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nord_571_3
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Affects of Hereditary Coproporphyria
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HCP is a rare disorder that can potentially affect males and females in equal numbers, although symptoms are more prevalent in females. The exact incidence and prevalence of HCP is unknown.
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Affects of Hereditary Coproporphyria. HCP is a rare disorder that can potentially affect males and females in equal numbers, although symptoms are more prevalent in females. The exact incidence and prevalence of HCP is unknown.
| 571 |
Hereditary Coproporphyria
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nord_571_4
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Related disorders of Hereditary Coproporphyria
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Symptoms of the following disorders can be similar to those of HCP. Comparisons may be useful for a differential diagnosis.Three other forms of porphyria, specifically variegate porphyria, acute intermittent porphyria, and ALA-D deficiency porphyria, may develop acute attacks that characterize HCP. Collectively, these four forms of the porphyria are classified as the acute porphyrias. The cutaneous symptoms that affect some individuals with HCP resemble those seen in variegate porphyria and porphyria cutanea tarda, one of the nonacute porphyrias. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)Guillain-Barré syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) causing muscle weakness, ascending paralysis and potentially complete paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the cases. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal neuropathy, acute motor axonal neuropathy. (For more information on this disorder, choose “Guillain Barre” as your search term in the Rare Disease Database.)
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Related disorders of Hereditary Coproporphyria. Symptoms of the following disorders can be similar to those of HCP. Comparisons may be useful for a differential diagnosis.Three other forms of porphyria, specifically variegate porphyria, acute intermittent porphyria, and ALA-D deficiency porphyria, may develop acute attacks that characterize HCP. Collectively, these four forms of the porphyria are classified as the acute porphyrias. The cutaneous symptoms that affect some individuals with HCP resemble those seen in variegate porphyria and porphyria cutanea tarda, one of the nonacute porphyrias. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)Guillain-Barré syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) causing muscle weakness, ascending paralysis and potentially complete paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the cases. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal neuropathy, acute motor axonal neuropathy. (For more information on this disorder, choose “Guillain Barre” as your search term in the Rare Disease Database.)
| 571 |
Hereditary Coproporphyria
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nord_571_5
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Diagnosis of Hereditary Coproporphyria
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A diagnosis of HCP is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. The observation of reddish brown urine that is free of blood is indicative, but not conclusive, of an acute porphyria. The intolerance of medications such as oral contraceptives is also suggestive of an acute porphyria.Clinical Testing and WorkupScreening tests can help diagnose HCP by measuring the levels of certain porphyrin precursors (e.g. porphobilinogen [PBG] and delta-aminolevulinic acid [ALA] in the urine. Acute attacks are always accompanied by markedly increased excretion of PBG. During a potential acute attack in an individual suspected of an acute porphyria, a random (spot) urine sample can be tested. If urinary PBG is sufficiently increased, then a qualitative 24-hour urine analysis for both PBG and ALA should be performed and compared to urine sample results from when the individual did not exhibit symptoms. Although PBG and ALA may be increased during an acute attack, they return to normal on recovery.Individuals with HCP may have elevated porphyrin levels such as coproporphyrin in the urine, but this finding is nonspecific (e.g. it can also be associated with other conditions) and therefore does not conclusively confirm a diagnosis of HCP.Further testing is necessary to exclude HCP from variegate porphyria or acute intermittent porphyria. Fecal CP analysis can be extremely helpful in obtaining the diagnosis. This test can reveal markedly increased levels of coproporphyrin in stool samples, which is characteristic of HCP.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the CPOX gene. Family members of an individual positive for a CPOX mutation can be offered testing for this mutation. Molecular genetic testing is available in certain laboratories specializing in porphyria diagnosis.Individuals and family members who have inherited HCP should be counseled on how to limit their risk of any future acute attacks. This should include information about HCP and what causes attacks, how to check if a prescribed medication is safe or unsafe, and details of relevant patient support groups. Membership in the American Porphyria Foundation is very helpful to affected individuals.
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Diagnosis of Hereditary Coproporphyria. A diagnosis of HCP is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. The observation of reddish brown urine that is free of blood is indicative, but not conclusive, of an acute porphyria. The intolerance of medications such as oral contraceptives is also suggestive of an acute porphyria.Clinical Testing and WorkupScreening tests can help diagnose HCP by measuring the levels of certain porphyrin precursors (e.g. porphobilinogen [PBG] and delta-aminolevulinic acid [ALA] in the urine. Acute attacks are always accompanied by markedly increased excretion of PBG. During a potential acute attack in an individual suspected of an acute porphyria, a random (spot) urine sample can be tested. If urinary PBG is sufficiently increased, then a qualitative 24-hour urine analysis for both PBG and ALA should be performed and compared to urine sample results from when the individual did not exhibit symptoms. Although PBG and ALA may be increased during an acute attack, they return to normal on recovery.Individuals with HCP may have elevated porphyrin levels such as coproporphyrin in the urine, but this finding is nonspecific (e.g. it can also be associated with other conditions) and therefore does not conclusively confirm a diagnosis of HCP.Further testing is necessary to exclude HCP from variegate porphyria or acute intermittent porphyria. Fecal CP analysis can be extremely helpful in obtaining the diagnosis. This test can reveal markedly increased levels of coproporphyrin in stool samples, which is characteristic of HCP.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the CPOX gene. Family members of an individual positive for a CPOX mutation can be offered testing for this mutation. Molecular genetic testing is available in certain laboratories specializing in porphyria diagnosis.Individuals and family members who have inherited HCP should be counseled on how to limit their risk of any future acute attacks. This should include information about HCP and what causes attacks, how to check if a prescribed medication is safe or unsafe, and details of relevant patient support groups. Membership in the American Porphyria Foundation is very helpful to affected individuals.
| 571 |
Hereditary Coproporphyria
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nord_571_6
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Therapies of Hereditary Coproporphyria
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Treatment The treatment of HCP 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, hematologists, dermatologists, hepatologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected person’s treatment. Genetic counseling may benefit affected individuals and their families. Initial treatment steps include stopping any medications that can potentially worsen HCP or cause an attack. All triggering factors should be identified, if possible, and discontinued. In addition, ensuring proper intake of carbohydrate, either orally or intravenously, is essential. An acute neurovisceral attack requires hospitalization and treatment with hematin. In the United States, affected individuals may be treated with Panhematin (hemin for injection), an enzyme inhibitor derived from red blood cells that is potent in suppressing acute attacks of porphyria. Panhematin almost always returns porphyrin and porphyrin precursor levels to normal values. The U.S. Food and Drug Administration (FDA) originally approved Panhematin for the treatment of recurrent attacks of AIP related to the menstrual cycle in susceptible women. Numerous symptoms including pain, hypertension, tachycardia and altered mental status, and neurologic signs have improved in individuals with acute porphyria after treatment with Panhematin. Because of its potency, it is usually given after a trial of high-dose carbohydrate of any sort, including glucose therapy and should be administered only by physicians experienced in the management of porphyrias in a hospital setting. In 2019, the FDA approved Givlaari (givosiran) to treat adults with acute hepatic porphyria, including HCP. Givlaari aims to prevent attacks from occuring. Normosang (heme arginate) is another heme preparation that can be used to treat individuals with HCP. Heme arginate is not available in the United States but is often used in other countries. Some individuals who experience recurrent attacks may benefit from chronic hematin infusion. This is sometimes recommended for women with severe symptoms during the time of their menses. Treatment for HCP may also include drugs to treat specific symptoms such as certain pain medications (analgesics), anti-anxiety drugs, anti-hypertensive drugs, and drugs to treat nausea and vomiting, tachycardia, or restlessness. Medications to treat any infections that may occur at the same time as an attack (intercurrent infection) may also be necessary. Seizures may require treatment with anti-seizure (anti-convulsant) medications, but many of the common options can worsen an attack and are contraindicated. A short-acting benzodiazepine or magnesium may be recommended. Gabapentin and propofol are considered effective and safe for prolonged control of seizures. Although many types of drugs are believed to be safe in individuals with HCP, recommendations about drugs for treating HCP are based upon experience and clinical study. Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible. If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted. A list of these institutions may be obtained from the American Porphyria Foundation (see the Resources section of this report). The Foundation also maintains an Acute Porphyria Drug Database (http://www.porphyriafoundation.com/drug-database) Additional treatment for individuals undergoing an attack includes monitoring for muscle weakness and respiratory issues and monitoring fluid and electrolyte balances. For example, if affected individuals develop hyponatremia, which can induce seizures, they should be treated by restricting the intake of water (water deprivation). If serum sodium is decreased severely, e.g. from normal (134 meq/dl) to very low (100-115 meq/dl), then saline infusion is indicated. Premenstrual attacks often resolve quickly with the onset of menstruation. Hormone manipulation may be effective in preventing such attacks. Some affected women have been treated with gonadotropin-releasing hormone analogues to suppress ovulation and prevent frequent cyclic attacks. In some cases, an attack is precipitated by a low intake of carbohydrates. Consequently, dietary counseling is very important. Affected individuals who are prone to attacks should eat a normal carbohydrate diet and should not greatly restrict their intake of carbohydrates or calories, even for short periods of time. In individuals who develop skin complications, avoidance of sunlight will be of benefit and can include the use of double layers of clothing, long sleeves, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective. Affected individuals will also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars. Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D. A liver transplant has been used to treat some individuals with acute forms of porphyria, specifically individuals with severe disease who have failed to respond to other treatment options. A liver transplant in individuals with HCP is an option of last resort. Wearing a Medic Alert bracelet or the use of a wallet card is advisable in individuals who have HCP.
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Therapies of Hereditary Coproporphyria. Treatment The treatment of HCP 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, hematologists, dermatologists, hepatologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected person’s treatment. Genetic counseling may benefit affected individuals and their families. Initial treatment steps include stopping any medications that can potentially worsen HCP or cause an attack. All triggering factors should be identified, if possible, and discontinued. In addition, ensuring proper intake of carbohydrate, either orally or intravenously, is essential. An acute neurovisceral attack requires hospitalization and treatment with hematin. In the United States, affected individuals may be treated with Panhematin (hemin for injection), an enzyme inhibitor derived from red blood cells that is potent in suppressing acute attacks of porphyria. Panhematin almost always returns porphyrin and porphyrin precursor levels to normal values. The U.S. Food and Drug Administration (FDA) originally approved Panhematin for the treatment of recurrent attacks of AIP related to the menstrual cycle in susceptible women. Numerous symptoms including pain, hypertension, tachycardia and altered mental status, and neurologic signs have improved in individuals with acute porphyria after treatment with Panhematin. Because of its potency, it is usually given after a trial of high-dose carbohydrate of any sort, including glucose therapy and should be administered only by physicians experienced in the management of porphyrias in a hospital setting. In 2019, the FDA approved Givlaari (givosiran) to treat adults with acute hepatic porphyria, including HCP. Givlaari aims to prevent attacks from occuring. Normosang (heme arginate) is another heme preparation that can be used to treat individuals with HCP. Heme arginate is not available in the United States but is often used in other countries. Some individuals who experience recurrent attacks may benefit from chronic hematin infusion. This is sometimes recommended for women with severe symptoms during the time of their menses. Treatment for HCP may also include drugs to treat specific symptoms such as certain pain medications (analgesics), anti-anxiety drugs, anti-hypertensive drugs, and drugs to treat nausea and vomiting, tachycardia, or restlessness. Medications to treat any infections that may occur at the same time as an attack (intercurrent infection) may also be necessary. Seizures may require treatment with anti-seizure (anti-convulsant) medications, but many of the common options can worsen an attack and are contraindicated. A short-acting benzodiazepine or magnesium may be recommended. Gabapentin and propofol are considered effective and safe for prolonged control of seizures. Although many types of drugs are believed to be safe in individuals with HCP, recommendations about drugs for treating HCP are based upon experience and clinical study. Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible. If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted. A list of these institutions may be obtained from the American Porphyria Foundation (see the Resources section of this report). The Foundation also maintains an Acute Porphyria Drug Database (http://www.porphyriafoundation.com/drug-database) Additional treatment for individuals undergoing an attack includes monitoring for muscle weakness and respiratory issues and monitoring fluid and electrolyte balances. For example, if affected individuals develop hyponatremia, which can induce seizures, they should be treated by restricting the intake of water (water deprivation). If serum sodium is decreased severely, e.g. from normal (134 meq/dl) to very low (100-115 meq/dl), then saline infusion is indicated. Premenstrual attacks often resolve quickly with the onset of menstruation. Hormone manipulation may be effective in preventing such attacks. Some affected women have been treated with gonadotropin-releasing hormone analogues to suppress ovulation and prevent frequent cyclic attacks. In some cases, an attack is precipitated by a low intake of carbohydrates. Consequently, dietary counseling is very important. Affected individuals who are prone to attacks should eat a normal carbohydrate diet and should not greatly restrict their intake of carbohydrates or calories, even for short periods of time. In individuals who develop skin complications, avoidance of sunlight will be of benefit and can include the use of double layers of clothing, long sleeves, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective. Affected individuals will also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars. Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D. A liver transplant has been used to treat some individuals with acute forms of porphyria, specifically individuals with severe disease who have failed to respond to other treatment options. A liver transplant in individuals with HCP is an option of last resort. Wearing a Medic Alert bracelet or the use of a wallet card is advisable in individuals who have HCP.
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Hereditary Coproporphyria
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nord_572_0
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Overview of Hereditary Hemorrhagic Telangiectasia
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SummaryHereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome) is an inherited disorder characterized by malformations of various blood vessels (vascular dysplasia), potentially resulting in bleeding (hemorrhaging) and shunting of blood. Chronic nosebleeds are often the first sign and malformation of various blood vessels may result in abnormalities affecting the lungs, brain, spinal cord and liver. A variety of treatments exist for the various features of HHT to improve quality of life and prevent life-threatening complications. With appropriate treatment, individuals with HHT can expect a near-normal life expectancy. HHT is inherited in an autosomal dominant pattern.IntroductionHHT was first described by Henry Gawen Sutton in 1864. With similar symptoms to hemophilia, the two diseases were differentiated by Henri Jules Louis Marie Rendu in 1896. William Osler connected the disease’s presence in families to establish it as an inherited disorder. In 1907 Frederick Parkes Weber continued the characterization of the disease, writing a report on a series of cases. In 1909, the name “hereditary hemorrhagic telangiectasia” was coined, but alternate names based on the scientists who first characterized it have also been commonly used. Since its first identification, HHT has been an underdiagnosed disease, affecting more than a million people worldwide.
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Overview of Hereditary Hemorrhagic Telangiectasia. SummaryHereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome) is an inherited disorder characterized by malformations of various blood vessels (vascular dysplasia), potentially resulting in bleeding (hemorrhaging) and shunting of blood. Chronic nosebleeds are often the first sign and malformation of various blood vessels may result in abnormalities affecting the lungs, brain, spinal cord and liver. A variety of treatments exist for the various features of HHT to improve quality of life and prevent life-threatening complications. With appropriate treatment, individuals with HHT can expect a near-normal life expectancy. HHT is inherited in an autosomal dominant pattern.IntroductionHHT was first described by Henry Gawen Sutton in 1864. With similar symptoms to hemophilia, the two diseases were differentiated by Henri Jules Louis Marie Rendu in 1896. William Osler connected the disease’s presence in families to establish it as an inherited disorder. In 1907 Frederick Parkes Weber continued the characterization of the disease, writing a report on a series of cases. In 1909, the name “hereditary hemorrhagic telangiectasia” was coined, but alternate names based on the scientists who first characterized it have also been commonly used. Since its first identification, HHT has been an underdiagnosed disease, affecting more than a million people worldwide.
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Hereditary Hemorrhagic Telangiectasia
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nord_572_1
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Symptoms of Hereditary Hemorrhagic Telangiectasia
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The symptoms associated with HHT vary from person to person. Differences in disease expression (phenotype) partially reflect the specific gene that is mutated in HHT. Phenotypic penetrance is age dependent with approximately 90% showing signs or symptoms by age 40-45 years. Some individuals may experience symptoms during infancy or early childhood; others may show few signs or symptoms until the thirties, forties or later in life.In many patients, the first apparent symptom of HHT is nosebleeds (epistaxis). While recurrent nosebleeds may develop as early as infancy they most often begin around puberty. Recurrent nosebleeds occur in approximately 90% of affected individuals. Nosebleeds occur because of the formation of small, fragile vascular malformations (telangiectases) in the mucous membranes lining the inside of the nose. Telangiectases occur when capillaries fail to develop between arterioles and venules and most often affect the skin and the mucous membranes. The tongue, lips, face, ears, and fingers are the areas most often affected. Telangiectases may develop at any age including during infancy, but usually become apparent during adolescence and later.Telangiectases also occur in the gastrointestinal tract. Gastrointestinal bleeding (hemorrhaging), which affects about 25-30%, usually does not present until the fourth decade of life or later. Affected individuals with gastrointestinal bleeding may note dark stools – sometimes black and tarry (melena) – but only rarely do they have red blood in their stools (hematochezia) or vomit (hematemesis). Commonly, blood loss is not detected by the patient, even when it leads to anemia.Because bleeding episodes become more severe with age, they often lead to chronically low levels of iron in the blood and eventually to a low red blood cell count (anemia). Anemia may result in chest pain, shortness of breath, and/or fatigue. Gastrointestinal bleeding can often be slow, chronic and intermittent, with few noticeable symptoms until the onset of anemia.Many individuals with HHT develop arteriovenous malformations (AVMs). AVMs, which are direct connections between blood vessels of larger caliber than in telangiectases, most commonly affect the lungs, brain, spinal cord, and liver. In recent years AVM have been noted in the pancreas, kidneys, and other organs, though they rarely cause complications in these locations.Pulmonary AVMs (PAVM) are seen in about 50% of individuals with HHT and are often asymptomatic. However, they may result in fatigue, difficulty breathing (dyspnea), episodes of coughing up of blood (hemoptysis), headaches, abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis) and/or abnormally increased levels of red cells in the blood (polycythemia). Serious neurological complications, including brain abscess and stroke, may occur due to passage of blood clots or bacteria through a PAVM.AVMs of the brain occur in about 10% of individuals with HHT and may result in headache, dizziness (vertigo), and seizures. In rare cases, individuals with AVMs of the brain may experience vision and hearing problems such as double vision (diplopia). However, usually they are asymptomatic prior to a hemorrhagic event. AVMs affecting the spinal cord (approximately 1% of those with HHT) are less common and may result in pain in the back and/or loss of feeling or functions of the arms and legs.Liver vascular malformations are seen in up to 75% of individuals with HHT. In most cases they remain asymptomatic, though over time 10-20% may develop liver or heart failure. Individuals may experience high blood pressure in the veins carrying blood from the gastrointestinal tract back to the heart through the liver (portal hypertension) and abnormalities of the bile ducts (biliary disease). The bile ducts are narrow tubes through which bile passes from the liver to the first section of the small intestine. Pressure on bile ducts from enlarged blood vessels may result in failure of bile to flow to the small intestine, instead becoming trapped in the liver, resulting in yellowing of the skin and the whites of the eyes (jaundice).Shunting of blood through liver AVM may result in excessive blood flow through the liver. Over time, high output heart failure may occur because the heart is forced to work harder to compensate for the extra blood flow through the liver, in addition to the normal blood flow to the rest of the body.
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Symptoms of Hereditary Hemorrhagic Telangiectasia. The symptoms associated with HHT vary from person to person. Differences in disease expression (phenotype) partially reflect the specific gene that is mutated in HHT. Phenotypic penetrance is age dependent with approximately 90% showing signs or symptoms by age 40-45 years. Some individuals may experience symptoms during infancy or early childhood; others may show few signs or symptoms until the thirties, forties or later in life.In many patients, the first apparent symptom of HHT is nosebleeds (epistaxis). While recurrent nosebleeds may develop as early as infancy they most often begin around puberty. Recurrent nosebleeds occur in approximately 90% of affected individuals. Nosebleeds occur because of the formation of small, fragile vascular malformations (telangiectases) in the mucous membranes lining the inside of the nose. Telangiectases occur when capillaries fail to develop between arterioles and venules and most often affect the skin and the mucous membranes. The tongue, lips, face, ears, and fingers are the areas most often affected. Telangiectases may develop at any age including during infancy, but usually become apparent during adolescence and later.Telangiectases also occur in the gastrointestinal tract. Gastrointestinal bleeding (hemorrhaging), which affects about 25-30%, usually does not present until the fourth decade of life or later. Affected individuals with gastrointestinal bleeding may note dark stools – sometimes black and tarry (melena) – but only rarely do they have red blood in their stools (hematochezia) or vomit (hematemesis). Commonly, blood loss is not detected by the patient, even when it leads to anemia.Because bleeding episodes become more severe with age, they often lead to chronically low levels of iron in the blood and eventually to a low red blood cell count (anemia). Anemia may result in chest pain, shortness of breath, and/or fatigue. Gastrointestinal bleeding can often be slow, chronic and intermittent, with few noticeable symptoms until the onset of anemia.Many individuals with HHT develop arteriovenous malformations (AVMs). AVMs, which are direct connections between blood vessels of larger caliber than in telangiectases, most commonly affect the lungs, brain, spinal cord, and liver. In recent years AVM have been noted in the pancreas, kidneys, and other organs, though they rarely cause complications in these locations.Pulmonary AVMs (PAVM) are seen in about 50% of individuals with HHT and are often asymptomatic. However, they may result in fatigue, difficulty breathing (dyspnea), episodes of coughing up of blood (hemoptysis), headaches, abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis) and/or abnormally increased levels of red cells in the blood (polycythemia). Serious neurological complications, including brain abscess and stroke, may occur due to passage of blood clots or bacteria through a PAVM.AVMs of the brain occur in about 10% of individuals with HHT and may result in headache, dizziness (vertigo), and seizures. In rare cases, individuals with AVMs of the brain may experience vision and hearing problems such as double vision (diplopia). However, usually they are asymptomatic prior to a hemorrhagic event. AVMs affecting the spinal cord (approximately 1% of those with HHT) are less common and may result in pain in the back and/or loss of feeling or functions of the arms and legs.Liver vascular malformations are seen in up to 75% of individuals with HHT. In most cases they remain asymptomatic, though over time 10-20% may develop liver or heart failure. Individuals may experience high blood pressure in the veins carrying blood from the gastrointestinal tract back to the heart through the liver (portal hypertension) and abnormalities of the bile ducts (biliary disease). The bile ducts are narrow tubes through which bile passes from the liver to the first section of the small intestine. Pressure on bile ducts from enlarged blood vessels may result in failure of bile to flow to the small intestine, instead becoming trapped in the liver, resulting in yellowing of the skin and the whites of the eyes (jaundice).Shunting of blood through liver AVM may result in excessive blood flow through the liver. Over time, high output heart failure may occur because the heart is forced to work harder to compensate for the extra blood flow through the liver, in addition to the normal blood flow to the rest of the body.
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Hereditary Hemorrhagic Telangiectasia
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nord_572_2
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Causes of Hereditary Hemorrhagic Telangiectasia
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HHT is caused by changes (mutations) in five different genes. It is likely that more genes are yet to be discovered.Mutations of the ENG gene and abnormalities of the protein it produces (endoglin) result in HHT-1. Endoglin is found on the surface of the cells that line the inside of the blood vessels. Scientists believe that endoglin binds to transforming growth factor-beta (TGF-ß). In mice that are deficient in endoglin, the blood vessels do not mature and there is a failure in vascular smooth muscle development.Mutations of the activin receptor-like kinase 1 (ACVRL1) gene and abnormalities of the protein in encodes (ALK1), result in HHT-2. People with mutations in this gene are more prone to complications from liver AVMs such as liver failure and elevated pressure on the right side of the heart (pulmonary hypertension).Approximately 1-2% of individuals with HHT have a combination of HHT and juvenile polyposis known as JPHT (or JPHHT) overlap syndrome, a disorder involving polyps in the gastrointestinal tract. This type of HHT is caused by mutations in the SMAD4 gene.Mutations in the BMPR9 and RASA1 genes produce syndromes that share phenotypic overlap with HHT including atypical telangiectases (similar to cutaneous capillary malformations), mild nosebleeds and AVMs typically in the brain and soft tissue. Whether these syndromes are truly HHT or merely HHT look-alikes remains controversial.With the exception of RASA1, the genes that cause HHT encode for proteins involved in the TGF-ß/BMP (for bone morphogenic protein) superfamily of signaling. This group of proteins helps regulate many cellular functions such as cell survival, proliferation and differentiation. With malfunctioning signaling, the cells formation of blood vessels (angiogenesis) is defective, causing the clinical features of HHT.HHT is inherited in an autosomal dominant pattern. In rare cases, the disorder occurs randomly as the result of a spontaneous genetic change (i.e., new mutation). All relatives affected in a family with HHT will have the same mutation. However, in different families the causative mutation is usually different, with over 900 different mutations found within the five genes known to cause HHT.In dominant disorders, only a single copy of the disease gene (received from either the mother or father) is required to cause the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
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Causes of Hereditary Hemorrhagic Telangiectasia. HHT is caused by changes (mutations) in five different genes. It is likely that more genes are yet to be discovered.Mutations of the ENG gene and abnormalities of the protein it produces (endoglin) result in HHT-1. Endoglin is found on the surface of the cells that line the inside of the blood vessels. Scientists believe that endoglin binds to transforming growth factor-beta (TGF-ß). In mice that are deficient in endoglin, the blood vessels do not mature and there is a failure in vascular smooth muscle development.Mutations of the activin receptor-like kinase 1 (ACVRL1) gene and abnormalities of the protein in encodes (ALK1), result in HHT-2. People with mutations in this gene are more prone to complications from liver AVMs such as liver failure and elevated pressure on the right side of the heart (pulmonary hypertension).Approximately 1-2% of individuals with HHT have a combination of HHT and juvenile polyposis known as JPHT (or JPHHT) overlap syndrome, a disorder involving polyps in the gastrointestinal tract. This type of HHT is caused by mutations in the SMAD4 gene.Mutations in the BMPR9 and RASA1 genes produce syndromes that share phenotypic overlap with HHT including atypical telangiectases (similar to cutaneous capillary malformations), mild nosebleeds and AVMs typically in the brain and soft tissue. Whether these syndromes are truly HHT or merely HHT look-alikes remains controversial.With the exception of RASA1, the genes that cause HHT encode for proteins involved in the TGF-ß/BMP (for bone morphogenic protein) superfamily of signaling. This group of proteins helps regulate many cellular functions such as cell survival, proliferation and differentiation. With malfunctioning signaling, the cells formation of blood vessels (angiogenesis) is defective, causing the clinical features of HHT.HHT is inherited in an autosomal dominant pattern. In rare cases, the disorder occurs randomly as the result of a spontaneous genetic change (i.e., new mutation). All relatives affected in a family with HHT will have the same mutation. However, in different families the causative mutation is usually different, with over 900 different mutations found within the five genes known to cause HHT.In dominant disorders, only a single copy of the disease gene (received from either the mother or father) is required to cause the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
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Hereditary Hemorrhagic Telangiectasia
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nord_572_3
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Affects of Hereditary Hemorrhagic Telangiectasia
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HHT affects males and females in equal numbers. Symptoms can occur at any age. The disorder is estimated to occur in approximately 1 per 5,000 people. However, because some affected individuals develop few obvious symptoms and findings, the disorder often remains unrecognized. HHT is known to be underdiagnosed. This makes it difficult to determine the true frequency of HHT in the general population.
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Affects of Hereditary Hemorrhagic Telangiectasia. HHT affects males and females in equal numbers. Symptoms can occur at any age. The disorder is estimated to occur in approximately 1 per 5,000 people. However, because some affected individuals develop few obvious symptoms and findings, the disorder often remains unrecognized. HHT is known to be underdiagnosed. This makes it difficult to determine the true frequency of HHT in the general population.
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Hereditary Hemorrhagic Telangiectasia
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Related disorders of Hereditary Hemorrhagic Telangiectasia
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Symptoms of the following disorders can be similar to those of hereditary hemorrhagic telangiectasia. Comparisons may be useful for a differential diagnosis:Von Willebrand disease (VWD) is a common inherited bleeding disorder in the general population affecting males and females equally. There are three main types of VWD each with differing degrees of severity and inheritance patterns, though AVM are not seen as part of VWD. Uncommonly, individuals with HHT may also have Von Willebrand disease due to random chance. (For more information on this disorder, choose “von Willebrand” as your search term in the Rare Disease Database.)Calcinosis-Raynaud’s-Sclerodactyly-Esophageal dysfunction-Telangiectasia syndrome (CREST syndrome) is a combination of various symptoms and is related to scleroderma. Scleroderma is a disorder characterized by thickening and hardening of the skin. Cutaneous telangiectases but not AVM may be present in this disorder. Rarely, individuals with HHT may also have CREST due to random chance. (For more information, choose “Scleroderma” as your search terms in the Rare Disease Database.)Ataxia telangiectasia (AT) is a complex genetic neurodegenerative disorder that may become apparent during infancy or early childhood. The disorder is characterized by progressively impaired coordination of voluntary movements (ataxia); the development of reddish lesions of the skin and mucous membranes due to permanent widening of groups of blood vessels (telangiectasia); and impaired functioning of the immune system (i.e., cellular and humoral immunodeficiency), resulting in increased susceptibility to upper and lower respiratory infections (sinopulmonary infections). Individuals with AT also have an increased risk of developing malignancies of the lymphatic system (lymphomas), the blood-forming organs (e.g., leukemia) and the brain. (For more information, choose “Ataxia-Telangiectasia” as your search terms in the Rare Disease Database.
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Related disorders of Hereditary Hemorrhagic Telangiectasia. Symptoms of the following disorders can be similar to those of hereditary hemorrhagic telangiectasia. Comparisons may be useful for a differential diagnosis:Von Willebrand disease (VWD) is a common inherited bleeding disorder in the general population affecting males and females equally. There are three main types of VWD each with differing degrees of severity and inheritance patterns, though AVM are not seen as part of VWD. Uncommonly, individuals with HHT may also have Von Willebrand disease due to random chance. (For more information on this disorder, choose “von Willebrand” as your search term in the Rare Disease Database.)Calcinosis-Raynaud’s-Sclerodactyly-Esophageal dysfunction-Telangiectasia syndrome (CREST syndrome) is a combination of various symptoms and is related to scleroderma. Scleroderma is a disorder characterized by thickening and hardening of the skin. Cutaneous telangiectases but not AVM may be present in this disorder. Rarely, individuals with HHT may also have CREST due to random chance. (For more information, choose “Scleroderma” as your search terms in the Rare Disease Database.)Ataxia telangiectasia (AT) is a complex genetic neurodegenerative disorder that may become apparent during infancy or early childhood. The disorder is characterized by progressively impaired coordination of voluntary movements (ataxia); the development of reddish lesions of the skin and mucous membranes due to permanent widening of groups of blood vessels (telangiectasia); and impaired functioning of the immune system (i.e., cellular and humoral immunodeficiency), resulting in increased susceptibility to upper and lower respiratory infections (sinopulmonary infections). Individuals with AT also have an increased risk of developing malignancies of the lymphatic system (lymphomas), the blood-forming organs (e.g., leukemia) and the brain. (For more information, choose “Ataxia-Telangiectasia” as your search terms in the Rare Disease Database.
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Hereditary Hemorrhagic Telangiectasia
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Diagnosis of Hereditary Hemorrhagic Telangiectasia
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A diagnosis of HHT is made based upon a detailed patient and family history, a thorough clinical examination, and imaging studies to identify characteristic findings in organs. An international group of experts on HHT established diagnostic criteria for HHT. The four criteria are: recurrent spontaneous nosebleeds; the presence of multiple telangiectases in characteristic locations; the presence of internal (visceral) telangiectases or AVMs; and a family history of definite HHT. A diagnosis is definite if at least three of the four criteria are present.Molecular genetic testing is available to determine if a mutation is present in ENG, ACVRL1, SMAD4, RASA1 or BMPR9 genes. This testing is particularly important for children of an affected parent whose mutation is known because each child has a 50% chance to inherit the mutation for HHT but may be too young to show signs. Appropriate screening and treatment, if necessary, can begin earlier for those found to carry an abnormal gene. Genetic testing will detect the mutation in nearly 90% of people who meet clinical criteria for definite HHT.Clinical Testing and Work-Up
After a diagnosis of HHT has been made from clinical assessment, detailed family history and/or genetic testing, an individual with HHT should have screening for asymptomatic AVMs and treatment of existing problems. Current symptoms will be identified and severity assessed for best possible treatment (for example nosebleeds). Standard screening tests for adults in North America include bloodwork to look for iron deficiency anemia, brain MRI with gadolinium to look for brain AVM, contrast echocardiography to look for PAVM and liver imaging (ultrasound, MRI or CT with contrast) to look for liver AVM. Pediatric patients should have a brain MRI with gadolinium and also be screened for lung AVM but the optimal method is controversial; some Centers use contrast echocardiography while others use pulse oximetry. If contrast echocardiography shows more than mild right to left shunting, CT of the chest with or without contrast is usually the next step to look for pulmonary AVM. If the child’s brain has no vascular malformations, the imaging should be repeated at least one more time in late adolescence. If the brain is unaffected in late adolescence, then it does not need to be screened again. Finally, patients will be referred to organ specialists for the various systems affected by HHT (lungs, liver, gastrointestinal tract, brain). Those specialists will consult with the patient to determine appropriate treatments or frequency of additional screening for AVMs
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Diagnosis of Hereditary Hemorrhagic Telangiectasia. A diagnosis of HHT is made based upon a detailed patient and family history, a thorough clinical examination, and imaging studies to identify characteristic findings in organs. An international group of experts on HHT established diagnostic criteria for HHT. The four criteria are: recurrent spontaneous nosebleeds; the presence of multiple telangiectases in characteristic locations; the presence of internal (visceral) telangiectases or AVMs; and a family history of definite HHT. A diagnosis is definite if at least three of the four criteria are present.Molecular genetic testing is available to determine if a mutation is present in ENG, ACVRL1, SMAD4, RASA1 or BMPR9 genes. This testing is particularly important for children of an affected parent whose mutation is known because each child has a 50% chance to inherit the mutation for HHT but may be too young to show signs. Appropriate screening and treatment, if necessary, can begin earlier for those found to carry an abnormal gene. Genetic testing will detect the mutation in nearly 90% of people who meet clinical criteria for definite HHT.Clinical Testing and Work-Up
After a diagnosis of HHT has been made from clinical assessment, detailed family history and/or genetic testing, an individual with HHT should have screening for asymptomatic AVMs and treatment of existing problems. Current symptoms will be identified and severity assessed for best possible treatment (for example nosebleeds). Standard screening tests for adults in North America include bloodwork to look for iron deficiency anemia, brain MRI with gadolinium to look for brain AVM, contrast echocardiography to look for PAVM and liver imaging (ultrasound, MRI or CT with contrast) to look for liver AVM. Pediatric patients should have a brain MRI with gadolinium and also be screened for lung AVM but the optimal method is controversial; some Centers use contrast echocardiography while others use pulse oximetry. If contrast echocardiography shows more than mild right to left shunting, CT of the chest with or without contrast is usually the next step to look for pulmonary AVM. If the child’s brain has no vascular malformations, the imaging should be repeated at least one more time in late adolescence. If the brain is unaffected in late adolescence, then it does not need to be screened again. Finally, patients will be referred to organ specialists for the various systems affected by HHT (lungs, liver, gastrointestinal tract, brain). Those specialists will consult with the patient to determine appropriate treatments or frequency of additional screening for AVMs
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Hereditary Hemorrhagic Telangiectasia
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Therapies of Hereditary Hemorrhagic Telangiectasia
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Treatment
The treatment of HHT is directed at specific symptoms present in each individual, as well as surveillance for undiagnosed AVMs. The Cure HHT Foundation has posted recommendations on its website (https://curehht.org/) regarding screening and treatment for various AVM. All patients with nosebleeds should use some type of nasal lubrication to prevent nosebleeds such as Vaseline, saline spray, or other products. Nasal trauma such as hard blowing, bumping or picking should be avoided. If conservative measures are insufficient, then oral tranexamic acid or surgical ablation using laser, bipolar cautery, coblation or sclerotherapy should be considered. Tranexamic acid is an antifibrinolytic agent that has been shown to be beneficial in two randomized clinical trials and seems to help about 50% of patients. Surgical ablation is best performed by a specialist (rhinologist) experienced with HHT and is usually >90% effective but the benefit typically lessens after 3-12 months. For patients who fail moisturization, tranexamic acid and ablative measures, systemic antiangiogenic agents should be considered (see below under Investigational Therapies). More aggressive surgical therapies including nasal closure and skin grafts are possible when the patient remains severely anemic from nasal blood loss. Patients with even small PAVM should receive antibiotic prophylaxis before dental procedures below the gum line, dental hygiene and potentially non-sterile surgeries such as rectal surgery. Small PAVM should also be monitored for growth every 5-10 years with either CT scanning or contrast echocardiography, depending on the patient. For patients with PAVMs that have a feeding artery of >2-3 mm in diameter, transcatheter embolization therapy, usually with coils or plugs, is currently recommended.Brain AVMs are usually treated by surgical removal, embolization, or treatment of the affected area with focused radiation (gamma knife). Such treatment should usually be provided at an HHT center or other center with expertise in brain vascular malformations.Because of the risk of complications, treatment of AVMs affecting the liver is usually only undertaken if an individual has symptomatic liver failure or high output heart failure. First line treatment for heart failure includes diuretics and correction of anemia and atrial fibrillation if present. For refractory cases, liver transplantation or intravenous bevacizumab might be considered, though the optimal choice is controversial at this time.For patients with bleeding AVMs of the gastrointestinal tract, especially if associated with anemia, endoscopy with cautery is usually the first line treatment, although it should be used sparingly. For persistent bleeding and/or anemia, tranexamic acid or antiangiogenic agents such as intravenous bevacizumab should be considered. Aggressive iron replacement therapy, either orally or by infusion, should be used to treat anemia secondary to the nose or GI bleeding associated with HHT. Blood transfusions are a last resort if frequent iron infusions and other therapies are not successful in reaching the target hemoglobin (usually >7 g/dl for most patients).
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Therapies of Hereditary Hemorrhagic Telangiectasia. Treatment
The treatment of HHT is directed at specific symptoms present in each individual, as well as surveillance for undiagnosed AVMs. The Cure HHT Foundation has posted recommendations on its website (https://curehht.org/) regarding screening and treatment for various AVM. All patients with nosebleeds should use some type of nasal lubrication to prevent nosebleeds such as Vaseline, saline spray, or other products. Nasal trauma such as hard blowing, bumping or picking should be avoided. If conservative measures are insufficient, then oral tranexamic acid or surgical ablation using laser, bipolar cautery, coblation or sclerotherapy should be considered. Tranexamic acid is an antifibrinolytic agent that has been shown to be beneficial in two randomized clinical trials and seems to help about 50% of patients. Surgical ablation is best performed by a specialist (rhinologist) experienced with HHT and is usually >90% effective but the benefit typically lessens after 3-12 months. For patients who fail moisturization, tranexamic acid and ablative measures, systemic antiangiogenic agents should be considered (see below under Investigational Therapies). More aggressive surgical therapies including nasal closure and skin grafts are possible when the patient remains severely anemic from nasal blood loss. Patients with even small PAVM should receive antibiotic prophylaxis before dental procedures below the gum line, dental hygiene and potentially non-sterile surgeries such as rectal surgery. Small PAVM should also be monitored for growth every 5-10 years with either CT scanning or contrast echocardiography, depending on the patient. For patients with PAVMs that have a feeding artery of >2-3 mm in diameter, transcatheter embolization therapy, usually with coils or plugs, is currently recommended.Brain AVMs are usually treated by surgical removal, embolization, or treatment of the affected area with focused radiation (gamma knife). Such treatment should usually be provided at an HHT center or other center with expertise in brain vascular malformations.Because of the risk of complications, treatment of AVMs affecting the liver is usually only undertaken if an individual has symptomatic liver failure or high output heart failure. First line treatment for heart failure includes diuretics and correction of anemia and atrial fibrillation if present. For refractory cases, liver transplantation or intravenous bevacizumab might be considered, though the optimal choice is controversial at this time.For patients with bleeding AVMs of the gastrointestinal tract, especially if associated with anemia, endoscopy with cautery is usually the first line treatment, although it should be used sparingly. For persistent bleeding and/or anemia, tranexamic acid or antiangiogenic agents such as intravenous bevacizumab should be considered. Aggressive iron replacement therapy, either orally or by infusion, should be used to treat anemia secondary to the nose or GI bleeding associated with HHT. Blood transfusions are a last resort if frequent iron infusions and other therapies are not successful in reaching the target hemoglobin (usually >7 g/dl for most patients).
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Hereditary Hemorrhagic Telangiectasia
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nord_573_0
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Overview of Hereditary Hyperphosphatasia
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Hereditary hyperphosphatasia is a rare genetic bone disorder (osteopathy) that usually becomes apparent during infancy or early childhood. Affected individuals develop progressive skeletal malformations especially in the long bones of the arms and legs. Skeletal malformations in the legs may cause problems walking and may eventually result in short stature. Additional symptoms include pain, fractures of affected bones and muscle weakness. Because the biochemical and radiographic findings of hereditary hyperphosphatasia are similar to those of Paget’s disease (a focal skeletal disorder of adults characterized by abnormal bone turnover), the disorder is sometimes referred to as juvenile Paget’s disease. However, despite these similarities, the two disorders are distinct. Hereditary hyperphosphatasia is inherited in an autosomal recessive pattern.
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Overview of Hereditary Hyperphosphatasia. Hereditary hyperphosphatasia is a rare genetic bone disorder (osteopathy) that usually becomes apparent during infancy or early childhood. Affected individuals develop progressive skeletal malformations especially in the long bones of the arms and legs. Skeletal malformations in the legs may cause problems walking and may eventually result in short stature. Additional symptoms include pain, fractures of affected bones and muscle weakness. Because the biochemical and radiographic findings of hereditary hyperphosphatasia are similar to those of Paget’s disease (a focal skeletal disorder of adults characterized by abnormal bone turnover), the disorder is sometimes referred to as juvenile Paget’s disease. However, despite these similarities, the two disorders are distinct. Hereditary hyperphosphatasia is inherited in an autosomal recessive pattern.
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Hereditary Hyperphosphatasia
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Symptoms of Hereditary Hyperphosphatasia
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The severity of symptoms associated with hereditary hyperphosphatasia varies from patient to patient. Symptoms usually become apparent during infancy or early childhood usually between 2 and 3 years of age. Most individuals develop widening and bowing of the long bones of the legs eventually resulting in problems walking and short stature. Thickening of the upper domelike portion of the skull (calvaria) is another common finding.Additional symptoms include pain, fractures of affected bones, abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and muscle weakness. Deafness is common – it arises because of an impaired ability of the auditory nerves to transmit input to the brain (sensorineural hearing loss).Ocular manifestations including optic nerve pallor, angioid streaks and retinal neovacularization may become evident in adolescence. Aneurysms of the internal carotid arteries and calcification of the external part of the ears (pinnae) have also been described.Laboratory findings include greatly elevated bone turnover markers (such as plasma alkaline phosphatase).
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Symptoms of Hereditary Hyperphosphatasia. The severity of symptoms associated with hereditary hyperphosphatasia varies from patient to patient. Symptoms usually become apparent during infancy or early childhood usually between 2 and 3 years of age. Most individuals develop widening and bowing of the long bones of the legs eventually resulting in problems walking and short stature. Thickening of the upper domelike portion of the skull (calvaria) is another common finding.Additional symptoms include pain, fractures of affected bones, abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and muscle weakness. Deafness is common – it arises because of an impaired ability of the auditory nerves to transmit input to the brain (sensorineural hearing loss).Ocular manifestations including optic nerve pallor, angioid streaks and retinal neovacularization may become evident in adolescence. Aneurysms of the internal carotid arteries and calcification of the external part of the ears (pinnae) have also been described.Laboratory findings include greatly elevated bone turnover markers (such as plasma alkaline phosphatase).
| 573 |
Hereditary Hyperphosphatasia
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Causes of Hereditary Hyperphosphatasia
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About two-thirds of cases of hereditary hyperphosphatasia are caused by changes (mutations or pathogenic variants) of the TNFRSF11B geneThe human skeleton is living tissue that is either growing (in childhood) or being renewed (in adulthood). Bone turnover is a normal process in which bone gradually breaks down (resorption) and then new bone is laid down (formation). The cells that resorb bone are called osteoclasts and those that form new bone are called osteoblasts. The processes of resorption and formation are linked by a complex process that involves many factors, including a protein called osteoprotegerin, which is coded for by the TNFRSF11B gene.Mutations affecting the TNFRSF11B gene result in deficiency of osteoprotegerin, which normally acts as a brake on bone resorption by regulating the activity of osteoclasts. Individuals with hereditary hyperphosphatasia have a deficiency of osteoprotegerin, which results in an increased rate of bone turnover.Hereditary hyperphosphatasia is inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from both the father and the mother.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.
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Causes of Hereditary Hyperphosphatasia. About two-thirds of cases of hereditary hyperphosphatasia are caused by changes (mutations or pathogenic variants) of the TNFRSF11B geneThe human skeleton is living tissue that is either growing (in childhood) or being renewed (in adulthood). Bone turnover is a normal process in which bone gradually breaks down (resorption) and then new bone is laid down (formation). The cells that resorb bone are called osteoclasts and those that form new bone are called osteoblasts. The processes of resorption and formation are linked by a complex process that involves many factors, including a protein called osteoprotegerin, which is coded for by the TNFRSF11B gene.Mutations affecting the TNFRSF11B gene result in deficiency of osteoprotegerin, which normally acts as a brake on bone resorption by regulating the activity of osteoclasts. Individuals with hereditary hyperphosphatasia have a deficiency of osteoprotegerin, which results in an increased rate of bone turnover.Hereditary hyperphosphatasia is inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from both the father and the mother.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.
| 573 |
Hereditary Hyperphosphatasia
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Affects of Hereditary Hyperphosphatasia
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Hereditary hyperphosphatasia affects males and females in equal numbers. Like all recessive disorders it is more common in countries where within-family marriage is practiced. More than 50 cases have been described since the disorder was first reported in the medical literature in 1956.
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Affects of Hereditary Hyperphosphatasia. Hereditary hyperphosphatasia affects males and females in equal numbers. Like all recessive disorders it is more common in countries where within-family marriage is practiced. More than 50 cases have been described since the disorder was first reported in the medical literature in 1956.
| 573 |
Hereditary Hyperphosphatasia
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nord_573_4
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Related disorders of Hereditary Hyperphosphatasia
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Symptoms of the following disorders can be similar to those of hereditary hyperphosphatasia. Comparisons may be useful for a differential diagnosis.Paget’s disease is a slowly progressive focal disease of the skeletal system characterized by abnormally rapid bone breakdown and formation, leading to the development of bones that are dense but fragile. The major symptom is bone pain. It usually affects middle-aged and elderly people: children are not affected. The disease most frequently occurs in the spine, skull, pelvis, thighs and lower legs. Most cases are asymptomatic or mild.Symptoms are often vague and may be hard to distinguish from those of many other bone diseases. Bowed long bones and frequent fractures are caused by abnormally soft bones. Enlargement of the head, headaches, sensation of heat, deep dull pain in the bones and hearing loss may also occur. About a third of patients with Paget’s disease have a family history of the disorder, and in about half of these cases, familial Paget’s disease is associated with mutations in the SQSTM1 gene. (For more information on this disorder, choose “Paget” as your search term in the Rare Disease Database.)Familial expansile osteolysis is a rare genetic bone disorder also characterized by excessive osteoclastic overactivity (osteolysis). Affected individuals experience painful bone deformities, early loss of teeth, increased susceptibility to fractures, and hearing loss. Familial expansile osteolysis and closely related disorders (such as expansile skeletal hyperphosphatasia) result from activating mutations in the TNFRSF11A gene and are inherited in an autosomal dominant pattern.Kenny-Caffey syndrome is a rare hereditary skeletal disorder characterized by thickening of the long bones, thin marrow cavities in the bones (medullary stenosis), and abnormalities affecting the head and eyes. Most cases are obvious at birth (congenital). The primary outcome of Kenny-Caffey syndrome is short stature. Mental abilities are rarely affected. Individuals with Kenny-Caffey syndrome may also have recurrent episodes of low levels of calcium in the blood stream (hypocalcemia) that is caused by insufficient production of parathyroid hormones (hpoparathyroidism). In most cases, Kenny-Caffey syndrome is inherited in an autosomal dominant pattern. Other cases are inherited in an autosomal recessive pattern, linked to the TBCE gene. (For more information on this disorder, choose “Kenny Caffey” as your search term in the Rare Disease Database.)Benign hyperphosphatasia is a biochemical finding unaccompanied by skeletal changes.
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Related disorders of Hereditary Hyperphosphatasia. Symptoms of the following disorders can be similar to those of hereditary hyperphosphatasia. Comparisons may be useful for a differential diagnosis.Paget’s disease is a slowly progressive focal disease of the skeletal system characterized by abnormally rapid bone breakdown and formation, leading to the development of bones that are dense but fragile. The major symptom is bone pain. It usually affects middle-aged and elderly people: children are not affected. The disease most frequently occurs in the spine, skull, pelvis, thighs and lower legs. Most cases are asymptomatic or mild.Symptoms are often vague and may be hard to distinguish from those of many other bone diseases. Bowed long bones and frequent fractures are caused by abnormally soft bones. Enlargement of the head, headaches, sensation of heat, deep dull pain in the bones and hearing loss may also occur. About a third of patients with Paget’s disease have a family history of the disorder, and in about half of these cases, familial Paget’s disease is associated with mutations in the SQSTM1 gene. (For more information on this disorder, choose “Paget” as your search term in the Rare Disease Database.)Familial expansile osteolysis is a rare genetic bone disorder also characterized by excessive osteoclastic overactivity (osteolysis). Affected individuals experience painful bone deformities, early loss of teeth, increased susceptibility to fractures, and hearing loss. Familial expansile osteolysis and closely related disorders (such as expansile skeletal hyperphosphatasia) result from activating mutations in the TNFRSF11A gene and are inherited in an autosomal dominant pattern.Kenny-Caffey syndrome is a rare hereditary skeletal disorder characterized by thickening of the long bones, thin marrow cavities in the bones (medullary stenosis), and abnormalities affecting the head and eyes. Most cases are obvious at birth (congenital). The primary outcome of Kenny-Caffey syndrome is short stature. Mental abilities are rarely affected. Individuals with Kenny-Caffey syndrome may also have recurrent episodes of low levels of calcium in the blood stream (hypocalcemia) that is caused by insufficient production of parathyroid hormones (hpoparathyroidism). In most cases, Kenny-Caffey syndrome is inherited in an autosomal dominant pattern. Other cases are inherited in an autosomal recessive pattern, linked to the TBCE gene. (For more information on this disorder, choose “Kenny Caffey” as your search term in the Rare Disease Database.)Benign hyperphosphatasia is a biochemical finding unaccompanied by skeletal changes.
| 573 |
Hereditary Hyperphosphatasia
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nord_573_5
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Diagnosis of Hereditary Hyperphosphatasia
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A diagnosis of hereditary hyperphosphatasia is made based upon a thorough clinical evaluation, identification of characteristic symptoms and a variety of x-rays tests that reveal distinct radiographic findings. Affected individuals also have elevated levels of serum alkaline phosphatase and other biochemical markers of bone turnover, detectable through blood and urine tests.
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Diagnosis of Hereditary Hyperphosphatasia. A diagnosis of hereditary hyperphosphatasia is made based upon a thorough clinical evaluation, identification of characteristic symptoms and a variety of x-rays tests that reveal distinct radiographic findings. Affected individuals also have elevated levels of serum alkaline phosphatase and other biochemical markers of bone turnover, detectable through blood and urine tests.
| 573 |
Hereditary Hyperphosphatasia
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nord_573_6
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Therapies of Hereditary Hyperphosphatasia
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Treatment
The treatment of hereditary hyperphosphatasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. This will commonly include pediatricians, specialists who assess and treat skeletal malformations (orthopedic surgeons) and specialists who assess and treat hearing problems (audiologists) or eye problems (ophthalmologists), and other healthcare professionals.Individuals with hereditary hyperphosphatasia have been treated with drugs known as bisphosphonates. These drugs reduce bone turnover by inhibiting bone resorption.According to the medical literature, treatment with these drugs has led to improvement of bone-associated symptoms. Although studies assessing long-term effectiveness have not been conducted, the studies do suggest that bisphosphonate therapy can suppress bone turnover and prevent malformations. These drugs probably do not affect the ocular and vascular manifestations. In theory, the novel drug, denosumab, that directly targets the effects of osteoprotegerin deficiency might be better in this regard, although only preliminary reports of its effectiveness have so far been reported in the medical literature.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Hereditary Hyperphosphatasia. Treatment
The treatment of hereditary hyperphosphatasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. This will commonly include pediatricians, specialists who assess and treat skeletal malformations (orthopedic surgeons) and specialists who assess and treat hearing problems (audiologists) or eye problems (ophthalmologists), and other healthcare professionals.Individuals with hereditary hyperphosphatasia have been treated with drugs known as bisphosphonates. These drugs reduce bone turnover by inhibiting bone resorption.According to the medical literature, treatment with these drugs has led to improvement of bone-associated symptoms. Although studies assessing long-term effectiveness have not been conducted, the studies do suggest that bisphosphonate therapy can suppress bone turnover and prevent malformations. These drugs probably do not affect the ocular and vascular manifestations. In theory, the novel drug, denosumab, that directly targets the effects of osteoprotegerin deficiency might be better in this regard, although only preliminary reports of its effectiveness have so far been reported in the medical literature.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Hereditary Hyperphosphatasia
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nord_574_0
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Overview of Hereditary Leiomyomatosis and Renal Cell Carcinoma
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SummaryHereditary leiomyomatosis and renal cell carcinoma, also known as HLRCC, is a rare genetic disorder characterized by smooth muscle growths (leiomyomas) on the skin and uterus and an increased risk of developing kidney (renal) cancer. Skin growths may appear as appear as small, firm bumps (papules) or tiny lumps (nodules) and are not cancerous (benign). Uterine leiomyomas, also known as uterine fibroids, may be numerous and are also benign, but can cause symptoms such as heavy menstrual periods or pelvic pressure or pain. Affected individuals are at an increased risk of developing kidney cancer, particularly a form known as type II papillary renal cell carcinoma. Kidney cancer associated with HLRCC is cancerous (malignant) and can be aggressive and spread (metastasize) to other areas of the body. HLRCC is caused by mutations in the fumarate hydratase (FH) gene and is inherited in an autosomal dominant pattern.IntroductionHLRCC is classified as a hereditary renal cancer syndrome, a group of disorders characterized by a genetic predisposition to renal cancer along with other symptoms. There are at least 10 identified hereditary renal cancer syndromes including Von-Hippel-Lindau disease, Birt-Hogg-Dube syndrome, and hereditary papillary renal cell carcinoma. The association of leiomyomas and uterine fibroids as a genetic disorder was first described in the medical literature by Dr. Reed in 1973 and subsequently termed multiple cutaneous and uterine leiomyoma (MCUL) or Reed’s syndrome. The additional association with renal carcinoma was not established until 2001 (Launonen et al.).
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Overview of Hereditary Leiomyomatosis and Renal Cell Carcinoma. SummaryHereditary leiomyomatosis and renal cell carcinoma, also known as HLRCC, is a rare genetic disorder characterized by smooth muscle growths (leiomyomas) on the skin and uterus and an increased risk of developing kidney (renal) cancer. Skin growths may appear as appear as small, firm bumps (papules) or tiny lumps (nodules) and are not cancerous (benign). Uterine leiomyomas, also known as uterine fibroids, may be numerous and are also benign, but can cause symptoms such as heavy menstrual periods or pelvic pressure or pain. Affected individuals are at an increased risk of developing kidney cancer, particularly a form known as type II papillary renal cell carcinoma. Kidney cancer associated with HLRCC is cancerous (malignant) and can be aggressive and spread (metastasize) to other areas of the body. HLRCC is caused by mutations in the fumarate hydratase (FH) gene and is inherited in an autosomal dominant pattern.IntroductionHLRCC is classified as a hereditary renal cancer syndrome, a group of disorders characterized by a genetic predisposition to renal cancer along with other symptoms. There are at least 10 identified hereditary renal cancer syndromes including Von-Hippel-Lindau disease, Birt-Hogg-Dube syndrome, and hereditary papillary renal cell carcinoma. The association of leiomyomas and uterine fibroids as a genetic disorder was first described in the medical literature by Dr. Reed in 1973 and subsequently termed multiple cutaneous and uterine leiomyoma (MCUL) or Reed’s syndrome. The additional association with renal carcinoma was not established until 2001 (Launonen et al.).
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Hereditary Leiomyomatosis and Renal Cell Carcinoma
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nord_574_1
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Symptoms of Hereditary Leiomyomatosis and Renal Cell Carcinoma
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The symptoms and progression of HLRCC can vary widely from one person to another, even among members of the same family. Some individuals who inherit a mutated gene for HLRCC will not develop any symptoms. The susceptibility to develop symptoms varies among family members as well. For example, if a parent develops kidney cancer, it does not mean necessarily that an affected child will.The most common symptom is benign skin lesions called leiomyomas or leiomyomata. Leiomyomas are small growths that are usually skin-colored, brownish, or reddish. Sometimes they can resemble a rash. They most often appear on the trunk, arms and legs (extremities) and face. These lesions are sensitive to touch and cold temperatures and, in rare cases, may be painful. Some individuals may have widespread disease, with multiple small leiomyomas covering a large area of the body; other individuals may only develop a few bumps. Some individuals may only have one small skin growth (leiomyoma) or have no detectable growths. Leiomyomas usually become apparent between 10 and 50 years of age (with a mean age of 25) and generally increase in size and number as an affected individual ages.Women with HLRCC may develop leiomyomas in the uterus (uterine fibroids). These growths are common in women in the general population and often go unnoticed because they do not cause any symptoms (asymptomatic). In women with HLRCC, uterine fibroids are more numerous, larger and have an early age of onset, most often being diagnosed between 18 and 52 years of age (with a mean age of 30). Affected women may have abnormally heavy menstrual periods and feel pelvic pressure or pain. Women with HLRCC tend to undergo a hysterectomy or myomectomy for symptomatic relief at a younger age than women in the general population.Individuals with HLRCC are at an increased risk of developing kidney (renal) cancer than individuals in the general population. However, most affected individuals do not develop kidney cancer. In individuals who have developed kidney cancer, the most common form has been type II papillary renal cell carcinoma, a potentially aggressive malignant cancer that can spread (metastasize) quickly. Most affected individuals develop a solitary kidney tumor, but even a small primary tumor can spread. Individuals with kidney cancer may not develop any outward symptoms. Symptoms that can develop include blood in the urine (hematuria), lower back pain, and the presence of mass that can be felt (palpable). Additional forms of kidney cancer have occurred in individuals with HLRCC including tubulo-papillary and renal collecting duct carcinomas.In extremely rare cases, some affected women have developed uterine leiomyosarcomas, a malignant tumor that arises from the smooth muscle lining the walls of the uterus (myometrium). (For more information on this disorder, choose “uterine leiomyosarcoma” as your search term in the Rare Disease Database.)Several other benign and malignant forms of cancer have been described in individuals with HLRCC including breast cancer, bladder cancer, gastrointestinal stromal tumors (GISTs), adrenal incidentaloma, Leydig-cell tumors of the testes, and ovarian cystadenomas. However, it is unknown whether these are simply coincidental findings or somehow related to HLRCC.
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Symptoms of Hereditary Leiomyomatosis and Renal Cell Carcinoma. The symptoms and progression of HLRCC can vary widely from one person to another, even among members of the same family. Some individuals who inherit a mutated gene for HLRCC will not develop any symptoms. The susceptibility to develop symptoms varies among family members as well. For example, if a parent develops kidney cancer, it does not mean necessarily that an affected child will.The most common symptom is benign skin lesions called leiomyomas or leiomyomata. Leiomyomas are small growths that are usually skin-colored, brownish, or reddish. Sometimes they can resemble a rash. They most often appear on the trunk, arms and legs (extremities) and face. These lesions are sensitive to touch and cold temperatures and, in rare cases, may be painful. Some individuals may have widespread disease, with multiple small leiomyomas covering a large area of the body; other individuals may only develop a few bumps. Some individuals may only have one small skin growth (leiomyoma) or have no detectable growths. Leiomyomas usually become apparent between 10 and 50 years of age (with a mean age of 25) and generally increase in size and number as an affected individual ages.Women with HLRCC may develop leiomyomas in the uterus (uterine fibroids). These growths are common in women in the general population and often go unnoticed because they do not cause any symptoms (asymptomatic). In women with HLRCC, uterine fibroids are more numerous, larger and have an early age of onset, most often being diagnosed between 18 and 52 years of age (with a mean age of 30). Affected women may have abnormally heavy menstrual periods and feel pelvic pressure or pain. Women with HLRCC tend to undergo a hysterectomy or myomectomy for symptomatic relief at a younger age than women in the general population.Individuals with HLRCC are at an increased risk of developing kidney (renal) cancer than individuals in the general population. However, most affected individuals do not develop kidney cancer. In individuals who have developed kidney cancer, the most common form has been type II papillary renal cell carcinoma, a potentially aggressive malignant cancer that can spread (metastasize) quickly. Most affected individuals develop a solitary kidney tumor, but even a small primary tumor can spread. Individuals with kidney cancer may not develop any outward symptoms. Symptoms that can develop include blood in the urine (hematuria), lower back pain, and the presence of mass that can be felt (palpable). Additional forms of kidney cancer have occurred in individuals with HLRCC including tubulo-papillary and renal collecting duct carcinomas.In extremely rare cases, some affected women have developed uterine leiomyosarcomas, a malignant tumor that arises from the smooth muscle lining the walls of the uterus (myometrium). (For more information on this disorder, choose “uterine leiomyosarcoma” as your search term in the Rare Disease Database.)Several other benign and malignant forms of cancer have been described in individuals with HLRCC including breast cancer, bladder cancer, gastrointestinal stromal tumors (GISTs), adrenal incidentaloma, Leydig-cell tumors of the testes, and ovarian cystadenomas. However, it is unknown whether these are simply coincidental findings or somehow related to HLRCC.
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Causes of Hereditary Leiomyomatosis and Renal Cell Carcinoma
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HLRCC is caused by a mutation (genetic alteration) in the FH gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The FH gene acts a tumor suppressor gene. The FH gene creates (encodes) a protein known as fumarate hydratase, also known as fumarase. A mutation in the FH gene results a deficiency of functional fumarate hydratase, which leads to a buildup of fumarate which plays a role in the development of the symptoms of HLRCC including cancer. The exact reasons how fumarate accumulation in cells ultimately leads to the symptoms of HLRCC is complex but are gradually becoming understood.In rare cases, mutations in the FH gene have resulted in the development of other forms of tumor known as pheochromocytoma and paraganglioma which may be malignant.The FH gene mutation is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (new gene alteration) 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. In some cases, an autosomal dominant disorders occurs as a new (sporadic or de novo) mutation, which means that 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.
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Causes of Hereditary Leiomyomatosis and Renal Cell Carcinoma. HLRCC is caused by a mutation (genetic alteration) in the FH gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The FH gene acts a tumor suppressor gene. The FH gene creates (encodes) a protein known as fumarate hydratase, also known as fumarase. A mutation in the FH gene results a deficiency of functional fumarate hydratase, which leads to a buildup of fumarate which plays a role in the development of the symptoms of HLRCC including cancer. The exact reasons how fumarate accumulation in cells ultimately leads to the symptoms of HLRCC is complex but are gradually becoming understood.In rare cases, mutations in the FH gene have resulted in the development of other forms of tumor known as pheochromocytoma and paraganglioma which may be malignant.The FH gene mutation is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (new gene alteration) 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. In some cases, an autosomal dominant disorders occurs as a new (sporadic or de novo) mutation, which means that 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.
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Affects of Hereditary Leiomyomatosis and Renal Cell Carcinoma
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HLRCC affects males and females in equal numbers. The disorder may be recognized more readily in females because of the development of uterine fibroid and associated symptoms. The exact incidence and prevalence of HLRCC in the general population is unknown.
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Affects of Hereditary Leiomyomatosis and Renal Cell Carcinoma. HLRCC affects males and females in equal numbers. The disorder may be recognized more readily in females because of the development of uterine fibroid and associated symptoms. The exact incidence and prevalence of HLRCC in the general population is unknown.
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Related disorders of Hereditary Leiomyomatosis and Renal Cell Carcinoma
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Symptoms of the following disorders can be similar to those of HLRCC. Comparisons may be useful for a differential diagnosis.There are several rare disorders that are characterized by a genetic predisposition to renal cell cancer. These disorders have additional symptoms as well. Such disorders include Von-Hippel-Lindau disease, Birt-Hogg-Dube syndrome, and hereditary papillary renal carcinoma, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, and familial renal oncocytoma. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Hereditary Leiomyomatosis and Renal Cell Carcinoma. Symptoms of the following disorders can be similar to those of HLRCC. Comparisons may be useful for a differential diagnosis.There are several rare disorders that are characterized by a genetic predisposition to renal cell cancer. These disorders have additional symptoms as well. Such disorders include Von-Hippel-Lindau disease, Birt-Hogg-Dube syndrome, and hereditary papillary renal carcinoma, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, and familial renal oncocytoma. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Hereditary Leiomyomatosis and Renal Cell Carcinoma
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A diagnosis of HLRCC is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Criteria required for diagnosing HLRCC have been proposed:1. Multiple cutaneous leiomyomas with at least one histologically confirmed leiomyoma.
2. A single leiomyoma in the presence of a positive family history of HLRCC.Because of the additional symptom of uterine fibroids, a diagnosis is usually suspected earlier in females than in males.Clinical Testing and Workup
A skin biopsy, which is the surgical removal and microscopic study of a small sample of skin tissue, is necessary in order to confirm the presence of leiomyomas. A leiomyoma cannot be diagnosed by its appearance on the skin because of it can resemble other skin conditions.The activity of fumarate hydratase, the enzyme encoded by the FH gene, can be measured in certain types of cells including skin fibroblasts and lymphoblastoid cells. Reduced activity of functional fumarate hydratase is indicative of HLRCC.Molecular genetic testing can confirm a diagnosis of HLRCC. In individuals suspected of having HLRCC, molecular genetic testing can detect mutations in the FH gene known to cause the disorder and so confirm the diagnosis.Pathologists may stain sections of leiomyomas and kidney cancers to detect protein changes which indicate the presence of increased fumarate in the tumor tissue. Individuals with HLRCC should receive regular (annual) screening for renal tumors may include a computed tomography (CT) scan or magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An ultrasound is another x-ray technique sometimes used to detect kidney cancer. However, in HLRCC, kidney tumors have unique qualities that may be seen on a CT scan or MRI, but missed on an ultrasound. In general, MRI scanning is preferred for screening in HLRCC as it avoids repeated radiation associated with regular CT scans. The exact age at which kidney screening should start requires careful discussion between parents and doctors and can differ between families but experts agreed that screening could be considered from age 10/11 years (Menko et al 2014).
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Diagnosis of Hereditary Leiomyomatosis and Renal Cell Carcinoma. A diagnosis of HLRCC is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Criteria required for diagnosing HLRCC have been proposed:1. Multiple cutaneous leiomyomas with at least one histologically confirmed leiomyoma.
2. A single leiomyoma in the presence of a positive family history of HLRCC.Because of the additional symptom of uterine fibroids, a diagnosis is usually suspected earlier in females than in males.Clinical Testing and Workup
A skin biopsy, which is the surgical removal and microscopic study of a small sample of skin tissue, is necessary in order to confirm the presence of leiomyomas. A leiomyoma cannot be diagnosed by its appearance on the skin because of it can resemble other skin conditions.The activity of fumarate hydratase, the enzyme encoded by the FH gene, can be measured in certain types of cells including skin fibroblasts and lymphoblastoid cells. Reduced activity of functional fumarate hydratase is indicative of HLRCC.Molecular genetic testing can confirm a diagnosis of HLRCC. In individuals suspected of having HLRCC, molecular genetic testing can detect mutations in the FH gene known to cause the disorder and so confirm the diagnosis.Pathologists may stain sections of leiomyomas and kidney cancers to detect protein changes which indicate the presence of increased fumarate in the tumor tissue. Individuals with HLRCC should receive regular (annual) screening for renal tumors may include a computed tomography (CT) scan or magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An ultrasound is another x-ray technique sometimes used to detect kidney cancer. However, in HLRCC, kidney tumors have unique qualities that may be seen on a CT scan or MRI, but missed on an ultrasound. In general, MRI scanning is preferred for screening in HLRCC as it avoids repeated radiation associated with regular CT scans. The exact age at which kidney screening should start requires careful discussion between parents and doctors and can differ between families but experts agreed that screening could be considered from age 10/11 years (Menko et al 2014).
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Therapies of Hereditary Leiomyomatosis and Renal Cell Carcinoma
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Treatment
The treatment of HLRCC is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, plastic surgeons, dermatologists, kidney specialists (nephrologists), gynecologists, oncologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families and genetic testing can usually determine which family members may be at risk of symptoms and require surveillance.Skin lesions may not require treatment and many dermatologists do not recommended surgical excision because it can lead to scarring and damage to the skin. Surgical excision is most often used for a solitary, painful lesion. If painful or unsightly or tightly-packed together skin lesions do require removal two methods that have been used are cryotherapy and CO2 laser ablation.Cryotherapy is the use of extreme cold to freeze and destroy the tissue and cells of skin lesions and is a minimally invasive treatment option. With cryotherapy a freezing substance such as liquid nitrogen or argon gas is applied directly to the lesion. Cryotherapy is most effective for single or small lesions. CO2 laser ablation is the use of a laser beam to directly destroy skin lesions.Pain relief is necessary for some individuals with HLRCC and can include a variety of medications including calcium channel blockers, alpha blockers, anti-depressants, nitroglycerine, and anti-seizure (anti-epileptic) medications.When uterine fibroids cause symptoms treatment may include the gonadotropin-releasing medications, anti-hormonal medications, and pain relievers. Uterine fibroids, in women with HLRCC, often eventually require surgical intervention including surgery designed to remove symptomatic fibroids and repair the damage to the uterus (myomectomy). In some cases, the surgical removal of the uterus (hysterectomy) may be necessary. These procedures generally prove necessary at a younger age than is normally found in the general population.Kidney tumors may be removed surgically. Because even a small, solitary tumor can be aggressive and metastasize, complete removal of the kidney (total nephrectomy) should be considered if there is any doubt that a partial nephrectomy would be curative.
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Therapies of Hereditary Leiomyomatosis and Renal Cell Carcinoma. Treatment
The treatment of HLRCC is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, plastic surgeons, dermatologists, kidney specialists (nephrologists), gynecologists, oncologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families and genetic testing can usually determine which family members may be at risk of symptoms and require surveillance.Skin lesions may not require treatment and many dermatologists do not recommended surgical excision because it can lead to scarring and damage to the skin. Surgical excision is most often used for a solitary, painful lesion. If painful or unsightly or tightly-packed together skin lesions do require removal two methods that have been used are cryotherapy and CO2 laser ablation.Cryotherapy is the use of extreme cold to freeze and destroy the tissue and cells of skin lesions and is a minimally invasive treatment option. With cryotherapy a freezing substance such as liquid nitrogen or argon gas is applied directly to the lesion. Cryotherapy is most effective for single or small lesions. CO2 laser ablation is the use of a laser beam to directly destroy skin lesions.Pain relief is necessary for some individuals with HLRCC and can include a variety of medications including calcium channel blockers, alpha blockers, anti-depressants, nitroglycerine, and anti-seizure (anti-epileptic) medications.When uterine fibroids cause symptoms treatment may include the gonadotropin-releasing medications, anti-hormonal medications, and pain relievers. Uterine fibroids, in women with HLRCC, often eventually require surgical intervention including surgery designed to remove symptomatic fibroids and repair the damage to the uterus (myomectomy). In some cases, the surgical removal of the uterus (hysterectomy) may be necessary. These procedures generally prove necessary at a younger age than is normally found in the general population.Kidney tumors may be removed surgically. Because even a small, solitary tumor can be aggressive and metastasize, complete removal of the kidney (total nephrectomy) should be considered if there is any doubt that a partial nephrectomy would be curative.
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Overview of Hereditary Lymphedema
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SummaryHereditary lymphedema is a genetic condition affecting the lymphatic system and is characterized by chronic swelling (edema) of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. In hereditary lymphedema, lymphatic fluid collects in the subcutaneous tissues under the outermost layer of skin (epidermis) due to obstruction, malformation or underdevelopment (hypoplasia) of various lymphatic vessels. This leads to swelling (lymphedema) and thickening as well as hardening of the skin in affected areas, most commonly in the legs and feet. Additional symptoms may include tingling, numbness and changes in the nails or skin. The degree of edema is often progressive, though it may improve in the early years in some patients.Lymphedema may be classified as primary or secondary. Hereditary lymphedema is a primary lymphedema caused by abnormalities in lymph vessels or nodes due to genetic changes (mutations). In contrast, secondary lymphedema is an acquired condition resulting from damage to the lymphatic system from surgery, tumor, radiation therapy, trauma or infection in the absence of any anatomical abnormalities.There are three forms of hereditary lymphedema which are characterized by age of onset: type I (congenital or up to 2 years of age); type II (from 2 to 35 years of age) and lymphedema tarda (after 35 years of age). Type I is often associated with mutations in the FLT4 gene, while type II and lymphedema tarda have been more recently associated with the FOXC2 gene. In most patients, hereditary lymphedema is inherited in an autosomal dominant manner; however, there is variability in symptoms and severity even within the same family.
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Overview of Hereditary Lymphedema. SummaryHereditary lymphedema is a genetic condition affecting the lymphatic system and is characterized by chronic swelling (edema) of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. In hereditary lymphedema, lymphatic fluid collects in the subcutaneous tissues under the outermost layer of skin (epidermis) due to obstruction, malformation or underdevelopment (hypoplasia) of various lymphatic vessels. This leads to swelling (lymphedema) and thickening as well as hardening of the skin in affected areas, most commonly in the legs and feet. Additional symptoms may include tingling, numbness and changes in the nails or skin. The degree of edema is often progressive, though it may improve in the early years in some patients.Lymphedema may be classified as primary or secondary. Hereditary lymphedema is a primary lymphedema caused by abnormalities in lymph vessels or nodes due to genetic changes (mutations). In contrast, secondary lymphedema is an acquired condition resulting from damage to the lymphatic system from surgery, tumor, radiation therapy, trauma or infection in the absence of any anatomical abnormalities.There are three forms of hereditary lymphedema which are characterized by age of onset: type I (congenital or up to 2 years of age); type II (from 2 to 35 years of age) and lymphedema tarda (after 35 years of age). Type I is often associated with mutations in the FLT4 gene, while type II and lymphedema tarda have been more recently associated with the FOXC2 gene. In most patients, hereditary lymphedema is inherited in an autosomal dominant manner; however, there is variability in symptoms and severity even within the same family.
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Symptoms of Hereditary Lymphedema
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The main symptom associated with hereditary lymphedema is edema in different parts of the body due to accumulation of lymph in the soft layers of tissue under the epidermis. Swelling frequently occurs in one or both legs, but may also be present in the trunk, face, genitalia and arms. When lymphedema develops in the legs, swelling is usually most noticeable in the foot and ankle but may also be present in the calf and thigh. In some people, swelling may cause tightness, discomfort and unusual tingling sensations (paresthesias) in the affected areas. The affected area heals poorly even after minor trauma (e.g., cut or insect bite). The skin of the affected area may become abnormally dry, thickened or scaly skin (hyperkeratosis) resulting in a “woody” texture.Hereditary lymphedema type I (Milroy disease) is characterized by edema that is present at or shortly after birth (congenital). Ultrasound scanning during pregnancy may indicate if a fetus is affected if swelling of the dorsum of the feet is noted in the second or third trimester. In rare cases, edema may develop later in life. The legs are most often affected, and in some patients, the genitals may also be affected. The extent and location of edema varies greatly from person to person even among individuals in the same family. Additional complications sometimes associated with hereditary lymphedema type I include upslanting toenails, small warty growths on the affected areas (papillomatosis), abnormally large or prominent veins below the knees and in males, urethral abnormalities and the development of a fluid-filled sac along the spermatic cord of the scrotum (hydrocele). Bacterial infection of the skin and underlying soft tissues (cellulitis) has also been reported in approximately 20% of individuals, which may increase swelling due to additional damage to lymphatic vessels.Hereditary lymphedema type II (Meige disease or lymphedema praecox) develops around puberty or shortly thereafter in most individuals. This is the most common type of primary lymphedema. In addition to lymphedema of the legs, other areas of the body such as the arms, face and voice box (larynx) may be affected. Some individuals may develop yellow nails.Lymphedema tarda is defined as primary lymphedema occurring after the age of 35. Edema primarily occurs in the legs, but the arms and other areas may be affected as well. In women, the lower extremities are most often affected.In all subtypes of hereditary lymphedema, the degree of edema can progress; in some people, especially in early years, edema may improve over time. Obesity makes management of lymphedema more difficult. Affected individuals with lymphedema are at risk for developing infections including cellulitis or infection of the lymphatic vessels (lymphangitis). These infections are characterized by areas of warm, painful and reddened skin. Red skin “streaks” may also develop in the infected area. Increased edema is common. A general feeling of ill health (malaise), fever, chills and/or headaches may also occur. If left untreated, cellulitis can lead to septicemia, skin abscesses, areas of ulceration and/or tissue damage (necrosis). Cellulitis is more common in males than females. Athlete’s foot (tinea pedis) can cause cracks in the interdigital skin, bacterial invasion and cellulitis. Pregnant individuals with hereditary lymphedema may experience increased swelling during pregnancy.In rare cases, additional complications can include accumulation of milky fluid consisting of fat droplets and lymph (chyle). Chyle is absorbed during digestion by the lymphatic vessels located around the intestine and drains into the thoracic duct in the upper chest before being deposited into veins, where it mixes with blood. In some individuals with hereditary lymphedema, the lymphatic vessels may rupture or become blocked (obstructed), causing chyle to accumulate in the chest cavity (chylothorax) or abdomen (chylous ascites). Affected individuals may also be at a greater risk than the general population for developing a malignancy at the affected site. These malignancies include angiosarcoma, which are cancerous tumors that develop from blood or lymphatic vessels. They may occur in any area of the body. A specific type of angiosarcoma is known as lymphangiosarcoma, or Stewart-Treves syndrome. Rarely, this cancerous tumor may develop in long-standing cases of primary or secondary lymphedema. Angiosarcoma occurs in the lymphedematous extremity but can spread to the adjacent trunk and lungs.
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Symptoms of Hereditary Lymphedema. The main symptom associated with hereditary lymphedema is edema in different parts of the body due to accumulation of lymph in the soft layers of tissue under the epidermis. Swelling frequently occurs in one or both legs, but may also be present in the trunk, face, genitalia and arms. When lymphedema develops in the legs, swelling is usually most noticeable in the foot and ankle but may also be present in the calf and thigh. In some people, swelling may cause tightness, discomfort and unusual tingling sensations (paresthesias) in the affected areas. The affected area heals poorly even after minor trauma (e.g., cut or insect bite). The skin of the affected area may become abnormally dry, thickened or scaly skin (hyperkeratosis) resulting in a “woody” texture.Hereditary lymphedema type I (Milroy disease) is characterized by edema that is present at or shortly after birth (congenital). Ultrasound scanning during pregnancy may indicate if a fetus is affected if swelling of the dorsum of the feet is noted in the second or third trimester. In rare cases, edema may develop later in life. The legs are most often affected, and in some patients, the genitals may also be affected. The extent and location of edema varies greatly from person to person even among individuals in the same family. Additional complications sometimes associated with hereditary lymphedema type I include upslanting toenails, small warty growths on the affected areas (papillomatosis), abnormally large or prominent veins below the knees and in males, urethral abnormalities and the development of a fluid-filled sac along the spermatic cord of the scrotum (hydrocele). Bacterial infection of the skin and underlying soft tissues (cellulitis) has also been reported in approximately 20% of individuals, which may increase swelling due to additional damage to lymphatic vessels.Hereditary lymphedema type II (Meige disease or lymphedema praecox) develops around puberty or shortly thereafter in most individuals. This is the most common type of primary lymphedema. In addition to lymphedema of the legs, other areas of the body such as the arms, face and voice box (larynx) may be affected. Some individuals may develop yellow nails.Lymphedema tarda is defined as primary lymphedema occurring after the age of 35. Edema primarily occurs in the legs, but the arms and other areas may be affected as well. In women, the lower extremities are most often affected.In all subtypes of hereditary lymphedema, the degree of edema can progress; in some people, especially in early years, edema may improve over time. Obesity makes management of lymphedema more difficult. Affected individuals with lymphedema are at risk for developing infections including cellulitis or infection of the lymphatic vessels (lymphangitis). These infections are characterized by areas of warm, painful and reddened skin. Red skin “streaks” may also develop in the infected area. Increased edema is common. A general feeling of ill health (malaise), fever, chills and/or headaches may also occur. If left untreated, cellulitis can lead to septicemia, skin abscesses, areas of ulceration and/or tissue damage (necrosis). Cellulitis is more common in males than females. Athlete’s foot (tinea pedis) can cause cracks in the interdigital skin, bacterial invasion and cellulitis. Pregnant individuals with hereditary lymphedema may experience increased swelling during pregnancy.In rare cases, additional complications can include accumulation of milky fluid consisting of fat droplets and lymph (chyle). Chyle is absorbed during digestion by the lymphatic vessels located around the intestine and drains into the thoracic duct in the upper chest before being deposited into veins, where it mixes with blood. In some individuals with hereditary lymphedema, the lymphatic vessels may rupture or become blocked (obstructed), causing chyle to accumulate in the chest cavity (chylothorax) or abdomen (chylous ascites). Affected individuals may also be at a greater risk than the general population for developing a malignancy at the affected site. These malignancies include angiosarcoma, which are cancerous tumors that develop from blood or lymphatic vessels. They may occur in any area of the body. A specific type of angiosarcoma is known as lymphangiosarcoma, or Stewart-Treves syndrome. Rarely, this cancerous tumor may develop in long-standing cases of primary or secondary lymphedema. Angiosarcoma occurs in the lymphedematous extremity but can spread to the adjacent trunk and lungs.
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Causes of Hereditary Lymphedema
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Most cases of hereditary lymphedema type I are caused by changes (mutations) in the FMS-like tyrosine kinase 4 (FLT4) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The FLT4 gene provides instructions to make a protein called vascular endothelial growth factor receptor 3 (VEGFR-3) that regulates the development and maintenance of the lymphatic system. Some cases of hereditary lymphedema type II and lymphedema tarda have been linked to mutations in the forkhead box C2 (FOXC2) gene, which plays an essential role in regulating lymphatic valve development. Mutations in these genes cause abnormalities in the lymphatic system that do not allow fluid to drain properly, resulting in edema.Most cases of hereditary lymphedema type I and type II are inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a 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. Most individuals diagnosed with hereditary lymphedema type I have an affected parent, though approximately 10% may have the disorder due to a non-inherited (de novo) FLT4 mutation. Approximately 85%-90% of individuals with a FLT4 mutation will develop edema in the lower extremities by 3 years of age, while 10%-15% will show no signs or symptoms of lymphedema (reduced penetrance). Types and severity of symptoms can vary widely even within the same family (variable expressivity).
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Causes of Hereditary Lymphedema. Most cases of hereditary lymphedema type I are caused by changes (mutations) in the FMS-like tyrosine kinase 4 (FLT4) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The FLT4 gene provides instructions to make a protein called vascular endothelial growth factor receptor 3 (VEGFR-3) that regulates the development and maintenance of the lymphatic system. Some cases of hereditary lymphedema type II and lymphedema tarda have been linked to mutations in the forkhead box C2 (FOXC2) gene, which plays an essential role in regulating lymphatic valve development. Mutations in these genes cause abnormalities in the lymphatic system that do not allow fluid to drain properly, resulting in edema.Most cases of hereditary lymphedema type I and type II are inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a 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. Most individuals diagnosed with hereditary lymphedema type I have an affected parent, though approximately 10% may have the disorder due to a non-inherited (de novo) FLT4 mutation. Approximately 85%-90% of individuals with a FLT4 mutation will develop edema in the lower extremities by 3 years of age, while 10%-15% will show no signs or symptoms of lymphedema (reduced penetrance). Types and severity of symptoms can vary widely even within the same family (variable expressivity).
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Affects of Hereditary Lymphedema
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Hereditary lymphedema affects females more often than males and is one of the most common causes of primary lymphedema. The estimated prevalence of these disorders is 1 in 6,000 – 10,000 individuals in the general population, and it occurs in all ethnic groups. Hereditary lymphedema type II (Meige syndrome) is the most common form accounting for approximately 80 percent of cases. The prevalence of hereditary lymphedema type I (Milroy disease) is unknown. Approximately 200 cases have been reported in the medical literature.
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Affects of Hereditary Lymphedema. Hereditary lymphedema affects females more often than males and is one of the most common causes of primary lymphedema. The estimated prevalence of these disorders is 1 in 6,000 – 10,000 individuals in the general population, and it occurs in all ethnic groups. Hereditary lymphedema type II (Meige syndrome) is the most common form accounting for approximately 80 percent of cases. The prevalence of hereditary lymphedema type I (Milroy disease) is unknown. Approximately 200 cases have been reported in the medical literature.
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Related disorders of Hereditary Lymphedema
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Symptoms of the following disorders can be similar to those of hereditary lymphedema. Comparisons may be useful for a differential diagnosis.Hereditary lymphedema may be associated with several genetic multisystem disorders including Noonan syndrome, Klippel-Trénaunay-Weber syndrome, lymphedema-hypoparathyroid syndrome and Turner syndrome. For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.Researchers have determined that hereditary lymphedema type II (Meige syndrome) and three other disorders occur due to different mutations of the same gene (FOXC2). These disorders include yellow nail syndrome, distichiasis-lymphedema syndrome, and lymphedema-ptosis syndrome. The exact relationship between these disorders is unknown.Yellow nail syndrome 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 fluid in the lungs (pleural effusion) and 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. Yellow nail syndrome occurs because of mutations in the FOXC2 gene and is inherited in an autosomal dominant manner. For more information on this disorder, choose “yellow nail” as your search term in the Rare Disease Database.Distichiasis-lymphedema syndrome is a rare autosomal dominant multisystem disorder characterized by swelling due to fluid accumulation that usually occurs around puberty and the development of extra eyelashes along the posterior border of the lid margins (distichiasis). Distichiasis may range from only a few to a full set of extra lashes. Swelling most often affects the legs. Additional anomalies associated with this disorder include cleft palate, droopy eyelids (ptosis), abnormalities of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea), cysts on the spinal cord, an abnormal sensitivity to light (photophobia) and cardiac (heart) defects. Distichiasis-lymphedema syndrome is caused by mutations of the FOXC2 gene and is inherited in an autosomal dominant manner.Lymphedema-ptosis syndrome is an extremely rare genetic disorder characterized by swelling because of fluid accumulation and droopy eyelids (ptosis). Swelling most often affects the legs. Lymphedema usually occurs at or shortly after puberty. Lymphedema-ptosis syndrome occurs because of mutations of the FOXC2 gene and is inherited in an autosomal dominant manner.
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Related disorders of Hereditary Lymphedema. Symptoms of the following disorders can be similar to those of hereditary lymphedema. Comparisons may be useful for a differential diagnosis.Hereditary lymphedema may be associated with several genetic multisystem disorders including Noonan syndrome, Klippel-Trénaunay-Weber syndrome, lymphedema-hypoparathyroid syndrome and Turner syndrome. For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.Researchers have determined that hereditary lymphedema type II (Meige syndrome) and three other disorders occur due to different mutations of the same gene (FOXC2). These disorders include yellow nail syndrome, distichiasis-lymphedema syndrome, and lymphedema-ptosis syndrome. The exact relationship between these disorders is unknown.Yellow nail syndrome 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 fluid in the lungs (pleural effusion) and 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. Yellow nail syndrome occurs because of mutations in the FOXC2 gene and is inherited in an autosomal dominant manner. For more information on this disorder, choose “yellow nail” as your search term in the Rare Disease Database.Distichiasis-lymphedema syndrome is a rare autosomal dominant multisystem disorder characterized by swelling due to fluid accumulation that usually occurs around puberty and the development of extra eyelashes along the posterior border of the lid margins (distichiasis). Distichiasis may range from only a few to a full set of extra lashes. Swelling most often affects the legs. Additional anomalies associated with this disorder include cleft palate, droopy eyelids (ptosis), abnormalities of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea), cysts on the spinal cord, an abnormal sensitivity to light (photophobia) and cardiac (heart) defects. Distichiasis-lymphedema syndrome is caused by mutations of the FOXC2 gene and is inherited in an autosomal dominant manner.Lymphedema-ptosis syndrome is an extremely rare genetic disorder characterized by swelling because of fluid accumulation and droopy eyelids (ptosis). Swelling most often affects the legs. Lymphedema usually occurs at or shortly after puberty. Lymphedema-ptosis syndrome occurs because of mutations of the FOXC2 gene and is inherited in an autosomal dominant manner.
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Diagnosis of Hereditary Lymphedema
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Hereditary lymphedema can be diagnosed thorough clinical evaluation and a variety of specialized imaging tests such as lymphoscintigraphy, ultrasound and magnetic resonance imaging (MRI). During lymphoscintigraphy, a radioactively labeled colloid substance (tracer) is injected through the skin (intradermally) into either the hands or feet and monitored as it is transported through the body. The time required for the tracer to be transported from the point of injection to the regional lymph nodes is recorded. In hereditary lymphedema type I, the tracer may move sluggishly or not at all from the site of injection.Other specialized imaging approaches include using reflected sound waves to create images (ultrasound) or magnetic field and radio waves to produce cross-sectional images (magnetic resonance imaging, MRI). A Doppler ultrasound can evaluate venous conditions such as varicose veins and venous blood clots. An MRI can detect findings characteristic of hereditary lymphedema including edema, a mass surrounded by a sac containing lymph fluid (lymphocele) and the formation of fibrous tissue (fibrosis). Ultrasound scanning during pregnancy may be able to identify an affected fetus if swelling of the top surface of the feet (dorsum) is visible in the second or third trimester.For hereditary lymphedema type I, a diagnosis can be made via clinical evaluation identifying lymphedema in the lower limbs before age one and either (1) molecular genetic testing identifying a mutation in the FLT4 gene or (2) lymphoscintigraphy showing reduced tracer movement. Because lymphedema can also be a part of many other conditions, genetic testing can sometimes distinguish between a diagnosis of hereditary lymphedema and other inherited disorders.
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Diagnosis of Hereditary Lymphedema. Hereditary lymphedema can be diagnosed thorough clinical evaluation and a variety of specialized imaging tests such as lymphoscintigraphy, ultrasound and magnetic resonance imaging (MRI). During lymphoscintigraphy, a radioactively labeled colloid substance (tracer) is injected through the skin (intradermally) into either the hands or feet and monitored as it is transported through the body. The time required for the tracer to be transported from the point of injection to the regional lymph nodes is recorded. In hereditary lymphedema type I, the tracer may move sluggishly or not at all from the site of injection.Other specialized imaging approaches include using reflected sound waves to create images (ultrasound) or magnetic field and radio waves to produce cross-sectional images (magnetic resonance imaging, MRI). A Doppler ultrasound can evaluate venous conditions such as varicose veins and venous blood clots. An MRI can detect findings characteristic of hereditary lymphedema including edema, a mass surrounded by a sac containing lymph fluid (lymphocele) and the formation of fibrous tissue (fibrosis). Ultrasound scanning during pregnancy may be able to identify an affected fetus if swelling of the top surface of the feet (dorsum) is visible in the second or third trimester.For hereditary lymphedema type I, a diagnosis can be made via clinical evaluation identifying lymphedema in the lower limbs before age one and either (1) molecular genetic testing identifying a mutation in the FLT4 gene or (2) lymphoscintigraphy showing reduced tracer movement. Because lymphedema can also be a part of many other conditions, genetic testing can sometimes distinguish between a diagnosis of hereditary lymphedema and other inherited disorders.
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Therapies of Hereditary Lymphedema
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TreatmentTreatment for hereditary lymphedema focuses on management of symptoms, primarily reducing edema and preventing infection. For lower leg edema, referral to a lymphedema therapist is recommended. Treatment approaches may include fitting compression hosiery and/or bandaging, massage, supportive shoes, and good skin care. Complete decongestive therapy (CDT) is a form of treatment in which specialized manual techniques (manual lymph drainage) is combined with multi-layered compression bandaging, meticulous skin care, exercise, and the use of well-fitted compression garments. Rehabilitation therapy may be necessary in cases where extreme lymphedema impairs daily activities.Various surgical techniques have been used to treat individuals with hereditary lymphedema, including the joining of small lymphatic vessels to nearby small veins (microsurgical anastomosis) with the goal of creating new pathways to “rechannel” lymphatic fluid flow into the venous system and thereby reduce swelling. However, this surgery is not generally recommended as limited effectiveness has been reported in the medical literature. Surgery to remove excess fibrous tissue (reducing operation) for cases of severe lymphedema is also available but continued use of compression garments is still necessary. Removal of fat from under the skin (liposuction) has not been found to be effective in primary lymphedema.To prevent progression of edema or infection, individuals with hereditary lymphedema should avoid long periods of immobility with their legs placed in a downward position at a level lower than the heart (dependent position) and reduce excessive salt intake to decrease fluid retention. Special care should be taken to avoid wounds in any affected area due to reduced resistance to infection. Certain medications such as calcium channel blocking drugs and non-steroidal anti-inflammatory drugs (NSAIDs) may worsen edema in the legs and the benefits and risks of using these medications should be thoroughly discussed with the patient’s physician. Antibiotics can be used to treat infections such as cellulitis or as a preventive (prophylactic) measure for recurrent infections and athlete’s foot can be treated with antifungal topical medications. Individuals with primary chylous ascites complications should follow a no-fat diet supplemented with medium chain triglycerides and vitamins. Addition of a diuretic such as spironolactone has been reported to be a valuable adjunct to dietary control.There are currently no available gene therapies or medications approved by the U.S. Food and Drug Administration (FDA) to treat hereditary lymphedema. Genetic counseling and testing may benefit individuals with hereditary lymphedema and their families.
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Therapies of Hereditary Lymphedema. TreatmentTreatment for hereditary lymphedema focuses on management of symptoms, primarily reducing edema and preventing infection. For lower leg edema, referral to a lymphedema therapist is recommended. Treatment approaches may include fitting compression hosiery and/or bandaging, massage, supportive shoes, and good skin care. Complete decongestive therapy (CDT) is a form of treatment in which specialized manual techniques (manual lymph drainage) is combined with multi-layered compression bandaging, meticulous skin care, exercise, and the use of well-fitted compression garments. Rehabilitation therapy may be necessary in cases where extreme lymphedema impairs daily activities.Various surgical techniques have been used to treat individuals with hereditary lymphedema, including the joining of small lymphatic vessels to nearby small veins (microsurgical anastomosis) with the goal of creating new pathways to “rechannel” lymphatic fluid flow into the venous system and thereby reduce swelling. However, this surgery is not generally recommended as limited effectiveness has been reported in the medical literature. Surgery to remove excess fibrous tissue (reducing operation) for cases of severe lymphedema is also available but continued use of compression garments is still necessary. Removal of fat from under the skin (liposuction) has not been found to be effective in primary lymphedema.To prevent progression of edema or infection, individuals with hereditary lymphedema should avoid long periods of immobility with their legs placed in a downward position at a level lower than the heart (dependent position) and reduce excessive salt intake to decrease fluid retention. Special care should be taken to avoid wounds in any affected area due to reduced resistance to infection. Certain medications such as calcium channel blocking drugs and non-steroidal anti-inflammatory drugs (NSAIDs) may worsen edema in the legs and the benefits and risks of using these medications should be thoroughly discussed with the patient’s physician. Antibiotics can be used to treat infections such as cellulitis or as a preventive (prophylactic) measure for recurrent infections and athlete’s foot can be treated with antifungal topical medications. Individuals with primary chylous ascites complications should follow a no-fat diet supplemented with medium chain triglycerides and vitamins. Addition of a diuretic such as spironolactone has been reported to be a valuable adjunct to dietary control.There are currently no available gene therapies or medications approved by the U.S. Food and Drug Administration (FDA) to treat hereditary lymphedema. Genetic counseling and testing may benefit individuals with hereditary lymphedema and their families.
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Overview of Hereditary Multiple Osteochondromas
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Hereditary multiple osteochondromas (HMO) is a rare genetic disorder characterized by multiple benign (noncancerous) bone tumors that are covered by cartilage (osteochondromas), often on the growing end (metaphysis) of the long bones of the legs, arms, and digits. These osteochondromas usually continue to grow until shortly after puberty and may lead to bone deformities, skeletal abnormalities, short stature, nerve compression and reduced range of motion. Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition and is associated with abnormalities (mutations) in the EXT1or EXT2 gene.Hereditary multiple osteochondromas was formerly called hereditary multiple exostoses.
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Overview of Hereditary Multiple Osteochondromas. Hereditary multiple osteochondromas (HMO) is a rare genetic disorder characterized by multiple benign (noncancerous) bone tumors that are covered by cartilage (osteochondromas), often on the growing end (metaphysis) of the long bones of the legs, arms, and digits. These osteochondromas usually continue to grow until shortly after puberty and may lead to bone deformities, skeletal abnormalities, short stature, nerve compression and reduced range of motion. Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition and is associated with abnormalities (mutations) in the EXT1or EXT2 gene.Hereditary multiple osteochondromas was formerly called hereditary multiple exostoses.
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Symptoms of Hereditary Multiple Osteochondromas
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Hereditary multiple osteochondromas is a rare disorder that affects bone growth. Bony tumors (exostoses or osteochondromas), covered with cartilage, typically appear in the growth zones (metaphyses) of the long bones adjacent to the areas where tendon and muscles attach to the bone. These growths vary in size and number among affected individuals, even within the same family. Some individuals will present with a few large “lumps” while others will show several small growths. The median age of diagnosis is three years and almost all affected individuals are diagnosed by 12 years of age. In many cases, no treatment is required. If the exostoses are small, they may have little or no effect on the patient. However, in more severe cases, the growths may cause deformities of the forearm, knees, ankles, spine and/or pelvis. They may impose upon nerves, tendons and/or blood vessels, and interfere with movement or circulation, causing substantial pain as a result of pinched nerves or compressed tendons.Bones that develop exostoses most often are the upper arm (humerus), forearm, knee and shoulder blades (scapulae). Bowing of the forearm and ankle are the problems that most often require surgical correction. Approximately 40 percent of affected individuals have mild short stature as a result of shortened and/or bowed legs. If the vertebrae are affected, spinal cord compression may result, causing numbness and/ or paralysis. Urinary obstruction has been observed due to exostoses of the pelvic area.The bony growths that characterize this disorder continue to grow until shortly after puberty at which time normally new growth no longer develops. The risk for development of malignant (cancerous) tumors, mostly chondrosarcomas, is approximately 1 to 5%.
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Symptoms of Hereditary Multiple Osteochondromas. Hereditary multiple osteochondromas is a rare disorder that affects bone growth. Bony tumors (exostoses or osteochondromas), covered with cartilage, typically appear in the growth zones (metaphyses) of the long bones adjacent to the areas where tendon and muscles attach to the bone. These growths vary in size and number among affected individuals, even within the same family. Some individuals will present with a few large “lumps” while others will show several small growths. The median age of diagnosis is three years and almost all affected individuals are diagnosed by 12 years of age. In many cases, no treatment is required. If the exostoses are small, they may have little or no effect on the patient. However, in more severe cases, the growths may cause deformities of the forearm, knees, ankles, spine and/or pelvis. They may impose upon nerves, tendons and/or blood vessels, and interfere with movement or circulation, causing substantial pain as a result of pinched nerves or compressed tendons.Bones that develop exostoses most often are the upper arm (humerus), forearm, knee and shoulder blades (scapulae). Bowing of the forearm and ankle are the problems that most often require surgical correction. Approximately 40 percent of affected individuals have mild short stature as a result of shortened and/or bowed legs. If the vertebrae are affected, spinal cord compression may result, causing numbness and/ or paralysis. Urinary obstruction has been observed due to exostoses of the pelvic area.The bony growths that characterize this disorder continue to grow until shortly after puberty at which time normally new growth no longer develops. The risk for development of malignant (cancerous) tumors, mostly chondrosarcomas, is approximately 1 to 5%.
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Causes of Hereditary Multiple Osteochondromas
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Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. Approximately 10% of cases of HMO are thought to be the result of new mutations. At present two genes, EXT1 and EXT2, are known to show mutations in HMO patients and it is thought that these genes function as tumor suppressors. For some affected individuals no mutation in either gene is detected. In almost all these cases, the “mutation negative” patients do not have a familial history for exostoses. Most likely, they have an EXT1 or EXT2 mutation in only part of their body cells and the mutation is absent or undetectable in blood cells, which are usually used for DNA analysis. Data indicates that individuals with EXT1 mutations may have more severe effects than those with EXT2 mutations. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Hereditary Multiple Osteochondromas. Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. Approximately 10% of cases of HMO are thought to be the result of new mutations. At present two genes, EXT1 and EXT2, are known to show mutations in HMO patients and it is thought that these genes function as tumor suppressors. For some affected individuals no mutation in either gene is detected. In almost all these cases, the “mutation negative” patients do not have a familial history for exostoses. Most likely, they have an EXT1 or EXT2 mutation in only part of their body cells and the mutation is absent or undetectable in blood cells, which are usually used for DNA analysis. Data indicates that individuals with EXT1 mutations may have more severe effects than those with EXT2 mutations. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Affects of Hereditary Multiple Osteochondromas
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The prevalence of HMO has been estimated to be about 1 of 50,000 live births. A high prevalence of this disorder has been reported in some isolated communities. Hereditary multiple osteochondromas is a disorder that affects males and females in equal numbers but in general males tend to be more severely affected.
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Affects of Hereditary Multiple Osteochondromas. The prevalence of HMO has been estimated to be about 1 of 50,000 live births. A high prevalence of this disorder has been reported in some isolated communities. Hereditary multiple osteochondromas is a disorder that affects males and females in equal numbers but in general males tend to be more severely affected.
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Related disorders of Hereditary Multiple Osteochondromas
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Symptoms of the following disorders can be similar to those of hereditary multiple exostoses. Comparisons may be useful for a differential diagnosis.Metachondromatosis is a very rare autosomal dominant genetic disorder characterized by both enchondromatosis and multiple exostoses. Enchondromatosis is characterized by slow growing tumors of cartilage cells near the ends of the long bones. The multiple exostoses associated with this condition occur mostly in the digits and do not lead to deformity of the long bones or joints. This condition is caused by a mutation in the PTPN11 gene.Langer-Giedion syndrome, also known as trichorhinophalangeal syndrome type II (TRPS2), is an extremely rare inherited multisystem disorder. TRPS2 is characterized by fine, thin hair; unusual facial features; progressive growth retardation resulting in short stature (dwarfism); abnormally short fingers and toes (brachydactyly); “cone-shaped” formation of the “growing ends” of certain bones (epiphyseal coning); and/or development of multiple bony growths (exostoses) projecting outward from the surfaces of various bones of the body. In addition, affected individuals may exhibit unusually flexible (hyperextensible) joints, diminished muscle tone (hypotonia), excess folds of skin (redundant skin), and/or discolored elevated spots on the skin (maculopapular nevi). Affected individuals may also exhibit mild to severe mental retardation, hearing loss (sensorineural deafness), and/or delayed speech development. The range and severity of symptoms varies greatly from case to case. TRPS2 is due to the absence of genetic material (chromosomal deletions) on chromosome 8. The size of the deletion varies from case to case but includes the EXT1 gene. (For more information on this disorder, choose “trichorhinophalangeal syndrome type II ” as your search term in the Rare Disease Database.) 11p11 deletion syndrome is a condition caused by a deletion of adjacent genes on chromosome 11 (contiguous gene syndrome) including the EXT2 gene. This condition is characterized by ossification defects of the skull, multiple exostoses and sometimes craniofacial abnormalities and mental retardation.
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Related disorders of Hereditary Multiple Osteochondromas. Symptoms of the following disorders can be similar to those of hereditary multiple exostoses. Comparisons may be useful for a differential diagnosis.Metachondromatosis is a very rare autosomal dominant genetic disorder characterized by both enchondromatosis and multiple exostoses. Enchondromatosis is characterized by slow growing tumors of cartilage cells near the ends of the long bones. The multiple exostoses associated with this condition occur mostly in the digits and do not lead to deformity of the long bones or joints. This condition is caused by a mutation in the PTPN11 gene.Langer-Giedion syndrome, also known as trichorhinophalangeal syndrome type II (TRPS2), is an extremely rare inherited multisystem disorder. TRPS2 is characterized by fine, thin hair; unusual facial features; progressive growth retardation resulting in short stature (dwarfism); abnormally short fingers and toes (brachydactyly); “cone-shaped” formation of the “growing ends” of certain bones (epiphyseal coning); and/or development of multiple bony growths (exostoses) projecting outward from the surfaces of various bones of the body. In addition, affected individuals may exhibit unusually flexible (hyperextensible) joints, diminished muscle tone (hypotonia), excess folds of skin (redundant skin), and/or discolored elevated spots on the skin (maculopapular nevi). Affected individuals may also exhibit mild to severe mental retardation, hearing loss (sensorineural deafness), and/or delayed speech development. The range and severity of symptoms varies greatly from case to case. TRPS2 is due to the absence of genetic material (chromosomal deletions) on chromosome 8. The size of the deletion varies from case to case but includes the EXT1 gene. (For more information on this disorder, choose “trichorhinophalangeal syndrome type II ” as your search term in the Rare Disease Database.) 11p11 deletion syndrome is a condition caused by a deletion of adjacent genes on chromosome 11 (contiguous gene syndrome) including the EXT2 gene. This condition is characterized by ossification defects of the skull, multiple exostoses and sometimes craniofacial abnormalities and mental retardation.
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Diagnosis of Hereditary Multiple Osteochondromas
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Diagnosis of Hereditary Multiple Osteochondromas.
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Therapies of Hereditary Multiple Osteochondromas
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The diagnosis of HMO is based on clinical features, X-ray findings and family history. Molecular genetic testing of the EXT1 and EXT2 genes is available to confirm the diagnosis.TreatmentSurgery may be required to relieve pain, improve movement, restore normal circulation, or for cosmetic reasons. Malignant degeneration of a tumor is treated surgically, possibly in combination with chemotherapy and radiation therapy.Most of the malignant degenerations to cancers are to cartilage tumors or chondrosarcomas, which are slow growing and generally insensitive to chemotherapy.Monitoring the size of affected bones by annual scans to screen for malignant degeneration is sometimes recommended. Rapid growth and increased pain are signs of a possible malignant change.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Hereditary Multiple Osteochondromas. The diagnosis of HMO is based on clinical features, X-ray findings and family history. Molecular genetic testing of the EXT1 and EXT2 genes is available to confirm the diagnosis.TreatmentSurgery may be required to relieve pain, improve movement, restore normal circulation, or for cosmetic reasons. Malignant degeneration of a tumor is treated surgically, possibly in combination with chemotherapy and radiation therapy.Most of the malignant degenerations to cancers are to cartilage tumors or chondrosarcomas, which are slow growing and generally insensitive to chemotherapy.Monitoring the size of affected bones by annual scans to screen for malignant degeneration is sometimes recommended. Rapid growth and increased pain are signs of a possible malignant change.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of Hereditary Neuralgic Amyotrophy
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SummaryHereditary neuralgic amyotrophy (HNA) is a rare genetic disorder characterized by recurrent episodes of severe pain in the shoulder and arm. In most cases, pain may persist for a few hours to a few weeks and is followed by wasting and weakness of the muscles (amyotrophy) in the affected areas. Additional symptoms including distinct facial features and skeletal abnormalities may also be present. HNA involves the brachial plexus, the interweaving network of nerves that extend from the spine through the neck, into each armpit and down the arms. These nerves control movements and sensations in the shoulders, arms, elbows, wrists and hands. They also control the opening and closing of small blood vessels in the skin, as in response to outside temperature. The number and frequency of episodes can vary greatly from one person to another. Approximately, 75% of affected individuals will have at least one recurrent episode. The severity of the disorder can also vary greatly due, in part, to the specific nerves involved. HNA may result in residual pain even between episodes and many individuals develop persistent pain due to altered posture and movement, and overuse of the affected shoulder and arm. Some patients have an inherited predisposition to developing HNA that is associated with changes (mutations) or duplications in the SEPT9 gene. The trait for developing NA symptoms is inherited in an autosomal dominant manner.
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Overview of Hereditary Neuralgic Amyotrophy. SummaryHereditary neuralgic amyotrophy (HNA) is a rare genetic disorder characterized by recurrent episodes of severe pain in the shoulder and arm. In most cases, pain may persist for a few hours to a few weeks and is followed by wasting and weakness of the muscles (amyotrophy) in the affected areas. Additional symptoms including distinct facial features and skeletal abnormalities may also be present. HNA involves the brachial plexus, the interweaving network of nerves that extend from the spine through the neck, into each armpit and down the arms. These nerves control movements and sensations in the shoulders, arms, elbows, wrists and hands. They also control the opening and closing of small blood vessels in the skin, as in response to outside temperature. The number and frequency of episodes can vary greatly from one person to another. Approximately, 75% of affected individuals will have at least one recurrent episode. The severity of the disorder can also vary greatly due, in part, to the specific nerves involved. HNA may result in residual pain even between episodes and many individuals develop persistent pain due to altered posture and movement, and overuse of the affected shoulder and arm. Some patients have an inherited predisposition to developing HNA that is associated with changes (mutations) or duplications in the SEPT9 gene. The trait for developing NA symptoms is inherited in an autosomal dominant manner.
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Hereditary Neuralgic Amyotrophy
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Symptoms of Hereditary Neuralgic Amyotrophy
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The hallmark finding is the abrupt onset of pain in one or both of the shoulders and/or arms. The right side of the body is affected more often than the left, but both shoulders are affected in approximately one-third of patients. When both shoulders are affected, symptoms are usually worse on one side.In the classic type, onset may be rapid in some patients, while in others pain onset is gradual and subtle (insidious), followed by a rapid increase in both intensity and severity. Pain has been described as sharp, aching, burning or stabbing. If patients rate the severity of their pain at onset on a scale from 0 (no pain) to 10 (most severe pain ever), they usually score a 7 or higher. Pain may also affect the neck and the arm, and hand on the same side as the affected shoulder.Onset is usually in the second or third decade of life. However, children as young as one year old have experienced recurrent episodes of HNA. Recurrent episodes may involve the same peripheral nerves that were originally affected, completely different peripheral nerves, or a mix of the same and different peripheral nerves.Pain at onset is often continuous, severe, and worse during the evening or at night. Pain can potentially be excruciating and debilitating and typically lasts for 1-3 weeks on average; although in some patients it may be longer. This initial period may be known as the acute phase. Eventually, affected individuals enter a period where the continuous pain lessens and there may be no pain when the affect shoulder and/or arm are not being used (i.e. at rest). However, specific movements may aggravate the condition, causing sharp, stabbing intense pain that persists for a few hours before lessening. This occurs because previously damaged nerves remain abnormally sensitive (hypersensitive). Eventually, around 2/3 of all affected individuals develop a chronic, more muscle ache type pain that can persist indefinitely. This is sometimes known as the chronic phase of HNA.Eventually, anywhere from a day to a few weeks after the onset of the disorder, a progressive weakness of several muscles in the affected shoulder and arm occurs. The severity of muscle weakness can vary greatly, ranging from mild weakness that may be barely noticeable to, in rare cases, almost complete paralysis of some affected muscles. In individuals with HNA, muscle weakness results from damage to the nerves that serve the muscles in the shoulders and arms. The degree of weakness is related to the number of nerve fibers affected in a nerve. In addition to weakness, the affected muscles may progressively shrink and thin (atrophy) due to lack of use. Muscle weakness may go unnoticed, unless atrophy and wasting of the affected muscles are severe and easy to observe, or when the person affected notices he or she can’t use the arm as well as before, especially during reaching or in overhead activities.Additional symptoms that can occur in HNA include absent or reduced reflexes and sensory deficits in the affected areas such as the loss of sensation or numbness (hypoesthesia), a sensation of tickling, prickling, or burning on the skin of the affected areas (paresthesia), or an abnormally unpleasant or painful sensation to a light touch (dysesthesia). These symptoms mainly occur when nerves that supply the forearm and hand are involved.Because nerve damage in HNA can affect blood vessel constriction, additional symptoms may develop including affected skin, particularly on the hands, becoming reddened, purplish or spotted. Swelling due to fluid retention (edema) may also occur. The skin, hair and nails may grow quickly than normal. Certain areas of the body particularly the hands and forearms may no longer be able to respond properly to outside temperature. Excessive sweating may occur or affected individuals may feel abnormally cold in the affected areas. Just as the sensory symptoms, these so-called autonomic nerve symptoms occur mainly occur in the forearms and hands.Additional complications can develop in some affected individuals. The position of the shoulders, arms, wrists, and hands can shift slightly because of atrophy and weakness of affected muscles. The most common finding is a combination of an abnormally moving shoulder blade, a decreased ability to extend the arm behind the back and some weakness in bending the tip of the thumb. The weakness and limitations of movement find their origin in the so-called serratus anterior muscle. This muscle is responsible for holding the shoulder blade close to the chest when someone is upright or trying to lift the arm. The nerve to this muscle is affected in around 70% of people with HNA. Weakness of the serratus anterior leads to loss of contact of the shoulder blade with the chest. As a result, the shoulder blade will protrude backwards during movement of the arm. This is called a winged scapula, or scapula alata. This can leave an affected individual at risk of secondary shoulder joint impingement or subluxation. Secondary impingement is a painful condition that occurs when the shoulder’s tendons are compressed or trapped during shoulder movements. Because the shoulder blade also forms the socket of the shoulder joint, it needs to rotate during movement of the arm to hold the socket and the upper arm bone neatly together without impinging tendons in the joint. If weakness causes this rotation to fail, the shoulder joint tendons will often become irritated as they are constantly impinged during movement of the arm. Subluxation refers to partial dislocation of the shoulder joint, which occurs when the muscle that supports the weight of the arm in the joint socket (the deltoid muscle) is too weak. Fortunately the arm will not completely luxate as a rule, because this type of weakness of this deltoid muscle automatically means people cannot lift their arm higher than elbow height, and hence cannot luxate the joint. Affected individuals may also be at risk of developing contractures, in which abnormal shortening of muscles or tendons leads to deformity or rigidity of an affected joint. Contracture of the shoulder, also known as adhesive capsulitis, can result in pain and limitation of normal range of movement of the joint.In some patients, nerves outside of the brachial plexus may be involved such as the nerves of the lumbosacral plexus (the nerves to the leg and foot), the phrenic nerve that supplies the main muscle for inspiration, or rarely the recurrent laryngeal nerve that supplies half of the vocal cords. Involvement of the nerves in the lower portion of the back (lumbosacral plexus) can cause pain, hypoesthesia, and paresthesia in the legs. The phrenic nerve sends signals between the brain and the diaphragm, the muscle that separates the lungs from the abdomen. Involvement of the phrenic nerve can result in a significant shortness of breath, especially when lying down or bending over and in trouble sleeping well. Involvement of the recurrent laryngeal nerve can result in weakness and partial paralysis of the vocal cords and, consequently, hoarseness and soft speech (hypophonia). In extremely rare cases, facial or other cranial nerves may be affected.Many individuals recover some strength and functionality of the shoulder or other affected areas. Numerous reports in the medical literature state that most individuals will regain up to 70%-90% of their original strength within two years. However, strength recovery does not automatically mean recovery of function in HNA. Recent studies indicate that recovery may take more than two years in some people, and may even take up to 3-4 years for phrenic nerve recovery. Many people will experience residual, chronic pain and complications such as impaired movement of the shoulder and/or affected joints. It is now known that these residual complaints have no relation with the strength of individual muscles anymore. There are two reasons that pain and fatigue may persist. The first reason is a loss of endurance, i.e. the ability to keep up a certain position or movement with a previously affected muscle. Decreased endurance is the price our body has to pay for how nerves are healed. It is the main reason why patients with (hereditary) NA can often not go back to a full day of work or home duties. The second reason is the changed, adaptive, posture and movement pattern that occurs after nerves have been damaged around the shoulder. These new movements that were initially less or lost causes every movement to cost more energy than the “normal” movement did, and can lead to significant fatigue. The pattern is also mechanically less healthy for your body and can lead to secondary injury to the shoulder joint and tendons. The resulting imbalance between one’s physical possibilities and what is required of someone in his or her daily life and work often leads to chronic pain and fatigue. In a small subset of individuals, HNA can also be associated with specific features or physical findings. Some affected individuals have distinctive facial features including deep-set eyes that are set abnormally close together (hypotelorism), skin folds that cover the inner corner of the eyes (epicanthal folds), an abnormally narrow distance between the eyelids (narrow palpebral fissures), a long bridge of the nose, a narrow, small mouth (microstomia), low-set ears, and wide-set teeth. Hypotelorism can be striking in some cases. Affected individuals may also display features that appear dissimilar from one side of the face to the other (facial asymmetry). Distinctive facial features usually become less pronounced with age. In these cases, additional physical findings can be present including partial webbing or fusion of the fingers or toes (partial syndactyly), hammer toes, fused bones in the forearms, and excess skin folds on the neck, a groove or gap in the roof of the mouth (cleft palate), and a cleft or split in the fleshy flap of tissue (uvula) that hangs in the back of the throat (bifid uvula). Short stature has also occurred in these individuals. However, on an individual level, there is no sure tell-sign that someone has hereditary NA versus the non-hereditary variant, unless there are other people affected in the same family.
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Symptoms of Hereditary Neuralgic Amyotrophy. The hallmark finding is the abrupt onset of pain in one or both of the shoulders and/or arms. The right side of the body is affected more often than the left, but both shoulders are affected in approximately one-third of patients. When both shoulders are affected, symptoms are usually worse on one side.In the classic type, onset may be rapid in some patients, while in others pain onset is gradual and subtle (insidious), followed by a rapid increase in both intensity and severity. Pain has been described as sharp, aching, burning or stabbing. If patients rate the severity of their pain at onset on a scale from 0 (no pain) to 10 (most severe pain ever), they usually score a 7 or higher. Pain may also affect the neck and the arm, and hand on the same side as the affected shoulder.Onset is usually in the second or third decade of life. However, children as young as one year old have experienced recurrent episodes of HNA. Recurrent episodes may involve the same peripheral nerves that were originally affected, completely different peripheral nerves, or a mix of the same and different peripheral nerves.Pain at onset is often continuous, severe, and worse during the evening or at night. Pain can potentially be excruciating and debilitating and typically lasts for 1-3 weeks on average; although in some patients it may be longer. This initial period may be known as the acute phase. Eventually, affected individuals enter a period where the continuous pain lessens and there may be no pain when the affect shoulder and/or arm are not being used (i.e. at rest). However, specific movements may aggravate the condition, causing sharp, stabbing intense pain that persists for a few hours before lessening. This occurs because previously damaged nerves remain abnormally sensitive (hypersensitive). Eventually, around 2/3 of all affected individuals develop a chronic, more muscle ache type pain that can persist indefinitely. This is sometimes known as the chronic phase of HNA.Eventually, anywhere from a day to a few weeks after the onset of the disorder, a progressive weakness of several muscles in the affected shoulder and arm occurs. The severity of muscle weakness can vary greatly, ranging from mild weakness that may be barely noticeable to, in rare cases, almost complete paralysis of some affected muscles. In individuals with HNA, muscle weakness results from damage to the nerves that serve the muscles in the shoulders and arms. The degree of weakness is related to the number of nerve fibers affected in a nerve. In addition to weakness, the affected muscles may progressively shrink and thin (atrophy) due to lack of use. Muscle weakness may go unnoticed, unless atrophy and wasting of the affected muscles are severe and easy to observe, or when the person affected notices he or she can’t use the arm as well as before, especially during reaching or in overhead activities.Additional symptoms that can occur in HNA include absent or reduced reflexes and sensory deficits in the affected areas such as the loss of sensation or numbness (hypoesthesia), a sensation of tickling, prickling, or burning on the skin of the affected areas (paresthesia), or an abnormally unpleasant or painful sensation to a light touch (dysesthesia). These symptoms mainly occur when nerves that supply the forearm and hand are involved.Because nerve damage in HNA can affect blood vessel constriction, additional symptoms may develop including affected skin, particularly on the hands, becoming reddened, purplish or spotted. Swelling due to fluid retention (edema) may also occur. The skin, hair and nails may grow quickly than normal. Certain areas of the body particularly the hands and forearms may no longer be able to respond properly to outside temperature. Excessive sweating may occur or affected individuals may feel abnormally cold in the affected areas. Just as the sensory symptoms, these so-called autonomic nerve symptoms occur mainly occur in the forearms and hands.Additional complications can develop in some affected individuals. The position of the shoulders, arms, wrists, and hands can shift slightly because of atrophy and weakness of affected muscles. The most common finding is a combination of an abnormally moving shoulder blade, a decreased ability to extend the arm behind the back and some weakness in bending the tip of the thumb. The weakness and limitations of movement find their origin in the so-called serratus anterior muscle. This muscle is responsible for holding the shoulder blade close to the chest when someone is upright or trying to lift the arm. The nerve to this muscle is affected in around 70% of people with HNA. Weakness of the serratus anterior leads to loss of contact of the shoulder blade with the chest. As a result, the shoulder blade will protrude backwards during movement of the arm. This is called a winged scapula, or scapula alata. This can leave an affected individual at risk of secondary shoulder joint impingement or subluxation. Secondary impingement is a painful condition that occurs when the shoulder’s tendons are compressed or trapped during shoulder movements. Because the shoulder blade also forms the socket of the shoulder joint, it needs to rotate during movement of the arm to hold the socket and the upper arm bone neatly together without impinging tendons in the joint. If weakness causes this rotation to fail, the shoulder joint tendons will often become irritated as they are constantly impinged during movement of the arm. Subluxation refers to partial dislocation of the shoulder joint, which occurs when the muscle that supports the weight of the arm in the joint socket (the deltoid muscle) is too weak. Fortunately the arm will not completely luxate as a rule, because this type of weakness of this deltoid muscle automatically means people cannot lift their arm higher than elbow height, and hence cannot luxate the joint. Affected individuals may also be at risk of developing contractures, in which abnormal shortening of muscles or tendons leads to deformity or rigidity of an affected joint. Contracture of the shoulder, also known as adhesive capsulitis, can result in pain and limitation of normal range of movement of the joint.In some patients, nerves outside of the brachial plexus may be involved such as the nerves of the lumbosacral plexus (the nerves to the leg and foot), the phrenic nerve that supplies the main muscle for inspiration, or rarely the recurrent laryngeal nerve that supplies half of the vocal cords. Involvement of the nerves in the lower portion of the back (lumbosacral plexus) can cause pain, hypoesthesia, and paresthesia in the legs. The phrenic nerve sends signals between the brain and the diaphragm, the muscle that separates the lungs from the abdomen. Involvement of the phrenic nerve can result in a significant shortness of breath, especially when lying down or bending over and in trouble sleeping well. Involvement of the recurrent laryngeal nerve can result in weakness and partial paralysis of the vocal cords and, consequently, hoarseness and soft speech (hypophonia). In extremely rare cases, facial or other cranial nerves may be affected.Many individuals recover some strength and functionality of the shoulder or other affected areas. Numerous reports in the medical literature state that most individuals will regain up to 70%-90% of their original strength within two years. However, strength recovery does not automatically mean recovery of function in HNA. Recent studies indicate that recovery may take more than two years in some people, and may even take up to 3-4 years for phrenic nerve recovery. Many people will experience residual, chronic pain and complications such as impaired movement of the shoulder and/or affected joints. It is now known that these residual complaints have no relation with the strength of individual muscles anymore. There are two reasons that pain and fatigue may persist. The first reason is a loss of endurance, i.e. the ability to keep up a certain position or movement with a previously affected muscle. Decreased endurance is the price our body has to pay for how nerves are healed. It is the main reason why patients with (hereditary) NA can often not go back to a full day of work or home duties. The second reason is the changed, adaptive, posture and movement pattern that occurs after nerves have been damaged around the shoulder. These new movements that were initially less or lost causes every movement to cost more energy than the “normal” movement did, and can lead to significant fatigue. The pattern is also mechanically less healthy for your body and can lead to secondary injury to the shoulder joint and tendons. The resulting imbalance between one’s physical possibilities and what is required of someone in his or her daily life and work often leads to chronic pain and fatigue. In a small subset of individuals, HNA can also be associated with specific features or physical findings. Some affected individuals have distinctive facial features including deep-set eyes that are set abnormally close together (hypotelorism), skin folds that cover the inner corner of the eyes (epicanthal folds), an abnormally narrow distance between the eyelids (narrow palpebral fissures), a long bridge of the nose, a narrow, small mouth (microstomia), low-set ears, and wide-set teeth. Hypotelorism can be striking in some cases. Affected individuals may also display features that appear dissimilar from one side of the face to the other (facial asymmetry). Distinctive facial features usually become less pronounced with age. In these cases, additional physical findings can be present including partial webbing or fusion of the fingers or toes (partial syndactyly), hammer toes, fused bones in the forearms, and excess skin folds on the neck, a groove or gap in the roof of the mouth (cleft palate), and a cleft or split in the fleshy flap of tissue (uvula) that hangs in the back of the throat (bifid uvula). Short stature has also occurred in these individuals. However, on an individual level, there is no sure tell-sign that someone has hereditary NA versus the non-hereditary variant, unless there are other people affected in the same family.
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Causes of Hereditary Neuralgic Amyotrophy
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Some cases of hereditary neuralgic amyotrophy are caused by mutations or duplications in the SEPT9 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Although SEPT9 mutations have been shown to cause HNA, these mutations have only been found in approximately 55% of affected individuals in the North Americas, and in only < 5% of the families from Europe. Therefore, it is likely that additional, as-yet-unidentified genes may also cause or contribute to HNA (genetic heterogeneity).
The SEPT9 gene creates (encodes) a protein known as septin 9, which is part of a group of proteins known as septins. Septins are involved in the formation and maintenance of the framework of a cell (cytoskeleton) and plays a role in cell division. Mutations in this gene lead to low levels of function septin 9. The exact, underlying manner in which SEPT9 mutations cause or predispose for HNA is not understood. It is possible that mutations in the SEPT9 gene convey a genetic susceptibility to brachial plexus injury. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors.The exact disease mechanism in HNA is not known, but it is thought to be complex and depending on multiple factors. An interplay between environmental factors (such as infections and other immune system activators) and mechanical factors (repetitive or strenuous motor tasks that stretch the nerves) placed upon a genetic predisposition, is assumed to be the cause of HNA episodes. Such episodes may occur seemingly spontaneously, but may also be preceded a “triggering” event that activates the body’s immune system. This can be any event that triggers the immune system. A recent viral illness is the most common ‘triggering’ factor associated with the development of HNA. Recently, is has become known that the hepatitis E virus is often a trigger of NA. It often affects middle-aged males, and overall the episodes seem to be more severe, with bilateral arm involvement and involvement of the phrenic nerve for breathing being quite common. Hepatitis E does not affect the prognosis and requires no specific treatment unless the patient already has a severe liver illness. Additional factors that have been known to trigger HNA episodes are recent immunization, surgery, unaccustomed strenuous exercise, minor trauma, bacterial infection, parasitic infection, anesthesia,. In women, childbirth can trigger HNA. However, in many cases, no triggering event or underlying factor can be identified.The SEPT9 mutations associated with HNA are inherited an autosomal dominant manner. 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. The risk is the same for males and females.
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Causes of Hereditary Neuralgic Amyotrophy. Some cases of hereditary neuralgic amyotrophy are caused by mutations or duplications in the SEPT9 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Although SEPT9 mutations have been shown to cause HNA, these mutations have only been found in approximately 55% of affected individuals in the North Americas, and in only < 5% of the families from Europe. Therefore, it is likely that additional, as-yet-unidentified genes may also cause or contribute to HNA (genetic heterogeneity).
The SEPT9 gene creates (encodes) a protein known as septin 9, which is part of a group of proteins known as septins. Septins are involved in the formation and maintenance of the framework of a cell (cytoskeleton) and plays a role in cell division. Mutations in this gene lead to low levels of function septin 9. The exact, underlying manner in which SEPT9 mutations cause or predispose for HNA is not understood. It is possible that mutations in the SEPT9 gene convey a genetic susceptibility to brachial plexus injury. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors.The exact disease mechanism in HNA is not known, but it is thought to be complex and depending on multiple factors. An interplay between environmental factors (such as infections and other immune system activators) and mechanical factors (repetitive or strenuous motor tasks that stretch the nerves) placed upon a genetic predisposition, is assumed to be the cause of HNA episodes. Such episodes may occur seemingly spontaneously, but may also be preceded a “triggering” event that activates the body’s immune system. This can be any event that triggers the immune system. A recent viral illness is the most common ‘triggering’ factor associated with the development of HNA. Recently, is has become known that the hepatitis E virus is often a trigger of NA. It often affects middle-aged males, and overall the episodes seem to be more severe, with bilateral arm involvement and involvement of the phrenic nerve for breathing being quite common. Hepatitis E does not affect the prognosis and requires no specific treatment unless the patient already has a severe liver illness. Additional factors that have been known to trigger HNA episodes are recent immunization, surgery, unaccustomed strenuous exercise, minor trauma, bacterial infection, parasitic infection, anesthesia,. In women, childbirth can trigger HNA. However, in many cases, no triggering event or underlying factor can be identified.The SEPT9 mutations associated with HNA are inherited an autosomal dominant manner. 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. The risk is the same for males and females.
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Affects of Hereditary Neuralgic Amyotrophy
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HNA is a rare disorder that affects males a little more often than females. The exact incidence or prevalence is unknown, but can be extrapolated from the incidence of sporadic, non-familial NA which is about 1 in 1000 per year and the fact that in a large group of 1300+ NA patients approximately 1 in 10 people had a family history for the disorder. This combined suggests that HNA occurs in about 1 in 10.000 people in the population.
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Affects of Hereditary Neuralgic Amyotrophy. HNA is a rare disorder that affects males a little more often than females. The exact incidence or prevalence is unknown, but can be extrapolated from the incidence of sporadic, non-familial NA which is about 1 in 1000 per year and the fact that in a large group of 1300+ NA patients approximately 1 in 10 people had a family history for the disorder. This combined suggests that HNA occurs in about 1 in 10.000 people in the population.
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Related disorders of Hereditary Neuralgic Amyotrophy
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Symptoms of the following disorders can be similar to those of HNA. Comparisons may be useful for a differential diagnosis.Parsonage-Turner syndrome (PTS), also known as idiopathic neuralgic amyotrophy, is a not uncommon neurological disorder, with clinical findings of this disorder that are identical to those seen in HNA. Affected individuals experience episodes of pain that last for a few hours to a few weeks and is followed by wasting and weakness of the muscles (amyotrophy) in the affected areas. As with HNA, PTS mainly involves the brachial plexus. The exact cause of PTS is unknown (idiopathic), but – just as in HNA – the disorder is believed to be caused by a combination of an underlying susceptibility, mechanical factors (such as strain on the arm or shoulder) that weaken the blood nerve barrier and a final immune “trigger” that sets of the attacks. The severity can vary widely from one individual to another due, in part, to the specific nerves involved. Rarely, affected individuals may recover without treatment, meaning that strength returns to the affected muscles and pain goes away. However, some individuals may experience recurrent episodes. Some affected individuals may experience residual pain and potentially significant disability. Unlike HNA, PTS usually occurs in a slightly older age group, with most people experiencing their first symptoms around the age of 40 years. The distinctive facial features found in some individuals with HNA do not occur in PTS. (For more information on this disorder, choose “Parsonage-Turner” as your search term in the Rare Disease Database.)HNA is only one cause of acute peripheral neuropathy. Diagnosis requires the exclusion of other causes including neuropathy caused by alcohol, poisons, drugs, inflammation of the blood vessels (vasculitis), and cancer. Additional conditions or disorders that can cause symptoms similar to those seen in PTS or HNA include shoulder bursitis, rotor cuff injury or disease, calcific tendonitis, impingement syndromes, Guillain-Barre syndrome, cervical disc disease, cervical radiculopathy, mononeuritis monoplex, amyotrophic lateral sclerosis (Lou Gehrig’s disease), chronic inflammatory demyelinating polyneuropathy, polymyalgica rheumatica, thoracic outlet syndrome, and brachial plexus injury secondary to cancer (neoplastic brachial plexopathy). Adhesive capsulitis, which can develop as a complication of HNA, can develop for other reasons as well. NORD has individual reports on some of these disorders and a general report on peripheral neuropathy. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Hereditary Neuralgic Amyotrophy. Symptoms of the following disorders can be similar to those of HNA. Comparisons may be useful for a differential diagnosis.Parsonage-Turner syndrome (PTS), also known as idiopathic neuralgic amyotrophy, is a not uncommon neurological disorder, with clinical findings of this disorder that are identical to those seen in HNA. Affected individuals experience episodes of pain that last for a few hours to a few weeks and is followed by wasting and weakness of the muscles (amyotrophy) in the affected areas. As with HNA, PTS mainly involves the brachial plexus. The exact cause of PTS is unknown (idiopathic), but – just as in HNA – the disorder is believed to be caused by a combination of an underlying susceptibility, mechanical factors (such as strain on the arm or shoulder) that weaken the blood nerve barrier and a final immune “trigger” that sets of the attacks. The severity can vary widely from one individual to another due, in part, to the specific nerves involved. Rarely, affected individuals may recover without treatment, meaning that strength returns to the affected muscles and pain goes away. However, some individuals may experience recurrent episodes. Some affected individuals may experience residual pain and potentially significant disability. Unlike HNA, PTS usually occurs in a slightly older age group, with most people experiencing their first symptoms around the age of 40 years. The distinctive facial features found in some individuals with HNA do not occur in PTS. (For more information on this disorder, choose “Parsonage-Turner” as your search term in the Rare Disease Database.)HNA is only one cause of acute peripheral neuropathy. Diagnosis requires the exclusion of other causes including neuropathy caused by alcohol, poisons, drugs, inflammation of the blood vessels (vasculitis), and cancer. Additional conditions or disorders that can cause symptoms similar to those seen in PTS or HNA include shoulder bursitis, rotor cuff injury or disease, calcific tendonitis, impingement syndromes, Guillain-Barre syndrome, cervical disc disease, cervical radiculopathy, mononeuritis monoplex, amyotrophic lateral sclerosis (Lou Gehrig’s disease), chronic inflammatory demyelinating polyneuropathy, polymyalgica rheumatica, thoracic outlet syndrome, and brachial plexus injury secondary to cancer (neoplastic brachial plexopathy). Adhesive capsulitis, which can develop as a complication of HNA, can develop for other reasons as well. NORD has individual reports on some of these disorders and a general report on peripheral neuropathy. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Hereditary Neuralgic Amyotrophy
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A diagnosis of HNA is based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests can help rule out other diagnoses.Clinical Testing and Workup
The most characteristic features of HNA are the very severe acute-onset pain in one or both shoulder girdles and arm, followed by patchy muscle weakness in the upper extremity. A thorough clinical examination will confirm that the symptoms do not match the distribution of for example a cervical root compression syndrome, and weakness and atrophy tell there is more going on than just a shoulder joint problem. Other than the typical clinical features, there are no tests that are specific for the diagnosis of HNA. Certain tests such as nerve conduction studies or electromyography can be used to assess the health of muscles and the nerves that control muscles. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. This test can help to pinpoint the site of disease or injury to the nerve, but is often non-informative when it comes to nerves affected in HNA.During an electromyography (EMG), a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control that muscle. Needle EMG can be helpful to detect affected nerves in HNA. But as not all 50 muscles of the arm are routinely examined, the test can also be falsely negative sometimes, when muscle are examined that are not clinically involved.A specialized imaging technique known as magnetic resonance imaging (MRI) can help to obtain a diagnosis of HNA. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can help to exclude other potential cause of shoulder pain, demonstrate atrophy of affected muscles, and detect signal changes caused by lack of nerve supply (denervation).Nerve ultrasound is a recently developed, non-invasive and painless technique that can look at the shoulder and arm nerves with much detail, and can see inflamed parts of the nerves in certain areas. Affected nerves can be seen in about 70% of HNA patients. This can confirm the diagnosis of HNA. Ultrasound can also help detect diaphragm weakness. However, currently not many centers offer ultrasound of the brachial plexus nerves and diaphragm.A traditional x-ray (radiograph) of the shoulder may be ordered to rule out specific conditions that can damage the shoulder.
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Diagnosis of Hereditary Neuralgic Amyotrophy. A diagnosis of HNA is based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests can help rule out other diagnoses.Clinical Testing and Workup
The most characteristic features of HNA are the very severe acute-onset pain in one or both shoulder girdles and arm, followed by patchy muscle weakness in the upper extremity. A thorough clinical examination will confirm that the symptoms do not match the distribution of for example a cervical root compression syndrome, and weakness and atrophy tell there is more going on than just a shoulder joint problem. Other than the typical clinical features, there are no tests that are specific for the diagnosis of HNA. Certain tests such as nerve conduction studies or electromyography can be used to assess the health of muscles and the nerves that control muscles. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. This test can help to pinpoint the site of disease or injury to the nerve, but is often non-informative when it comes to nerves affected in HNA.During an electromyography (EMG), a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control that muscle. Needle EMG can be helpful to detect affected nerves in HNA. But as not all 50 muscles of the arm are routinely examined, the test can also be falsely negative sometimes, when muscle are examined that are not clinically involved.A specialized imaging technique known as magnetic resonance imaging (MRI) can help to obtain a diagnosis of HNA. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can help to exclude other potential cause of shoulder pain, demonstrate atrophy of affected muscles, and detect signal changes caused by lack of nerve supply (denervation).Nerve ultrasound is a recently developed, non-invasive and painless technique that can look at the shoulder and arm nerves with much detail, and can see inflamed parts of the nerves in certain areas. Affected nerves can be seen in about 70% of HNA patients. This can confirm the diagnosis of HNA. Ultrasound can also help detect diaphragm weakness. However, currently not many centers offer ultrasound of the brachial plexus nerves and diaphragm.A traditional x-ray (radiograph) of the shoulder may be ordered to rule out specific conditions that can damage the shoulder.
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Therapies of Hereditary Neuralgic Amyotrophy
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Treatment
The treatment of HNA is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Most patients primarily need a team consisting of a (pediatric) neurologist, physiatrist, physical therapist and occupational therapist. In case of phrenic nerve palsy a specialized pulmonologist and sometimes home nighttime ventilation is needed. Recurrent laryngeal nerve palsy may require the help of a speech therapist. For HNA patients with rare and special features of craniofacial abnormalities, the help of specialized dentists or maxillofacial surgeons may be warranted.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with HNA. An episode may resolve on its own without treatment and only require support measures such as various pain management strategies including pain medications (analgesics). Specific pain medications used to treat HNA include opiates and non-steroidal anti-inflammatory drugs (NSAIDs), which are usually used in combination. Some physicians have recommended using oral corticosteroids such as prednisone, which has led to a decreased duration of pain and accelerated the healing process in some cases, especially if they can be started early (i.e. within the first 1-2 weeks) However, corticosteroids have proven ineffective for many individuals and are potentially associated with adverse side effects. In some patients, intravenous immunoglobulin (IVIG) seems to be effective in the acute phase. This treatment, however, is very expensive and not well researched yet.After the acute phase, different medications known as co-analgesics may be administered. Such medications include gabapentin, carbamazepine, and amitryptiline and they specifically treat nerve pain. Their effect, however, is usually limited.Physical and rehabilitation therapy are also used to treat individuals with HNA in order to preserve muscle strength and range of motion of affected joints. Specific techniques include scapular coordination training using kinetic control strategies and occupational therapy to increase self-management and energy conservation strategies. In severe cases, active and passive range of motion exercises may to help to prevent muscle atrophy and contractures. In most patients, muscle strengthening exercises cannot be used during the acute phase of the disorder because they worsen pain and because strength training is generally ineffective in muscles below that cannot reach 75% of their maximum contraction strength (i.e. MRC grade 4). In a pilot study, a specific rehabilitation approach that focused on scapular coordination, energy distribution strategies and self-management, was found helpful to improve functioning and performance satisfaction in daily life.Other techniques used to treat individuals with HNA include the application of heat or cold or transcutaneous electrical nerve stimulation (TENS), a procedure during which electrical impulses a sent through the skin to help to control pain by altering or blocking nerve transmissions. The effect is usually limited.Specific symptoms associated with HNA are treated by standard protocols. For example, cleft palate may require surgical repair from an experienced craniofacial team.The prognosis for HNA varies greatly. Occasionally individuals fully recover their strength and functional level in the shoulder and other affected areas. According to the older medical literature, most affected individuals will recover up to 90% of their original strength and functional level. However, more recent medical articles suggest that residual complications are more common than previously believed. This is because the decreased muscle endurance and altered movement patterns do not tend to go away by themselves. Many individuals experience repeated episodes, which increases the risk of long-term complications or disability. Most affected individuals experience residual persistent pain and decreased endurance or exercise intolerance in the affected shoulder. Affected individuals often experience significant disability that can impact quality of life by making basic household tasks or work extremely difficult. For example, some individuals may have difficulty reaching or lifting. Other people may have difficulty with repetitive tasks that involve the shoulder or arm. Genetic counseling is recommended for affected individuals and their families.
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Therapies of Hereditary Neuralgic Amyotrophy. Treatment
The treatment of HNA is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Most patients primarily need a team consisting of a (pediatric) neurologist, physiatrist, physical therapist and occupational therapist. In case of phrenic nerve palsy a specialized pulmonologist and sometimes home nighttime ventilation is needed. Recurrent laryngeal nerve palsy may require the help of a speech therapist. For HNA patients with rare and special features of craniofacial abnormalities, the help of specialized dentists or maxillofacial surgeons may be warranted.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with HNA. An episode may resolve on its own without treatment and only require support measures such as various pain management strategies including pain medications (analgesics). Specific pain medications used to treat HNA include opiates and non-steroidal anti-inflammatory drugs (NSAIDs), which are usually used in combination. Some physicians have recommended using oral corticosteroids such as prednisone, which has led to a decreased duration of pain and accelerated the healing process in some cases, especially if they can be started early (i.e. within the first 1-2 weeks) However, corticosteroids have proven ineffective for many individuals and are potentially associated with adverse side effects. In some patients, intravenous immunoglobulin (IVIG) seems to be effective in the acute phase. This treatment, however, is very expensive and not well researched yet.After the acute phase, different medications known as co-analgesics may be administered. Such medications include gabapentin, carbamazepine, and amitryptiline and they specifically treat nerve pain. Their effect, however, is usually limited.Physical and rehabilitation therapy are also used to treat individuals with HNA in order to preserve muscle strength and range of motion of affected joints. Specific techniques include scapular coordination training using kinetic control strategies and occupational therapy to increase self-management and energy conservation strategies. In severe cases, active and passive range of motion exercises may to help to prevent muscle atrophy and contractures. In most patients, muscle strengthening exercises cannot be used during the acute phase of the disorder because they worsen pain and because strength training is generally ineffective in muscles below that cannot reach 75% of their maximum contraction strength (i.e. MRC grade 4). In a pilot study, a specific rehabilitation approach that focused on scapular coordination, energy distribution strategies and self-management, was found helpful to improve functioning and performance satisfaction in daily life.Other techniques used to treat individuals with HNA include the application of heat or cold or transcutaneous electrical nerve stimulation (TENS), a procedure during which electrical impulses a sent through the skin to help to control pain by altering or blocking nerve transmissions. The effect is usually limited.Specific symptoms associated with HNA are treated by standard protocols. For example, cleft palate may require surgical repair from an experienced craniofacial team.The prognosis for HNA varies greatly. Occasionally individuals fully recover their strength and functional level in the shoulder and other affected areas. According to the older medical literature, most affected individuals will recover up to 90% of their original strength and functional level. However, more recent medical articles suggest that residual complications are more common than previously believed. This is because the decreased muscle endurance and altered movement patterns do not tend to go away by themselves. Many individuals experience repeated episodes, which increases the risk of long-term complications or disability. Most affected individuals experience residual persistent pain and decreased endurance or exercise intolerance in the affected shoulder. Affected individuals often experience significant disability that can impact quality of life by making basic household tasks or work extremely difficult. For example, some individuals may have difficulty reaching or lifting. Other people may have difficulty with repetitive tasks that involve the shoulder or arm. Genetic counseling is recommended for affected individuals and their families.
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Hereditary Neuralgic Amyotrophy
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Overview of Hereditary Nonspherocytic Hemolytic Anemia
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SummaryHereditary nonspherocytic hemolytic anemia refers to a group of conditions for which the main feature is the premature destruction of red blood cells. Red blood cells move oxygen throughout the body. Premature destruction of red blood cells is called hemolytic anemia. “Nonspherocytic” means the red blood cells are not sphere-shaped like normal red blood cells, and “hereditary” means the conditions are inherited. There are over 16 conditions that fall under the category of hereditary nonspherocytic hemolytic anemia, but they all share these common features. For some people, symptoms are present at birth, but for others, symptoms do not appear until adulthood.The most common forms of hereditary nonspherocytic hemolytic anemia are G6PD deficiency (https://rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-deficiency/) and pyruvate kinase deficiency (https://rarediseases.org/rare-diseases/pyruvate-kinase-deficiency/).
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Overview of Hereditary Nonspherocytic Hemolytic Anemia. SummaryHereditary nonspherocytic hemolytic anemia refers to a group of conditions for which the main feature is the premature destruction of red blood cells. Red blood cells move oxygen throughout the body. Premature destruction of red blood cells is called hemolytic anemia. “Nonspherocytic” means the red blood cells are not sphere-shaped like normal red blood cells, and “hereditary” means the conditions are inherited. There are over 16 conditions that fall under the category of hereditary nonspherocytic hemolytic anemia, but they all share these common features. For some people, symptoms are present at birth, but for others, symptoms do not appear until adulthood.The most common forms of hereditary nonspherocytic hemolytic anemia are G6PD deficiency (https://rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-deficiency/) and pyruvate kinase deficiency (https://rarediseases.org/rare-diseases/pyruvate-kinase-deficiency/).
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Hereditary Nonspherocytic Hemolytic Anemia
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Symptoms of Hereditary Nonspherocytic Hemolytic Anemia
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Symptoms
People with hereditary nonspherocytic hemolytic anemia may experience yellowing of the skin (jaundice), tiredness, a large spleen (splenomegaly) and/or liver (hepatomegaly). Lab findings
People with anemia may have the following results in bloodwork: increase in immature red blood cells (reticulocytosis), decrease in mature red blood cells (anemia), increased lactate dehydrogenase and increased bilirubin.
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Symptoms of Hereditary Nonspherocytic Hemolytic Anemia. Symptoms
People with hereditary nonspherocytic hemolytic anemia may experience yellowing of the skin (jaundice), tiredness, a large spleen (splenomegaly) and/or liver (hepatomegaly). Lab findings
People with anemia may have the following results in bloodwork: increase in immature red blood cells (reticulocytosis), decrease in mature red blood cells (anemia), increased lactate dehydrogenase and increased bilirubin.
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Hereditary Nonspherocytic Hemolytic Anemia
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Causes of Hereditary Nonspherocytic Hemolytic Anemia
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Hereditary nonspherocytic hemolytic anemias are inherited disorders, meaning they are caused by a harmful change (mutation) in a specific gene. Many different genes can cause different types of hereditary anemia. The specific gene involved determines the exact type of anemia a person has, and how it is inherited. A mutation can cause a gene to not work properly, meaning the person’s body does not produce enough of related protein. In some anemias, this leads to a fragile membrane, or outer layer, of the red blood cells, causing the cells to die more quickly. In other types of anemia, the gene change causes a problem with the way red blood cells get the energy they need to function properly. Some people with a non-working gene only have symptoms of hereditary nonsphyrocytic hemolytic anemia after a trigger, such as an illness, taking a certain medication or eating specific foods. Some forms of hereditary nonsphyrocytic hemolytic anemia are inherited as recessive disorders. Recessive genetic disorders occur when a person inherits a non-working gene from each parent. If a person 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 chance for two carrier parents to both pass on 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. Other types of anemia are inherited as dominant conditions. Dominant genetic conditions occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a new gene change in that person. 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. There are some types of hereditary nonspherocytic hemolytic anemia that are X-linked disorders. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have only one X chromosome that is inherited from their mother, and a Y chromosome that is inherited from their father. If a male inherits an X chromosome that contains a non-working 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. If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Hereditary Nonspherocytic Hemolytic Anemia. Hereditary nonspherocytic hemolytic anemias are inherited disorders, meaning they are caused by a harmful change (mutation) in a specific gene. Many different genes can cause different types of hereditary anemia. The specific gene involved determines the exact type of anemia a person has, and how it is inherited. A mutation can cause a gene to not work properly, meaning the person’s body does not produce enough of related protein. In some anemias, this leads to a fragile membrane, or outer layer, of the red blood cells, causing the cells to die more quickly. In other types of anemia, the gene change causes a problem with the way red blood cells get the energy they need to function properly. Some people with a non-working gene only have symptoms of hereditary nonsphyrocytic hemolytic anemia after a trigger, such as an illness, taking a certain medication or eating specific foods. Some forms of hereditary nonsphyrocytic hemolytic anemia are inherited as recessive disorders. Recessive genetic disorders occur when a person inherits a non-working gene from each parent. If a person 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 chance for two carrier parents to both pass on 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. Other types of anemia are inherited as dominant conditions. Dominant genetic conditions occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a new gene change in that person. 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. There are some types of hereditary nonspherocytic hemolytic anemia that are X-linked disorders. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have only one X chromosome that is inherited from their mother, and a Y chromosome that is inherited from their father. If a male inherits an X chromosome that contains a non-working 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. If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Hereditary Nonspherocytic Hemolytic Anemia
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Affects of Hereditary Nonspherocytic Hemolytic Anemia
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The most common form of hereditary nonspherocytic hemolytic anemia, G6PD deficiency, is thought to affect 400 million people worldwide. In general, hereditary nonspherocytic hemolytic anemias affect more males than females.
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Affects of Hereditary Nonspherocytic Hemolytic Anemia. The most common form of hereditary nonspherocytic hemolytic anemia, G6PD deficiency, is thought to affect 400 million people worldwide. In general, hereditary nonspherocytic hemolytic anemias affect more males than females.
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Related disorders of Hereditary Nonspherocytic Hemolytic Anemia
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Symptoms of the following disorders can be similar to those of hereditary nonspherocytic hemolytic anemia: Hereditary spherocytosis (HS) is an inherited disease that affects the red blood cells. Symptoms of HS are the destruction of red blood cells in the spleen and their removal from the blood stream (hemolytic anemia), a yellow tone to the skin (jaundice), and an enlarged spleen (splenomegaly). HS affects about 1 in 2,000 people in North America. People with HS have been reported in other areas of the world as well. HS is caused by harmful changes in five different genes: ANK1, SLC4A1, SPTA1, SPTB, and EPB42. Age of onset varies, but often occurs between 3-7 years of age. Symptoms can develop in infancy, but some people with HS have no symptoms or only minor symptoms and are diagnosed later in life. Suspicion for a diagnosis of HS is based on symptoms and a family history of spherocytosis or related symptoms. Diagnosis is confirmed based on blood tests. Surgical removal of the spleen (splenectomy) is used as a cure for HS in the case of severe anemia. Other treatments include extra folate (folate supplementation) and blood transfusions. (For more information on this disorder, choose “hereditary spherocytosis” as your search term in the Rare Disease Database.) Thalassemia is a general term for a group of hereditary disorders that are caused by low levels of hemoglobin, the protein in red blood cells that carries oxygen. Other symptoms are decreased red blood cell production and anemia. There are two main forms: alpha thalassemia and beta thalassemia. Alpha thalassemia is caused by reduced or absent production of alpha-globin subunits of hemoglobin, while beta thalassemia is caused by reduced or absent production of beta-globin subunits. Alpha thalassemia minor and beta thalassemia minor, also known as alpha thalassemia trait or beta thalassemia trait, are common conditions in many demographics. (For more information on these disorders, choose “alpha thalassemia” or “beta thalassemia” as your search term in the Rare Disease Database.) Other types of anemias include: aplastic anemia, megaloblastic anemia, warm antibody hemolytic anemia, cold antibody hemolytic anemia, acquired autoimmune hemolytic anemia, pernicious anemia, folic acid deficiency anemia, Blackfan-Diamond anemia, sickle cell anemia, and Fanconi’s anemia. (For information on other types of anemias, use the name of the specific anemia as your search term in the Rare Disease Database.)
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Related disorders of Hereditary Nonspherocytic Hemolytic Anemia. Symptoms of the following disorders can be similar to those of hereditary nonspherocytic hemolytic anemia: Hereditary spherocytosis (HS) is an inherited disease that affects the red blood cells. Symptoms of HS are the destruction of red blood cells in the spleen and their removal from the blood stream (hemolytic anemia), a yellow tone to the skin (jaundice), and an enlarged spleen (splenomegaly). HS affects about 1 in 2,000 people in North America. People with HS have been reported in other areas of the world as well. HS is caused by harmful changes in five different genes: ANK1, SLC4A1, SPTA1, SPTB, and EPB42. Age of onset varies, but often occurs between 3-7 years of age. Symptoms can develop in infancy, but some people with HS have no symptoms or only minor symptoms and are diagnosed later in life. Suspicion for a diagnosis of HS is based on symptoms and a family history of spherocytosis or related symptoms. Diagnosis is confirmed based on blood tests. Surgical removal of the spleen (splenectomy) is used as a cure for HS in the case of severe anemia. Other treatments include extra folate (folate supplementation) and blood transfusions. (For more information on this disorder, choose “hereditary spherocytosis” as your search term in the Rare Disease Database.) Thalassemia is a general term for a group of hereditary disorders that are caused by low levels of hemoglobin, the protein in red blood cells that carries oxygen. Other symptoms are decreased red blood cell production and anemia. There are two main forms: alpha thalassemia and beta thalassemia. Alpha thalassemia is caused by reduced or absent production of alpha-globin subunits of hemoglobin, while beta thalassemia is caused by reduced or absent production of beta-globin subunits. Alpha thalassemia minor and beta thalassemia minor, also known as alpha thalassemia trait or beta thalassemia trait, are common conditions in many demographics. (For more information on these disorders, choose “alpha thalassemia” or “beta thalassemia” as your search term in the Rare Disease Database.) Other types of anemias include: aplastic anemia, megaloblastic anemia, warm antibody hemolytic anemia, cold antibody hemolytic anemia, acquired autoimmune hemolytic anemia, pernicious anemia, folic acid deficiency anemia, Blackfan-Diamond anemia, sickle cell anemia, and Fanconi’s anemia. (For information on other types of anemias, use the name of the specific anemia as your search term in the Rare Disease Database.)
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Hereditary Nonspherocytic Hemolytic Anemia
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Diagnosis of Hereditary Nonspherocytic Hemolytic Anemia
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A diagnosis of hereditary nonspherocytic hemolytic anemia can be made based on results from a person’s bloodwork. Using a microscope to look at the membrane, or outer layer, of a red blood cell can determine what type of anemia a person has. Genetic testing can also help determine the exact type of anemia. Genetic testing is often done as a multigene panel, which is one test that can look for changes in multiple genes. Genetic counseling can be helpful to better understand genetic testing options, as well as how the condition is inherited, and the impact on family members.
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Diagnosis of Hereditary Nonspherocytic Hemolytic Anemia. A diagnosis of hereditary nonspherocytic hemolytic anemia can be made based on results from a person’s bloodwork. Using a microscope to look at the membrane, or outer layer, of a red blood cell can determine what type of anemia a person has. Genetic testing can also help determine the exact type of anemia. Genetic testing is often done as a multigene panel, which is one test that can look for changes in multiple genes. Genetic counseling can be helpful to better understand genetic testing options, as well as how the condition is inherited, and the impact on family members.
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Hereditary Nonspherocytic Hemolytic Anemia
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Therapies of Hereditary Nonspherocytic Hemolytic Anemia
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Treatment
For some people with hereditary nonspherocytic hemolytic anemia, symptoms are mild, and no specific treatment is needed. Others require regular blood transfusions to replace red blood cells. People should avoid any drugs or foods that trigger their anemia, such as certain antibiotics. For some people with severe anemia, removal of the spleen (splenectomy) is considered. However, splenectomy can have complications, and is not appropriate for all types of hereditary nonspherocytic hemolytic anemia.
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Therapies of Hereditary Nonspherocytic Hemolytic Anemia. Treatment
For some people with hereditary nonspherocytic hemolytic anemia, symptoms are mild, and no specific treatment is needed. Others require regular blood transfusions to replace red blood cells. People should avoid any drugs or foods that trigger their anemia, such as certain antibiotics. For some people with severe anemia, removal of the spleen (splenectomy) is considered. However, splenectomy can have complications, and is not appropriate for all types of hereditary nonspherocytic hemolytic anemia.
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Hereditary Nonspherocytic Hemolytic Anemia
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Overview of Hereditary Orotic Aciduria
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Hereditary orotic aciduria is an extremely rare genetic disorder. When untreated, affected infants can develop a blood (hematologic) disorder called megaloblastic anemia as well as failure to thrive, susceptibility to infection, and orotic acid crystals in the urine (crystalluria) resulting from excretion of orotic acid in the urine. Impaired neurological development has been observed, but invariably, especially since a treatment has become available.Because so few individuals have been identified with this disorder, much about hereditary orotic aciduria is not fully understood. The disorder is caused by variations in the UMPS gene. In 2015, the U.S. Food and Drug Administration (FDA) approved a treatment called uridine triacetate (Xuriden) for this disorder.
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Overview of Hereditary Orotic Aciduria. Hereditary orotic aciduria is an extremely rare genetic disorder. When untreated, affected infants can develop a blood (hematologic) disorder called megaloblastic anemia as well as failure to thrive, susceptibility to infection, and orotic acid crystals in the urine (crystalluria) resulting from excretion of orotic acid in the urine. Impaired neurological development has been observed, but invariably, especially since a treatment has become available.Because so few individuals have been identified with this disorder, much about hereditary orotic aciduria is not fully understood. The disorder is caused by variations in the UMPS gene. In 2015, the U.S. Food and Drug Administration (FDA) approved a treatment called uridine triacetate (Xuriden) for this disorder.
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Hereditary Orotic Aciduria
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Symptoms of Hereditary Orotic Aciduria
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Some affected infants develop megaloblastic anemia, a condition in which the bone marrow produces unusually large, structurally-abnormal, immature red blood cells (megaloblasts). Megaloblastic anemia usually becomes apparent within the first few months of life.Some infants and children may have neurological problems including delays in reaching developmental milestones (developmental delays). There may also be delays or issues with intellectual development including mild intellectual disability. Seizures (epilepsy) have been reported in some individuals. Some infants fail to gain weight and grow as they normally would for their age and gender (failure to thrive), but others are normal. As all children grow older, height and weight appear to fall in the normal range. Sometimes, the urine of people with hereditary orotic aciduria is cloudy because of the presence of orotic acid crystals (crystalluria). These crystals may also play a role in episodes of obstructive uropathy that have can also occur. Obstructive uropathy is a condition in which there is some type of obstruction of the urinary tract, which can cause urine to back up, lead to blood to appear in the urine (hematuria), and other complications.Other symptoms have been reported in one or two individuals, but researchers are not sure if they are features of the disorder, or if they occurred for other reasons or were coincidental findings. These symptoms include diarrhea, congenital malformations, inflammation of the mouth and lips (stomatitis), and misalignment of the eyes (strabismus). Some affected infants had congenital heart disease, including septal defects. Septal defects are abnormalities in the walls (septum) that separate the lower chambers of the heart (ventricles), or the upper chambers of the heart (atria).
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Symptoms of Hereditary Orotic Aciduria. Some affected infants develop megaloblastic anemia, a condition in which the bone marrow produces unusually large, structurally-abnormal, immature red blood cells (megaloblasts). Megaloblastic anemia usually becomes apparent within the first few months of life.Some infants and children may have neurological problems including delays in reaching developmental milestones (developmental delays). There may also be delays or issues with intellectual development including mild intellectual disability. Seizures (epilepsy) have been reported in some individuals. Some infants fail to gain weight and grow as they normally would for their age and gender (failure to thrive), but others are normal. As all children grow older, height and weight appear to fall in the normal range. Sometimes, the urine of people with hereditary orotic aciduria is cloudy because of the presence of orotic acid crystals (crystalluria). These crystals may also play a role in episodes of obstructive uropathy that have can also occur. Obstructive uropathy is a condition in which there is some type of obstruction of the urinary tract, which can cause urine to back up, lead to blood to appear in the urine (hematuria), and other complications.Other symptoms have been reported in one or two individuals, but researchers are not sure if they are features of the disorder, or if they occurred for other reasons or were coincidental findings. These symptoms include diarrhea, congenital malformations, inflammation of the mouth and lips (stomatitis), and misalignment of the eyes (strabismus). Some affected infants had congenital heart disease, including septal defects. Septal defects are abnormalities in the walls (septum) that separate the lower chambers of the heart (ventricles), or the upper chambers of the heart (atria).
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Hereditary Orotic Aciduria
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Causes of Hereditary Orotic Aciduria
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Hereditary orotic aciduria is caused by variations in the uridine monophosphate synthetase (UMPS) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The UMPS gene produces (encodes) a specialized protein (enzyme) called uridine 5’-monophosphate synthase. This enzyme is a bifunctional, which means it has the capacity to cause (catalyze) two consecutive metabolic reactions. In this case, it catalyzes the last two steps of the de novo pyrimidine biosynthesis pathway. A pathway is a series of biochemical processes in which certain substances are broken down or created. This pathway creates a type of pyrimidine called uridine monophosphate. Pyrimidines are compounds found in deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and certain molecules within the body. One of these final two steps is to convert orotic acid into another chemical substance. Because of a variation in the UMPS gene, affected individuals have very low levels of the enzyme needed to break down orotic acid. This causes orotic acid to buildup in the body. Some of this excess orotic acid is passed through the urine. In addition to being broken down in the pyrimidine biosynthesis pathway, orotic acid is also believed to improve the metabolism of folic acid and vitamin B12, and may play a role in gene transcription, which is the process by which genetic information is copied from DNA to RNA in order to create a useful product like a specific protein. There are reports in the medical literature of individuals who have a variation in the UMPS gene, but have only developed very mild symptoms that did not cause any significant consequences. The exact manner by which orotic acid buildup and uridine monophosphate synthase deficiency ultimately lead to the signs and symptoms associated with this disorder is not completely understood yet. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits the same variant 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.
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Causes of Hereditary Orotic Aciduria. Hereditary orotic aciduria is caused by variations in the uridine monophosphate synthetase (UMPS) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The UMPS gene produces (encodes) a specialized protein (enzyme) called uridine 5’-monophosphate synthase. This enzyme is a bifunctional, which means it has the capacity to cause (catalyze) two consecutive metabolic reactions. In this case, it catalyzes the last two steps of the de novo pyrimidine biosynthesis pathway. A pathway is a series of biochemical processes in which certain substances are broken down or created. This pathway creates a type of pyrimidine called uridine monophosphate. Pyrimidines are compounds found in deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and certain molecules within the body. One of these final two steps is to convert orotic acid into another chemical substance. Because of a variation in the UMPS gene, affected individuals have very low levels of the enzyme needed to break down orotic acid. This causes orotic acid to buildup in the body. Some of this excess orotic acid is passed through the urine. In addition to being broken down in the pyrimidine biosynthesis pathway, orotic acid is also believed to improve the metabolism of folic acid and vitamin B12, and may play a role in gene transcription, which is the process by which genetic information is copied from DNA to RNA in order to create a useful product like a specific protein. There are reports in the medical literature of individuals who have a variation in the UMPS gene, but have only developed very mild symptoms that did not cause any significant consequences. The exact manner by which orotic acid buildup and uridine monophosphate synthase deficiency ultimately lead to the signs and symptoms associated with this disorder is not completely understood yet. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits the same variant 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.
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Hereditary Orotic Aciduria
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Affects of Hereditary Orotic Aciduria
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Hereditary orotic aciduria is an extremely rare disorder that affects both men and women. Only about 20 individuals with this disorder have been reported in the medical literature. The birth prevalence, which is the number of babies born with a disorder compared to the total number of live births, is estimated to be less than 1 in 1,000,000 live births. Because rare diseases often go misdiagnosed or undiagnosed, determining their true frequency in the general population is extremely difficult.
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Affects of Hereditary Orotic Aciduria. Hereditary orotic aciduria is an extremely rare disorder that affects both men and women. Only about 20 individuals with this disorder have been reported in the medical literature. The birth prevalence, which is the number of babies born with a disorder compared to the total number of live births, is estimated to be less than 1 in 1,000,000 live births. Because rare diseases often go misdiagnosed or undiagnosed, determining their true frequency in the general population is extremely difficult.
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Hereditary Orotic Aciduria
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nord_579_4
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Related disorders of Hereditary Orotic Aciduria
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Symptoms of the following disorders can be similar to those of hereditary orotic aciduria. Comparisons may be useful for a differential diagnosis.The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood. Urea cycle disorders can also have elevated levels of orotic aid in the urine. (For more information on these disorders, choose the specific urea cycle disorder as your search term in the Rare Disease Database.)Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Elevated levels or orotic acid in the urine has also been seen in lysinuric protein intolerance, Rett syndrome, certain forms of liver disease, certain forms of cancer and secondary to the use of certain medications. Several other conditions can cause megaloblastic anemia include various forms of leukemia, Lesch-Nyhan disease, and deficiencies in cobalamin (vitamin B12) or folate (vitamin B9). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Hereditary Orotic Aciduria. Symptoms of the following disorders can be similar to those of hereditary orotic aciduria. Comparisons may be useful for a differential diagnosis.The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood. Urea cycle disorders can also have elevated levels of orotic aid in the urine. (For more information on these disorders, choose the specific urea cycle disorder as your search term in the Rare Disease Database.)Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Elevated levels or orotic acid in the urine has also been seen in lysinuric protein intolerance, Rett syndrome, certain forms of liver disease, certain forms of cancer and secondary to the use of certain medications. Several other conditions can cause megaloblastic anemia include various forms of leukemia, Lesch-Nyhan disease, and deficiencies in cobalamin (vitamin B12) or folate (vitamin B9). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Hereditary Orotic Aciduria
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Diagnosis of Hereditary Orotic Aciduria
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A diagnosis of hereditary orotic aciduria is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and examination of the urine. Clinical Testing and Workup
Examination of the urine (urinalysis) can reveal elevated levels of orotic acid. Other conditions, namely the urea cycle disorders, can also cause elevated levels of orotic acid. However, these disorders also cause elevated levels of ammonia in the blood, while hereditary orotic aciduria does not. Most affected individuals have had their diagnosis confirmed through molecular genetic testing. Molecular genetic testing can detect variations in the UMPS gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Hereditary Orotic Aciduria. A diagnosis of hereditary orotic aciduria is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and examination of the urine. Clinical Testing and Workup
Examination of the urine (urinalysis) can reveal elevated levels of orotic acid. Other conditions, namely the urea cycle disorders, can also cause elevated levels of orotic acid. However, these disorders also cause elevated levels of ammonia in the blood, while hereditary orotic aciduria does not. Most affected individuals have had their diagnosis confirmed through molecular genetic testing. Molecular genetic testing can detect variations in the UMPS gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
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Hereditary Orotic Aciduria
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Therapies of Hereditary Orotic Aciduria
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Treatment
In 2015, the U.S. Food and Drug Administration (FDA) approved a treatment called uridine triacetate (Xuriden) for hereditary orotic aciduria. This medication restores the chemical compound called uridine monophosphate (sometimes just called uridine). Because of the underlying genetic defect, affected individuals cannot create (synthesize) sufficient amounts of uridine monophosphate on their own. Clinical trials investigating this medication showed improvement in anemia and disappearance of megaloblastosis and a decrease in orotic acid levels in the urine. Affected individuals also showed improvement in or remained stable in weight or height growth. Researchers believe that affected individuals must remain on this treatment throughout their lives to assure orotic acid levels remain decreased. Although only a small number of people have been diagnosed with hereditary orotic aciduria, some affected individuals who were treated have gone to school, gotten married, have had children, and have lived a relatively unaffected lifestyle. Researchers do not know whether hereditary orotic aciduria can cause long-term complications. Any additional treatment would be direct toward the specific symptoms that are present in each individual. Genetic counseling can be of benefit for affected individuals and their families.
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Therapies of Hereditary Orotic Aciduria. Treatment
In 2015, the U.S. Food and Drug Administration (FDA) approved a treatment called uridine triacetate (Xuriden) for hereditary orotic aciduria. This medication restores the chemical compound called uridine monophosphate (sometimes just called uridine). Because of the underlying genetic defect, affected individuals cannot create (synthesize) sufficient amounts of uridine monophosphate on their own. Clinical trials investigating this medication showed improvement in anemia and disappearance of megaloblastosis and a decrease in orotic acid levels in the urine. Affected individuals also showed improvement in or remained stable in weight or height growth. Researchers believe that affected individuals must remain on this treatment throughout their lives to assure orotic acid levels remain decreased. Although only a small number of people have been diagnosed with hereditary orotic aciduria, some affected individuals who were treated have gone to school, gotten married, have had children, and have lived a relatively unaffected lifestyle. Researchers do not know whether hereditary orotic aciduria can cause long-term complications. Any additional treatment would be direct toward the specific symptoms that are present in each individual. Genetic counseling can be of benefit for affected individuals and their families.
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Hereditary Orotic Aciduria
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nord_580_0
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Overview of Hereditary Sensory and Autonomic Neuropathy Type 1E
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Hereditary sensory and autonomic neuropathy type 1E (HSAN1E) is a rare genetic disorder. It is considered an adult-onset disorder with symptoms usually starting to occur in the 20-30’s. Although HSAN1E is considered to be a subtype of HSAN, a group of genetic disorders most-ly affecting the sensory and autonomic neurons of the peripheral nervous system, the central nervous system is also severely affected in HSAN1E patients, especially in the later stage of the disease. HSAN1E patients usually have three main symptoms, hearing loss, sensory neu-ropathy, and cognitive decline (dementia), and many have other various symptoms such as sleep disorders and epilepsy. The symptoms are progressive, worsening with age. At this time, there are no available treatments other than management for each specific symptom, (i.e., hearing aids for the hearing loss) and there is currently no cure for HSAN1E. Based on a re-cent study, the average life span of HSAN1E patients is approximately 50 years. HSAN1E is an autosomal dominant genetic disorder caused by a mutation in the DNMT1 gene.
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Overview of Hereditary Sensory and Autonomic Neuropathy Type 1E. Hereditary sensory and autonomic neuropathy type 1E (HSAN1E) is a rare genetic disorder. It is considered an adult-onset disorder with symptoms usually starting to occur in the 20-30’s. Although HSAN1E is considered to be a subtype of HSAN, a group of genetic disorders most-ly affecting the sensory and autonomic neurons of the peripheral nervous system, the central nervous system is also severely affected in HSAN1E patients, especially in the later stage of the disease. HSAN1E patients usually have three main symptoms, hearing loss, sensory neu-ropathy, and cognitive decline (dementia), and many have other various symptoms such as sleep disorders and epilepsy. The symptoms are progressive, worsening with age. At this time, there are no available treatments other than management for each specific symptom, (i.e., hearing aids for the hearing loss) and there is currently no cure for HSAN1E. Based on a re-cent study, the average life span of HSAN1E patients is approximately 50 years. HSAN1E is an autosomal dominant genetic disorder caused by a mutation in the DNMT1 gene.
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Hereditary Sensory and Autonomic Neuropathy Type 1E
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nord_580_1
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Symptoms of Hereditary Sensory and Autonomic Neuropathy Type 1E
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The signs and symptoms of HSAN1E and the age of onset are variable, even within members of the same family. HSAN1E typically runs a 15 to 30 year progressive course.HSAN1E is an adult-onset disorder with an average onset age of 37 years. All HSAN1E pa-tients have presented with a triad of symptoms: hearing loss, sensory neuropathy, and cogni-tive decline. Bilateral hearing loss is often the first symptom and it continues to get worse over time. Peripheral neuropathy occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain. As it progresses, peripheral neuropathy can lead to sores or infections in the feet that don’t heal, weakness, and balance and walking problems.The cognitive decline (dementia) often starts with personality changes, poor decision making, memory loss, irritability, impulsivity, apathy, and sleepiness. Some other symptoms of HSAN1E are seizures, auditory or visual hallucinations, renal fail-ure, and sleep disorders.
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Symptoms of Hereditary Sensory and Autonomic Neuropathy Type 1E. The signs and symptoms of HSAN1E and the age of onset are variable, even within members of the same family. HSAN1E typically runs a 15 to 30 year progressive course.HSAN1E is an adult-onset disorder with an average onset age of 37 years. All HSAN1E pa-tients have presented with a triad of symptoms: hearing loss, sensory neuropathy, and cogni-tive decline. Bilateral hearing loss is often the first symptom and it continues to get worse over time. Peripheral neuropathy occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain. As it progresses, peripheral neuropathy can lead to sores or infections in the feet that don’t heal, weakness, and balance and walking problems.The cognitive decline (dementia) often starts with personality changes, poor decision making, memory loss, irritability, impulsivity, apathy, and sleepiness. Some other symptoms of HSAN1E are seizures, auditory or visual hallucinations, renal fail-ure, and sleep disorders.
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Hereditary Sensory and Autonomic Neuropathy Type 1E
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nord_580_2
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Causes of Hereditary Sensory and Autonomic Neuropathy Type 1E
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HSAN1E is caused by a mutation in the DNMT1 gene. Genes provide instructions for creating proteins that play critical roles to allow the body to function normally. When a deleterious mu-tation occurs within a gene, the protein produced will not function normally, and this can af-fect a specific organ or multiple organs of the body. The disease mechanism of the HSAN1E mutations is still being investigated. The DNMT1 gene is located on the short (p) arm of chromosome 19p13.2. Chromosomes are located on the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes 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, “chromosomes 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. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a sin-gle copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that oc-curs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Causes of Hereditary Sensory and Autonomic Neuropathy Type 1E. HSAN1E is caused by a mutation in the DNMT1 gene. Genes provide instructions for creating proteins that play critical roles to allow the body to function normally. When a deleterious mu-tation occurs within a gene, the protein produced will not function normally, and this can af-fect a specific organ or multiple organs of the body. The disease mechanism of the HSAN1E mutations is still being investigated. The DNMT1 gene is located on the short (p) arm of chromosome 19p13.2. Chromosomes are located on the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes 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, “chromosomes 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. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a sin-gle copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that oc-curs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Hereditary Sensory and Autonomic Neuropathy Type 1E
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nord_580_3
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Affects of Hereditary Sensory and Autonomic Neuropathy Type 1E
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HSAN1E affects both genders equally. Due to the complexity of disease and relatively lack of awareness of this disease, HSAN1E is often misdiagnosed or undiagnosed, making it difficult to assess its prevalence and incidence in the population.
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Affects of Hereditary Sensory and Autonomic Neuropathy Type 1E. HSAN1E affects both genders equally. Due to the complexity of disease and relatively lack of awareness of this disease, HSAN1E is often misdiagnosed or undiagnosed, making it difficult to assess its prevalence and incidence in the population.
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Hereditary Sensory and Autonomic Neuropathy Type 1E
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nord_580_4
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Related disorders of Hereditary Sensory and Autonomic Neuropathy Type 1E
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DNMT1 gene mutations have also found to cause autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN). ADCA-DN patients share the same triad of core symp-toms, hearing loss, sensory neuropathy and cognitive decline, and also have adult onset. Progressive cerebellar ataxia and narcolepsy are other common features. Hereditary sensory neuropathy type I (HSN1) belongs to a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of the hands and feet. These degenerative disorders of the nervous system (neurodegenerative disorders) are slowly progressive and predominantly affect the sensory nerves, which frequently leads to loss of feeling (sensation) in the hands and feet. This sensory loss is due to abnormal func-tioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body pro-cesses. Specific symptoms can vary widely from one person to another. HSN1 occurs due to mutations in specific genes and is inherited as an autosomal dominant trait. There are several subtypes of HSN1 designated A through E, each one associated with a different gene. (For more information on this disorder, choose “HSN1” as your search term in the Rare Disease Database.)
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Related disorders of Hereditary Sensory and Autonomic Neuropathy Type 1E. DNMT1 gene mutations have also found to cause autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN). ADCA-DN patients share the same triad of core symp-toms, hearing loss, sensory neuropathy and cognitive decline, and also have adult onset. Progressive cerebellar ataxia and narcolepsy are other common features. Hereditary sensory neuropathy type I (HSN1) belongs to a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of the hands and feet. These degenerative disorders of the nervous system (neurodegenerative disorders) are slowly progressive and predominantly affect the sensory nerves, which frequently leads to loss of feeling (sensation) in the hands and feet. This sensory loss is due to abnormal func-tioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body pro-cesses. Specific symptoms can vary widely from one person to another. HSN1 occurs due to mutations in specific genes and is inherited as an autosomal dominant trait. There are several subtypes of HSN1 designated A through E, each one associated with a different gene. (For more information on this disorder, choose “HSN1” as your search term in the Rare Disease Database.)
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Hereditary Sensory and Autonomic Neuropathy Type 1E
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nord_580_5
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Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type 1E
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A diagnosis of HSAN1E may be suspected based on the identification of the three main symptoms, a detailed patient history, and a family history. DNA testing for mutations in the DNMT1 gene is necessary to confirm the diagnosis of HSAN1E. Clinical Testing and Work-upNerve conduction studies (NCS) are a standard test for diagnosing peripheral neuropathy. These studies are tests that measure how well individual nerves can send an electrical signal from the spinal cord to the muscles. NCS can determine nerve damage and destruction.A complete hearing test should be done as well as testing for cognitive function which often shows up in later stage. Individuals who test positive for HSN1E should continue with regular check-ups for hearing tests and clinical testing for dementia.
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Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type 1E. A diagnosis of HSAN1E may be suspected based on the identification of the three main symptoms, a detailed patient history, and a family history. DNA testing for mutations in the DNMT1 gene is necessary to confirm the diagnosis of HSAN1E. Clinical Testing and Work-upNerve conduction studies (NCS) are a standard test for diagnosing peripheral neuropathy. These studies are tests that measure how well individual nerves can send an electrical signal from the spinal cord to the muscles. NCS can determine nerve damage and destruction.A complete hearing test should be done as well as testing for cognitive function which often shows up in later stage. Individuals who test positive for HSN1E should continue with regular check-ups for hearing tests and clinical testing for dementia.
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Hereditary Sensory and Autonomic Neuropathy Type 1E
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nord_580_6
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Therapies of Hereditary Sensory and Autonomic Neuropathy Type 1E
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TreatmentThe treatment of HSAN1E is management of symptoms. Treatment may require a team of specialists including a neurologist, audiologist, and podiatrist. Prompt recognition and treatment of wounds on affected areas (e.g. the feet) is critical. Ulcera-tion of the feet of individuals with HSAN1E is extremely similar to ulcers found on the feet of individuals with diabetic neuropathy. Therefore, treatment of foot ulcerations and infections may follow similar guidelines. Such treatment can include medical removal of diseased skin and tissue (debridement), applying medications and dressing to the wound, and keeping the wound clean and bandaged. Antibiotics may be used to treat infection.Affected individuals should receive instruction on proper care of their feet, including avoiding risk factors for developing foot ulceration such as removing sources of pressure (e.g. shoes with pressure points). It is recommended that affected individuals receive routine foot care from a diabetic clinic or a podiatrist familiar with the treatment of diabetic foot ulcers.Shooting pains may be treated with medications commonly used for peripheral neuropathies including amitryptiline, carbamazepine, and gabapentin. Hearing aides are effective for the hearing loss. As the hearing loss progresses, stronger hearing aids are prescribed. Sedatives or antipsychotic drugs are often prescribed for the symptoms that are associated with dementia (i.e., roaming behavior, extreme restlessness, delusions, and hallucinations).As HSAN1E progresses, partners and caregivers may need help from support groups.Genetic counseling is recommended for individuals with HSAN1 and their family members.
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Therapies of Hereditary Sensory and Autonomic Neuropathy Type 1E. TreatmentThe treatment of HSAN1E is management of symptoms. Treatment may require a team of specialists including a neurologist, audiologist, and podiatrist. Prompt recognition and treatment of wounds on affected areas (e.g. the feet) is critical. Ulcera-tion of the feet of individuals with HSAN1E is extremely similar to ulcers found on the feet of individuals with diabetic neuropathy. Therefore, treatment of foot ulcerations and infections may follow similar guidelines. Such treatment can include medical removal of diseased skin and tissue (debridement), applying medications and dressing to the wound, and keeping the wound clean and bandaged. Antibiotics may be used to treat infection.Affected individuals should receive instruction on proper care of their feet, including avoiding risk factors for developing foot ulceration such as removing sources of pressure (e.g. shoes with pressure points). It is recommended that affected individuals receive routine foot care from a diabetic clinic or a podiatrist familiar with the treatment of diabetic foot ulcers.Shooting pains may be treated with medications commonly used for peripheral neuropathies including amitryptiline, carbamazepine, and gabapentin. Hearing aides are effective for the hearing loss. As the hearing loss progresses, stronger hearing aids are prescribed. Sedatives or antipsychotic drugs are often prescribed for the symptoms that are associated with dementia (i.e., roaming behavior, extreme restlessness, delusions, and hallucinations).As HSAN1E progresses, partners and caregivers may need help from support groups.Genetic counseling is recommended for individuals with HSAN1 and their family members.
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Hereditary Sensory and Autonomic Neuropathy Type 1E
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nord_581_0
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Overview of Hereditary Sensory and Autonomic Neuropathy Type II
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SummaryHereditary sensory and autonomic neuropathy type II (HSAN2) is a rare genetic disorder that usually begins in childhood, affecting the nerves that serve the lower legs and feet and the lower arms and hands. Symptoms start with inflamed fingers or toes, especially around the nails. Numbness and tingling sensations in the hands and feet may also occur. Eventually, affected individuals lose feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Chronic infection of the affected areas is common and worsens as ulcers form on the fingers or the soles of the hands and feet. The loss of sensation in the hands and feet often leads to neglect of the wounds. This can become serious even leading to amputation in extreme cases if left untreated. The disorder affects many of the body’s systems, is characterized by early onset (infancy or childhood) and follows an autosomal recessive pattern of inheritance. HSAN2 occurs due to changes (mutations) in specific genes. There are a few subtypes designated A through D, each one associated with a different gene.IntroductionThe hereditary sensory and autonomic neuropathies (HSAN), also known as the hereditary sensory neuropathies, include at least eight similar but distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. Some of these disorders have several subtypes based upon the specific associated genes. Some types of HSAN are related to or identical with some forms of Charcot-Marie-Tooth disease, congenital insensitivity to pain (CIP), and others are related to or identical to familial dysautonomia (Riley-Day syndrome). The classification of the HSANs is complicated, and the experts to not always agree on it. Furthermore, HSANs are classified as broadly as peripheral neuropathies or disorders or the peripheral nervous system, which encompasses all of the nerves outside of the central nervous system (i.e. brain and spinal cord).
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Overview of Hereditary Sensory and Autonomic Neuropathy Type II. SummaryHereditary sensory and autonomic neuropathy type II (HSAN2) is a rare genetic disorder that usually begins in childhood, affecting the nerves that serve the lower legs and feet and the lower arms and hands. Symptoms start with inflamed fingers or toes, especially around the nails. Numbness and tingling sensations in the hands and feet may also occur. Eventually, affected individuals lose feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Chronic infection of the affected areas is common and worsens as ulcers form on the fingers or the soles of the hands and feet. The loss of sensation in the hands and feet often leads to neglect of the wounds. This can become serious even leading to amputation in extreme cases if left untreated. The disorder affects many of the body’s systems, is characterized by early onset (infancy or childhood) and follows an autosomal recessive pattern of inheritance. HSAN2 occurs due to changes (mutations) in specific genes. There are a few subtypes designated A through D, each one associated with a different gene.IntroductionThe hereditary sensory and autonomic neuropathies (HSAN), also known as the hereditary sensory neuropathies, include at least eight similar but distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. Some of these disorders have several subtypes based upon the specific associated genes. Some types of HSAN are related to or identical with some forms of Charcot-Marie-Tooth disease, congenital insensitivity to pain (CIP), and others are related to or identical to familial dysautonomia (Riley-Day syndrome). The classification of the HSANs is complicated, and the experts to not always agree on it. Furthermore, HSANs are classified as broadly as peripheral neuropathies or disorders or the peripheral nervous system, which encompasses all of the nerves outside of the central nervous system (i.e. brain and spinal cord).
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Symptoms of Hereditary Sensory and Autonomic Neuropathy Type II
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The symptoms of HSNs are highly variable, even among members of the same family. HSNs of various types may attack a single nerve (mononeuropathy) or many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex or blood vessel (vasomotor) function.Although researchers have been able to establish HSANs as a distinct group of disorders with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis of all subtypes. Many of the reported individuals of HSAN2 are inconsistent in terms of symptomology and progression. This is partially caused by case reports that include cases that are not molecularly confirmed to be HSAN2. Consequently, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms, and overall prognosis.HSAN2 is characterized by sensory loss of the distal portions of the legs. Distal refers to those areas that are farther from the center of the body and includes the lower arms and legs and the hands and feet. The legs and feet are more severely affected than the arms and hands. Onset is usually shortly after birth or during childhood.Affected individuals may experience progressive numbness and tingling in the hands and feet. They may also experience reduced sensation to temperature, pain and touch. Eventually, affected individuals will be unable to distinguish between cold or warm stimuli and be unable to feel pain in the affected area. Because of the loss of sensation, affected individuals may develop chronic skin erosions, ulcers (open sores), or blisters that are slow to heal. These normally painful conditions do not hurt because of the loss of sensation. If unrecognized and left untreated, these painless injuries can progress to cause more serious complications such as recurrent infections. Eventually, affected individuals can develop infection of the surrounding bone (osteomyelitis), loss of bone and tissue in the fingers and toes (acroosteolysis), spontaneous, painless fractures, and inflammation and damage to the surrounding joints (neuropathic arthropathy).Most reports describe autonomic problems as less pronounced than sensory abnormalities in individuals with HSAN2. Many affected individuals have sweating abnormalities including episodes of excessive sweating (hyperhidrosis), reduced sweating (hypohidrosis), or an inability to sweat (anhidrosis). Individuals can experience hyperhidrosis along with patchy areas of anhidrosis. Hyperhidrosis can also lead to excessive tear production. Additional autonomic findings include backflow of the stomach contents into the esophagus (gastroesophageal reflux) and low blood pressure upon standing (postural hypotension) causing lightheadedness or dizziness.Some individuals with HSAN2 exhibit self-mutilation, usually around the time of the eruption of primary teeth. Additional symptoms have been reported in some patients including dry scaly patches on the skin of the palms and soles (hyperkeratosis), diminished taste sensation, diminishment of certain reflexes, and abnormal sideways curvature of the spine (scoliosis). Some infants and children may have difficulty swallowing. Sleep apnea, in which breathing slows or stops briefly during sleep, may also occur. Later in the course of the disorder, urinary incontinence or signs of spasticity may develop.
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Symptoms of Hereditary Sensory and Autonomic Neuropathy Type II. The symptoms of HSNs are highly variable, even among members of the same family. HSNs of various types may attack a single nerve (mononeuropathy) or many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex or blood vessel (vasomotor) function.Although researchers have been able to establish HSANs as a distinct group of disorders with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis of all subtypes. Many of the reported individuals of HSAN2 are inconsistent in terms of symptomology and progression. This is partially caused by case reports that include cases that are not molecularly confirmed to be HSAN2. Consequently, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms, and overall prognosis.HSAN2 is characterized by sensory loss of the distal portions of the legs. Distal refers to those areas that are farther from the center of the body and includes the lower arms and legs and the hands and feet. The legs and feet are more severely affected than the arms and hands. Onset is usually shortly after birth or during childhood.Affected individuals may experience progressive numbness and tingling in the hands and feet. They may also experience reduced sensation to temperature, pain and touch. Eventually, affected individuals will be unable to distinguish between cold or warm stimuli and be unable to feel pain in the affected area. Because of the loss of sensation, affected individuals may develop chronic skin erosions, ulcers (open sores), or blisters that are slow to heal. These normally painful conditions do not hurt because of the loss of sensation. If unrecognized and left untreated, these painless injuries can progress to cause more serious complications such as recurrent infections. Eventually, affected individuals can develop infection of the surrounding bone (osteomyelitis), loss of bone and tissue in the fingers and toes (acroosteolysis), spontaneous, painless fractures, and inflammation and damage to the surrounding joints (neuropathic arthropathy).Most reports describe autonomic problems as less pronounced than sensory abnormalities in individuals with HSAN2. Many affected individuals have sweating abnormalities including episodes of excessive sweating (hyperhidrosis), reduced sweating (hypohidrosis), or an inability to sweat (anhidrosis). Individuals can experience hyperhidrosis along with patchy areas of anhidrosis. Hyperhidrosis can also lead to excessive tear production. Additional autonomic findings include backflow of the stomach contents into the esophagus (gastroesophageal reflux) and low blood pressure upon standing (postural hypotension) causing lightheadedness or dizziness.Some individuals with HSAN2 exhibit self-mutilation, usually around the time of the eruption of primary teeth. Additional symptoms have been reported in some patients including dry scaly patches on the skin of the palms and soles (hyperkeratosis), diminished taste sensation, diminishment of certain reflexes, and abnormal sideways curvature of the spine (scoliosis). Some infants and children may have difficulty swallowing. Sleep apnea, in which breathing slows or stops briefly during sleep, may also occur. Later in the course of the disorder, urinary incontinence or signs of spasticity may develop.
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Causes of Hereditary Sensory and Autonomic Neuropathy Type II
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HSAN2 is caused by a mutation in the one of four genes. HSAN2A is caused by mutations in the WNK1 gene, HSAN2B is caused by mutations in the FAM134B gene, lately renamed to RETREG1. HSAN2C is caused by mutations in the KIF1A gene, HSAN2D is caused by mutations in the SCN9A gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.HSAN2 is an autosomal recessive genetic condition. 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.
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Causes of Hereditary Sensory and Autonomic Neuropathy Type II. HSAN2 is caused by a mutation in the one of four genes. HSAN2A is caused by mutations in the WNK1 gene, HSAN2B is caused by mutations in the FAM134B gene, lately renamed to RETREG1. HSAN2C is caused by mutations in the KIF1A gene, HSAN2D is caused by mutations in the SCN9A gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.HSAN2 is an autosomal recessive genetic condition. 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.
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Affects of Hereditary Sensory and Autonomic Neuropathy Type II
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HSAN2 affects males and females in equal numbers. The exact incidence and prevalence is unknown. HSAN2 may go misdiagnosed or undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.
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Affects of Hereditary Sensory and Autonomic Neuropathy Type II. HSAN2 affects males and females in equal numbers. The exact incidence and prevalence is unknown. HSAN2 may go misdiagnosed or undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.
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Related disorders of Hereditary Sensory and Autonomic Neuropathy Type II
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Symptoms of the following disorders can be similar to those of HSAN2. Comparisons may be useful for a differential diagnosis.Hereditary sensory and autonomic neuropathy type I (HSAN1) belongs to a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of those of the hands and feet. These degenerative disorders of the nervous system (neurodegenerative disorders) are slowly progressive and frequently progress to loss of feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Specific symptoms can vary widely from one person to another. HSAN1 occurs due to mutations in specific genes and is inherited in an autosomal dominant pattern. There are several subtypes of HSAN1 designated A through F, each one associated with a different gene. (For more information on this disorder, choose “HSAN1” as your search term in the Rare Disease Database.). Other subtypes, which are usually follow autosomal recessive inheritance, include HSAN3-8.There are additional disorders and condition that must be differentiated from HSAN2 including diabetic foot syndrome, alcoholic neuropathy, hereditary neuropathy with liability to pressure palsies (tomaculous neuropathy), immune-mediated neuropathy, certain spinal cord diseases such as syringomyelia, amyloidosis, Roussy-Levy disease, Dejerine-Sottas syndrome, Charcot-Marie-Tooth disease, Fabry disease, and neuropathies caused by specific drugs or neurotoxins. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Hereditary Sensory and Autonomic Neuropathy Type II. Symptoms of the following disorders can be similar to those of HSAN2. Comparisons may be useful for a differential diagnosis.Hereditary sensory and autonomic neuropathy type I (HSAN1) belongs to a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of those of the hands and feet. These degenerative disorders of the nervous system (neurodegenerative disorders) are slowly progressive and frequently progress to loss of feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Specific symptoms can vary widely from one person to another. HSAN1 occurs due to mutations in specific genes and is inherited in an autosomal dominant pattern. There are several subtypes of HSAN1 designated A through F, each one associated with a different gene. (For more information on this disorder, choose “HSAN1” as your search term in the Rare Disease Database.). Other subtypes, which are usually follow autosomal recessive inheritance, include HSAN3-8.There are additional disorders and condition that must be differentiated from HSAN2 including diabetic foot syndrome, alcoholic neuropathy, hereditary neuropathy with liability to pressure palsies (tomaculous neuropathy), immune-mediated neuropathy, certain spinal cord diseases such as syringomyelia, amyloidosis, Roussy-Levy disease, Dejerine-Sottas syndrome, Charcot-Marie-Tooth disease, Fabry disease, and neuropathies caused by specific drugs or neurotoxins. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type II
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A diagnosis of HSAN2 is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Congenital or early onset of sensory deficits and a family history consistent with autosomal recessive inheritance are indicative of HSAN2.Clinical Testing and Workup
Electromyography (EMG) and nerve conduction studies may be abnormal. During EMG, a thin electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscles at rest and during contraction. This record, called an electromyogram, shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. Nerve conduction studies, which measure the speed of conduction of an electrical impulse through a nerve, may be reduced in individuals with HSAN2.Surgical removal and microscopic examination (biopsy) of affected nerve fibers / skin may be used to aid in the diagnosis of HSAN2 by revealing characteristic changes to nerves.
An axonal flare test is sometimes used to aid in diagnosing HSAN2. During this test, a small amount of diluted histamine is injected underneath the skin. Histamine is a chemical compound produce by the body that helps the immune system and acts as a neurotransmitter (a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another). An injection of histamine causes a distinctive skin eruption around the site of injection. In affected individuals, the skin eruption is different and indicative of HSAN2. In mild cases of HSAN2, however, this test may be normal.Molecular genetic testing can confirm a diagnosis in some cases. Molecular genetic testing can detect mutations in the specific genes known to cause HSAN2, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type II. A diagnosis of HSAN2 is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Congenital or early onset of sensory deficits and a family history consistent with autosomal recessive inheritance are indicative of HSAN2.Clinical Testing and Workup
Electromyography (EMG) and nerve conduction studies may be abnormal. During EMG, a thin electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscles at rest and during contraction. This record, called an electromyogram, shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. Nerve conduction studies, which measure the speed of conduction of an electrical impulse through a nerve, may be reduced in individuals with HSAN2.Surgical removal and microscopic examination (biopsy) of affected nerve fibers / skin may be used to aid in the diagnosis of HSAN2 by revealing characteristic changes to nerves.
An axonal flare test is sometimes used to aid in diagnosing HSAN2. During this test, a small amount of diluted histamine is injected underneath the skin. Histamine is a chemical compound produce by the body that helps the immune system and acts as a neurotransmitter (a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another). An injection of histamine causes a distinctive skin eruption around the site of injection. In affected individuals, the skin eruption is different and indicative of HSAN2. In mild cases of HSAN2, however, this test may be normal.Molecular genetic testing can confirm a diagnosis in some cases. Molecular genetic testing can detect mutations in the specific genes known to cause HSAN2, but is available only as a diagnostic service at specialized laboratories.
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Therapies of Hereditary Sensory and Autonomic Neuropathy Type II
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TreatmentThe treatment of HSAN2 is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, orthopedic surgeons, dermatologists, physiotherapists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families.Prompt recognition and treatment of wounds on affected areas (e.g. the feet) is critically important. Ulceration of the feet of individuals with HSAN2 is extremely similar to ulcers found on the feet of individuals with diabetic neuropathy. Therefore, the treatment of foot ulcerations and infections may follow similar guidelines. Such treatment can include medical removal of diseased skin and tissue (debridement), applying medications and dressing to the wound, and keeping the wound clean and bandaged. Antibiotics may be used to treat infection.
Affected individuals should receive instruction on proper care of their feet including avoiding risk factors for developing foot ulceration such as removing sources of pressure (e.g. shoes with pressure points). It is recommended that affected individuals receive routine foot care from a diabetic clinic or a podiatrist familiar with the treatment of diabetic foot ulcers.Additional treatment is symptomatic and supportive.
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Therapies of Hereditary Sensory and Autonomic Neuropathy Type II. TreatmentThe treatment of HSAN2 is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, orthopedic surgeons, dermatologists, physiotherapists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families.Prompt recognition and treatment of wounds on affected areas (e.g. the feet) is critically important. Ulceration of the feet of individuals with HSAN2 is extremely similar to ulcers found on the feet of individuals with diabetic neuropathy. Therefore, the treatment of foot ulcerations and infections may follow similar guidelines. Such treatment can include medical removal of diseased skin and tissue (debridement), applying medications and dressing to the wound, and keeping the wound clean and bandaged. Antibiotics may be used to treat infection.
Affected individuals should receive instruction on proper care of their feet including avoiding risk factors for developing foot ulceration such as removing sources of pressure (e.g. shoes with pressure points). It is recommended that affected individuals receive routine foot care from a diabetic clinic or a podiatrist familiar with the treatment of diabetic foot ulcers.Additional treatment is symptomatic and supportive.
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Overview of Hereditary Sensory and Autonomic Neuropathy Type IV
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SummaryHereditary sensory and autonomic neuropathy type IV (HSAN4 or HSAN IV) is a rare genetic disorder that usually begins in infancy and is characterized by an inability to feel pain and an inability to sweat (anhidrosis). Affected individuals also cannot feel temperature and cannot distinguish between hot and cold. The sensory loss in individuals with HSAN IV is due to abnormal functioning of the sensory nerves that control responses to pain and temperature. Anhidrosis can cause recurrent episodes of fever and high body temperature. An inability to feel pain can lead to unintentional self-mutation, repeated fractures, and joint damage. Affected individuals and especially children or infants may be unaware of injury delaying treatment. HSAN IV is caused by changes (mutations) in the NTRK1 gene. The disorder is inherited in an autosomal recessive manner.IntroductionThe hereditary sensory and autonomic neuropathies (HSAN), also known as the hereditary sensory neuropathies, include distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. Some of these disorders have several subtypes based upon the specific associated genes and about 20 genes have been identified as disease-causative. Some types of HSAN are related to or identical with some forms of Charcot-Marie-Tooth disease, and others are related to or identical with familial dysautonomia (Riley-Day syndrome). The classification of the HSANs is complicated, and the experts to not always agree on it. Furthermore, HSANs are classified more broadly as peripheral neuropathies or disorders or the peripheral nervous system, which encompasses all of the nerves outside of the central nervous system (i.e. brain and spinal cord). HSAN IV is also known as congenital insensitivity to pain with anhidrosis (CIPA).
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Overview of Hereditary Sensory and Autonomic Neuropathy Type IV. SummaryHereditary sensory and autonomic neuropathy type IV (HSAN4 or HSAN IV) is a rare genetic disorder that usually begins in infancy and is characterized by an inability to feel pain and an inability to sweat (anhidrosis). Affected individuals also cannot feel temperature and cannot distinguish between hot and cold. The sensory loss in individuals with HSAN IV is due to abnormal functioning of the sensory nerves that control responses to pain and temperature. Anhidrosis can cause recurrent episodes of fever and high body temperature. An inability to feel pain can lead to unintentional self-mutation, repeated fractures, and joint damage. Affected individuals and especially children or infants may be unaware of injury delaying treatment. HSAN IV is caused by changes (mutations) in the NTRK1 gene. The disorder is inherited in an autosomal recessive manner.IntroductionThe hereditary sensory and autonomic neuropathies (HSAN), also known as the hereditary sensory neuropathies, include distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. Some of these disorders have several subtypes based upon the specific associated genes and about 20 genes have been identified as disease-causative. Some types of HSAN are related to or identical with some forms of Charcot-Marie-Tooth disease, and others are related to or identical with familial dysautonomia (Riley-Day syndrome). The classification of the HSANs is complicated, and the experts to not always agree on it. Furthermore, HSANs are classified more broadly as peripheral neuropathies or disorders or the peripheral nervous system, which encompasses all of the nerves outside of the central nervous system (i.e. brain and spinal cord). HSAN IV is also known as congenital insensitivity to pain with anhidrosis (CIPA).
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Symptoms of Hereditary Sensory and Autonomic Neuropathy Type IV
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Infants cannot or have a markedly decreased ability to sweat (anhidrosis). Sweating is the body’s way of cooling itself and maintaining proper body temperature. The inability to sweat can cause recurrent episodes of fever including extremely high fevers that result in a significant elevation of body temperature (hyperpyrexia). When someone has a significantly increased body temperature it is known as hyperthermia and this can be the initial sign of the disorder. The inability to sweat can affect the entire body, but the trunk and arms are mostly affected. Seizures are sometimes associated with fever episodes. The skin may become abnormally thickened and callused with an exaggeration of normal skin lines (lichenification). There may be areas of hair loss of the scalp (hypotrichosis) and malformation of the fingernails and toenails.Affected infants fail to feel pain in response to stimuli that normally should produce pain such as failing to respond to routine injections that are part of pediatric immunizations. Pain is essential to protect people from injury and to alert the body of injury. Because of the inability to feel pain, affected infants and children may suffer repeated injuries and may demonstrate behaviors that cause injury to themselves (self-mutilation) including biting one’s tongue, lips and the lining of the inside of the mouth (buccal mucosa). Affected infants often develop ulcers on their tongues from repeatedly biting their tongues. When the primary teeth first erupt, affected children often bite their fingertips or toes; in severe cases, they can chew or bite off the tips of their fingers or toes.Affected individuals will be unable to distinguish between cold or warm stimuli and be unable to feel pain in the affected area. Because of the loss of sensation, affected individuals may be unaware of injury. For example, affected individuals may develop chronic skin erosions, ulcers (open sores), or blisters that are slow to heal. These normally painful conditions do not hurt because of the loss of sensation. If unrecognized and left untreated, these painless injuries can progress to cause more serious complications such as recurrent infections. Eventually, affected individuals can develop infection of the surrounding bone (osteomyelitis), loss of bone and tissue in the fingers and toes (acroosteolysis), and spontaneous, repeated fractures. Repeated trauma to joints results in progressive inflammation, damage, and deformity of the affected joints (Charcot joint or neuropathic arthropathy). The large, weight-bearing joints are especially prone to this complication.Children with HSAN IV may show delays in attaining developmental milestones (developmental delays) and learning disabilities are common. Intellectual disability has been reported in some cases, but the severity of this finding has varied widely and some children are only mildly affected. Behavioral problems including irritability, hyperactivity, an inability to control one’s emotions (emotional lability), and episodes of anger or rage have also been reported.Diminished muscle tone (hypotonia) may be present at birth or during infancy. Hypotonia, also known as a “floppy baby,” may cause affected infants to be abnormally limp. Although hypotonia is common at birth, strength and tone improves with age.Some individuals experience postural hypotension, a condition in which there is a drop in blood pressure upon a change in body position such as upon standing. Sometimes, postural hypotension is accompanied by a faster than normal heart rate (compensatory tachycardia), in which the body attempts to compensate for the decreased blood pressure.Eye abnormalities may develop, specifically neurotrophic keratitis, a condition characterized by damage to the corneas of the eyes. The cornea is the transparent membrane that covers the front of the eyes. Affected individuals can develop lesions (ulcerations) on the cornea; these lesions can cause corneal scarring. Infection can also occur.
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Symptoms of Hereditary Sensory and Autonomic Neuropathy Type IV. Infants cannot or have a markedly decreased ability to sweat (anhidrosis). Sweating is the body’s way of cooling itself and maintaining proper body temperature. The inability to sweat can cause recurrent episodes of fever including extremely high fevers that result in a significant elevation of body temperature (hyperpyrexia). When someone has a significantly increased body temperature it is known as hyperthermia and this can be the initial sign of the disorder. The inability to sweat can affect the entire body, but the trunk and arms are mostly affected. Seizures are sometimes associated with fever episodes. The skin may become abnormally thickened and callused with an exaggeration of normal skin lines (lichenification). There may be areas of hair loss of the scalp (hypotrichosis) and malformation of the fingernails and toenails.Affected infants fail to feel pain in response to stimuli that normally should produce pain such as failing to respond to routine injections that are part of pediatric immunizations. Pain is essential to protect people from injury and to alert the body of injury. Because of the inability to feel pain, affected infants and children may suffer repeated injuries and may demonstrate behaviors that cause injury to themselves (self-mutilation) including biting one’s tongue, lips and the lining of the inside of the mouth (buccal mucosa). Affected infants often develop ulcers on their tongues from repeatedly biting their tongues. When the primary teeth first erupt, affected children often bite their fingertips or toes; in severe cases, they can chew or bite off the tips of their fingers or toes.Affected individuals will be unable to distinguish between cold or warm stimuli and be unable to feel pain in the affected area. Because of the loss of sensation, affected individuals may be unaware of injury. For example, affected individuals may develop chronic skin erosions, ulcers (open sores), or blisters that are slow to heal. These normally painful conditions do not hurt because of the loss of sensation. If unrecognized and left untreated, these painless injuries can progress to cause more serious complications such as recurrent infections. Eventually, affected individuals can develop infection of the surrounding bone (osteomyelitis), loss of bone and tissue in the fingers and toes (acroosteolysis), and spontaneous, repeated fractures. Repeated trauma to joints results in progressive inflammation, damage, and deformity of the affected joints (Charcot joint or neuropathic arthropathy). The large, weight-bearing joints are especially prone to this complication.Children with HSAN IV may show delays in attaining developmental milestones (developmental delays) and learning disabilities are common. Intellectual disability has been reported in some cases, but the severity of this finding has varied widely and some children are only mildly affected. Behavioral problems including irritability, hyperactivity, an inability to control one’s emotions (emotional lability), and episodes of anger or rage have also been reported.Diminished muscle tone (hypotonia) may be present at birth or during infancy. Hypotonia, also known as a “floppy baby,” may cause affected infants to be abnormally limp. Although hypotonia is common at birth, strength and tone improves with age.Some individuals experience postural hypotension, a condition in which there is a drop in blood pressure upon a change in body position such as upon standing. Sometimes, postural hypotension is accompanied by a faster than normal heart rate (compensatory tachycardia), in which the body attempts to compensate for the decreased blood pressure.Eye abnormalities may develop, specifically neurotrophic keratitis, a condition characterized by damage to the corneas of the eyes. The cornea is the transparent membrane that covers the front of the eyes. Affected individuals can develop lesions (ulcerations) on the cornea; these lesions can cause corneal scarring. Infection can also occur.
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Causes of Hereditary Sensory and Autonomic Neuropathy Type IV
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HSAN IV is caused by mutations in the neurotrophic tyrosine kinase receptor type I (NTRK1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The NTRK1 gene creates (encodes) neurotrophic tyrosine receptor type 1, a protein that is found on the surface of certain cells, especially nerve cells (neurons) that transmit pain, temperature, and touch sensations. Another protein known as nerve growth factor (NGF) binds to the NTRK1 receptor, which allows nerve signals that are essential for the growth and survival of the cell to be transmitted into the cell. Mutations in the NTRK1 gene result in faulty or deficient neurotrophic tyrosine receptor type 1, which prevents the binding of NGF and, consequently, the transmission of nerve signals. Ultimately, the affected neurons die prematurely. The symptoms of HSAN IV result from this premature destruction of sensory nerve cells. HSAN IV is inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk 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.
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Causes of Hereditary Sensory and Autonomic Neuropathy Type IV. HSAN IV is caused by mutations in the neurotrophic tyrosine kinase receptor type I (NTRK1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The NTRK1 gene creates (encodes) neurotrophic tyrosine receptor type 1, a protein that is found on the surface of certain cells, especially nerve cells (neurons) that transmit pain, temperature, and touch sensations. Another protein known as nerve growth factor (NGF) binds to the NTRK1 receptor, which allows nerve signals that are essential for the growth and survival of the cell to be transmitted into the cell. Mutations in the NTRK1 gene result in faulty or deficient neurotrophic tyrosine receptor type 1, which prevents the binding of NGF and, consequently, the transmission of nerve signals. Ultimately, the affected neurons die prematurely. The symptoms of HSAN IV result from this premature destruction of sensory nerve cells. HSAN IV is inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk 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.
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Hereditary Sensory and Autonomic Neuropathy Type IV
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nord_582_3
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Affects of Hereditary Sensory and Autonomic Neuropathy Type IV
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HSAN IV affects males and females in equal numbers. Several hundred cases have been reported in the medical literature. The exact incidence and prevalence is unknown. Many patients have been reported in Japan and the frequency of the disorder is higher in the Japanese and Israeli-Bedouin populations due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a particular genetic trait. Regions with a high rate of consanguinity also show a higher prevalence. Onset of the disorder is at birth.
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Affects of Hereditary Sensory and Autonomic Neuropathy Type IV. HSAN IV affects males and females in equal numbers. Several hundred cases have been reported in the medical literature. The exact incidence and prevalence is unknown. Many patients have been reported in Japan and the frequency of the disorder is higher in the Japanese and Israeli-Bedouin populations due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a particular genetic trait. Regions with a high rate of consanguinity also show a higher prevalence. Onset of the disorder is at birth.
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Hereditary Sensory and Autonomic Neuropathy Type IV
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nord_582_4
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Related disorders of Hereditary Sensory and Autonomic Neuropathy Type IV
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Symptoms of the following disorders can be similar to those of HSAN IV. Comparisons may be useful for a differential diagnosis.The hereditary sensory and autonomic neuropathies are a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of those of the hands and feet. These degenerative disorders of the nervous system (neurodegenerative disorders) are slowly progressive and frequently progress to loss of feeling (sensation). This sensory loss is due to abnormal functioning or structure of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Specific symptoms can vary widely from one person to another, even among individuals with the same subtype. HSAN1 occurs due to mutations in specific genes and is inherited in an autosomal dominant pattern. The other forms of HSAN are inherited in a autosomal recessive pattern. (For more information on this disorder, choose “hereditary sensory and autonomic neuropathy” as your search term in the Rare Disease Database.) Congenital insensitivity to pain is another differential diagnosis with a high degree of overlap to HSAN.
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Related disorders of Hereditary Sensory and Autonomic Neuropathy Type IV. Symptoms of the following disorders can be similar to those of HSAN IV. Comparisons may be useful for a differential diagnosis.The hereditary sensory and autonomic neuropathies are a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of those of the hands and feet. These degenerative disorders of the nervous system (neurodegenerative disorders) are slowly progressive and frequently progress to loss of feeling (sensation). This sensory loss is due to abnormal functioning or structure of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Specific symptoms can vary widely from one person to another, even among individuals with the same subtype. HSAN1 occurs due to mutations in specific genes and is inherited in an autosomal dominant pattern. The other forms of HSAN are inherited in a autosomal recessive pattern. (For more information on this disorder, choose “hereditary sensory and autonomic neuropathy” as your search term in the Rare Disease Database.) Congenital insensitivity to pain is another differential diagnosis with a high degree of overlap to HSAN.
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Hereditary Sensory and Autonomic Neuropathy Type IV
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nord_582_5
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Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type IV
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A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests, mainly genetic testing. Characterized symptoms proposed as necessary for a diagnosis are insensitivity to pain, anhidrosis and intellectual disability. However, the severity of these symptoms is highly variable.Clinical Testing and Workup
Surgical removal and microscopic examination of affected skin tissue (skin biopsy) may reveal a lack of functioning nerves supplying the sweat glands (eccrine sweat gland innervation). A biopsy of nerve tissue from the calf of the leg (sural nerve biopsy) may reveal characteristic findings including reduced numbers of myelinated and unmyelinated small-diameter fibers with normal numbers of large-diameter fibers, but is largely replaced by molecular genetic testing.An axonal flare test is sometimes used to aid in diagnosing HSAN IV. During this test, a small amount of diluted histamine is injected underneath the skin. Histamine is a chemical compound produced by the body that helps the immune system and acts as a neurotransmitter (a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell to another). An injection of histamine causes a distinctive skin eruption around the site of injection.Molecular genetic testing for mutations in the NTRK1 gene can confirm the diagnosis and is often done by next-generation sequencing (NGS) from a blood sample.
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Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type IV. A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests, mainly genetic testing. Characterized symptoms proposed as necessary for a diagnosis are insensitivity to pain, anhidrosis and intellectual disability. However, the severity of these symptoms is highly variable.Clinical Testing and Workup
Surgical removal and microscopic examination of affected skin tissue (skin biopsy) may reveal a lack of functioning nerves supplying the sweat glands (eccrine sweat gland innervation). A biopsy of nerve tissue from the calf of the leg (sural nerve biopsy) may reveal characteristic findings including reduced numbers of myelinated and unmyelinated small-diameter fibers with normal numbers of large-diameter fibers, but is largely replaced by molecular genetic testing.An axonal flare test is sometimes used to aid in diagnosing HSAN IV. During this test, a small amount of diluted histamine is injected underneath the skin. Histamine is a chemical compound produced by the body that helps the immune system and acts as a neurotransmitter (a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell to another). An injection of histamine causes a distinctive skin eruption around the site of injection.Molecular genetic testing for mutations in the NTRK1 gene can confirm the diagnosis and is often done by next-generation sequencing (NGS) from a blood sample.
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Hereditary Sensory and Autonomic Neuropathy Type IV
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nord_582_6
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Therapies of Hereditary Sensory and Autonomic Neuropathy Type IV
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TreatmentTreatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, neurologists, dental specialists, orthopedists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan for an affect child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families.Affected individuals may be treated with acetaminophen or ibuprofen when fevers are present. Direct cooling in a bath or with a blanket designed to lower body temperature (cooling blanket) may also be used.Various orthopedic measures may be necessary to treat abnormalities affecting the bones and joints including surgery or the use of braces or orthopedic devices.Various dental procedures may be used to treat individuals. Smoothing over or grinding down the sharp edges of teeth, prophylactic use of crowns, the use of a night-guard and other orthodontic treatments may be considered. Extracting teeth to prevent self-mutilation has also been done.Treatment of neurotrophic keratitis can include a procedure in which the eyelids are sewn together to narrow the opening (tarsorrhaphy), plastic surgery to repair the cornea (keratoplasty), replacement of part or all of an affected cornea with healthy corneal tissue from a donor (scleral corneal graft), and special contact lenses that protect the cornea (scleral bandage lens). These contact lenses create a space between the front of the cornea and the back of the lenses that fills with a sterile saline solution.Behavioral issues tend to improve with age. These issues have been treated with behavior modification techniques along with anti-psychotic medications or attention deficit hyperactivity disorder medications.Regular, daily inspection for unrecognized or unrealized injury is important as well.
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Therapies of Hereditary Sensory and Autonomic Neuropathy Type IV. TreatmentTreatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, neurologists, dental specialists, orthopedists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan for an affect child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families.Affected individuals may be treated with acetaminophen or ibuprofen when fevers are present. Direct cooling in a bath or with a blanket designed to lower body temperature (cooling blanket) may also be used.Various orthopedic measures may be necessary to treat abnormalities affecting the bones and joints including surgery or the use of braces or orthopedic devices.Various dental procedures may be used to treat individuals. Smoothing over or grinding down the sharp edges of teeth, prophylactic use of crowns, the use of a night-guard and other orthodontic treatments may be considered. Extracting teeth to prevent self-mutilation has also been done.Treatment of neurotrophic keratitis can include a procedure in which the eyelids are sewn together to narrow the opening (tarsorrhaphy), plastic surgery to repair the cornea (keratoplasty), replacement of part or all of an affected cornea with healthy corneal tissue from a donor (scleral corneal graft), and special contact lenses that protect the cornea (scleral bandage lens). These contact lenses create a space between the front of the cornea and the back of the lenses that fills with a sterile saline solution.Behavioral issues tend to improve with age. These issues have been treated with behavior modification techniques along with anti-psychotic medications or attention deficit hyperactivity disorder medications.Regular, daily inspection for unrecognized or unrealized injury is important as well.
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Hereditary Sensory and Autonomic Neuropathy Type IV
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nord_583_0
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Overview of Hereditary Sensory Neuropathy Type I
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SummaryHereditary sensory neuropathy type I (HSN1) belongs to a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of those of the hands and feet. These degenerative disorders of the nervous system (neurodegenerative disorders) are slowly progressive and predominantly affect the sensory nerves, which frequently leads to loss of feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to touch, pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Specific symptoms can vary widely from one person to another. HSN1 occurs due to mutations in specific genes and is inherited as an autosomal dominant trait. There are several subtypes of HSN1 designated A through F, each one associated with a different gene.IntroductionThe hereditary sensory neuropathies (HSNs), also known as the hereditary sensory and autonomic neuropathies, include at least six similar, but distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. Some of these disorders have several subtypes based upon the specific associated genes. The classification of the HSNs is complicated, and the experts do not always agree on it. Furthermore, HSNs are classified more broadly as peripheral neuropathies or disorders of the peripheral nervous system, which encompasses all of the nerves outside of the central nervous system. NORD’s Rare Disease Database has separate reports on HSN2, HSN3 (which is related to or identical to familial dysautonomia), HSN4, and HSAN1E. New genes are frequently identified so the classification is constantly being updated.The HSNs are similar to the related disorders Charcot Marie Tooth disease (CMT) and hereditary motor neuropathy (HMN) and this group of disorders is commonly referred to as CMT and related disorders. HSN predominantly affects the sensory nerves whereas CMT affects the sensory and motor nerves and HMN predominantly the motor nerves. There is overlap in the causative genes for these three related disorders.
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Overview of Hereditary Sensory Neuropathy Type I. SummaryHereditary sensory neuropathy type I (HSN1) belongs to a group of similar but distinct genetic disorders characterized by abnormalities affecting the nerves, especially of those of the hands and feet. These degenerative disorders of the nervous system (neurodegenerative disorders) are slowly progressive and predominantly affect the sensory nerves, which frequently leads to loss of feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to touch, pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Specific symptoms can vary widely from one person to another. HSN1 occurs due to mutations in specific genes and is inherited as an autosomal dominant trait. There are several subtypes of HSN1 designated A through F, each one associated with a different gene.IntroductionThe hereditary sensory neuropathies (HSNs), also known as the hereditary sensory and autonomic neuropathies, include at least six similar, but distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. Some of these disorders have several subtypes based upon the specific associated genes. The classification of the HSNs is complicated, and the experts do not always agree on it. Furthermore, HSNs are classified more broadly as peripheral neuropathies or disorders of the peripheral nervous system, which encompasses all of the nerves outside of the central nervous system. NORD’s Rare Disease Database has separate reports on HSN2, HSN3 (which is related to or identical to familial dysautonomia), HSN4, and HSAN1E. New genes are frequently identified so the classification is constantly being updated.The HSNs are similar to the related disorders Charcot Marie Tooth disease (CMT) and hereditary motor neuropathy (HMN) and this group of disorders is commonly referred to as CMT and related disorders. HSN predominantly affects the sensory nerves whereas CMT affects the sensory and motor nerves and HMN predominantly the motor nerves. There is overlap in the causative genes for these three related disorders.
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Hereditary Sensory Neuropathy Type I
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nord_583_1
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Symptoms of Hereditary Sensory Neuropathy Type I
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The symptoms of the HSNs are highly variable, even among members of the same family. HSNs of various types usually involve many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex or blood vessel (vasomotor) function.Although researchers have been able to establish HSNs as a distinct group of disorders with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis for all subtypes although the main features of each subtype are well described. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their own or their children’s physician and medical team about their specific case, associated symptoms and overall prognosis. It is also important to note that more than 50% of the causative genes have yet to be identified for the HSNs so many patients will receive a diagnosis of HSN without a specific genetic cause being identified.The symptoms described below are common in individuals with HSN1A the best known form of HSN. Some symptoms such as progressive distal sensory loss are characteristic of all forms of HSN. Certain symptoms are associated with specific subtypes. HSN1A and HSN1C and a form of Charcot-Marie-Tooth, CMT2B, are all very similar but patients with HSN1A and HSN1C have more neuropathic pain and patients with CMT2B have less pain but more motor involvement at an early stage of the disease. Individuals with HSN1B often do not have foot ulcers, but may experience gastroesophageal reflux and cough in adulthood. HSN1D is caused by a gene, ATL1, which more commonly causes a central nervous system disease called hereditary spastic paraparesis (HSP) and those patients who get HSN1D often have central nervous system signs such as brisk reflexes. HSN1F is a due to a related gene ATL3. HSN1E is a late onset disease with a mean age of onset of 37 years. It presents with a triad of symptoms: hearing loss, sensory neuropathy, and cognitive decline (dementia) but it can also present with only one or two of triad. Sensory loss of the distal portions of the legs is the characteristic finding of the HSNs. Distal refers to those areas that are farther from the center of the body and includes the lower arms and hands and the lower legs and feet. Onset can be anywhere from childhood to the sixth decade although HSN1 does not usually present before the teenage years. The characteristic finding of the HSNs is loss of sensation in the lower portions of the arms and legs, especially the hands and feet. The feet are nearly always involved first as these are further from the center of the body than the hands. Affected individuals will be unable to distinguish between cold or warm stimuli and be unable to feel touch or pain normally in the affected areas. Because of the loss of sensation, affected individuals may develop chronic skin erosions, ulcers (open sores), or blisters that are slow to heal. Patients frequently do not realize they have injured themselves until they see the damage as they often do not feel such damage occurring e.g. putting their feet against a heater. These normally painful conditions do not hurt because of the loss of sensation. If unrecognized and left untreated, these painless injuries can progress to cause more serious complications such as recurrent infections. Eventually, affected individuals can develop infection of the surrounding bone (osteomyelitis), bone loss (osteonecrosis), spontaneous fractures, and inflammation and damage to the surrounding joints (neuropathic arthropathy). Severe cases may eventually require amputation.Although sensory loss and numbness is the characteristic feature of the HSNs, some affected individuals, especially those with HSNIA or HSN1C may develop sensory symptoms such as burning or tingling sensations in the hands or feet. Some individuals may experience spontaneous shooting pains in the feet, legs, hands or shoulders.Some affected individuals may have deformities of the feet such as highly arched feet (pes cavus), flat feet (pes planus), or hammertoes. Recurrent fungal or bacterial infections of the toenails (onchymocosis or paronychia) may also occur.Muscle weakness and muscle wasting can occur in some affected individuals, although these findings are highly variable and usually occur after the sensory symptoms. In rare cases, muscle weakness in the hands and feet can be the initial sign of HSN. Muscle weakness usually begins in the lower legs and then the lower arms. Progress is usually slow, but in severe cases, muscle weakness can progress to affect the proximal portions of the arms and legs. Proximal refers to those areas that are nearer to the center of the body such as the upper portions of the arms and legs. Muscle weakness can cause weak ankles and eventually progress to difficulty walking (gait disturbances). Some older affected individuals (e.g. those in their 60s or 70s) may eventually require a wheelchair.Sensorineural hearing loss, which is caused by an impaired ability of the auditory nerves to transmit sensory input to the brain, has rarely been associated with HSN1A. Onset of hearing loss is usually in middle to late adulthood.Some individuals with HSNs develop sweating abnormalities such as excessive sweating (hyperhidrosis), reduced sweating (hypohidrosis) or lack of sweating (anhidrosis). The hands and feet are most often affected. Less often, additional autonomic findings may occur such as low blood pressure (hypotension). All of these symptoms are extremely rare with HSN1 and are more common with some of the other forms of HSN.
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Symptoms of Hereditary Sensory Neuropathy Type I. The symptoms of the HSNs are highly variable, even among members of the same family. HSNs of various types usually involve many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex or blood vessel (vasomotor) function.Although researchers have been able to establish HSNs as a distinct group of disorders with characteristic or “core” symptoms, much about these disorders is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis for all subtypes although the main features of each subtype are well described. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their own or their children’s physician and medical team about their specific case, associated symptoms and overall prognosis. It is also important to note that more than 50% of the causative genes have yet to be identified for the HSNs so many patients will receive a diagnosis of HSN without a specific genetic cause being identified.The symptoms described below are common in individuals with HSN1A the best known form of HSN. Some symptoms such as progressive distal sensory loss are characteristic of all forms of HSN. Certain symptoms are associated with specific subtypes. HSN1A and HSN1C and a form of Charcot-Marie-Tooth, CMT2B, are all very similar but patients with HSN1A and HSN1C have more neuropathic pain and patients with CMT2B have less pain but more motor involvement at an early stage of the disease. Individuals with HSN1B often do not have foot ulcers, but may experience gastroesophageal reflux and cough in adulthood. HSN1D is caused by a gene, ATL1, which more commonly causes a central nervous system disease called hereditary spastic paraparesis (HSP) and those patients who get HSN1D often have central nervous system signs such as brisk reflexes. HSN1F is a due to a related gene ATL3. HSN1E is a late onset disease with a mean age of onset of 37 years. It presents with a triad of symptoms: hearing loss, sensory neuropathy, and cognitive decline (dementia) but it can also present with only one or two of triad. Sensory loss of the distal portions of the legs is the characteristic finding of the HSNs. Distal refers to those areas that are farther from the center of the body and includes the lower arms and hands and the lower legs and feet. Onset can be anywhere from childhood to the sixth decade although HSN1 does not usually present before the teenage years. The characteristic finding of the HSNs is loss of sensation in the lower portions of the arms and legs, especially the hands and feet. The feet are nearly always involved first as these are further from the center of the body than the hands. Affected individuals will be unable to distinguish between cold or warm stimuli and be unable to feel touch or pain normally in the affected areas. Because of the loss of sensation, affected individuals may develop chronic skin erosions, ulcers (open sores), or blisters that are slow to heal. Patients frequently do not realize they have injured themselves until they see the damage as they often do not feel such damage occurring e.g. putting their feet against a heater. These normally painful conditions do not hurt because of the loss of sensation. If unrecognized and left untreated, these painless injuries can progress to cause more serious complications such as recurrent infections. Eventually, affected individuals can develop infection of the surrounding bone (osteomyelitis), bone loss (osteonecrosis), spontaneous fractures, and inflammation and damage to the surrounding joints (neuropathic arthropathy). Severe cases may eventually require amputation.Although sensory loss and numbness is the characteristic feature of the HSNs, some affected individuals, especially those with HSNIA or HSN1C may develop sensory symptoms such as burning or tingling sensations in the hands or feet. Some individuals may experience spontaneous shooting pains in the feet, legs, hands or shoulders.Some affected individuals may have deformities of the feet such as highly arched feet (pes cavus), flat feet (pes planus), or hammertoes. Recurrent fungal or bacterial infections of the toenails (onchymocosis or paronychia) may also occur.Muscle weakness and muscle wasting can occur in some affected individuals, although these findings are highly variable and usually occur after the sensory symptoms. In rare cases, muscle weakness in the hands and feet can be the initial sign of HSN. Muscle weakness usually begins in the lower legs and then the lower arms. Progress is usually slow, but in severe cases, muscle weakness can progress to affect the proximal portions of the arms and legs. Proximal refers to those areas that are nearer to the center of the body such as the upper portions of the arms and legs. Muscle weakness can cause weak ankles and eventually progress to difficulty walking (gait disturbances). Some older affected individuals (e.g. those in their 60s or 70s) may eventually require a wheelchair.Sensorineural hearing loss, which is caused by an impaired ability of the auditory nerves to transmit sensory input to the brain, has rarely been associated with HSN1A. Onset of hearing loss is usually in middle to late adulthood.Some individuals with HSNs develop sweating abnormalities such as excessive sweating (hyperhidrosis), reduced sweating (hypohidrosis) or lack of sweating (anhidrosis). The hands and feet are most often affected. Less often, additional autonomic findings may occur such as low blood pressure (hypotension). All of these symptoms are extremely rare with HSN1 and are more common with some of the other forms of HSN.
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Hereditary Sensory Neuropathy Type I
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nord_583_2
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Causes of Hereditary Sensory Neuropathy Type I
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HSN1A is caused by a mutation in the SPTLC1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.Investigators have determined that the SPTLC1 gene is located on the long arm (q) of chromosome 9 (9q22.31). 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 9q22.31” refers to band 22.13 on the long arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The gene that causes HSN1B is unknown, but believed to be located on chromosome 3p24-p22. HSN1C is caused by mutations in the SPTLC2 gene, located on chromosome 14q24. SPTLC2 is a very similar gene to SPTLC1 which is why patients with HSN1A and HSN1C are very similar. HSN1D is caused by mutations in the ATL1 gene, located on chromosome 14q and HSN1F is caused by mutations in ATL3, a similar gene on chromosome 11q12.3-q13.1. HSN1E is caused by mutations in the DNMT1 gene, located on chromosome 19p13.Mutations associated with HSN1 are usually inherited as autosomal dominant disorders (where a trait is transmitted from either an affected mother or father to their child). In very rare cases, a mutation occurs sporadically as a new mutation without a previously family history (de novo mutation).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 to cause a particular disease. The abnormal gene is usually inherited from either parent. 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.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell of the affected individual. In such situations, the disorder is not inherited from the parents.
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Causes of Hereditary Sensory Neuropathy Type I. HSN1A is caused by a mutation in the SPTLC1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.Investigators have determined that the SPTLC1 gene is located on the long arm (q) of chromosome 9 (9q22.31). 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 9q22.31” refers to band 22.13 on the long arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The gene that causes HSN1B is unknown, but believed to be located on chromosome 3p24-p22. HSN1C is caused by mutations in the SPTLC2 gene, located on chromosome 14q24. SPTLC2 is a very similar gene to SPTLC1 which is why patients with HSN1A and HSN1C are very similar. HSN1D is caused by mutations in the ATL1 gene, located on chromosome 14q and HSN1F is caused by mutations in ATL3, a similar gene on chromosome 11q12.3-q13.1. HSN1E is caused by mutations in the DNMT1 gene, located on chromosome 19p13.Mutations associated with HSN1 are usually inherited as autosomal dominant disorders (where a trait is transmitted from either an affected mother or father to their child). In very rare cases, a mutation occurs sporadically as a new mutation without a previously family history (de novo mutation).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 to cause a particular disease. The abnormal gene is usually inherited from either parent. 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.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell of the affected individual. In such situations, the disorder is not inherited from the parents.
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Hereditary Sensory Neuropathy Type I
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nord_583_3
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Affects of Hereditary Sensory Neuropathy Type I
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HSN1 affects males and females in equal numbers. The exact incidence and prevalence is unknown. The prevalence is estimated to be approximately 2 in 1,000,000 people in the general population. HSN1 frequently goes undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Affects of Hereditary Sensory Neuropathy Type I. HSN1 affects males and females in equal numbers. The exact incidence and prevalence is unknown. The prevalence is estimated to be approximately 2 in 1,000,000 people in the general population. HSN1 frequently goes undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Hereditary Sensory Neuropathy Type I
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nord_583_4
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Related disorders of Hereditary Sensory Neuropathy Type I
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Symptoms of the following disorders can be similar to those of HSN1. Comparisons may be useful for a differential diagnosis.Hereditary sensory and autonomic neuropathy type II (HSAN2) is a rare genetic disorder that usually begins in childhood by affecting the nerves that serve the lower arms and hands and the lower legs and feet. Symptoms usually start with sensory loss in the toes, especially around the nails. Infection is common and worsens as ulcers form on the fingers or the soles of the feet. The loss of sensation in both hands and feet often leads to neglect of the wounds. This can become serious even leading to amputation in extreme cases if left untreated. The disorder affects many of the body’s systems, is characterized by early onset (infancy or childhood) and is transmitted genetically as an autosomal recessive trait. (For more information on this disorder, choose “hereditary sensory neuropathy type II” as your search term in the Rare Disease Database.)There are additional disorders and conditions that must be differentiated from HSN1 including diabetic foot syndrome, alcoholic neuropathy, immune-mediated neuropathy, certain spinal cord diseases such as syringomyelia, amyloidosis, Roussy-Levy disease, Dejerine-Sottas syndrome, Charcot-Marie-Tooth disease, Fabry disease, and neuropathies caused by specific drugs or neurotoxins. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Hereditary Sensory Neuropathy Type I. Symptoms of the following disorders can be similar to those of HSN1. Comparisons may be useful for a differential diagnosis.Hereditary sensory and autonomic neuropathy type II (HSAN2) is a rare genetic disorder that usually begins in childhood by affecting the nerves that serve the lower arms and hands and the lower legs and feet. Symptoms usually start with sensory loss in the toes, especially around the nails. Infection is common and worsens as ulcers form on the fingers or the soles of the feet. The loss of sensation in both hands and feet often leads to neglect of the wounds. This can become serious even leading to amputation in extreme cases if left untreated. The disorder affects many of the body’s systems, is characterized by early onset (infancy or childhood) and is transmitted genetically as an autosomal recessive trait. (For more information on this disorder, choose “hereditary sensory neuropathy type II” as your search term in the Rare Disease Database.)There are additional disorders and conditions that must be differentiated from HSN1 including diabetic foot syndrome, alcoholic neuropathy, immune-mediated neuropathy, certain spinal cord diseases such as syringomyelia, amyloidosis, Roussy-Levy disease, Dejerine-Sottas syndrome, Charcot-Marie-Tooth disease, Fabry disease, and neuropathies caused by specific drugs or neurotoxins. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Hereditary Sensory Neuropathy Type I
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nord_583_5
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Diagnosis of Hereditary Sensory Neuropathy Type I
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A diagnosis of HSN1 is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Characteristic symptoms along with a family history consistent with autosomal dominant inheritance are suggestive of HSN1.Clinical Testing and WorkupNerve conduction studies (NCS) and electromyography (EMG) are very useful. Nerve conduction studies measure the size and the speed of conduction of an electrical impulse through a nerve and can reveal nerve damage in both sensory and motor nerves. The sensory nerves are usually abnormal and the motor nerves become abnormal once there is weakness. During EMG, a thin electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscles at rest and during contraction. This record, called an electromyogram, shows how well a muscle responds to the motor nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles.Surgical removal and microscopic examination (biopsy) of affected nerve fibers may be used to aid in the diagnosis of HSN1 by revealing characteristic changes to nerve tissue but this is now rarely needed as genetic testing is widely available and is usually only used if other causes (other than HSN1) are suspected.Molecular genetic testing can confirm a diagnosis in some people. Molecular genetic testing can detect mutations in specific genes known to cause HSN1, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Hereditary Sensory Neuropathy Type I. A diagnosis of HSN1 is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Characteristic symptoms along with a family history consistent with autosomal dominant inheritance are suggestive of HSN1.Clinical Testing and WorkupNerve conduction studies (NCS) and electromyography (EMG) are very useful. Nerve conduction studies measure the size and the speed of conduction of an electrical impulse through a nerve and can reveal nerve damage in both sensory and motor nerves. The sensory nerves are usually abnormal and the motor nerves become abnormal once there is weakness. During EMG, a thin electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscles at rest and during contraction. This record, called an electromyogram, shows how well a muscle responds to the motor nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles.Surgical removal and microscopic examination (biopsy) of affected nerve fibers may be used to aid in the diagnosis of HSN1 by revealing characteristic changes to nerve tissue but this is now rarely needed as genetic testing is widely available and is usually only used if other causes (other than HSN1) are suspected.Molecular genetic testing can confirm a diagnosis in some people. Molecular genetic testing can detect mutations in specific genes known to cause HSN1, but is available only as a diagnostic service at specialized laboratories.
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Hereditary Sensory Neuropathy Type I
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nord_583_6
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Therapies of Hereditary Sensory Neuropathy Type I
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TreatmentThe treatment of the HSNs is directed toward managing the specific symptoms that are apparent in each individual. Prompt recognition and treatment of wounds on affected areas (e.g. the feet) is critically important. Ulceration of the feet of individuals with HSN is extremely similar to ulcers found on the feet of individuals with diabetic neuropathy. Therefore the treatment of foot ulcerations and infections may follow similar guidelines. Such treatment can include medical removal of diseased skin and tissue (debridement), applying medications and dressing to the wound, and keeping the wound clean and bandaged. Antibiotics may be used to treat infection.Affected individuals should receive instruction on proper care of their feet including avoiding risk factors for developing foot ulceration such as removing sources of pressure (e.g. shoes with pressure points). It is recommended that affected individuals receive routine foot care from a diabetic clinic or a podiatrist familiar with the treatment of diabetic foot ulcers.Additional treatment is symptomatic and supportive. Shooting pains may be treated with medications commonly used for painful peripheral neuropathies including amitriptyline, gabapentin and pregabalin. Damaged joints may need a specialized orthopedic opinion and occasionally surgery. Weakened ankles can be treated with orthotics, but special care (e.g. sleeves, etc.) may be necessary to prevent skin abrasion.
Genetic counseling may be of benefit for affected individuals and their families.
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Therapies of Hereditary Sensory Neuropathy Type I. TreatmentThe treatment of the HSNs is directed toward managing the specific symptoms that are apparent in each individual. Prompt recognition and treatment of wounds on affected areas (e.g. the feet) is critically important. Ulceration of the feet of individuals with HSN is extremely similar to ulcers found on the feet of individuals with diabetic neuropathy. Therefore the treatment of foot ulcerations and infections may follow similar guidelines. Such treatment can include medical removal of diseased skin and tissue (debridement), applying medications and dressing to the wound, and keeping the wound clean and bandaged. Antibiotics may be used to treat infection.Affected individuals should receive instruction on proper care of their feet including avoiding risk factors for developing foot ulceration such as removing sources of pressure (e.g. shoes with pressure points). It is recommended that affected individuals receive routine foot care from a diabetic clinic or a podiatrist familiar with the treatment of diabetic foot ulcers.Additional treatment is symptomatic and supportive. Shooting pains may be treated with medications commonly used for painful peripheral neuropathies including amitriptyline, gabapentin and pregabalin. Damaged joints may need a specialized orthopedic opinion and occasionally surgery. Weakened ankles can be treated with orthotics, but special care (e.g. sleeves, etc.) may be necessary to prevent skin abrasion.
Genetic counseling may be of benefit for affected individuals and their families.
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Hereditary Sensory Neuropathy Type I
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nord_584_0
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Overview of Hereditary Spastic Paraplegia
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OverviewThe hereditary spastic paraplegias (HSP) are a large group of inherited neurologic disorders that share the primary symptom of difficulty walking due to muscle weakness and muscle tightness (spasticity) in the legs. There are more than 80 different genetic types of HSP.There may be significant variation in the severity of leg weakness (varying from none to marked), the degree of spasticity (varying from minimal to severe), and the occurrence of other neurologic symptoms between different genetic types of HSP; as well differences in the nature and severity of symptoms between individuals who have exactly the same genetic type of HSP.For additional reviews of HSP including molecular pathogenesis, please refer to references 1 through 4 and Online Mendelian Inheritance in Man (www.omim.org).ClassificationVarious types of HSP are classified according to a) the mode of inheritance (dominant, recessive, X-linked, maternal); b) the gene in which the mutation occurs; and c) the clinical syndrome (pattern of symptoms and neurologic findings). HSP syndromes are classified as “uncomplicated” when symptoms are confined to leg weakness and tightness and urinary urgency. HSP syndromes are classified as “complicated” when leg weakness and tightness (spasticity) are accompanied by other neurologic disturbance such as peripheral nerve impairment, muscle atrophy, or intellectual impairment.There are more than 80 genetic types of HSP. The chromosome locations (“loci”) of HSP genes are designated “SPastic parapleGia, loci (“SPG”) and numbered in order of their discovery (for example, SPG1 through SPG80).
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Overview of Hereditary Spastic Paraplegia. OverviewThe hereditary spastic paraplegias (HSP) are a large group of inherited neurologic disorders that share the primary symptom of difficulty walking due to muscle weakness and muscle tightness (spasticity) in the legs. There are more than 80 different genetic types of HSP.There may be significant variation in the severity of leg weakness (varying from none to marked), the degree of spasticity (varying from minimal to severe), and the occurrence of other neurologic symptoms between different genetic types of HSP; as well differences in the nature and severity of symptoms between individuals who have exactly the same genetic type of HSP.For additional reviews of HSP including molecular pathogenesis, please refer to references 1 through 4 and Online Mendelian Inheritance in Man (www.omim.org).ClassificationVarious types of HSP are classified according to a) the mode of inheritance (dominant, recessive, X-linked, maternal); b) the gene in which the mutation occurs; and c) the clinical syndrome (pattern of symptoms and neurologic findings). HSP syndromes are classified as “uncomplicated” when symptoms are confined to leg weakness and tightness and urinary urgency. HSP syndromes are classified as “complicated” when leg weakness and tightness (spasticity) are accompanied by other neurologic disturbance such as peripheral nerve impairment, muscle atrophy, or intellectual impairment.There are more than 80 genetic types of HSP. The chromosome locations (“loci”) of HSP genes are designated “SPastic parapleGia, loci (“SPG”) and numbered in order of their discovery (for example, SPG1 through SPG80).
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Hereditary Spastic Paraplegia
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nord_584_1
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Symptoms of Hereditary Spastic Paraplegia
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Symptoms describe an individual’s experience of a medical disorder. Signs are the objective evidence of the disorder, documented, for example by physician examination, laboratory studies, or magnetic resonance images (MRI). The primary symptom of HSP is difficulty walking due to weakness and tightness (spasticity) in the legs. Both legs are affected, usually to a relatively similar degree. The term “paraplegia” means severe weakness in both legs including paralysis. “Paraparesis” indicates weakness in both legs of lesser severity than paraplegia. Although the disorder is typically referred to as hereditary spastic paraplegia the degree of weakness is variable and ranges from no weakness (full strength) to marked weakness (paraplegia). When present, weakness does not affect all leg muscles, but rather is most obvious in muscles of hip flexion (iliopsoas), hip abduction (gluteus medius), knee flexion (hamstrings), and foot dorsiflexsion (bending the foot back toward the shin via tibialis anterior muscle). In contrast, muscles of leg extension (quadriceps) and foot extension (gastrocnemius-soleus) usually are not affected in uncomplicated HSP.Spasticity primarily affects muscles of leg extension (quadriceps), knee flexion (hamstrings), hip adduction (bringing the knees together, thigh adductor muscles), and muscles that extend the feet (gastrocnemius-soleus [Achilles tendon]).Walking pattern described as “spastic gait” occurs in which the following elements are present, each to variable degree in different individuals: a) heel strike is shifted forward (landing on the mid-foot or even further forward on the balls of the feet); b) there is reduced foot dorsiflexion (not bending the toes up, but instead tending to drag the toes, often catching them on carpet or when stepping over curbs, and causing the toes of the shoes to be worn out); c) stride length may become shorter; d) there may be “circumduction” or “scissoring”, with one leg crossing into the path of the other; e) there is a tendency for the knees to be maintained flexed (not fully extended in mid-stride), f) for thighs to be close together (adductor tightness), and g) hip flexion (knee lifting) to be reduced. Balance difficulty, often worse when walking in the dark or on uneven surfaces is not uncommon in individuals with HSP.Tightness in the legs and leg muscle spasm (often at night) are not uncommon.
The consequences of abnormal walking pattern cause strain on the ankles, knees, hips, and back and often cause pain in these areas.Urinary urgency, the symptom of experiencing a very short interval between the sensation of need to urinate and difficulty remaining continent, is very common in HSP and occasionally may be an early symptom. Bowel urgency is less common but may occur. Medications such as oxybutynin may reduce urinary urgency. If urinary urgency is severe or accompanied by difficulty initiating urination, consultation with a urologist is recommended. Some genetic types of HSP tend to cause only spastic weakness in the legs and urinary urgency. These syndromes are referred to as “uncomplicated HSP”. Other genetic types of HSP tend to be associated with additional symptoms (“complicated HSP”) including difficulty with coordination (“ataxia”), impaired vision, seizures (epilepsy), muscle atrophy, disturbance of the nerves in the arms and legs (neuropathy), and disturbance cognitive ability (intellectual impairment and dementia). Previously, it was considered that HSP caused symptoms only in the legs, and therefore, did not affect the strength or coordination of the arms and hands, or speech or swallowing. As the number of HSP types has grown, it is now recognized that the arms, hands, and speech and swallowing may be affected in some genetic types of complicated HSP When HSP begins in very early childhood (before age two years, for example), symptoms may not worsen even over many years or decades. Individuals with this “non-progressive” (non-worsening) pattern may resemble subjects with spastic cerebral palsy, a life-long disorder that also remains relatively stable. One caveat however: although early childhood-onset forms of HSP may be “non-progressive”, the degree of spasticity may increase slowly if adequate range-of-motion is not maintained through stretching exercises and muscle spasticity reduction.In contrast, when HSP symptoms begin after early childhood (in adolescence or adulthood), symptoms usually worsen very slowly over a number of years. Sudden onset or rapid worsening over weeks or months is not typical of HSP and suggests an alternate disorder or co-existing condition. After a number of years of very gradual worsening, the rate of worsening appears to slow down for many (not all) subjects. These subjects seem to reach a “functional plateau” beyond which the degree of worsening seems to be similar to that expected for age and similar degrees of physical exercise. Nonetheless, not all patients reach an apparent “leveling off” or functional plateau but instead experience continuous worsening of walking ability due to very slowly progressive muscle weakness and tightness . There may be significant variability in the type of symptoms and their severity. For example, symptoms may remain mild in some patients or become quite severe in others patients. This variability may occur between different genetic types of HSP as well as in between individuals with the same genetic type of HSP including family members who share not only the same genetic type of HSP but also precisely the same genetic mutation.There is not a perfect correlation between the genetic type of HSP and the pattern of symptoms. For example, while some genetic types of HSP (e.g. dominantly inherited HSP due to SPG4/spastin mutation) usually are associated with “uncomplicated” HSP syndromes, some patients with these types of HSP develop additional neurologic symptoms. As another example, although SPG7 and SPG11 typically are associated with additional neurologic symptoms (ataxia, neuropathy, cognitive impairment, for example), some subjects with mutations in these genes have uncomplicated HSP (only spastic weakness in the legs). There also may be variation in severity and the nature of symptoms between affected family members. Therefore, it is generally not possible to predict with certainty the severity or exact nature of symptoms associated with given genetic type of HSP. A cautious, “wait and see” approach, combined with pro-active, individualized physical therapy is recommended.Prognosis: predicting symptoms and course of HSP
As noted above, there is significant variation in HSP symptoms and their severity. This limits the certainty of making predictions. In general however, some genetic types of HSP are usually associated with only leg weakness, spasticity, and urinary urgency (“uncomplicated HSP”). Other types of HSP are usually associated with other neurologic disturbances in addition to these symptoms (“complicated HSP”). Although there are exceptions (discussed above), an individual with a genetic type of HSP usually associated with “uncomplicated” syndrome would be expected to have only spastic weakness and urinary urgency. Symptoms of HSP vary from mild to severe. Individuals with severe symptoms may be unable to walk independently. In general, however, HSP does not shorten lifespan.
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Symptoms of Hereditary Spastic Paraplegia. Symptoms describe an individual’s experience of a medical disorder. Signs are the objective evidence of the disorder, documented, for example by physician examination, laboratory studies, or magnetic resonance images (MRI). The primary symptom of HSP is difficulty walking due to weakness and tightness (spasticity) in the legs. Both legs are affected, usually to a relatively similar degree. The term “paraplegia” means severe weakness in both legs including paralysis. “Paraparesis” indicates weakness in both legs of lesser severity than paraplegia. Although the disorder is typically referred to as hereditary spastic paraplegia the degree of weakness is variable and ranges from no weakness (full strength) to marked weakness (paraplegia). When present, weakness does not affect all leg muscles, but rather is most obvious in muscles of hip flexion (iliopsoas), hip abduction (gluteus medius), knee flexion (hamstrings), and foot dorsiflexsion (bending the foot back toward the shin via tibialis anterior muscle). In contrast, muscles of leg extension (quadriceps) and foot extension (gastrocnemius-soleus) usually are not affected in uncomplicated HSP.Spasticity primarily affects muscles of leg extension (quadriceps), knee flexion (hamstrings), hip adduction (bringing the knees together, thigh adductor muscles), and muscles that extend the feet (gastrocnemius-soleus [Achilles tendon]).Walking pattern described as “spastic gait” occurs in which the following elements are present, each to variable degree in different individuals: a) heel strike is shifted forward (landing on the mid-foot or even further forward on the balls of the feet); b) there is reduced foot dorsiflexion (not bending the toes up, but instead tending to drag the toes, often catching them on carpet or when stepping over curbs, and causing the toes of the shoes to be worn out); c) stride length may become shorter; d) there may be “circumduction” or “scissoring”, with one leg crossing into the path of the other; e) there is a tendency for the knees to be maintained flexed (not fully extended in mid-stride), f) for thighs to be close together (adductor tightness), and g) hip flexion (knee lifting) to be reduced. Balance difficulty, often worse when walking in the dark or on uneven surfaces is not uncommon in individuals with HSP.Tightness in the legs and leg muscle spasm (often at night) are not uncommon.
The consequences of abnormal walking pattern cause strain on the ankles, knees, hips, and back and often cause pain in these areas.Urinary urgency, the symptom of experiencing a very short interval between the sensation of need to urinate and difficulty remaining continent, is very common in HSP and occasionally may be an early symptom. Bowel urgency is less common but may occur. Medications such as oxybutynin may reduce urinary urgency. If urinary urgency is severe or accompanied by difficulty initiating urination, consultation with a urologist is recommended. Some genetic types of HSP tend to cause only spastic weakness in the legs and urinary urgency. These syndromes are referred to as “uncomplicated HSP”. Other genetic types of HSP tend to be associated with additional symptoms (“complicated HSP”) including difficulty with coordination (“ataxia”), impaired vision, seizures (epilepsy), muscle atrophy, disturbance of the nerves in the arms and legs (neuropathy), and disturbance cognitive ability (intellectual impairment and dementia). Previously, it was considered that HSP caused symptoms only in the legs, and therefore, did not affect the strength or coordination of the arms and hands, or speech or swallowing. As the number of HSP types has grown, it is now recognized that the arms, hands, and speech and swallowing may be affected in some genetic types of complicated HSP When HSP begins in very early childhood (before age two years, for example), symptoms may not worsen even over many years or decades. Individuals with this “non-progressive” (non-worsening) pattern may resemble subjects with spastic cerebral palsy, a life-long disorder that also remains relatively stable. One caveat however: although early childhood-onset forms of HSP may be “non-progressive”, the degree of spasticity may increase slowly if adequate range-of-motion is not maintained through stretching exercises and muscle spasticity reduction.In contrast, when HSP symptoms begin after early childhood (in adolescence or adulthood), symptoms usually worsen very slowly over a number of years. Sudden onset or rapid worsening over weeks or months is not typical of HSP and suggests an alternate disorder or co-existing condition. After a number of years of very gradual worsening, the rate of worsening appears to slow down for many (not all) subjects. These subjects seem to reach a “functional plateau” beyond which the degree of worsening seems to be similar to that expected for age and similar degrees of physical exercise. Nonetheless, not all patients reach an apparent “leveling off” or functional plateau but instead experience continuous worsening of walking ability due to very slowly progressive muscle weakness and tightness . There may be significant variability in the type of symptoms and their severity. For example, symptoms may remain mild in some patients or become quite severe in others patients. This variability may occur between different genetic types of HSP as well as in between individuals with the same genetic type of HSP including family members who share not only the same genetic type of HSP but also precisely the same genetic mutation.There is not a perfect correlation between the genetic type of HSP and the pattern of symptoms. For example, while some genetic types of HSP (e.g. dominantly inherited HSP due to SPG4/spastin mutation) usually are associated with “uncomplicated” HSP syndromes, some patients with these types of HSP develop additional neurologic symptoms. As another example, although SPG7 and SPG11 typically are associated with additional neurologic symptoms (ataxia, neuropathy, cognitive impairment, for example), some subjects with mutations in these genes have uncomplicated HSP (only spastic weakness in the legs). There also may be variation in severity and the nature of symptoms between affected family members. Therefore, it is generally not possible to predict with certainty the severity or exact nature of symptoms associated with given genetic type of HSP. A cautious, “wait and see” approach, combined with pro-active, individualized physical therapy is recommended.Prognosis: predicting symptoms and course of HSP
As noted above, there is significant variation in HSP symptoms and their severity. This limits the certainty of making predictions. In general however, some genetic types of HSP are usually associated with only leg weakness, spasticity, and urinary urgency (“uncomplicated HSP”). Other types of HSP are usually associated with other neurologic disturbances in addition to these symptoms (“complicated HSP”). Although there are exceptions (discussed above), an individual with a genetic type of HSP usually associated with “uncomplicated” syndrome would be expected to have only spastic weakness and urinary urgency. Symptoms of HSP vary from mild to severe. Individuals with severe symptoms may be unable to walk independently. In general, however, HSP does not shorten lifespan.
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Hereditary Spastic Paraplegia
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nord_584_2
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Causes of Hereditary Spastic Paraplegia
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As with all inherited disorders, the HSPs are due to gene mutations. Each genetic type of HSP is due to a mutation in a specific “HSP gene”. For example, mutations in SPG3A/atlastin, SPG4/spastin, and SPG7/paraplegin genes cause SPG3A, SPG4, and SPG7 HSP, respectively. Depending on the genetic type of HSP, HSP may be transmitted to offspring (and inherited from parents) as dominant, recessive, X-linked, and “maternal” traits. The various genetic types of HSP and their inheritance patterns are summarized in the table below. The following discussion of inheritance patterns is intended as an overview. Individuals seeking genetic counseling for HSP are recommended to consult a genetic counselor or medical geneticist for specific information. In general, dominantly inherited forms of HSP can be transmitted by (or inherited from) an individual who has the disorder. In general, each child of an individual who has a dominantly inherited form of HSP has a 50% chance of inheriting the gene mutation and a similar (approximately 50% chance) of developing the condition. Occasionally, dominantly inherited HSP “skips” a generation. (i.e. genetic penetrance is very high, exceeding 90%, but is occasionally incomplete). Although the chance of inheriting the condition can be estimated, it is difficult to predict with certainty the age at which symptoms would begin or their severity. There may be significant differences in the severity of the disorder between family members.For recessively inherited forms of HSP, both parents are usually carriers of the gene mutation and usually do not have symptoms (there are exceptions to this generalization: occasionally, parents who are carriers of some forms of recessively inherited HSP have had symptoms of HSP). In general, if one individual in a family has a recessively inherited disorder, each of this individual’s full siblings (for example, another child in this family) has approximately a 25% chance of having the same disorder. In general, individuals who have recessively inherited disorders do not transmit the disorder to their children. There have been some reported exceptions to this however.X-linked disorders are transmitted from women to their sons. Daughters may carry X-linked gene mutations, but like their mothers, usually do not have symptoms although they may have mild symptoms and rarely, may have more significant symptoms of the disorder.Maternally transmitted disorders are those in which the gene mutation involves a mitochondrial gene, are transmitted from mothers to sons or daughters (not transmitted from males).Underlying causes of HSP: Each of the more than 80 genetic types of HSP is due to mutations in a different gene. These genes encode proteins that have diverse molecular functions including movement of chemicals from one part of the cell to another (“axon transport”), energy production (“mitochondrial disturbance”), and disorders of specific lipid metabolism, among others. [1,4] Disturbance in some of these functions appears to lead to altered nerve cell (neuron) development. For these types of HSP, the disorder is not a degenerative process, but rather a developmental disturbance in which the formation of selected nerve pathways during intra-uterine development was abnormal. For other genetic types, HSP gene mutations cause the ends of very long nerve processes (axons) to slowly degenerate within the spinal cord. This impairs nerve transmission from the brain through the spinal cord. To be clear, the entire spinal cord is not degenerating. Rather, the abnormalities in HSP appear to selectively affect only specific nerve pathways, particularly the very long nerve processes (axons) that carry signals from the brain motor cortex to the lower part of the thoracic spinal cord. In some types, this disturbance is not limited to the spinal cord but also affects nerves in the legs (and arms, to a lesser extent). This latter process is termed “peripheral neuropathy”.Genetic Types of HSP
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Causes of Hereditary Spastic Paraplegia. As with all inherited disorders, the HSPs are due to gene mutations. Each genetic type of HSP is due to a mutation in a specific “HSP gene”. For example, mutations in SPG3A/atlastin, SPG4/spastin, and SPG7/paraplegin genes cause SPG3A, SPG4, and SPG7 HSP, respectively. Depending on the genetic type of HSP, HSP may be transmitted to offspring (and inherited from parents) as dominant, recessive, X-linked, and “maternal” traits. The various genetic types of HSP and their inheritance patterns are summarized in the table below. The following discussion of inheritance patterns is intended as an overview. Individuals seeking genetic counseling for HSP are recommended to consult a genetic counselor or medical geneticist for specific information. In general, dominantly inherited forms of HSP can be transmitted by (or inherited from) an individual who has the disorder. In general, each child of an individual who has a dominantly inherited form of HSP has a 50% chance of inheriting the gene mutation and a similar (approximately 50% chance) of developing the condition. Occasionally, dominantly inherited HSP “skips” a generation. (i.e. genetic penetrance is very high, exceeding 90%, but is occasionally incomplete). Although the chance of inheriting the condition can be estimated, it is difficult to predict with certainty the age at which symptoms would begin or their severity. There may be significant differences in the severity of the disorder between family members.For recessively inherited forms of HSP, both parents are usually carriers of the gene mutation and usually do not have symptoms (there are exceptions to this generalization: occasionally, parents who are carriers of some forms of recessively inherited HSP have had symptoms of HSP). In general, if one individual in a family has a recessively inherited disorder, each of this individual’s full siblings (for example, another child in this family) has approximately a 25% chance of having the same disorder. In general, individuals who have recessively inherited disorders do not transmit the disorder to their children. There have been some reported exceptions to this however.X-linked disorders are transmitted from women to their sons. Daughters may carry X-linked gene mutations, but like their mothers, usually do not have symptoms although they may have mild symptoms and rarely, may have more significant symptoms of the disorder.Maternally transmitted disorders are those in which the gene mutation involves a mitochondrial gene, are transmitted from mothers to sons or daughters (not transmitted from males).Underlying causes of HSP: Each of the more than 80 genetic types of HSP is due to mutations in a different gene. These genes encode proteins that have diverse molecular functions including movement of chemicals from one part of the cell to another (“axon transport”), energy production (“mitochondrial disturbance”), and disorders of specific lipid metabolism, among others. [1,4] Disturbance in some of these functions appears to lead to altered nerve cell (neuron) development. For these types of HSP, the disorder is not a degenerative process, but rather a developmental disturbance in which the formation of selected nerve pathways during intra-uterine development was abnormal. For other genetic types, HSP gene mutations cause the ends of very long nerve processes (axons) to slowly degenerate within the spinal cord. This impairs nerve transmission from the brain through the spinal cord. To be clear, the entire spinal cord is not degenerating. Rather, the abnormalities in HSP appear to selectively affect only specific nerve pathways, particularly the very long nerve processes (axons) that carry signals from the brain motor cortex to the lower part of the thoracic spinal cord. In some types, this disturbance is not limited to the spinal cord but also affects nerves in the legs (and arms, to a lesser extent). This latter process is termed “peripheral neuropathy”.Genetic Types of HSP
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Hereditary Spastic Paraplegia
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nord_584_3
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Affects of Hereditary Spastic Paraplegia
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HSP affects males and females of all ethnic groups from around the world.
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Affects of Hereditary Spastic Paraplegia. HSP affects males and females of all ethnic groups from around the world.
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Hereditary Spastic Paraplegia
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nord_584_4
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Related disorders of Hereditary Spastic Paraplegia
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The primary symptom of HSP, walking disturbance due to leg weakness and spasticity also occurs in many other conditions, including non-inherited (non-genetic) conditions, and as a feature of other inherited neurologic conditions. Some of these disorders have specific treatments (e.g. B12 deficiency, 5-methyltetrahydrofolate reductase deficiency, DOPA-responsive dystonia, cervical spondylosis, multiple sclerosis, HIV, and copper deficiency); and others, though not treatable, have prognoses that differ significantly from HSP (e.g. amyotrophic lateral sclerosis and primary lateral sclerosis).Detailed discussion of these alternative or co-existing diagnoses is beyond the scope of this review. In general, the differential diagnosis of HSP includes structural abnormalities of the brain or spinal cord (including, but not limited to tethered cord syndrome, tumors affecting the brain or spinal cord, and spinal cord compression); amyotrophic lateral sclerosis, primary lateral sclerosis, leukodystrophy (including steadily progressive multiple sclerosis and B12 deficiency, 5-methyltetrahydrofolate reductase deficiency, Krabbe, and metachromatic leukodystrophy), other neurodegenerative disorders (e.g. adrenomyeloneuropathy, mitochondrial myelopathy, spinocerebellar ataxia [SCA] including SCA3 and Friedreich’s ataxia), cerebrotendinous xanthomatosis, copper deficiency (sometimes related to zinc toxicity), familial Alzheimer’s disease, [e.g. due to presenilin 1 mutation and frontotemporal dementia due to C9orf72 mutation], olivopontocerebellar degeneration,); CNS infection (e.g. tertiary syphilis, HIV, and tropical spastic paraparesis due to HTLV1 infection); dopa-responsive dystonia;, and cerebral palsy (an important consideration for non-progressive, early childhood-onset HSP). Consultation with a neurologist is recommended who can exclude these conditions by the nature of signs and symptoms and through laboratory testing and imaging (e.g. MRI) studies as needed.
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Related disorders of Hereditary Spastic Paraplegia. The primary symptom of HSP, walking disturbance due to leg weakness and spasticity also occurs in many other conditions, including non-inherited (non-genetic) conditions, and as a feature of other inherited neurologic conditions. Some of these disorders have specific treatments (e.g. B12 deficiency, 5-methyltetrahydrofolate reductase deficiency, DOPA-responsive dystonia, cervical spondylosis, multiple sclerosis, HIV, and copper deficiency); and others, though not treatable, have prognoses that differ significantly from HSP (e.g. amyotrophic lateral sclerosis and primary lateral sclerosis).Detailed discussion of these alternative or co-existing diagnoses is beyond the scope of this review. In general, the differential diagnosis of HSP includes structural abnormalities of the brain or spinal cord (including, but not limited to tethered cord syndrome, tumors affecting the brain or spinal cord, and spinal cord compression); amyotrophic lateral sclerosis, primary lateral sclerosis, leukodystrophy (including steadily progressive multiple sclerosis and B12 deficiency, 5-methyltetrahydrofolate reductase deficiency, Krabbe, and metachromatic leukodystrophy), other neurodegenerative disorders (e.g. adrenomyeloneuropathy, mitochondrial myelopathy, spinocerebellar ataxia [SCA] including SCA3 and Friedreich’s ataxia), cerebrotendinous xanthomatosis, copper deficiency (sometimes related to zinc toxicity), familial Alzheimer’s disease, [e.g. due to presenilin 1 mutation and frontotemporal dementia due to C9orf72 mutation], olivopontocerebellar degeneration,); CNS infection (e.g. tertiary syphilis, HIV, and tropical spastic paraparesis due to HTLV1 infection); dopa-responsive dystonia;, and cerebral palsy (an important consideration for non-progressive, early childhood-onset HSP). Consultation with a neurologist is recommended who can exclude these conditions by the nature of signs and symptoms and through laboratory testing and imaging (e.g. MRI) studies as needed.
| 584 |
Hereditary Spastic Paraplegia
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nord_584_5
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Diagnosis of Hereditary Spastic Paraplegia
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HSP is diagnosed by the following: 1) typical symptoms (lower extremity spastic weakness that may be non-worsening (early childhood onset) or slowly progressive over many years; 2) findings on neurologic examination (lower extremity hyperreflexia usually accompanied by some degree of spasticity and sometimes a specific pattern of muscle weakness); and 3) by the exclusion of alternate disorders (by history, examination, neuroimaging, and laboratory studies as needed). The occurrence of similarly affected family members is helpful in recognizing HSP but is not required for the diagnosis of HSP. Many individuals with HSP do not have similarly affected family members. Such individuals could represent the first occurrence of a genetic mutation (“de novo mutation”). Depending on the genetic type of HSP (dominant, recessive, X-linked, or maternal transmission), there may be a possibility that the disorder could be transmitted to the offspring of these individuals. Genetic testing is often helpful in confirming the clinical diagnosis of HSP and in determining the genetic type of HSP. Results of genetic testing can be used, together with clinical information, to provide genetic counseling. Diagnostic evaluation
Neurologic examination is important for patients with symptoms of HSP. First, this establishes the diagnosis and excludes alternative and co-existing disorders, some of which may have specific treatments. Second, neurologic examination helps identify the specific features of an individual’s walking disturbance. Knowing which specific muscles need strengthening, which specific muscles need spasticity-reduction (through medication, Botox injection, and stretching), and the degree of impairment of balance, speed, and precision of movement helps neurologists and physiatrists develop a proactive therapy approach to improve and maintain the ability to walk; and limit the cumulative impact of abnormal walking patterns on ankles, knees, hips, and spine.Laboratory tests, neurophysiologic testing, and neuroimaging: Routine laboratory studies (such as blood counts, serum electrolytes, and tests of kidney, liver, and endocrine functions) including analysis of cerebrospinal fluid (obtained by “spinal tap”) are normal in most types of HSP. The primary role of such testing is to help exclude alternate and co-existing diagnoses. MRI scans of the brain and spinal cord are important in diagnosing HSP because they help exclude other disorders such as multiple sclerosis and structural abnormalities of the brain and spinal cord. Routine magnetic resonance imaging (MRI) of the brain is usually normal in uncomplicated HSP, and, depending on the genetic type and its neurologic features, in many forms of complicated HSP. In contrast to routine brain MRI, which is usually normal in uncomplicated HSP, special MRI techniques such as diffusion tensor imaging, reserved primarily for research purposes often show more widespread nerve pathway abnormalities in uncomplicated and complicated HSP.In contrast to the typically normal brain MRI in subjects with uncomplicated HSP, there are many types of complicated HSP in which brain MRI demonstrates specific abnormalities including reduced size of the corpus callosum (a structure containing nerve fibers that transit from one brain hemisphere to the other).Thin corpus callosum is a frequent (but not constant) feature of SPG11 and SPG15 and has also been present in many other types of HSP (including SPG3A, SPG4, SPG7, SPG15, SPG21, SPG32, SPG47, PG49, SPG54, and SPG56). (2,5) In addition to thin corpus callosum, many genetic types of HSP have abnormal appearing brain white matter (e.g. due SPG5/CYPB7, SPG7/paraplegin, SPG21/maspardin, and SPG35/FA2H gene mutations). [2,5] Spinal cord MRI scan in HSP is usually normal although may show somewhat smaller diameter of the thoracic spinal cord. [6]Genetic testing: Testing for HSP genes is available and performed for individual HSP genes, for panels containing dozens of HSP genes, and by analysis of all genes (whole exome and whole genome analysis). Genetic testing is often helpful to confirm the clinical diagnosis of HSP. Genetic testing is most often able to find causative gene mutations for subjects with HSP who have a family history of a similarly affected first-degree relative.Despite discovery of more than 60 genes in which mutations cause various types of HSP, many individuals with HSP do not have an identified gene mutation. This is because: a) genes for all types of HSP have not been discovered and furthermore, some discovered genes are not yet included in clinical testing panels; b) methods of gene sequencing typically used to analyze large panels of genes do not analyze all regions of genes. Furthermore, while sensitively detecting gene sequence changes, these “next generation sequencing” methods are less sensitive in detecting gene insertions and deletions that do not change the sequence of the remaining portion of the gene.Genetic testing is expensive and not all insurance companies provide reimbursement for this analysis. Identifying a causative gene mutation can bring closure to a diagnostic odyssey, contribute insight into the prognosis and can be applied to genetic counseling and prenatal diagnosis. Nonetheless at present, genetic testing results very rarely influence treatment which is largely directed toward reducing symptoms.Interpreting HSP genetic test results may be straightforward. Genetic testing may identify a gene mutation that is known to be associated with HSP in other subjects, absent in unaffected subjects, and known or predicted to change the protein function. These mutations are termed “likely pathogenic” (likely to be disease causing). On the other hand, genetic testing may also identify gene variations that are considered normal variations (for example, they may be present in subjects who do not have HSP and may be predicted to not change the protein function). Such mutations are considered “benign” variations and are not likely to cause HSP. In addition to “likely pathogenic” and “likely benign” mutations”, it is not uncommon for genetic testing to identify gene variations that are “of uncertain significance”. Such mutations may not have been reported to be associated with the disorder or may not be predicted to disturb the function of the protein. By definition, it is not known if gene variations of uncertain significance cause HSP (i.e. are pathogenic) or are actually normal variations that are of no medical consequence. Individuals seeking more information regarding results of genetic testing are recommended to consult a medical geneticist or genetic counselor.
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Diagnosis of Hereditary Spastic Paraplegia. HSP is diagnosed by the following: 1) typical symptoms (lower extremity spastic weakness that may be non-worsening (early childhood onset) or slowly progressive over many years; 2) findings on neurologic examination (lower extremity hyperreflexia usually accompanied by some degree of spasticity and sometimes a specific pattern of muscle weakness); and 3) by the exclusion of alternate disorders (by history, examination, neuroimaging, and laboratory studies as needed). The occurrence of similarly affected family members is helpful in recognizing HSP but is not required for the diagnosis of HSP. Many individuals with HSP do not have similarly affected family members. Such individuals could represent the first occurrence of a genetic mutation (“de novo mutation”). Depending on the genetic type of HSP (dominant, recessive, X-linked, or maternal transmission), there may be a possibility that the disorder could be transmitted to the offspring of these individuals. Genetic testing is often helpful in confirming the clinical diagnosis of HSP and in determining the genetic type of HSP. Results of genetic testing can be used, together with clinical information, to provide genetic counseling. Diagnostic evaluation
Neurologic examination is important for patients with symptoms of HSP. First, this establishes the diagnosis and excludes alternative and co-existing disorders, some of which may have specific treatments. Second, neurologic examination helps identify the specific features of an individual’s walking disturbance. Knowing which specific muscles need strengthening, which specific muscles need spasticity-reduction (through medication, Botox injection, and stretching), and the degree of impairment of balance, speed, and precision of movement helps neurologists and physiatrists develop a proactive therapy approach to improve and maintain the ability to walk; and limit the cumulative impact of abnormal walking patterns on ankles, knees, hips, and spine.Laboratory tests, neurophysiologic testing, and neuroimaging: Routine laboratory studies (such as blood counts, serum electrolytes, and tests of kidney, liver, and endocrine functions) including analysis of cerebrospinal fluid (obtained by “spinal tap”) are normal in most types of HSP. The primary role of such testing is to help exclude alternate and co-existing diagnoses. MRI scans of the brain and spinal cord are important in diagnosing HSP because they help exclude other disorders such as multiple sclerosis and structural abnormalities of the brain and spinal cord. Routine magnetic resonance imaging (MRI) of the brain is usually normal in uncomplicated HSP, and, depending on the genetic type and its neurologic features, in many forms of complicated HSP. In contrast to routine brain MRI, which is usually normal in uncomplicated HSP, special MRI techniques such as diffusion tensor imaging, reserved primarily for research purposes often show more widespread nerve pathway abnormalities in uncomplicated and complicated HSP.In contrast to the typically normal brain MRI in subjects with uncomplicated HSP, there are many types of complicated HSP in which brain MRI demonstrates specific abnormalities including reduced size of the corpus callosum (a structure containing nerve fibers that transit from one brain hemisphere to the other).Thin corpus callosum is a frequent (but not constant) feature of SPG11 and SPG15 and has also been present in many other types of HSP (including SPG3A, SPG4, SPG7, SPG15, SPG21, SPG32, SPG47, PG49, SPG54, and SPG56). (2,5) In addition to thin corpus callosum, many genetic types of HSP have abnormal appearing brain white matter (e.g. due SPG5/CYPB7, SPG7/paraplegin, SPG21/maspardin, and SPG35/FA2H gene mutations). [2,5] Spinal cord MRI scan in HSP is usually normal although may show somewhat smaller diameter of the thoracic spinal cord. [6]Genetic testing: Testing for HSP genes is available and performed for individual HSP genes, for panels containing dozens of HSP genes, and by analysis of all genes (whole exome and whole genome analysis). Genetic testing is often helpful to confirm the clinical diagnosis of HSP. Genetic testing is most often able to find causative gene mutations for subjects with HSP who have a family history of a similarly affected first-degree relative.Despite discovery of more than 60 genes in which mutations cause various types of HSP, many individuals with HSP do not have an identified gene mutation. This is because: a) genes for all types of HSP have not been discovered and furthermore, some discovered genes are not yet included in clinical testing panels; b) methods of gene sequencing typically used to analyze large panels of genes do not analyze all regions of genes. Furthermore, while sensitively detecting gene sequence changes, these “next generation sequencing” methods are less sensitive in detecting gene insertions and deletions that do not change the sequence of the remaining portion of the gene.Genetic testing is expensive and not all insurance companies provide reimbursement for this analysis. Identifying a causative gene mutation can bring closure to a diagnostic odyssey, contribute insight into the prognosis and can be applied to genetic counseling and prenatal diagnosis. Nonetheless at present, genetic testing results very rarely influence treatment which is largely directed toward reducing symptoms.Interpreting HSP genetic test results may be straightforward. Genetic testing may identify a gene mutation that is known to be associated with HSP in other subjects, absent in unaffected subjects, and known or predicted to change the protein function. These mutations are termed “likely pathogenic” (likely to be disease causing). On the other hand, genetic testing may also identify gene variations that are considered normal variations (for example, they may be present in subjects who do not have HSP and may be predicted to not change the protein function). Such mutations are considered “benign” variations and are not likely to cause HSP. In addition to “likely pathogenic” and “likely benign” mutations”, it is not uncommon for genetic testing to identify gene variations that are “of uncertain significance”. Such mutations may not have been reported to be associated with the disorder or may not be predicted to disturb the function of the protein. By definition, it is not known if gene variations of uncertain significance cause HSP (i.e. are pathogenic) or are actually normal variations that are of no medical consequence. Individuals seeking more information regarding results of genetic testing are recommended to consult a medical geneticist or genetic counselor.
| 584 |
Hereditary Spastic Paraplegia
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nord_584_6
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Therapies of Hereditary Spastic Paraplegia
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Treatment: management of symptoms
Despite encouraging progress in many research laboratories (see reference 7 for example), treatment for HSP is presently limited to reducing symptoms of muscle weakness, spasticity, and urinary urgency. A pro-active regimen of daily physical exercise, guided by physical therapist or personal trainer and developed for each patient’s unique constellation of symptoms is recommended. This recommendation is based not on peer-reviewed scientific publications but rather on the reports of large numbers of HSP subjects who state that exercise helps and that periods of reduced exercise are associated with increased symptoms. HSP symptoms are variable. One type of exercise may not benefit all individuals. Exercise programs should be developed by a neurologist, physiatrist, physical therapist or personal trainer who is experienced with HSP or similar disorders and should focus on the specific factors that make walking difficult for the specific individual. Individuals are advised to consult their primary care physician before beginning exercise programs, to begin with low intensity, increase slowly, set small goals, keep records of their progress, add variety, and be creative.Exercise goals are to 1) improve and maintain cardiovascular fitness; 2) reverse the reduced functional capacity, stiffness, and weakness due to relatively sedentary lifestyle that often accompanies chronic gait disorders and which are superimposed on walking disturbance due to HSP; 3) improve the mechanics of walking, facilitate neurologic circuits underlying walking reflexes, reduce falling, and maintain bone and joint fitness; and 4) maximize an individual’s independence and sense of control.For some patients, weakness in certain muscles is the most significant factor making walking difficult. For these patients, daily exercise programs should focus on resistance exercises designed to maintain and very gradually increase the strength of these weak muscles. For others, spasticity is a more significant factor than weakness in limiting the ability to walk. For these patients, stretching exercises and muscle relaxant medication may be more beneficial than muscle strengthening exercises alone. A variety of exercises is recommended including walking, for example in shallow swimming pool, water aerobics, swimming, bicycling (including pedaling in reverse to exercise the strength and speed of hip flexion), yoga, dance, core exercises, balance exercises, and therapeutic horseback riding. Patients with significant degrees of spasticity may benefit from medications such as Lioresal. In general, reducing spasticity through medication improves walking primarily when spasticity, not weakness is the primary factor limiting the ability to walk. When weakness is the major factor, markedly reducing spasticity (e.g. through intrathecal Lioresal pump) may make the legs very relaxed (even hypotonic or “floppy”) but actually make walking and standing more difficult. Patients considering intrathecal baclofen pumps should undergo at least one trial in which the important criteria is not simply if spasticity reduction occurred, but rather if spasticity reduction resulted in improved walking ability. Botulinum toxin (“Botox”) injection may be helpful when muscle tightness particular affects a limited number of muscles (e.g. adductors or ankles). Oxybutynin and related medications may reduce urinary urgency. Individuals with more advanced bladder or bowel symptoms are recommended to consult urology or gastroenterology specialists, respectively. Ankle-foot orthotics may be useful to reduce the tendency for the feet to be extended (toes down) causing toe dragging and tripping. Ankle-foot orthotics are often used in combination with medications (e.g. Lioresal or Botox) that reduce muscle spasticity. There have been rapid advances in our knowledge of the causes of HSP. Discovery of dozens of genes implicated in HSP is providing insight into molecular pathways involved. Gene discoveries have permitted development of diverse animal models (in mice, rats, fruit flies, zebrafish, C. elegans) in which to explore disease mechanisms and potential treatments. Parallel advances in gene transfer (gene therapy) and gene modification (e.g. utilizing CRISPR/Cas9 methods) approaches offer additional treatment strategies. Nonetheless, the process of drug discovery, development, and testing takes many years. Until (and even after) specific treatments become widely available, individuals with HSP are recommended to pursue active lifestyles including physical rehabilitation in order to maintain and improve functional abilities and cardiovascular fitness.
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Therapies of Hereditary Spastic Paraplegia. Treatment: management of symptoms
Despite encouraging progress in many research laboratories (see reference 7 for example), treatment for HSP is presently limited to reducing symptoms of muscle weakness, spasticity, and urinary urgency. A pro-active regimen of daily physical exercise, guided by physical therapist or personal trainer and developed for each patient’s unique constellation of symptoms is recommended. This recommendation is based not on peer-reviewed scientific publications but rather on the reports of large numbers of HSP subjects who state that exercise helps and that periods of reduced exercise are associated with increased symptoms. HSP symptoms are variable. One type of exercise may not benefit all individuals. Exercise programs should be developed by a neurologist, physiatrist, physical therapist or personal trainer who is experienced with HSP or similar disorders and should focus on the specific factors that make walking difficult for the specific individual. Individuals are advised to consult their primary care physician before beginning exercise programs, to begin with low intensity, increase slowly, set small goals, keep records of their progress, add variety, and be creative.Exercise goals are to 1) improve and maintain cardiovascular fitness; 2) reverse the reduced functional capacity, stiffness, and weakness due to relatively sedentary lifestyle that often accompanies chronic gait disorders and which are superimposed on walking disturbance due to HSP; 3) improve the mechanics of walking, facilitate neurologic circuits underlying walking reflexes, reduce falling, and maintain bone and joint fitness; and 4) maximize an individual’s independence and sense of control.For some patients, weakness in certain muscles is the most significant factor making walking difficult. For these patients, daily exercise programs should focus on resistance exercises designed to maintain and very gradually increase the strength of these weak muscles. For others, spasticity is a more significant factor than weakness in limiting the ability to walk. For these patients, stretching exercises and muscle relaxant medication may be more beneficial than muscle strengthening exercises alone. A variety of exercises is recommended including walking, for example in shallow swimming pool, water aerobics, swimming, bicycling (including pedaling in reverse to exercise the strength and speed of hip flexion), yoga, dance, core exercises, balance exercises, and therapeutic horseback riding. Patients with significant degrees of spasticity may benefit from medications such as Lioresal. In general, reducing spasticity through medication improves walking primarily when spasticity, not weakness is the primary factor limiting the ability to walk. When weakness is the major factor, markedly reducing spasticity (e.g. through intrathecal Lioresal pump) may make the legs very relaxed (even hypotonic or “floppy”) but actually make walking and standing more difficult. Patients considering intrathecal baclofen pumps should undergo at least one trial in which the important criteria is not simply if spasticity reduction occurred, but rather if spasticity reduction resulted in improved walking ability. Botulinum toxin (“Botox”) injection may be helpful when muscle tightness particular affects a limited number of muscles (e.g. adductors or ankles). Oxybutynin and related medications may reduce urinary urgency. Individuals with more advanced bladder or bowel symptoms are recommended to consult urology or gastroenterology specialists, respectively. Ankle-foot orthotics may be useful to reduce the tendency for the feet to be extended (toes down) causing toe dragging and tripping. Ankle-foot orthotics are often used in combination with medications (e.g. Lioresal or Botox) that reduce muscle spasticity. There have been rapid advances in our knowledge of the causes of HSP. Discovery of dozens of genes implicated in HSP is providing insight into molecular pathways involved. Gene discoveries have permitted development of diverse animal models (in mice, rats, fruit flies, zebrafish, C. elegans) in which to explore disease mechanisms and potential treatments. Parallel advances in gene transfer (gene therapy) and gene modification (e.g. utilizing CRISPR/Cas9 methods) approaches offer additional treatment strategies. Nonetheless, the process of drug discovery, development, and testing takes many years. Until (and even after) specific treatments become widely available, individuals with HSP are recommended to pursue active lifestyles including physical rehabilitation in order to maintain and improve functional abilities and cardiovascular fitness.
| 584 |
Hereditary Spastic Paraplegia
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nord_585_0
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Overview of Hereditary Spherocytosis
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SummaryHereditary spherocytosis (HS) is an inherited disease that affects the red blood cells. Characteristic symptoms of HS are the destruction of red blood cells in the spleen and their removal from the blood stream (hemolytic anemia), a yellow tone to the skin (jaundice), and an enlarged spleen (splenomegaly). HS affects about 1 in 2,000 individuals in North America. People with HS have been reported in other areas of the world as well. HS is caused by genetic changes in five different genes; ANK1, SLC4A1, SPTA1, SPTB, and EPB42. Age of onset varies, but often occurs between 3 – 7 years of age. Symptoms can develop in infancy, but some people with HS have no symptoms or minor symptoms and are diagnosed later in life. Suspicion for HS is based on clinical features and a family history of spherocytosis or related symptoms. Diagnosis is confirmed based on blood tests. Surgical removal of the spleen (splenectomy) is used as a cure for HS in the case of severe anemia. Other treatments include extra folate (folate supplementation) and blood transfusions.
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Overview of Hereditary Spherocytosis. SummaryHereditary spherocytosis (HS) is an inherited disease that affects the red blood cells. Characteristic symptoms of HS are the destruction of red blood cells in the spleen and their removal from the blood stream (hemolytic anemia), a yellow tone to the skin (jaundice), and an enlarged spleen (splenomegaly). HS affects about 1 in 2,000 individuals in North America. People with HS have been reported in other areas of the world as well. HS is caused by genetic changes in five different genes; ANK1, SLC4A1, SPTA1, SPTB, and EPB42. Age of onset varies, but often occurs between 3 – 7 years of age. Symptoms can develop in infancy, but some people with HS have no symptoms or minor symptoms and are diagnosed later in life. Suspicion for HS is based on clinical features and a family history of spherocytosis or related symptoms. Diagnosis is confirmed based on blood tests. Surgical removal of the spleen (splenectomy) is used as a cure for HS in the case of severe anemia. Other treatments include extra folate (folate supplementation) and blood transfusions.
| 585 |
Hereditary Spherocytosis
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nord_585_1
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Symptoms of Hereditary Spherocytosis
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HS is divided into mild, moderate, and severe forms of the disease. Classification is based on the amounts of hemoglobin, reticulocytes, and bilirubin and the amount of spectrin in red blood cells. Hemoglobin transports oxygen in the blood. Reticulocytes are immature red blood cells. Bilirubin is formed in the liver when hemoglobin is broken down. Spectrin is a protein that helps keep the shape of a cell. Decreased hemoglobin and spectrin and increased reticulocytes and bilirubin are associated with more severe HS. People with severe HS are usually diagnosed at younger ages than those with moderate or mild disease. Those with mild HS may have compensated hemolysis. This means that red blood cells are created at the same rate as they are destroyed. These individuals may not have noticeable symptoms, and thus be diagnosed later in life.People with HS have red blood cells that are round like a ball (spherocytes) instead of the typical donut shape. These cells are more likely to break down under stress than normal red blood cells (osmotic fragility). The most common findings in people with HS are anemia, an enlarged spleen (splenomegaly), and a yellow tone to the skin or eyes (jaundice and icterus, respectively). Anemia can cause extreme tiredness (fatigue) and a pale tone of the skin (pallor). Splenomegaly can cause stomach pain. People with HS often present to care with recent or ongoing fever or infection. Other findings in people with HS are less common. These include an enlarged liver (hepatomegaly), growth failure, and allergic diseases. Some people with HS who are diagnosed in infancy may require regular blood transfusions (transfusion dependency). However, typically they grow out of transfusion dependency as they get older.The most common problem seen in people with HS is gallstone development (cholelithiasis). Gallstones can be detected by ultrasound, which allows early diagnosis and treatment. People with HS may also have hemolytic, aplastic, and megaloblastic crises. Hemolytic crises are often triggered by viral illness and cause more destruction of red blood cells. Blood transfusions may be needed, but hemolytic crises are typically mild. Aplastic crises are less common and more severe than hemolytic crises, but are also triggered by viral illness, particularly parovirus B19. After an individual has been infected with parovirus B19, they are immune for the rest of their lives. Megaloblastic crises are caused by not having enough folate. Children, pregnant women, and people recovering from aplastic crises need more folate, so they are more susceptible. Folate supplementation can prevent megaloblastic crises.In people with HS, the tissue that creates blood cells may grow outside of the bone marrow, where it is typically found (extramedullary hematopoiesis). There have also been reports of leg ulcers, cancers of the blood, and small cracks in a layer of the retina at the back of the eye (angioid streaks). However, these problems are not believed to be common and have only been reported in a few people with HS.
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Symptoms of Hereditary Spherocytosis. HS is divided into mild, moderate, and severe forms of the disease. Classification is based on the amounts of hemoglobin, reticulocytes, and bilirubin and the amount of spectrin in red blood cells. Hemoglobin transports oxygen in the blood. Reticulocytes are immature red blood cells. Bilirubin is formed in the liver when hemoglobin is broken down. Spectrin is a protein that helps keep the shape of a cell. Decreased hemoglobin and spectrin and increased reticulocytes and bilirubin are associated with more severe HS. People with severe HS are usually diagnosed at younger ages than those with moderate or mild disease. Those with mild HS may have compensated hemolysis. This means that red blood cells are created at the same rate as they are destroyed. These individuals may not have noticeable symptoms, and thus be diagnosed later in life.People with HS have red blood cells that are round like a ball (spherocytes) instead of the typical donut shape. These cells are more likely to break down under stress than normal red blood cells (osmotic fragility). The most common findings in people with HS are anemia, an enlarged spleen (splenomegaly), and a yellow tone to the skin or eyes (jaundice and icterus, respectively). Anemia can cause extreme tiredness (fatigue) and a pale tone of the skin (pallor). Splenomegaly can cause stomach pain. People with HS often present to care with recent or ongoing fever or infection. Other findings in people with HS are less common. These include an enlarged liver (hepatomegaly), growth failure, and allergic diseases. Some people with HS who are diagnosed in infancy may require regular blood transfusions (transfusion dependency). However, typically they grow out of transfusion dependency as they get older.The most common problem seen in people with HS is gallstone development (cholelithiasis). Gallstones can be detected by ultrasound, which allows early diagnosis and treatment. People with HS may also have hemolytic, aplastic, and megaloblastic crises. Hemolytic crises are often triggered by viral illness and cause more destruction of red blood cells. Blood transfusions may be needed, but hemolytic crises are typically mild. Aplastic crises are less common and more severe than hemolytic crises, but are also triggered by viral illness, particularly parovirus B19. After an individual has been infected with parovirus B19, they are immune for the rest of their lives. Megaloblastic crises are caused by not having enough folate. Children, pregnant women, and people recovering from aplastic crises need more folate, so they are more susceptible. Folate supplementation can prevent megaloblastic crises.In people with HS, the tissue that creates blood cells may grow outside of the bone marrow, where it is typically found (extramedullary hematopoiesis). There have also been reports of leg ulcers, cancers of the blood, and small cracks in a layer of the retina at the back of the eye (angioid streaks). However, these problems are not believed to be common and have only been reported in a few people with HS.
| 585 |
Hereditary Spherocytosis
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nord_585_2
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Causes of Hereditary Spherocytosis
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HS is caused by changes (mutations) in five different genes that code for proteins that are part of the membrane of red blood cells. These genes are ANK1, SLC4A1, SPTA1, SPTB, and EPB42. HS is inherited in an autosomal dominant manner 75% of the time and an autosomal recessive manner 25% of the time.We all have two copies of all our genes. One copy is passed down from mom and one is passed down from dad.Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Disease-causing changes in the genes associated with HS cause defects in membrane proteins of red blood cells. This reduces the surface area of the cells and leaves the cells unable to change shape under pressure. These are the rounded spherocytes. Spherocytes are trapped in the spleen. In the spleen, spherocytes are further damaged and many are destroyed. Those that escape the spleen re-enter circulation.
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Causes of Hereditary Spherocytosis. HS is caused by changes (mutations) in five different genes that code for proteins that are part of the membrane of red blood cells. These genes are ANK1, SLC4A1, SPTA1, SPTB, and EPB42. HS is inherited in an autosomal dominant manner 75% of the time and an autosomal recessive manner 25% of the time.We all have two copies of all our genes. One copy is passed down from mom and one is passed down from dad.Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Disease-causing changes in the genes associated with HS cause defects in membrane proteins of red blood cells. This reduces the surface area of the cells and leaves the cells unable to change shape under pressure. These are the rounded spherocytes. Spherocytes are trapped in the spleen. In the spleen, spherocytes are further damaged and many are destroyed. Those that escape the spleen re-enter circulation.
| 585 |
Hereditary Spherocytosis
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nord_585_3
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Affects of Hereditary Spherocytosis
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HS affects 1 in 2,000 people in North America. It also occurs in other regions of the world, although not as well studied. No genetic changes that are more common in certain groups of people (founder mutations) have been reported. HS affects males and females equally. Age at diagnosis of HS is often between 3 – 7 years but can occur in infancy with severe disease or into adulthood with mild disease.
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Affects of Hereditary Spherocytosis. HS affects 1 in 2,000 people in North America. It also occurs in other regions of the world, although not as well studied. No genetic changes that are more common in certain groups of people (founder mutations) have been reported. HS affects males and females equally. Age at diagnosis of HS is often between 3 – 7 years but can occur in infancy with severe disease or into adulthood with mild disease.
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Hereditary Spherocytosis
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Related disorders of Hereditary Spherocytosis
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Hereditary nonspherocytic hemolytic anemia (HNSHA) is a term used to describe a group of rare, genetically transmitted blood disorders involving destruction of red blood cells. Anemia happens when the red blood cells are destroyed faster than they are replaced. In these disorders, the outside membrane of the cell is weakened, causing it to have an irregular, non-spherical shape and to burst (hemolyze) easily. These disorders are mainly caused by defects in the chemical processes involved in the breakdown of sugar molecules (glycolysis). Red blood cells depend on this process for energy. If this process is not working, the red blood cell cannot function properly and breaks down. The more common forms of HNSHA involve glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency and hexokinase deficiency. There may be as many as 16 red blood cell enzyme abnormalities that may cause hereditary nonspherocytic hemolytic anemia. In addition, HNSHA may arise as the result of immune disorders, toxic chemicals and drugs, antiviral agents (eg, ribavirin), physical damage, and infections. (For more information on this disorder, choose “hereditary hemolytic nonspherocytic anemia” as your search term in the Rare Disease Database.)The autoimmune hemolytic anemias are rare disorders involving the destruction (hemolysis) of red blood cells faster than they can be replaced. Acquired hemolytic anemias are not genetic. Acquired autoimmune diseases occur when the body's immune system attacks its own red blood cells for no known reason. Normally, the red blood cells (erythrocytes) have a life span of approximately 120 days before being removed by the spleen. The severity of this type of anemia is determined by the life span of the red blood cell and by the rate at which these cells are replaced by the bone marrow. (For more information on this disorder, choose “acquired autoimmune hemolytic anemia” as your search term in the Rare Disease Database.)Beta thalassemia is an inherited blood disorder characterized by low levels of working hemoglobin. Hemoglobin is found in red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood. A main function of red blood cells is to deliver oxygen throughout the body. Beta thalassemia has three main forms – minor, intermedia and major, which indicate the severity of the disease. Individuals with beta thalassemia minor usually do not have any symptoms (asymptomatic) and individuals often are unaware that they have the condition. Some individuals do experience a very mild anemia. Individuals with beta thalassemia major have a severe expression of the disorder; they often require regular blood transfusions and lifelong, ongoing medical care. The symptoms of beta thalassemia intermedia are variable and severity falls in the broad range between the two extremes of the major and minor forms. The characteristic finding of beta thalassemia is anemia, which is caused because red blood cells are abnormally small (microcytic), are not produced at the normal amounts, and do not contain enough functional hemoglobin. Consequently, affected individuals do not receive enough oxygen-rich blood (microcytic anemia) throughout the body. Affected individuals may experience classic signs of anemia including fatigue, weakness, shortness of breath, dizziness or headaches. Severe anemia can cause serious, even life-threatening complications if left untreated. Affected individuals are treated by regular blood transfusions. Because of repeated blood transfusions individuals with beta thalassemia major and intermedia may develop excess levels of iron in the body (iron overload). Iron overload can cause a variety of symptoms affecting multiple systems of the body, but can be treated with medications. Beta thalassemia is caused by mutations in the hemoglobin beta (HBB) gene. Individuals with beta thalassemia minor have a mutation in one HBB gene, while individuals with the intermediate and major forms have mutations in both HBB genes. (For more information on this disorder, choose “beta thalassemia” as your search term in the Rare Disease Database.)Alpha thalassemia is a general term for a group of inherited blood disorders involving low levels of hemoglobin, which happens when the body is not producing enough alpha-globin, a building block of hemoglobin. Hemoglobin is found in red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood. A main function of red blood cells is to deliver oxygen throughout the body. There are two main forms of alpha thalassemia that are associated with significant health problems – hemoglobin (Hb) Bart’s hydrops fetalis and hemoglobin H (HbH) disease. Hb Bart’s hydrops fetalis is a severe syndrome that is usually fatal to the developing embryo during gestation or shortly after birth; however, recent advances have led to improved treatments for this condition. HbH disease is highly variable, and the specific symptoms and severity can vary greatly from one person to another. Some individuals will have only minor symptoms, while others will develop potentially serious complications. The characteristic finding of all forms of alpha thalassemia is anemia, with red blood cells that are small (microcytic), contain low levels of functional hemoglobin (hypochromic), and may break down in prematurely in both the bone marrow (ineffective erythropoiesis) and in the peripheral circulation (hemolysis). Consequently, severely affected individuals may not circulate sufficient oxygen-rich blood throughout the body. These individuals may experience fatigue, weakness, shortness of breath, dizziness or headaches. Severe anemia can cause serious, even life-threatening, complications if left untreated. Individuals with severe forms of HbH disease are usually treated with regular blood transfusions, which can result in the accumulation of excess iron in the body (iron overload). Although iron overload can damage numerous organs in the body, it can be effectively treated using several highly effective medications. (For more information on this disorder, choose “alpha thalassemia” as your search term in the Rare Disease Database.)
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Related disorders of Hereditary Spherocytosis. Hereditary nonspherocytic hemolytic anemia (HNSHA) is a term used to describe a group of rare, genetically transmitted blood disorders involving destruction of red blood cells. Anemia happens when the red blood cells are destroyed faster than they are replaced. In these disorders, the outside membrane of the cell is weakened, causing it to have an irregular, non-spherical shape and to burst (hemolyze) easily. These disorders are mainly caused by defects in the chemical processes involved in the breakdown of sugar molecules (glycolysis). Red blood cells depend on this process for energy. If this process is not working, the red blood cell cannot function properly and breaks down. The more common forms of HNSHA involve glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency and hexokinase deficiency. There may be as many as 16 red blood cell enzyme abnormalities that may cause hereditary nonspherocytic hemolytic anemia. In addition, HNSHA may arise as the result of immune disorders, toxic chemicals and drugs, antiviral agents (eg, ribavirin), physical damage, and infections. (For more information on this disorder, choose “hereditary hemolytic nonspherocytic anemia” as your search term in the Rare Disease Database.)The autoimmune hemolytic anemias are rare disorders involving the destruction (hemolysis) of red blood cells faster than they can be replaced. Acquired hemolytic anemias are not genetic. Acquired autoimmune diseases occur when the body's immune system attacks its own red blood cells for no known reason. Normally, the red blood cells (erythrocytes) have a life span of approximately 120 days before being removed by the spleen. The severity of this type of anemia is determined by the life span of the red blood cell and by the rate at which these cells are replaced by the bone marrow. (For more information on this disorder, choose “acquired autoimmune hemolytic anemia” as your search term in the Rare Disease Database.)Beta thalassemia is an inherited blood disorder characterized by low levels of working hemoglobin. Hemoglobin is found in red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood. A main function of red blood cells is to deliver oxygen throughout the body. Beta thalassemia has three main forms – minor, intermedia and major, which indicate the severity of the disease. Individuals with beta thalassemia minor usually do not have any symptoms (asymptomatic) and individuals often are unaware that they have the condition. Some individuals do experience a very mild anemia. Individuals with beta thalassemia major have a severe expression of the disorder; they often require regular blood transfusions and lifelong, ongoing medical care. The symptoms of beta thalassemia intermedia are variable and severity falls in the broad range between the two extremes of the major and minor forms. The characteristic finding of beta thalassemia is anemia, which is caused because red blood cells are abnormally small (microcytic), are not produced at the normal amounts, and do not contain enough functional hemoglobin. Consequently, affected individuals do not receive enough oxygen-rich blood (microcytic anemia) throughout the body. Affected individuals may experience classic signs of anemia including fatigue, weakness, shortness of breath, dizziness or headaches. Severe anemia can cause serious, even life-threatening complications if left untreated. Affected individuals are treated by regular blood transfusions. Because of repeated blood transfusions individuals with beta thalassemia major and intermedia may develop excess levels of iron in the body (iron overload). Iron overload can cause a variety of symptoms affecting multiple systems of the body, but can be treated with medications. Beta thalassemia is caused by mutations in the hemoglobin beta (HBB) gene. Individuals with beta thalassemia minor have a mutation in one HBB gene, while individuals with the intermediate and major forms have mutations in both HBB genes. (For more information on this disorder, choose “beta thalassemia” as your search term in the Rare Disease Database.)Alpha thalassemia is a general term for a group of inherited blood disorders involving low levels of hemoglobin, which happens when the body is not producing enough alpha-globin, a building block of hemoglobin. Hemoglobin is found in red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood. A main function of red blood cells is to deliver oxygen throughout the body. There are two main forms of alpha thalassemia that are associated with significant health problems – hemoglobin (Hb) Bart’s hydrops fetalis and hemoglobin H (HbH) disease. Hb Bart’s hydrops fetalis is a severe syndrome that is usually fatal to the developing embryo during gestation or shortly after birth; however, recent advances have led to improved treatments for this condition. HbH disease is highly variable, and the specific symptoms and severity can vary greatly from one person to another. Some individuals will have only minor symptoms, while others will develop potentially serious complications. The characteristic finding of all forms of alpha thalassemia is anemia, with red blood cells that are small (microcytic), contain low levels of functional hemoglobin (hypochromic), and may break down in prematurely in both the bone marrow (ineffective erythropoiesis) and in the peripheral circulation (hemolysis). Consequently, severely affected individuals may not circulate sufficient oxygen-rich blood throughout the body. These individuals may experience fatigue, weakness, shortness of breath, dizziness or headaches. Severe anemia can cause serious, even life-threatening, complications if left untreated. Individuals with severe forms of HbH disease are usually treated with regular blood transfusions, which can result in the accumulation of excess iron in the body (iron overload). Although iron overload can damage numerous organs in the body, it can be effectively treated using several highly effective medications. (For more information on this disorder, choose “alpha thalassemia” as your search term in the Rare Disease Database.)
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Hereditary Spherocytosis
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