow donor can be found and the procedure done before the child reaches the age of two years. The principle of BMT is to replace the bone marrow, and therefore the whole blood system, of an individual affected by a particular disease with marrow from another person who is healthy. BMT is under investigation for the treatment of other lysosomal storage diseases. So far, none has shown as much benefit as patients with MPS IH (Hurler disease).Enzyme replacement therapy (ERT) has proven effective for individuals with Gaucher disease type I. Anemia and low platelet counts have improved, enlargement of the liver and spleen have been greatly reduced, and skeletal findings have improved. These systemic manifestations also improve in individuals with Gaucher disease types II and III who receive ERT. However, ERT has not been effective in reducing or reversing neurological symptoms associated with Gaucher disease types II and III.The orphan drug alglucerase injection (Ceredase), which is a placenta-derived enzyme, was approved by the U.S. Food and Drug Administration (FDA) in April 1991 for the treatment of Gaucher disease type I. It was the first ERT proven effective for the treatment of Gaucher disease type I, and it continues to be studied for the treatment of types II and III.The synthetic form of this drug, imiglucerase (Cerezyme), was approved by the FDA in 1994. Recombinant DNA technology, or genetic engineering, is used to produce Cerezyme. This was an important step in overcoming limitations of the availability of Ceredase, which is derived from human tissue sources. Ceredase and Cerezyme are manufactured by the Genzyme Corporation of Cambridge, MA. They replace, glucocerebrosidase, the enzyme that individuals with Gaucher lack.In 2003, the FDA approved the use of miglustat (Zavesca) tablets as the first oral treatment option for individuals with Gaucher disease type I. Zavesca is the first of a new class of drugs known as substrate reduction therapy. Zavesca is used for individuals with mild to moderate Gaucher disease type I who do not respond to enzyme replacement therapy. For information on Zavesca, contact:Actelion Pharmaceuticals Ltd.Gewerbestrasse 164123 Allschwil, SwitzerlandTel: +41 61 487 45 45Fax: +41 61 487 45 00www.actelion.comEnzyme replacement therapies for Fabry disease and MPS I, earlier designated as orphan drugs, were approved by the FDA in the spring of 2003.The FDA approved Fabrazyme for Fabry disease making it the first specific treatment approved for that disease. Fabry results from a deficiency of the enzyme alpha-galactosidase A, and Fabrazyme is a version of the human form of this natural enzyme produced by recombinant DNA technology. It is given intravenously. The replacement of this missing enzyme reduces lipid accumulation in many types of cells, including blood vessels in the kidney and other organs. Fabrazyme was approved under an accelerated or early approval mechanism that expedites the approval of therapies that treat serious or life-threatening illnesses when studies indicate early favorable outcomes that are likely to predict clinical benefit. Fabrazyme is manufactured by the Genzyme Corporation of Cambridge, MA.The FDA also granted marketing approval for Aldurazyme, the first specific treatment for MPS I, during the spring of 2003. Aldurazyme is indicated for patients with the Hurler and Hurler-Scheie forms of MPS I, and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established.MPS I is caused by a deficiency of the enzyme alpha L-iduronidase, leading to the accumulation of a carbohydrate called glycosaminoglycan (GAG) in tissues and organ systems.Hurler is the most severe form of MPS I, Scheie is a milder form, and Hurler-Scheie is an intermediate form. Until the approval of Aldurazyme, it was possible to treat only the neurological symptoms of MPS I by bone marrow transplantation. Treatment with Aldurazyme is the first specific treatment for the non-neurological complications of this disease.Enzyme replacement therapies have also been approved by FDA for Pompe disease and Hunter syndrome.Aside from these therapies for specific disorders, much of the treatment that is currently available for lysosomal storage diseases involves treating symptoms rather than treating the underlying disease.
| 741 |
Lysosomal Storage Disorders
|
nord_742_0
|
Overview of Machado-Joseph Disease
|
Machado-Joseph Disease (MJD-III), also called spinocerebellar ataxia type III, is a rare, inherited, ataxia (lack of muscular control) affecting the central nervous system and characterized by the slow degeneration of particular areas of the brain called the hindbrain. Patients with MJD may eventually become crippled and/or paralyzed but their intellect remains intact. The onset of symptoms of MJD varies from early teens to late adulthood.Three forms of Machado-Joseph Disease are recognized: Types MJD-I, MJD-II, and MJD-III. The differences in the types of MJD relate to the age of onset and severity. Earlier onset usually produces more severe symptoms.
|
Overview of Machado-Joseph Disease. Machado-Joseph Disease (MJD-III), also called spinocerebellar ataxia type III, is a rare, inherited, ataxia (lack of muscular control) affecting the central nervous system and characterized by the slow degeneration of particular areas of the brain called the hindbrain. Patients with MJD may eventually become crippled and/or paralyzed but their intellect remains intact. The onset of symptoms of MJD varies from early teens to late adulthood.Three forms of Machado-Joseph Disease are recognized: Types MJD-I, MJD-II, and MJD-III. The differences in the types of MJD relate to the age of onset and severity. Earlier onset usually produces more severe symptoms.
| 742 |
Machado-Joseph Disease
|
nord_742_1
|
Symptoms of Machado-Joseph Disease
|
The symptoms of MJD Type I present between the ages of 10 and 30 years and progress rapidly. They may include severe weakness in the arms and legs (dystonia), spasticity or muscle rigidity, (hypertonia), awkward body movements (ataxia) often involving a slow, staggering, lurching gait (athetosis) that may be mistaken for drunkenness, slurred speech and swallowing (dysarthria), and possible damage to the muscles that control eye movements (ophthalmoplegia) and bulging eyes (exophthalmia). Mental alertness and intellectual capacities are unaffected. MJD-Type II symptoms are similar to those of Type I, but the disease progresses at a slower rate. Onset of Type II disease is usually between 20 and 50 years of age. The distinctive characteristic of Type II is increased dysfunction of the cerebellum that results in an unsteady gait (ataxia) and difficulty coordinating movements of the arms and legs, as well as spastic muscle movements. MJD-Type III presents later in life, between years 40 and 70, and is characterized by an unsteady gait (ataxia) and is distinguished from the other forms of this disease by loss of muscle mass (amyotrophy) due to inflammation and degeneration of the peripheral nerves (motor polyneuropathy). Loss of feeling, lack of sensitivity to pain, abnormal sensations, impaired ability to coordinate movement of the arms and legs, and diabetes are also common. The progression of Type III disease is slowest of the three types.A number of the symptoms, and their appearance in combination, resemble the symptoms of other neurologic disorders such as Parkinson's disease or multiple sclerosis. A proper diagnosis is therefore difficult and should be the responsibility of an experienced neurologist.
|
Symptoms of Machado-Joseph Disease. The symptoms of MJD Type I present between the ages of 10 and 30 years and progress rapidly. They may include severe weakness in the arms and legs (dystonia), spasticity or muscle rigidity, (hypertonia), awkward body movements (ataxia) often involving a slow, staggering, lurching gait (athetosis) that may be mistaken for drunkenness, slurred speech and swallowing (dysarthria), and possible damage to the muscles that control eye movements (ophthalmoplegia) and bulging eyes (exophthalmia). Mental alertness and intellectual capacities are unaffected. MJD-Type II symptoms are similar to those of Type I, but the disease progresses at a slower rate. Onset of Type II disease is usually between 20 and 50 years of age. The distinctive characteristic of Type II is increased dysfunction of the cerebellum that results in an unsteady gait (ataxia) and difficulty coordinating movements of the arms and legs, as well as spastic muscle movements. MJD-Type III presents later in life, between years 40 and 70, and is characterized by an unsteady gait (ataxia) and is distinguished from the other forms of this disease by loss of muscle mass (amyotrophy) due to inflammation and degeneration of the peripheral nerves (motor polyneuropathy). Loss of feeling, lack of sensitivity to pain, abnormal sensations, impaired ability to coordinate movement of the arms and legs, and diabetes are also common. The progression of Type III disease is slowest of the three types.A number of the symptoms, and their appearance in combination, resemble the symptoms of other neurologic disorders such as Parkinson's disease or multiple sclerosis. A proper diagnosis is therefore difficult and should be the responsibility of an experienced neurologist.
| 742 |
Machado-Joseph Disease
|
nord_742_2
|
Causes of Machado-Joseph Disease
|
The gene responsible for MJD has been identified and mapped to Gene Map Locus; 14q24.3-q31. This gene is associated with an abnormal number of CAG trinucleotide repeats (sometimes called triplets) in the DNA. (CAG refers to the Cytosine-Adenine-Guanine trinucleotide structure.) “Normal” DNA usually has between 12 and 43 copies of the CAG trinucleotide. In persons with the disease, the DNA contains from 56-86 copies of this trinucleotide. Severity of symptoms and age of onset are related directly to the number of the repeats. Thus, MJD-I will have fewer of these triplets while MJD-III will have the greater number. The number of the CAG triplets found in the DNA of patients with MJD-II lies between the two extremes.MJD is inherited as an autosomal dominant trait. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
|
Causes of Machado-Joseph Disease. The gene responsible for MJD has been identified and mapped to Gene Map Locus; 14q24.3-q31. This gene is associated with an abnormal number of CAG trinucleotide repeats (sometimes called triplets) in the DNA. (CAG refers to the Cytosine-Adenine-Guanine trinucleotide structure.) “Normal” DNA usually has between 12 and 43 copies of the CAG trinucleotide. In persons with the disease, the DNA contains from 56-86 copies of this trinucleotide. Severity of symptoms and age of onset are related directly to the number of the repeats. Thus, MJD-I will have fewer of these triplets while MJD-III will have the greater number. The number of the CAG triplets found in the DNA of patients with MJD-II lies between the two extremes.MJD is inherited as an autosomal dominant trait. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
| 742 |
Machado-Joseph Disease
|
nord_742_3
|
Affects of Machado-Joseph Disease
|
MJD is a rare inherited neurological disorder that disproportionately affects individuals of Portuguese descent, especially those from the Azores, an island colonized by Portuguese people. MJD appears to affect slightly more males than females.
|
Affects of Machado-Joseph Disease. MJD is a rare inherited neurological disorder that disproportionately affects individuals of Portuguese descent, especially those from the Azores, an island colonized by Portuguese people. MJD appears to affect slightly more males than females.
| 742 |
Machado-Joseph Disease
|
nord_742_4
|
Related disorders of Machado-Joseph Disease
|
Symptoms of the following disorders can be similar to those of Machado-Joseph Disease. Comparisons may be useful for a differential diagnosis:Hallervorden-Spatz Disease is a rare inherited disorder characterized by neurological degeneration. Symptoms may include slow, steady muscle contractions of the arms, legs, neck, face, mouth, or trunk. Other symptoms may include muscle spasms, slurred speech (dysarthria), mental retardation, impaired speech (dysphasia), and the loss of muscle mass (amyotrophy). (For more information on this disorder choose “Hallervorden-Spatz” as your search term on the Rare Disease Database.)Olivopontocerebellar Atrophy is a group of rare inherited neurological disorders characterized by progressive neurological degeneration. These diseases effect the brain (outer layers of cerebellum) and result in impaired ability to coordinate movement (ataxia). Symptoms vary and may include muscle spasms, involuntary movements, abnormal posture, slurred speech (dysarthria), and changes in muscle tone (extrapyramidal signs). The symptoms and age of onset vary according to the type of Olivopontocerebellar Atrophy. (For more information on this disorder, choose “Olivopontocerebellar Atrophy” as your search term on the Rare Disease Database.)Progressive Supranuclear Palsy (PSP) is a rare neurological disorder characterized by spastic weakness of muscles controlled by the cranial nerves (i.e., face, throat and tongue). The symptoms usually begin during middle age and may include loss of balance while walking, a stiff gait (ataxia), or unexplained falls. Different symptoms can develop during the course of this disorder, and previously mild problems may become more severe with time. (For more information on this disorder, choose “Progressive Supranuclear Palsy” as your search term on the Rare Disease Database.)Amyotrophic Lateral Sclerosis (ALS) is a rare disease of the skeletal muscle nerve cells (motor neurons). It effects the motor neurons that control the upper and lower parts of the body and results in muscle weakness and the progressive wasting of muscles. The early symptoms of Amyotrophic Lateral Sclerosis may include muscle weakness, clumsy hand movements, and difficulty performing tasks that require delicate movements of the fingers and hands. Other symptoms may include weakness of the muscles of the lips, tongue, mouth, and voice. (For more information on this disorder, choose “Amyotrophic Lateral Sclerosis” as your search term in the Rare Disease Database.)Friedreich's Ataxia is a rare inherited disorder characterized by degenerative changes and the progressive deterioration of the brain and spinal cord. Symptoms may include muscle weakness and numbness in the arms and legs, curvature of the spine (secondary lateral scoliosis), and paralysis of the legs. (For more information on this disorder, choose “Friedreich's Ataxia” as your search term in the Rare Disease Database.)Marie's Ataxia is a rare inherited neurological disorder characterized by progressive loss of muscle coordination and an awkward, unsteady gait (ataxia). Progressive spinal nerve degeneration leads to the loss of muscle mass (amyotrophy) in the arms, legs, head, and neck. (For more information on this disorder, choose “Marie's Ataxia” as your search term in the Rare Disease Database.)Parenchymatous Cortical Degeneration of the Cerebellum is a rare neurological disorder characterized by the progressive deterioration of areas of the brain which coordinate movement and muscle coordination. This disease may be inherited or acquired. Symptoms may include slurred speech and a halting, unsteady gait (ataxia). (For more information on this disorder, choose “Parenchymatous Cortical Degeneration” as your search term in the Rare Disease Database.)
|
Related disorders of Machado-Joseph Disease. Symptoms of the following disorders can be similar to those of Machado-Joseph Disease. Comparisons may be useful for a differential diagnosis:Hallervorden-Spatz Disease is a rare inherited disorder characterized by neurological degeneration. Symptoms may include slow, steady muscle contractions of the arms, legs, neck, face, mouth, or trunk. Other symptoms may include muscle spasms, slurred speech (dysarthria), mental retardation, impaired speech (dysphasia), and the loss of muscle mass (amyotrophy). (For more information on this disorder choose “Hallervorden-Spatz” as your search term on the Rare Disease Database.)Olivopontocerebellar Atrophy is a group of rare inherited neurological disorders characterized by progressive neurological degeneration. These diseases effect the brain (outer layers of cerebellum) and result in impaired ability to coordinate movement (ataxia). Symptoms vary and may include muscle spasms, involuntary movements, abnormal posture, slurred speech (dysarthria), and changes in muscle tone (extrapyramidal signs). The symptoms and age of onset vary according to the type of Olivopontocerebellar Atrophy. (For more information on this disorder, choose “Olivopontocerebellar Atrophy” as your search term on the Rare Disease Database.)Progressive Supranuclear Palsy (PSP) is a rare neurological disorder characterized by spastic weakness of muscles controlled by the cranial nerves (i.e., face, throat and tongue). The symptoms usually begin during middle age and may include loss of balance while walking, a stiff gait (ataxia), or unexplained falls. Different symptoms can develop during the course of this disorder, and previously mild problems may become more severe with time. (For more information on this disorder, choose “Progressive Supranuclear Palsy” as your search term on the Rare Disease Database.)Amyotrophic Lateral Sclerosis (ALS) is a rare disease of the skeletal muscle nerve cells (motor neurons). It effects the motor neurons that control the upper and lower parts of the body and results in muscle weakness and the progressive wasting of muscles. The early symptoms of Amyotrophic Lateral Sclerosis may include muscle weakness, clumsy hand movements, and difficulty performing tasks that require delicate movements of the fingers and hands. Other symptoms may include weakness of the muscles of the lips, tongue, mouth, and voice. (For more information on this disorder, choose “Amyotrophic Lateral Sclerosis” as your search term in the Rare Disease Database.)Friedreich's Ataxia is a rare inherited disorder characterized by degenerative changes and the progressive deterioration of the brain and spinal cord. Symptoms may include muscle weakness and numbness in the arms and legs, curvature of the spine (secondary lateral scoliosis), and paralysis of the legs. (For more information on this disorder, choose “Friedreich's Ataxia” as your search term in the Rare Disease Database.)Marie's Ataxia is a rare inherited neurological disorder characterized by progressive loss of muscle coordination and an awkward, unsteady gait (ataxia). Progressive spinal nerve degeneration leads to the loss of muscle mass (amyotrophy) in the arms, legs, head, and neck. (For more information on this disorder, choose “Marie's Ataxia” as your search term in the Rare Disease Database.)Parenchymatous Cortical Degeneration of the Cerebellum is a rare neurological disorder characterized by the progressive deterioration of areas of the brain which coordinate movement and muscle coordination. This disease may be inherited or acquired. Symptoms may include slurred speech and a halting, unsteady gait (ataxia). (For more information on this disorder, choose “Parenchymatous Cortical Degeneration” as your search term in the Rare Disease Database.)
| 742 |
Machado-Joseph Disease
|
nord_742_5
|
Diagnosis of Machado-Joseph Disease
|
While a family history and physical examination help in the diagnosis, the gold standard of diagnostic tests that detects 100% of the cases is the direct determination of the number of suspect CAG triplets in a patient's DNA. This may be readily done at a specialized genetic clinical laboratory.
|
Diagnosis of Machado-Joseph Disease. While a family history and physical examination help in the diagnosis, the gold standard of diagnostic tests that detects 100% of the cases is the direct determination of the number of suspect CAG triplets in a patient's DNA. This may be readily done at a specialized genetic clinical laboratory.
| 742 |
Machado-Joseph Disease
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.