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nord_1057_1
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Symptoms of Refractory Celiac Disease
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The symptoms of refractory disease are not unlike those of untreated celiac disease except that they are usually more severe and more disabling. The more common symptoms include weight loss, diarrhea, abdominal pain, malnutrition and anemia.Occasionally, examination of the intestine of an RCD patient, by means of a swallowed, picture taking, camera-like device (intestinal endoscope) reveals evidence of inflammation and ulceration of the middle portion (jejunum) of the small intestine (ulcerative jejunitis). This may be a significant warning that refractory celiac disease may progress to form an enteropathy-associated T-cell lymphoma (EATL). Thus, there is an intimate link between refractory disease and celiac-associated intestinal lymphoma.
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Symptoms of Refractory Celiac Disease. The symptoms of refractory disease are not unlike those of untreated celiac disease except that they are usually more severe and more disabling. The more common symptoms include weight loss, diarrhea, abdominal pain, malnutrition and anemia.Occasionally, examination of the intestine of an RCD patient, by means of a swallowed, picture taking, camera-like device (intestinal endoscope) reveals evidence of inflammation and ulceration of the middle portion (jejunum) of the small intestine (ulcerative jejunitis). This may be a significant warning that refractory celiac disease may progress to form an enteropathy-associated T-cell lymphoma (EATL). Thus, there is an intimate link between refractory disease and celiac-associated intestinal lymphoma.
| 1,057 |
Refractory Celiac Disease
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nord_1057_2
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Causes of Refractory Celiac Disease
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The exact series of events that leads to refractory celiac disease remains unresolved. Involved are the body’s immune system, especially T lymphocytes and intraepithelial lymphocytes (IEL), cytokines, and antigens. Lymphocytes make up about 25% of a person’s white blood cells and include the B-cells (mature in bone marrow) and T-cells (mature in the thymus), each of which play key roles in the development of immunity. Intraepithelial lymphocytes (IELs) are T-cells that exist in the lining (intraepithelial) of the intestine. A protein on the surface of T lymphocytes called the T-cell receptor (TCR) serves as a “docking bay” for specific antigens. In celiac disease, T-cells that recognize gluten proteins are activated and proliferate. When gluten is removed from the diet, these T-cells become inactive and the intestinal damage heals. In refractory celiac disease, intestinal T cells are activated without gluten stimulation and intestinal injury persists despite the removal of dietary gluten.Cytokines are small proteins that help to regulate communication among the cells of the immune system or between cells of the immune system and cells of another tissue. Some researchers suggest that patients with refractory celiac disease show a remarkable increase in the “proinflammatory cytokine” known as interleukin-15 (IL-15). IL-15 appears to stimulate the secretion of another cytokine known as interferon-gamma (INF-gamma) that seems to increase the toxicity of the IELs against the cells lining the surface of the intestine. As more and more cells from the lining of the intestine are damaged, symptoms and signs of refractory celiac disease develop. The alterations in the balance of intestinal T-cell activation that are induced by IL-15 may be instrumental in the development of RCD and its transition to intestinal lymphoma.Disorders that are characterized by atrophy of the villi of the intestine are known, generally, as enteropathies (meaning damaged small intestine). There is a link between some enteropathies such as refractory celiac disease and lymphoma. That link is not completely understood, but it is thought that RCD may be just one step along a path of increasingly severe intestinal damage that may culminate in a special form of lymphoma known as “enteropathy-associated T-cell lymphoma” (EATL). RCD is sometimes divided into Type I and Type II. Type I RCD has a better prognosis and a lower risk for EATL. In Type II RCD, abnormal, immature IELs are found on intestinal biopsy and the risks for severe complications of malnutrition and EATL are greater.
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Causes of Refractory Celiac Disease. The exact series of events that leads to refractory celiac disease remains unresolved. Involved are the body’s immune system, especially T lymphocytes and intraepithelial lymphocytes (IEL), cytokines, and antigens. Lymphocytes make up about 25% of a person’s white blood cells and include the B-cells (mature in bone marrow) and T-cells (mature in the thymus), each of which play key roles in the development of immunity. Intraepithelial lymphocytes (IELs) are T-cells that exist in the lining (intraepithelial) of the intestine. A protein on the surface of T lymphocytes called the T-cell receptor (TCR) serves as a “docking bay” for specific antigens. In celiac disease, T-cells that recognize gluten proteins are activated and proliferate. When gluten is removed from the diet, these T-cells become inactive and the intestinal damage heals. In refractory celiac disease, intestinal T cells are activated without gluten stimulation and intestinal injury persists despite the removal of dietary gluten.Cytokines are small proteins that help to regulate communication among the cells of the immune system or between cells of the immune system and cells of another tissue. Some researchers suggest that patients with refractory celiac disease show a remarkable increase in the “proinflammatory cytokine” known as interleukin-15 (IL-15). IL-15 appears to stimulate the secretion of another cytokine known as interferon-gamma (INF-gamma) that seems to increase the toxicity of the IELs against the cells lining the surface of the intestine. As more and more cells from the lining of the intestine are damaged, symptoms and signs of refractory celiac disease develop. The alterations in the balance of intestinal T-cell activation that are induced by IL-15 may be instrumental in the development of RCD and its transition to intestinal lymphoma.Disorders that are characterized by atrophy of the villi of the intestine are known, generally, as enteropathies (meaning damaged small intestine). There is a link between some enteropathies such as refractory celiac disease and lymphoma. That link is not completely understood, but it is thought that RCD may be just one step along a path of increasingly severe intestinal damage that may culminate in a special form of lymphoma known as “enteropathy-associated T-cell lymphoma” (EATL). RCD is sometimes divided into Type I and Type II. Type I RCD has a better prognosis and a lower risk for EATL. In Type II RCD, abnormal, immature IELs are found on intestinal biopsy and the risks for severe complications of malnutrition and EATL are greater.
| 1,057 |
Refractory Celiac Disease
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nord_1057_3
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Affects of Refractory Celiac Disease
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Refractory celiac disease is rare among adults and is almost never seen in children. Data regarding the true incidence and prevalence of RCD are unreliable, but some have estimated that there might be 20,000 patients in the USA. However, those estimations are based on incomplete data. In one recent study, 1.5% of patients diagnosed with celiac disease at a single US center developed RCD. Of those with RCD 85% had the less severe Type I RCD.
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Affects of Refractory Celiac Disease. Refractory celiac disease is rare among adults and is almost never seen in children. Data regarding the true incidence and prevalence of RCD are unreliable, but some have estimated that there might be 20,000 patients in the USA. However, those estimations are based on incomplete data. In one recent study, 1.5% of patients diagnosed with celiac disease at a single US center developed RCD. Of those with RCD 85% had the less severe Type I RCD.
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Refractory Celiac Disease
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nord_1057_4
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Related disorders of Refractory Celiac Disease
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Disaccharide intolerance I is a rare inherited metabolic disorder characterized by the deficiency or absence of the enzymes sucrase and isomaltase. This enzyme complex (sucrase-isomaltase) assists in the breakdown of certain sugars (i.e., sucrose) and certain products of starch digestion (dextrins). The sucrase-isomaltase enzyme complex is normally found within the tiny, finger-like projections (microvilli or brush border) lining the small intestine. When this enzyme complex is deficient, nutrients based on ingested sucrose and starch cannot be absorbed properly from the gut.Symptoms of this disorder become evident soon after sucrose or starches are ingested by an affected infant. Breast-fed infants or those on lactose-only formula manifest no symptoms until such time as sucrose (found in fruit juices, solid foods, and/or some medications) is introduced into the diet. Symptoms are variable among affected individuals but usually include watery diarrhea, abdominal swelling (distension) and/or discomfort, among others. Intolerance to starch often disappears within the first few years of life and the symptoms of sucrose intolerance usually improve as the affected child ages. Disaccharide intolerance I is inherited as an autosomal recessive genetic trait.Enteropathy-associated T-cell lymphoma (EATL) is an aggressive lymphoma of the small intestine that almost always arises in association with celiac disease. Rarely, the lymphoma may arise in extraintestinal sites. The most common location is the jejunum, and the lymphoma presents as single or multiple tumors or as a diffusely infiltrating intestinal malignancy. EATL typically presents with tumor involvement of the middle or lower thirds of the small intestine leading to obstruction (blockage), bleeding, and pain from ulcer formation or perforation (puncture).Irritable bowel syndrome (IBS), previously known as spastic colon or mucous colitis, is a digestive disorder characterized by abnormal movement (motility) of the intestines (both small and large) and altered intestinal sensation (visceral hypersensitivity). Symptoms vary widely and include abdominal pain, bloating, constipation, and diarrhea. IBS is very common; about 50 percent of all patients referred to a gastrointestinal specialist have IBS. There is no obvious organic disease present; only the function of the intestines is affected. However, based on the symptoms, this disease can be confused easily with other bowel diseases including celiac disease.Microscopic colitis (collagenous colitis, lymphocytic colitis) is not a single disease but comprises two related entities, collagenous colitis and lymphocytic colitis, both characterized by chronic watery diarrhea. Lymphocytic colitis is distinguished primarily by intraepithelial lymphocytic (IEL) infiltration and collagenous colitis by an abnormal layer of fibrous tissue (collagen) beneath the surface layer of the intestine. The cause of microscopic colitis is unknown.Pancreatic insufficiency is the inability of the pancreas to produce and/or transport enough digestive enzymes to break down food in the intestine and allow its absorption. It typically occurs as a result of chronic pancreatic damage, which may be caused by a variety of conditions including cystic fibrosis (in children and young adults), excessive alcohol intake, gallstone disease and medications (in older individuals). It is less frequently but occasionally associated with pancreatic cancer or celiac disease.Pancreatic insufficiency usually presents with symptoms of malabsorption, malnutrition, vitamin deficiencies, and weight loss (or inability to gain weight in children) and is often associated with steatorrhea (fatty, loose, bulky and foul-smelling stools).
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Related disorders of Refractory Celiac Disease. Disaccharide intolerance I is a rare inherited metabolic disorder characterized by the deficiency or absence of the enzymes sucrase and isomaltase. This enzyme complex (sucrase-isomaltase) assists in the breakdown of certain sugars (i.e., sucrose) and certain products of starch digestion (dextrins). The sucrase-isomaltase enzyme complex is normally found within the tiny, finger-like projections (microvilli or brush border) lining the small intestine. When this enzyme complex is deficient, nutrients based on ingested sucrose and starch cannot be absorbed properly from the gut.Symptoms of this disorder become evident soon after sucrose or starches are ingested by an affected infant. Breast-fed infants or those on lactose-only formula manifest no symptoms until such time as sucrose (found in fruit juices, solid foods, and/or some medications) is introduced into the diet. Symptoms are variable among affected individuals but usually include watery diarrhea, abdominal swelling (distension) and/or discomfort, among others. Intolerance to starch often disappears within the first few years of life and the symptoms of sucrose intolerance usually improve as the affected child ages. Disaccharide intolerance I is inherited as an autosomal recessive genetic trait.Enteropathy-associated T-cell lymphoma (EATL) is an aggressive lymphoma of the small intestine that almost always arises in association with celiac disease. Rarely, the lymphoma may arise in extraintestinal sites. The most common location is the jejunum, and the lymphoma presents as single or multiple tumors or as a diffusely infiltrating intestinal malignancy. EATL typically presents with tumor involvement of the middle or lower thirds of the small intestine leading to obstruction (blockage), bleeding, and pain from ulcer formation or perforation (puncture).Irritable bowel syndrome (IBS), previously known as spastic colon or mucous colitis, is a digestive disorder characterized by abnormal movement (motility) of the intestines (both small and large) and altered intestinal sensation (visceral hypersensitivity). Symptoms vary widely and include abdominal pain, bloating, constipation, and diarrhea. IBS is very common; about 50 percent of all patients referred to a gastrointestinal specialist have IBS. There is no obvious organic disease present; only the function of the intestines is affected. However, based on the symptoms, this disease can be confused easily with other bowel diseases including celiac disease.Microscopic colitis (collagenous colitis, lymphocytic colitis) is not a single disease but comprises two related entities, collagenous colitis and lymphocytic colitis, both characterized by chronic watery diarrhea. Lymphocytic colitis is distinguished primarily by intraepithelial lymphocytic (IEL) infiltration and collagenous colitis by an abnormal layer of fibrous tissue (collagen) beneath the surface layer of the intestine. The cause of microscopic colitis is unknown.Pancreatic insufficiency is the inability of the pancreas to produce and/or transport enough digestive enzymes to break down food in the intestine and allow its absorption. It typically occurs as a result of chronic pancreatic damage, which may be caused by a variety of conditions including cystic fibrosis (in children and young adults), excessive alcohol intake, gallstone disease and medications (in older individuals). It is less frequently but occasionally associated with pancreatic cancer or celiac disease.Pancreatic insufficiency usually presents with symptoms of malabsorption, malnutrition, vitamin deficiencies, and weight loss (or inability to gain weight in children) and is often associated with steatorrhea (fatty, loose, bulky and foul-smelling stools).
| 1,057 |
Refractory Celiac Disease
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nord_1057_5
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Diagnosis of Refractory Celiac Disease
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Virtually all clinicians studying refractory celiac disease emphasize that the diagnosis is based on eliminating all other possible sources of the symptoms and intestinal injury. One article lists more than 10 conditions that must be considered and eliminated before a convincing diagnosis of refractory celiac disease may be made. As noted above, examination of the interior wall of the intestine (upper and lower) by means of an enteroscope or colonoscope as well as obtaining intestinal biopsies to be examined under a microscope is useful, especially to determine if the symptoms are the result of intestinal disorders other than RCD. Capsule endoscopy, which examines the small intestinal lining using a camera mounted on a swallowed pill, may also be useful in evaluating the degree of small intestinal inflammation and injury. Some specialized centers are able to offer sophisticated examinations of the biopsy materials that in many cases will assist in the diagnosis. These studies emphasize the presence of abnormal populations of T lymphocytes in the tissue indicating a diagnosis of the more aggressive Type II RCD. Other imaging studies (barium X-ray, CT scan, capsule enteroscopy and MRE) may be undertaken, especially if there is concern for the presence of a lymphoma.
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Diagnosis of Refractory Celiac Disease. Virtually all clinicians studying refractory celiac disease emphasize that the diagnosis is based on eliminating all other possible sources of the symptoms and intestinal injury. One article lists more than 10 conditions that must be considered and eliminated before a convincing diagnosis of refractory celiac disease may be made. As noted above, examination of the interior wall of the intestine (upper and lower) by means of an enteroscope or colonoscope as well as obtaining intestinal biopsies to be examined under a microscope is useful, especially to determine if the symptoms are the result of intestinal disorders other than RCD. Capsule endoscopy, which examines the small intestinal lining using a camera mounted on a swallowed pill, may also be useful in evaluating the degree of small intestinal inflammation and injury. Some specialized centers are able to offer sophisticated examinations of the biopsy materials that in many cases will assist in the diagnosis. These studies emphasize the presence of abnormal populations of T lymphocytes in the tissue indicating a diagnosis of the more aggressive Type II RCD. Other imaging studies (barium X-ray, CT scan, capsule enteroscopy and MRE) may be undertaken, especially if there is concern for the presence of a lymphoma.
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Refractory Celiac Disease
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nord_1057_6
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Therapies of Refractory Celiac Disease
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Several therapies for RCD have been tried in uncontrolled tests with inconclusive results. Among the therapies tested in this way are: elemental diet (an elemental diet is a liquid diet consisting of nutrients that require no digestion, including amino acids, carbohydrates, vitamins, minerals, and triglycerides); and total parental nutrition (TPN) that is defined as nutrition maintained entirely by intravenous injection or by some other nongastrointestinal route. Steroid therapy is a mainstay of treatment but its beneficial effect is short-lived in patients of lymphoma. Treatment involving other immunosuppressive drugs such as azathioprine, cyclosporine, enteric-coated budesonide, 5-aminosalicylic acid (5-ASA), or inflixamab has been used with a limited number of patients. More recently chemotherapy with cladribine with or without autologous stem cell transplantation has also been reported to be useful.
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Therapies of Refractory Celiac Disease. Several therapies for RCD have been tried in uncontrolled tests with inconclusive results. Among the therapies tested in this way are: elemental diet (an elemental diet is a liquid diet consisting of nutrients that require no digestion, including amino acids, carbohydrates, vitamins, minerals, and triglycerides); and total parental nutrition (TPN) that is defined as nutrition maintained entirely by intravenous injection or by some other nongastrointestinal route. Steroid therapy is a mainstay of treatment but its beneficial effect is short-lived in patients of lymphoma. Treatment involving other immunosuppressive drugs such as azathioprine, cyclosporine, enteric-coated budesonide, 5-aminosalicylic acid (5-ASA), or inflixamab has been used with a limited number of patients. More recently chemotherapy with cladribine with or without autologous stem cell transplantation has also been reported to be useful.
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Refractory Celiac Disease
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nord_1058_0
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Overview of Refsum Disease
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Summary Refsum disease is a metabolic disorder characterized by the build-up of a fat (lipid) called phytanic acid in blood plasma and tissues. Individuals with Refsum disease are usually normal at birth, but between the ages of 10 and 20 years old, symptoms begin to develop starting with loss of night vision (retinitis pigmentosa), and eventually including weakness in arms and legs or unsteadiness (cerebellar ataxia). Other common symptoms include a loss of sense of smell (anosmia), rough, scaly skin (ichthyosis) and after many years, deafness.Treatment for Refsum disease is based on limiting the intake of foods high in phytanic acid. Our bodies cannot make phytanic acid; rather, it is found in foods such as dairy, beef, lamb, and some seafoods. Refsum disease is caused by a change (mutation) in the gene that makes an enzyme responsible for breaking down phytanic acid, a particular type of fatty acid which is derived by bacterial fermentation of green plants or algae. The lack of function of the enzyme (phytanoyl-CoA hydroxylase) leads to a build-up of phytanic acid in blood plasma and tissues. The disorder is inherited in an autosomal recessive manner.IntroductionRefsum disease is a member of a family of genetic disorders known as leukodystrophies, which result due to errors in lipid metabolism. This error affecting a single process prevents the myelin sheath, the insulating layer that consists of fats and proteins surrounding our nerve cells including those in the eye, from growing or functioning properly.Refsum disease is sometimes called adult Refsum disease or classic Refsum disease. It was first described by Dr. Sigwald Refsum in 1946. This condition is different from infantile Refsum disease, which has a different cause and is in the group of conditions called Zellweger spectrum disorders (see Related Disorders below) caused by defects in assembling cell sub-compartments called peroxisomes.
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Overview of Refsum Disease. Summary Refsum disease is a metabolic disorder characterized by the build-up of a fat (lipid) called phytanic acid in blood plasma and tissues. Individuals with Refsum disease are usually normal at birth, but between the ages of 10 and 20 years old, symptoms begin to develop starting with loss of night vision (retinitis pigmentosa), and eventually including weakness in arms and legs or unsteadiness (cerebellar ataxia). Other common symptoms include a loss of sense of smell (anosmia), rough, scaly skin (ichthyosis) and after many years, deafness.Treatment for Refsum disease is based on limiting the intake of foods high in phytanic acid. Our bodies cannot make phytanic acid; rather, it is found in foods such as dairy, beef, lamb, and some seafoods. Refsum disease is caused by a change (mutation) in the gene that makes an enzyme responsible for breaking down phytanic acid, a particular type of fatty acid which is derived by bacterial fermentation of green plants or algae. The lack of function of the enzyme (phytanoyl-CoA hydroxylase) leads to a build-up of phytanic acid in blood plasma and tissues. The disorder is inherited in an autosomal recessive manner.IntroductionRefsum disease is a member of a family of genetic disorders known as leukodystrophies, which result due to errors in lipid metabolism. This error affecting a single process prevents the myelin sheath, the insulating layer that consists of fats and proteins surrounding our nerve cells including those in the eye, from growing or functioning properly.Refsum disease is sometimes called adult Refsum disease or classic Refsum disease. It was first described by Dr. Sigwald Refsum in 1946. This condition is different from infantile Refsum disease, which has a different cause and is in the group of conditions called Zellweger spectrum disorders (see Related Disorders below) caused by defects in assembling cell sub-compartments called peroxisomes.
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Refsum Disease
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nord_1058_1
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Symptoms of Refsum Disease
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At birth, individuals with Refsum disease generally appear normal although they may show shorter bones in the hands and feet (metacarpals and metatarsals, respectively). Between 10 and 20 years old, individuals may show their first symptom which is most frequently the loss of night vision (retinitis pigmentosa). Some people may not show any symptoms until up to 50 years of age. Retinitis pigmentosa occurs because light-sensing cells in the retina, a layer in the back of the eye, gradually deteriorate. The initial loss of night vision usually occurs during childhood, and the progression toward loss of peripheral vision and full blindness may occur over the course of years. Individuals with Refsum disease often present with retinitis pigmentosa and a combination of other symptoms. Other possible issues in the eye include abnormally small pupils, rapid, involuntary eye movement (nystagmus) and cloudiness in the eye that causes individuals to see starburst-type haloes around bright objects (cataracts). Individuals may experience a loss of their sense of smell and taste (anosmia) and after many years, deafness. Affected individuals also may experience numbness, weakness, a tingling sensation or loss of reflexes in their hands and feet (peripheral polyneuropathy) associated with an unsteady gait (cerebellar ataxia) as they deteriorate. Additionally, individuals with Refsum disease may have rough, scaly patches of skin (ichthyosis) and general weakness throughout the body. Shortening of bones in the hands and feet and abnormal growth plate formation affecting the knees, shoulders and elbows (skeletal dysplasia) may be seen. Although it is rare, if phytanic acid levels become very high in people with Refsum disease, then a cardiac arrhythmia (irregular heartbeat) can occur which could be life threatening. The type and number of symptoms present in individuals with Refsum disease varies greatly from person to person and the severity depends on the level of phytanic acid in the body. If a person has a greater build-up of phytanic acid, they are expected to show more severe symptoms. The number and severity of symptoms also may increase with age.
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Symptoms of Refsum Disease. At birth, individuals with Refsum disease generally appear normal although they may show shorter bones in the hands and feet (metacarpals and metatarsals, respectively). Between 10 and 20 years old, individuals may show their first symptom which is most frequently the loss of night vision (retinitis pigmentosa). Some people may not show any symptoms until up to 50 years of age. Retinitis pigmentosa occurs because light-sensing cells in the retina, a layer in the back of the eye, gradually deteriorate. The initial loss of night vision usually occurs during childhood, and the progression toward loss of peripheral vision and full blindness may occur over the course of years. Individuals with Refsum disease often present with retinitis pigmentosa and a combination of other symptoms. Other possible issues in the eye include abnormally small pupils, rapid, involuntary eye movement (nystagmus) and cloudiness in the eye that causes individuals to see starburst-type haloes around bright objects (cataracts). Individuals may experience a loss of their sense of smell and taste (anosmia) and after many years, deafness. Affected individuals also may experience numbness, weakness, a tingling sensation or loss of reflexes in their hands and feet (peripheral polyneuropathy) associated with an unsteady gait (cerebellar ataxia) as they deteriorate. Additionally, individuals with Refsum disease may have rough, scaly patches of skin (ichthyosis) and general weakness throughout the body. Shortening of bones in the hands and feet and abnormal growth plate formation affecting the knees, shoulders and elbows (skeletal dysplasia) may be seen. Although it is rare, if phytanic acid levels become very high in people with Refsum disease, then a cardiac arrhythmia (irregular heartbeat) can occur which could be life threatening. The type and number of symptoms present in individuals with Refsum disease varies greatly from person to person and the severity depends on the level of phytanic acid in the body. If a person has a greater build-up of phytanic acid, they are expected to show more severe symptoms. The number and severity of symptoms also may increase with age.
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Refsum Disease
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nord_1058_2
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Causes of Refsum Disease
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Most cases (90%) of Refsum disease result from a change (mutation) in the PHYH gene. Most of the remaining cases result from a mutation in the PEX7 gene which transports PHYH into the peroxisomal compartment in cells. Mutations in PHYH and PEX7 genes cause abnormal functioning of peroxisomes, which are structures that allow for the breakdown of fatty acids, including phytanic acid. Specifically, PHYH codes for the phytanoyl-CoA hydroxylase enzyme that is used in the peroxisome to break down phytanic acid. Phytanic acid comes from the diet and is derived from bacterial fermentation of green plants or algae. It is commonly found in dairy, beef, lamb and other ruminant animal-derived food stuffs as well as some seafood. The improper functioning of the peroxisome and related enzymes means that phytanic acid cannot be broken down and thus accumulates in the cell. It is currently unclear how the buildup of phytanic acid is toxic and affects vision or how it causes other features of the disease. Refsum disease is an autosomal recessive genetic disorder. 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 Refsum Disease. Most cases (90%) of Refsum disease result from a change (mutation) in the PHYH gene. Most of the remaining cases result from a mutation in the PEX7 gene which transports PHYH into the peroxisomal compartment in cells. Mutations in PHYH and PEX7 genes cause abnormal functioning of peroxisomes, which are structures that allow for the breakdown of fatty acids, including phytanic acid. Specifically, PHYH codes for the phytanoyl-CoA hydroxylase enzyme that is used in the peroxisome to break down phytanic acid. Phytanic acid comes from the diet and is derived from bacterial fermentation of green plants or algae. It is commonly found in dairy, beef, lamb and other ruminant animal-derived food stuffs as well as some seafood. The improper functioning of the peroxisome and related enzymes means that phytanic acid cannot be broken down and thus accumulates in the cell. It is currently unclear how the buildup of phytanic acid is toxic and affects vision or how it causes other features of the disease. Refsum disease is an autosomal recessive genetic disorder. 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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Refsum Disease
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nord_1058_3
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Affects of Refsum Disease
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Refsum disease occurs in approximately 1 in 1,000,000 people. Males and females are affected in equal numbers.
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Affects of Refsum Disease. Refsum disease occurs in approximately 1 in 1,000,000 people. Males and females are affected in equal numbers.
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Refsum Disease
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nord_1058_4
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Related disorders of Refsum Disease
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Phytanic acid levels can also be raised in other disorders. Zellweger spectrum disorders (ZSD) are a group of rare, genetic, multisystem disorders that were once thought to be separate entities. These disorders are now classified as different expressions (variants) of one disease process due to their shared biochemical basis. Collectively, they form a spectrum or continuum of disease. The most severe form of these disorders was previously referred to as Zellweger syndrome, the intermediate form was referred to as neonatal adrenoleukodystrophy, and the milder forms were referred to as infantile Refsum disease or Heimler syndrome, depending on the clinical presentation. ZSD can affect most organs of the body. Neurological deficits, loss of muscle tone (hypotonia), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common findings. ZSD often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. ZSD are inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Zellweger” as your search term in the Rare Disease Database) Other defects in the pathway for degrading phytanic acid are likely to share features with Refsum disease. Defects have been described in enzymes such as alpha-methyl-acyl-oA racemase (AMACR) which are associated with symptoms affecting long nerves (tingling, numbness) but less often with severe eye disease. AMACR also affects processes dealing with some specific bile acids. A very rare early onset disorder called polyneuropathy (numbness, tingling), hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) shares many clinical features with Refsum disease but is caused by a defect in a different enzyme called abhydrolase domain containing 12-Lysophospholipase (ABHD12) which is involved in degrading natural cannabinoids.
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Related disorders of Refsum Disease. Phytanic acid levels can also be raised in other disorders. Zellweger spectrum disorders (ZSD) are a group of rare, genetic, multisystem disorders that were once thought to be separate entities. These disorders are now classified as different expressions (variants) of one disease process due to their shared biochemical basis. Collectively, they form a spectrum or continuum of disease. The most severe form of these disorders was previously referred to as Zellweger syndrome, the intermediate form was referred to as neonatal adrenoleukodystrophy, and the milder forms were referred to as infantile Refsum disease or Heimler syndrome, depending on the clinical presentation. ZSD can affect most organs of the body. Neurological deficits, loss of muscle tone (hypotonia), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common findings. ZSD often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. ZSD are inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Zellweger” as your search term in the Rare Disease Database) Other defects in the pathway for degrading phytanic acid are likely to share features with Refsum disease. Defects have been described in enzymes such as alpha-methyl-acyl-oA racemase (AMACR) which are associated with symptoms affecting long nerves (tingling, numbness) but less often with severe eye disease. AMACR also affects processes dealing with some specific bile acids. A very rare early onset disorder called polyneuropathy (numbness, tingling), hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) shares many clinical features with Refsum disease but is caused by a defect in a different enzyme called abhydrolase domain containing 12-Lysophospholipase (ABHD12) which is involved in degrading natural cannabinoids.
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Refsum Disease
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nord_1058_5
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Diagnosis of Refsum Disease
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Refsum disease can be diagnosed based on the finding of highly raised phytanic acid in a blood sample. Levels of pristanic acid, the next step in the pathway, are usually low. This initial diagnosis must then be confirmed with either molecular genetic testing for mutations in either the PHYH or PEX7 genes or by enzyme analysis in a skin biopsy to determine if there is abnormal activity of the enzyme phytanoyl-CoA hydroxylase pathway.
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Diagnosis of Refsum Disease. Refsum disease can be diagnosed based on the finding of highly raised phytanic acid in a blood sample. Levels of pristanic acid, the next step in the pathway, are usually low. This initial diagnosis must then be confirmed with either molecular genetic testing for mutations in either the PHYH or PEX7 genes or by enzyme analysis in a skin biopsy to determine if there is abnormal activity of the enzyme phytanoyl-CoA hydroxylase pathway.
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Refsum Disease
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Therapies of Refsum Disease
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Treatment
Treatment of Refsum disease requires minimizing intake of beef, lamb, certain seafood, and dairy products while maintaining carbohydrate intake, which helps prevent phytanic acid from entering the blood from fat or liver stores. Removal and reinfusion of blood (plasmapheresis or apheresis) may also be necessary if levels are very high or general symptoms such as profound weakness are present. Other treatments are tailored based on symptoms and are usually supportive measures. Patients with Refsum disease should avoid fasting and rapid weight loss because this causes release of phytanic acid stored in the body. Patients should using ibuprofen as this may interfere with the degradation pathway of phytanic acid. Patients should receive guidance from a trained dietician and physician on how to minimize risks of acute phytanic acid release and how to manage a low phytanic acid diet. Genetic counseling is recommended for affected individuals and their family members.
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Therapies of Refsum Disease. Treatment
Treatment of Refsum disease requires minimizing intake of beef, lamb, certain seafood, and dairy products while maintaining carbohydrate intake, which helps prevent phytanic acid from entering the blood from fat or liver stores. Removal and reinfusion of blood (plasmapheresis or apheresis) may also be necessary if levels are very high or general symptoms such as profound weakness are present. Other treatments are tailored based on symptoms and are usually supportive measures. Patients with Refsum disease should avoid fasting and rapid weight loss because this causes release of phytanic acid stored in the body. Patients should using ibuprofen as this may interfere with the degradation pathway of phytanic acid. Patients should receive guidance from a trained dietician and physician on how to minimize risks of acute phytanic acid release and how to manage a low phytanic acid diet. Genetic counseling is recommended for affected individuals and their family members.
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Refsum Disease
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Overview of Relapsing Polychondritis
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Relapsing polychondritis is a rare degenerative disease characterized by recurrent inflammation of the cartilage in the body. Deterioration of the cartilage may affect any site of the body where cartilage is present. Ears, larynx and trachea may become “floppy,” and the bridge of the nose can collapse into a “saddlenose” shape. The aortic heart valve may also be affected.
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Overview of Relapsing Polychondritis. Relapsing polychondritis is a rare degenerative disease characterized by recurrent inflammation of the cartilage in the body. Deterioration of the cartilage may affect any site of the body where cartilage is present. Ears, larynx and trachea may become “floppy,” and the bridge of the nose can collapse into a “saddlenose” shape. The aortic heart valve may also be affected.
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Relapsing Polychondritis
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Symptoms of Relapsing Polychondritis
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Symptoms of relapsing polychondritis usually begin with the sudden onset of pain, tenderness and swelling of the cartilage of one or both ears. This inflammation may spread to the fleshy portion of the outer ear causing it to narrow. Attacks may last several days to weeks before subsiding. Middle ear inflammation can cause obstruction of the eustachian tube. Recurrent attacks may lead to hearing loss.Nasal chondritis may be marked by cartilage collapse at the bridge of the nose resulting in a saddle nose deformity, nasal stuffiness or fullness and crusting.Inflammation of both large and small joints can occur. Classic symptoms of pain and swelling are similar to those of arthritis.Involvement of the cartilage of the larynx and bronchial tubes may cause breathing and speech difficulties.Heart valve abnormalities may occur.Relapsing polychondritis may also cause kidney inflammation and dysfunction.
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Symptoms of Relapsing Polychondritis. Symptoms of relapsing polychondritis usually begin with the sudden onset of pain, tenderness and swelling of the cartilage of one or both ears. This inflammation may spread to the fleshy portion of the outer ear causing it to narrow. Attacks may last several days to weeks before subsiding. Middle ear inflammation can cause obstruction of the eustachian tube. Recurrent attacks may lead to hearing loss.Nasal chondritis may be marked by cartilage collapse at the bridge of the nose resulting in a saddle nose deformity, nasal stuffiness or fullness and crusting.Inflammation of both large and small joints can occur. Classic symptoms of pain and swelling are similar to those of arthritis.Involvement of the cartilage of the larynx and bronchial tubes may cause breathing and speech difficulties.Heart valve abnormalities may occur.Relapsing polychondritis may also cause kidney inflammation and dysfunction.
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Relapsing Polychondritis
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Causes of Relapsing Polychondritis
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The exact cause of relapsing polychondritis is not known. It is thought to be an autoimmune disease. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. Some cases may be linked to abnormal reactions by blood cells (serum antibodies), to a thyroid protein (thyroglobulin), organ wall (parietal) cells, adrenal cells, or thyroid. Symptoms of relapsing polychondritis may arise when autoantibodies attack human cartilage.Some researchers believe that relapsing relapsing polychondritis may be caused by an immunologic sensitivity to type II collagen, a normal substance found in skin and connective tissue.
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Causes of Relapsing Polychondritis. The exact cause of relapsing polychondritis is not known. It is thought to be an autoimmune disease. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. Some cases may be linked to abnormal reactions by blood cells (serum antibodies), to a thyroid protein (thyroglobulin), organ wall (parietal) cells, adrenal cells, or thyroid. Symptoms of relapsing polychondritis may arise when autoantibodies attack human cartilage.Some researchers believe that relapsing relapsing polychondritis may be caused by an immunologic sensitivity to type II collagen, a normal substance found in skin and connective tissue.
| 1,059 |
Relapsing Polychondritis
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Affects of Relapsing Polychondritis
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Relapsing polychondritis affects males and females in equal numbers. Symptoms usually begin between forty and sixty years of age.
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Affects of Relapsing Polychondritis. Relapsing polychondritis affects males and females in equal numbers. Symptoms usually begin between forty and sixty years of age.
| 1,059 |
Relapsing Polychondritis
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Related disorders of Relapsing Polychondritis
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Symptoms of the following disorders can be similar to those of relapsing polychondritis. Comparisons may be useful for a differential diagnosis:Rheumatoid arthritis is a disease of unknown origin which may have a relationship to autoimmune processes. This disorder is characterized by lack of appetite (anorexia), tiredness, painful and deformed joints, early morning stiffness chiefly in the hands, knees, feet, jaw, and spine. Once affected, a patient’s joints remain painful or uncomfortable for weeks, months, or even years.Osteoarthritis is a degenerative joint disease of unknown origin characterized by loss of cartilage, deformities of bones with joints, and extra cartilage and bone growth at the joint margins with subsequent bony enlargement. Osteoarthritis develops when cartilage repair does not keep pace with degeneration. It may occur as a result of trauma to the bony or underlying joint disease.Behcet syndrome is an inflammatory disorder affecting a number of organs. The most constant symptom is of oral and genital ulcers. Eye and joint inflammation, similar to Polychondritis, occurs. Blood vessels, the central nervous system, and the gastrointestinal tract may also be involved. Attacks last a week to a month, and can recur spontaneously. Some symptoms can appear as late as several years after onset of the disease which usually occurs between age 20 and 30. Twice as many men as women are affected. The disease is most common in the Middle East and Japan. For more information on the above disorder, choose “Behcet” as your search term in the Rare Disease Database.
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Related disorders of Relapsing Polychondritis. Symptoms of the following disorders can be similar to those of relapsing polychondritis. Comparisons may be useful for a differential diagnosis:Rheumatoid arthritis is a disease of unknown origin which may have a relationship to autoimmune processes. This disorder is characterized by lack of appetite (anorexia), tiredness, painful and deformed joints, early morning stiffness chiefly in the hands, knees, feet, jaw, and spine. Once affected, a patient’s joints remain painful or uncomfortable for weeks, months, or even years.Osteoarthritis is a degenerative joint disease of unknown origin characterized by loss of cartilage, deformities of bones with joints, and extra cartilage and bone growth at the joint margins with subsequent bony enlargement. Osteoarthritis develops when cartilage repair does not keep pace with degeneration. It may occur as a result of trauma to the bony or underlying joint disease.Behcet syndrome is an inflammatory disorder affecting a number of organs. The most constant symptom is of oral and genital ulcers. Eye and joint inflammation, similar to Polychondritis, occurs. Blood vessels, the central nervous system, and the gastrointestinal tract may also be involved. Attacks last a week to a month, and can recur spontaneously. Some symptoms can appear as late as several years after onset of the disease which usually occurs between age 20 and 30. Twice as many men as women are affected. The disease is most common in the Middle East and Japan. For more information on the above disorder, choose “Behcet” as your search term in the Rare Disease Database.
| 1,059 |
Relapsing Polychondritis
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Diagnosis of Relapsing Polychondritis
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Diagnosis of Relapsing Polychondritis.
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Relapsing Polychondritis
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Therapies of Relapsing Polychondritis
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Treatment
Treatment of relapsing polychondritis usually involves the administration of corticosteroid drugs (e.g., prednisone), aspirin and non-steroidal anti-inflammatory compounds such as dapsone and/or colchicine. In extreme cases, drugs that suppress the immune system such as cyclophosphamide, 6-mercaptopurine and azathioprine may be recommended. In the most severe cases replacement of heart valves or the insertion of a breathing tube (tracheotomy) for collapsed airways may be necessary.
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Therapies of Relapsing Polychondritis. Treatment
Treatment of relapsing polychondritis usually involves the administration of corticosteroid drugs (e.g., prednisone), aspirin and non-steroidal anti-inflammatory compounds such as dapsone and/or colchicine. In extreme cases, drugs that suppress the immune system such as cyclophosphamide, 6-mercaptopurine and azathioprine may be recommended. In the most severe cases replacement of heart valves or the insertion of a breathing tube (tracheotomy) for collapsed airways may be necessary.
| 1,059 |
Relapsing Polychondritis
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Overview of Renal Agenesis, Bilateral
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Bilateral Renal Agenesis is the absence of both kidneys at birth. It is a genetic disorder characterized by a failure of the kidneys to develop in a fetus. This absence of kidneys causes a deficiency of amniotic fluid (Oligohydramnios) in a pregnant woman. Normally, the amniotic fluid acts as a cushion for the developing fetus. When there is an insufficient amount of this fluid, compression of the fetus may occur resulting in further malformations of the baby.This disorder is more common in infants born of a parent who has a kidney malformation, particularly the absence of one kidney (unilateral renal agenesis). Studies have proven that unilateral renal agenesis and bilateral renal agenesis are genetically related.
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Overview of Renal Agenesis, Bilateral. Bilateral Renal Agenesis is the absence of both kidneys at birth. It is a genetic disorder characterized by a failure of the kidneys to develop in a fetus. This absence of kidneys causes a deficiency of amniotic fluid (Oligohydramnios) in a pregnant woman. Normally, the amniotic fluid acts as a cushion for the developing fetus. When there is an insufficient amount of this fluid, compression of the fetus may occur resulting in further malformations of the baby.This disorder is more common in infants born of a parent who has a kidney malformation, particularly the absence of one kidney (unilateral renal agenesis). Studies have proven that unilateral renal agenesis and bilateral renal agenesis are genetically related.
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Renal Agenesis, Bilateral
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Symptoms of Renal Agenesis, Bilateral
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Bilateral renal agenesis is characterized by the absence of kidneys and of urine in a baby. The face usually consists of wide-set eyes; a “parrot beak” nose; a receding chin, and large low set ears deficient in cartilage. Other symptoms may include excess and dehydrated skin, a prominent fold at the corner of each eye, the facial expression of an older infant, and deformities of the hands and feet.Premature labor, breech delivery and a disproportionately low birthweight are often associated with bilateral renal agenesis. The baby may also have multiple malformations including in females the absence of a uterus and upper vagina, or in males an absence of seminal vesicles and spermatic duct. Gastro-intestinal malformations such as the absence of a rectum, esophagus and duodenum may also occur. Symptoms may further include the presence of only a single umbilical artery, and major deformities of the lower part of the body and the lower limbs.
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Symptoms of Renal Agenesis, Bilateral. Bilateral renal agenesis is characterized by the absence of kidneys and of urine in a baby. The face usually consists of wide-set eyes; a “parrot beak” nose; a receding chin, and large low set ears deficient in cartilage. Other symptoms may include excess and dehydrated skin, a prominent fold at the corner of each eye, the facial expression of an older infant, and deformities of the hands and feet.Premature labor, breech delivery and a disproportionately low birthweight are often associated with bilateral renal agenesis. The baby may also have multiple malformations including in females the absence of a uterus and upper vagina, or in males an absence of seminal vesicles and spermatic duct. Gastro-intestinal malformations such as the absence of a rectum, esophagus and duodenum may also occur. Symptoms may further include the presence of only a single umbilical artery, and major deformities of the lower part of the body and the lower limbs.
| 1,060 |
Renal Agenesis, Bilateral
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Causes of Renal Agenesis, Bilateral
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Bilateral renal agenesis is an autosomal dominant genetic disorder. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. Bilateral renal agenesis tends to occur when at least one parent has a kidney malformation or the absence of a kidney (unilateral kidney agenesis).
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Causes of Renal Agenesis, Bilateral. Bilateral renal agenesis is an autosomal dominant genetic disorder. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. Bilateral renal agenesis tends to occur when at least one parent has a kidney malformation or the absence of a kidney (unilateral kidney agenesis).
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Renal Agenesis, Bilateral
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Affects of Renal Agenesis, Bilateral
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Bilateral renal agenesis is found in male infants more frequently than females. It tends to occur in the children of parents having kidney abnormalities. It is a very rare disorder.
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Affects of Renal Agenesis, Bilateral. Bilateral renal agenesis is found in male infants more frequently than females. It tends to occur in the children of parents having kidney abnormalities. It is a very rare disorder.
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Renal Agenesis, Bilateral
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Related disorders of Renal Agenesis, Bilateral
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Symptoms of the following disorders can be similar to those of Bilateral Renal Agenesis. Comparisons may be useful for a differential diagnosis:Oligohydramnios Sequence (Potter Syndrome) is characterized by an insufficient level of amniotic fluid. It may be caused by the absence of urinary output by the fetus or by chronic leakage of fluid from the amniotic sack.Cat-Eye Syndrome (Coloboma of Iris-Anal Atresis Syndrome), is a disorder which is characterized by a fissure in the iris of the eye and the absence of an anal opening. Other abnormalities may include renal agenesis.Fraser Syndrome (Cryptophthalmos Syndrome) is a genetic disorder in which the infant is born with sealed eyelids and incomplete development of the sexual organs.Melnick-Fraser Syndrome (Branchio-Oto-Renal Syndrome) is a genetic disorder characterized by hearing loss and kidney malformations, including renal agenesis.MURCS Association (Mullerian Duct, Renal and Cervical Vertebral Defects) is a rare disorder characterized by malformation of the vertebrae, and absence of a vagina and kidneys.Rokitansky Sequence is a disorder in which the vagina and uterus are incompletely formed.Sirenomelia Sequence results in the growth of a single lower extremity. (For more information on this disorder, choose “Sirenomelia” as your search term in the Rare Disease Database.Unilateral Renal Agenesis is the presence of only one kidney at birth.
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Related disorders of Renal Agenesis, Bilateral. Symptoms of the following disorders can be similar to those of Bilateral Renal Agenesis. Comparisons may be useful for a differential diagnosis:Oligohydramnios Sequence (Potter Syndrome) is characterized by an insufficient level of amniotic fluid. It may be caused by the absence of urinary output by the fetus or by chronic leakage of fluid from the amniotic sack.Cat-Eye Syndrome (Coloboma of Iris-Anal Atresis Syndrome), is a disorder which is characterized by a fissure in the iris of the eye and the absence of an anal opening. Other abnormalities may include renal agenesis.Fraser Syndrome (Cryptophthalmos Syndrome) is a genetic disorder in which the infant is born with sealed eyelids and incomplete development of the sexual organs.Melnick-Fraser Syndrome (Branchio-Oto-Renal Syndrome) is a genetic disorder characterized by hearing loss and kidney malformations, including renal agenesis.MURCS Association (Mullerian Duct, Renal and Cervical Vertebral Defects) is a rare disorder characterized by malformation of the vertebrae, and absence of a vagina and kidneys.Rokitansky Sequence is a disorder in which the vagina and uterus are incompletely formed.Sirenomelia Sequence results in the growth of a single lower extremity. (For more information on this disorder, choose “Sirenomelia” as your search term in the Rare Disease Database.Unilateral Renal Agenesis is the presence of only one kidney at birth.
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Renal Agenesis, Bilateral
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Diagnosis of Renal Agenesis, Bilateral
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Diagnosis of Renal Agenesis, Bilateral.
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Renal Agenesis, Bilateral
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Therapies of Renal Agenesis, Bilateral
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Treatment of bilateral renal agenesis is symptomatic and supportive.
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Therapies of Renal Agenesis, Bilateral. Treatment of bilateral renal agenesis is symptomatic and supportive.
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Renal Agenesis, Bilateral
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nord_1061_0
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Overview of Renal Cell Carcinoma
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Renal cell carcinoma is a form of kidney cancer. Some patients with renal cell carcinoma do not have symptoms (asymptomatic). When symptoms are present, they may include blood in the urine; urine that is brown or rusty-colored; abdominal pain; weight loss; enlargement of one testicle or varicose veins of the testis (varicocele) in a male patient; fever; a thin, malnourished appearance; vision abnormalities; and elevated blood pressure. The most common feature of the syndrome is the passing of blood in the urine (hematuria).
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Overview of Renal Cell Carcinoma. Renal cell carcinoma is a form of kidney cancer. Some patients with renal cell carcinoma do not have symptoms (asymptomatic). When symptoms are present, they may include blood in the urine; urine that is brown or rusty-colored; abdominal pain; weight loss; enlargement of one testicle or varicose veins of the testis (varicocele) in a male patient; fever; a thin, malnourished appearance; vision abnormalities; and elevated blood pressure. The most common feature of the syndrome is the passing of blood in the urine (hematuria).
| 1,061 |
Renal Cell Carcinoma
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Symptoms of Renal Cell Carcinoma
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Renal cell carcinoma, though rare, is the most common form of kidney cancer found in adults. Usually the first sign that something is wrong is the passing of blood in the urine. Other signs may include flank pain and an abdominal mass that can be felt by the examining doctor. Other symptoms of renal cell carcinoma may include high blood pressure (hypertension), anemia, abnormal liver function and fever. Sometimes symptoms do not appear until the cancer has spread to another part of the body, usually the lymph nodes, lungs or the long bones.The most common method of diagnosis is through the use of CT scans or sonography. It is very important to diagnose the disorder in the early stages so that prompt treatment can begin. Staging is a very important system to determine if and where the cancer has spread. Staging progresses from 1 to 4:Stage 1 occurs when the tumor is confined to the kidney tissues themselves; Stage 2 occurs when the tumor involves the fat or adrenal tissues of the kidney; Stage 3 occurs when there is a tumor in the veins or vena cava of the kidney, the tumor has spread to the regional kidney nodes, or the tumor has involved lymph nodes and kidney veins or vena cava; Stage 4 occurs when the tumor has spread to other organs (liver, colon, pancreas, or stomach) or spread to distant sites in the body.
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Symptoms of Renal Cell Carcinoma. Renal cell carcinoma, though rare, is the most common form of kidney cancer found in adults. Usually the first sign that something is wrong is the passing of blood in the urine. Other signs may include flank pain and an abdominal mass that can be felt by the examining doctor. Other symptoms of renal cell carcinoma may include high blood pressure (hypertension), anemia, abnormal liver function and fever. Sometimes symptoms do not appear until the cancer has spread to another part of the body, usually the lymph nodes, lungs or the long bones.The most common method of diagnosis is through the use of CT scans or sonography. It is very important to diagnose the disorder in the early stages so that prompt treatment can begin. Staging is a very important system to determine if and where the cancer has spread. Staging progresses from 1 to 4:Stage 1 occurs when the tumor is confined to the kidney tissues themselves; Stage 2 occurs when the tumor involves the fat or adrenal tissues of the kidney; Stage 3 occurs when there is a tumor in the veins or vena cava of the kidney, the tumor has spread to the regional kidney nodes, or the tumor has involved lymph nodes and kidney veins or vena cava; Stage 4 occurs when the tumor has spread to other organs (liver, colon, pancreas, or stomach) or spread to distant sites in the body.
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Renal Cell Carcinoma
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Causes of Renal Cell Carcinoma
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The exact cause of renal cell carcinoma is not known. However, a history of smoking does increase the risk for developing this disease. Patients with von Hippel-Lindau disease, horseshoe kidneys, adult polycystic kidney disease and kidney failure are also more prone to develop renal cell carcinoma.Recent research suggests that two genes on the short arm of chromosome 3 (i.e., PRC and TFE 3) may be involved in the development of this particular type of malignancy. This form of kidney cancer has developed in several members of the same family, leading scientists to believe that there may be a genetic form of the disorder or perhaps a genetic predisposition toward developing renal cell carcinoma. However, exactly how the disease may be inherited is still unknown. Another gene, known as VHL, has also been linked with kidney cancer.Renal cell carcinoma spreads (metastasizes) easily to the lungs and other organs.
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Causes of Renal Cell Carcinoma. The exact cause of renal cell carcinoma is not known. However, a history of smoking does increase the risk for developing this disease. Patients with von Hippel-Lindau disease, horseshoe kidneys, adult polycystic kidney disease and kidney failure are also more prone to develop renal cell carcinoma.Recent research suggests that two genes on the short arm of chromosome 3 (i.e., PRC and TFE 3) may be involved in the development of this particular type of malignancy. This form of kidney cancer has developed in several members of the same family, leading scientists to believe that there may be a genetic form of the disorder or perhaps a genetic predisposition toward developing renal cell carcinoma. However, exactly how the disease may be inherited is still unknown. Another gene, known as VHL, has also been linked with kidney cancer.Renal cell carcinoma spreads (metastasizes) easily to the lungs and other organs.
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Renal Cell Carcinoma
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Affects of Renal Cell Carcinoma
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Renal cell carcinoma is more common in males than in females (ratio of 2 or 3 to 1) and in persons with a history of smoking. It is also more common in persons with other types of kidney disorders and tends to run in some families. Renal cell carcinoma accounts for approximately 30,000 new cases of kidney malignancies per year in the United States.
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Affects of Renal Cell Carcinoma. Renal cell carcinoma is more common in males than in females (ratio of 2 or 3 to 1) and in persons with a history of smoking. It is also more common in persons with other types of kidney disorders and tends to run in some families. Renal cell carcinoma accounts for approximately 30,000 new cases of kidney malignancies per year in the United States.
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Renal Cell Carcinoma
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Related disorders of Renal Cell Carcinoma
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Symptoms of the following disorders can be similar to those of renal cell carcinoma. Comparisons may be useful for a differential diagnosis:Benign familial hematuria is a nonprogressive kidney disorder that usually begins in childhood and is characterized by red blood cells in the urine, and thinning of the microscopic parts of the kidney. It is often preceded by a respiratory infection. (For more information on this disorder, choose “Hematuria” as your search term in the Rare Disease Database.)IGA nephropathy is a kidney disorder usually occurring during childhood and young adulthood. It usually follows a viral infection of the upper respiratory or gastrointestinal tracts. The major symptom is the passing of blood in the urine. There may be associated pain in the loin area. (For more information on this disorder, choose “IGA” as your search term in the Rare Disease Database.)Polycystic kidney disease is an inherited disorder that is characterized by many cysts in both kidneys. This causes enlargement of the kidney size, while reducing the functional kidney tissue. In addition there may be pain in the loin area, blood in the urine, infection and colic. (For more information on this disorder, choose “Polycystic Kidney” as your search term in the Rare Disease Database.)Additionally, many types of common kidney and bladder infections can cause blood to appear in the urine. These infections are treated with antibiotics.
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Related disorders of Renal Cell Carcinoma. Symptoms of the following disorders can be similar to those of renal cell carcinoma. Comparisons may be useful for a differential diagnosis:Benign familial hematuria is a nonprogressive kidney disorder that usually begins in childhood and is characterized by red blood cells in the urine, and thinning of the microscopic parts of the kidney. It is often preceded by a respiratory infection. (For more information on this disorder, choose “Hematuria” as your search term in the Rare Disease Database.)IGA nephropathy is a kidney disorder usually occurring during childhood and young adulthood. It usually follows a viral infection of the upper respiratory or gastrointestinal tracts. The major symptom is the passing of blood in the urine. There may be associated pain in the loin area. (For more information on this disorder, choose “IGA” as your search term in the Rare Disease Database.)Polycystic kidney disease is an inherited disorder that is characterized by many cysts in both kidneys. This causes enlargement of the kidney size, while reducing the functional kidney tissue. In addition there may be pain in the loin area, blood in the urine, infection and colic. (For more information on this disorder, choose “Polycystic Kidney” as your search term in the Rare Disease Database.)Additionally, many types of common kidney and bladder infections can cause blood to appear in the urine. These infections are treated with antibiotics.
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Renal Cell Carcinoma
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Diagnosis of Renal Cell Carcinoma
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Imaging studies, typically computerized tomography (CT) and abdominal ultrasonography (USG), are used in the diagnosis of renal cell carcinoma. Blood and urine testing may also be helpful.
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Diagnosis of Renal Cell Carcinoma. Imaging studies, typically computerized tomography (CT) and abdominal ultrasonography (USG), are used in the diagnosis of renal cell carcinoma. Blood and urine testing may also be helpful.
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Renal Cell Carcinoma
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Therapies of Renal Cell Carcinoma
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TherapyThe drug sorafenib (Nexavar) was approved in 2005 by the Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma. Nexavar was developed through a partnership of Onyx Pharmaceuticals and the Bayer Pharmaceutical Corporation.Treatment for kidney cancer often involves the surgical removal of all or part of the kidney (nephrectomy). This may also involve removal of the bladder or surrounding tissues. Hormone treatments may reduce the growth of the tumor in some cases. Chemotherapy may also be used.Proleukin (interleukin-2 [IL-2]) was approved by the FDA in 1992 for the treatment of renal cell carcinoma. The drug is an anti-tumor agent usually given after surgery (nephrectomy) to slow tumor growth at sites to which the cancer may have spread (metastatic).In 2009, Afinitor® (everolimus) tablets were approved by the US Food and Drug Administration (FDA) for patients with advanced renal cell carcinoma (RCC) after failure of treatment with Sutent® (sunitinib) or Nexavar® (sorafenib).For more information contact:Novartis PharmaceuticalsCorporationOne Health PlazaEast Hanover, NJ 07936-1080http://www.pharma.us.novartis.comInlyta (also known as axitinib) by Pfizer In. was approved by the FDA in 2012 as a treatment for patients with renal cell carcinoma who have not responded to another drug for this type of cancer.
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Therapies of Renal Cell Carcinoma. TherapyThe drug sorafenib (Nexavar) was approved in 2005 by the Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma. Nexavar was developed through a partnership of Onyx Pharmaceuticals and the Bayer Pharmaceutical Corporation.Treatment for kidney cancer often involves the surgical removal of all or part of the kidney (nephrectomy). This may also involve removal of the bladder or surrounding tissues. Hormone treatments may reduce the growth of the tumor in some cases. Chemotherapy may also be used.Proleukin (interleukin-2 [IL-2]) was approved by the FDA in 1992 for the treatment of renal cell carcinoma. The drug is an anti-tumor agent usually given after surgery (nephrectomy) to slow tumor growth at sites to which the cancer may have spread (metastatic).In 2009, Afinitor® (everolimus) tablets were approved by the US Food and Drug Administration (FDA) for patients with advanced renal cell carcinoma (RCC) after failure of treatment with Sutent® (sunitinib) or Nexavar® (sorafenib).For more information contact:Novartis PharmaceuticalsCorporationOne Health PlazaEast Hanover, NJ 07936-1080http://www.pharma.us.novartis.comInlyta (also known as axitinib) by Pfizer In. was approved by the FDA in 2012 as a treatment for patients with renal cell carcinoma who have not responded to another drug for this type of cancer.
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Renal Cell Carcinoma
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Overview of Renal Glycosuria
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Renal (kidney) glycosuria is a rare condition in which too much of the simple sugar glucose is removed through the urine. This happens even though there are normal or low levels of glucose in the blood. When the kidney is working correctly, glucose is only removed into the urine when there is too much in the blood. However, in people with renal glycosuria, glucose is removed in the urine when it should not be because the renal tubules in the kidneys are not working properly. The renal tubules are the part of the kidney that cleans the blood. Most affected people have no symptoms (asymptomatic). When renal glycosuria occurs by itself, the condition can be inherited in an autosomal dominant or autosomal recessive pattern.
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Overview of Renal Glycosuria. Renal (kidney) glycosuria is a rare condition in which too much of the simple sugar glucose is removed through the urine. This happens even though there are normal or low levels of glucose in the blood. When the kidney is working correctly, glucose is only removed into the urine when there is too much in the blood. However, in people with renal glycosuria, glucose is removed in the urine when it should not be because the renal tubules in the kidneys are not working properly. The renal tubules are the part of the kidney that cleans the blood. Most affected people have no symptoms (asymptomatic). When renal glycosuria occurs by itself, the condition can be inherited in an autosomal dominant or autosomal recessive pattern.
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Renal Glycosuria
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Symptoms of Renal Glycosuria
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In people with renal glycosuria, glucose is removed in the urine even though there are normal or low levels of glucose in the blood. As blood flows through the kidneys, glucose and other substances are cleaned from the liquid portion of the blood. The newly cleaned blood then moves through tubes in the kidneys (renal tubules). Helpful substances, including glucose, sodium, and wate, are reabsorbed and returned to the bloodstream. Unwanted substances are removed from the bloodstream through the urine. When the kidney is working, glucose is only removed into the urine when there is too much sugar in the blood. However, in people with renal glycosuria, extra glucose is removed and/or, the kidney is unable to reabsorb glucose as quickly as it should. (For more, see “Causes” below.)Most people with renal glycosuria have no obvious symptoms (asymptomatic). Sometimes, glycosuria can cause excess urination (polyuria), extreme thirst(polydipsia), and other symptoms. Involuntary urination (enuresis) and mild delays in growth and maturation during puberty have been reported in rare cases. When a person with renal glycosuria is pregnant or starving, this may cause low levels of fluid in the body (dehydration). It can also cause a tissue build-up of certain chemical substances (ketone bodies). Fluids also build up due to too much breakdown of fats (ketosis).
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Symptoms of Renal Glycosuria. In people with renal glycosuria, glucose is removed in the urine even though there are normal or low levels of glucose in the blood. As blood flows through the kidneys, glucose and other substances are cleaned from the liquid portion of the blood. The newly cleaned blood then moves through tubes in the kidneys (renal tubules). Helpful substances, including glucose, sodium, and wate, are reabsorbed and returned to the bloodstream. Unwanted substances are removed from the bloodstream through the urine. When the kidney is working, glucose is only removed into the urine when there is too much sugar in the blood. However, in people with renal glycosuria, extra glucose is removed and/or, the kidney is unable to reabsorb glucose as quickly as it should. (For more, see “Causes” below.)Most people with renal glycosuria have no obvious symptoms (asymptomatic). Sometimes, glycosuria can cause excess urination (polyuria), extreme thirst(polydipsia), and other symptoms. Involuntary urination (enuresis) and mild delays in growth and maturation during puberty have been reported in rare cases. When a person with renal glycosuria is pregnant or starving, this may cause low levels of fluid in the body (dehydration). It can also cause a tissue build-up of certain chemical substances (ketone bodies). Fluids also build up due to too much breakdown of fats (ketosis).
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Causes of Renal Glycosuria
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Renal glycosuria is an inherited problem of membrane transport (i.e., an abnormal renal transport syndrome). Membrane transport disorders are marked by problems with the movement (i.e., transport) of one or more compounds across the outer layer of the cell (cell membranes). They are thought to result from harmful genetic changes (mutations) that cause certain membrane proteins to not be made correctly.Because the renal tubules are not working well, there is a reduction in the levels of glucose in the blood. The body begins to accept this lower level as the new normal and interprets normal levels of glucose as excess, causing the body to remove glucose through urine when levels are not increased (low renal threshold for glucose). In some people, there is a reduction in the maximum rate at which glucose may be reabsorbed into the bloodstream (reduced transport maximum [tubular maximum for glucose or “TmG”]). Renal glycosuria is divided into two major subtypes. Type A has a low renal threshold, and reduced TmG. Type B has a low renal threshold and normal TmG. In addition, there is renal glycosuria type 0, in which there is no renal tubular glucose reabsorption.The primary cause of renal glycosuria is a harmful change (mutation) in a gene known as “SLC5A2” (also called the renal sodium-glucose cotransporter gene).Many inheritance patterns have been reported for renal glycosuria, and more research is needed to clarify the pattern of inheritance. Renal glycosuria can be inherited autosomal recessive manner. Recessive genetic conditions 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 chance 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.Autosomal dominant inheritance with reduced penetrance has also been reported. Reduced penetrance means that someone with a genetic mutation may or may not develop symptoms. 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.People who inherit two copies of a gene for renal glycosuria (homozygosity) may have more severe symptoms, as do those who inherit one copy of a gene mutation for renal glycosuria and a second copy with a different gene mutation for renal glycosuria in the same gene (compound heterozygotes). Based on such evidence, a codominant inheritance pattern with reduced penetrance has been recently proposed as the best fit. Codominance occurs when both copies of the gene are equally expressed, with neither being dominant or recessive.Renal glycosuria types A and B have occurred in members of the same family. In such cases, both parents may be normal or may have abnormal renal tubular transport of glucose. Such evidence leads experts to suggest that other genetic or non-genetic factors may be involved in causing renal glycosuria.
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Causes of Renal Glycosuria. Renal glycosuria is an inherited problem of membrane transport (i.e., an abnormal renal transport syndrome). Membrane transport disorders are marked by problems with the movement (i.e., transport) of one or more compounds across the outer layer of the cell (cell membranes). They are thought to result from harmful genetic changes (mutations) that cause certain membrane proteins to not be made correctly.Because the renal tubules are not working well, there is a reduction in the levels of glucose in the blood. The body begins to accept this lower level as the new normal and interprets normal levels of glucose as excess, causing the body to remove glucose through urine when levels are not increased (low renal threshold for glucose). In some people, there is a reduction in the maximum rate at which glucose may be reabsorbed into the bloodstream (reduced transport maximum [tubular maximum for glucose or “TmG”]). Renal glycosuria is divided into two major subtypes. Type A has a low renal threshold, and reduced TmG. Type B has a low renal threshold and normal TmG. In addition, there is renal glycosuria type 0, in which there is no renal tubular glucose reabsorption.The primary cause of renal glycosuria is a harmful change (mutation) in a gene known as “SLC5A2” (also called the renal sodium-glucose cotransporter gene).Many inheritance patterns have been reported for renal glycosuria, and more research is needed to clarify the pattern of inheritance. Renal glycosuria can be inherited autosomal recessive manner. Recessive genetic conditions 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 chance 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.Autosomal dominant inheritance with reduced penetrance has also been reported. Reduced penetrance means that someone with a genetic mutation may or may not develop symptoms. 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.People who inherit two copies of a gene for renal glycosuria (homozygosity) may have more severe symptoms, as do those who inherit one copy of a gene mutation for renal glycosuria and a second copy with a different gene mutation for renal glycosuria in the same gene (compound heterozygotes). Based on such evidence, a codominant inheritance pattern with reduced penetrance has been recently proposed as the best fit. Codominance occurs when both copies of the gene are equally expressed, with neither being dominant or recessive.Renal glycosuria types A and B have occurred in members of the same family. In such cases, both parents may be normal or may have abnormal renal tubular transport of glucose. Such evidence leads experts to suggest that other genetic or non-genetic factors may be involved in causing renal glycosuria.
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Affects of Renal Glycosuria
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Renal glycosuria occurs in about 1/33,000 people in the general population and affects males and females equally. Most people with renal glycosuria have no symptoms (asymptomatic). Less commonly, serious symptoms (e.g., dehydration, ketosis) may be seen. This happens most often under certain conditions such as pregnancy or starvation.
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Affects of Renal Glycosuria. Renal glycosuria occurs in about 1/33,000 people in the general population and affects males and females equally. Most people with renal glycosuria have no symptoms (asymptomatic). Less commonly, serious symptoms (e.g., dehydration, ketosis) may be seen. This happens most often under certain conditions such as pregnancy or starvation.
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Related disorders of Renal Glycosuria
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Certain features of the following disorders may be similar to those connected to renal glycosuria. Comparisons may be useful for a making a correct diagnosis:Diabetes mellitus is a common disorder of high blood sugar (glucose) levels. It is due to a lack of insulin or an inability to use insulin. The hormone insulin helps with movement of glucose into cells for the body’s energy needs. Insulin may also go into liver and fat cells for storage. Too little insulin may lead to poor absorption of glucose leading to increased levels of glucose in the blood (hyperglycemia) and high levels of glucose in the urine (glycosuria). Not enough insulin may lead to reduced breakdown of fat (fat metabolism) and degeneration or loss of function of certain blood vessels. Symptoms may include excessive urination (polyuria) and increased thirst (polydipsia), and excessive hunger and eating (polyphagia). Other complications may arise without proper treatment. Although the exact causes of diabetes mellitus are not known, genetic factors are thought to play some role.Fanconi syndrome is renal (kidney) condition that may occur on its own or as part of a genetic condition, most often cystinosis. It can also develop due to environmental factors. Examples include drug toxicity, kidney transplantation, vitamin D deficiency or heavy metal exposure. Fanconi syndrome occurs when the first portion of the renal tubules (proximal renal tubules) is not working. Findings may include high acidity of the blood and increased levels of glucose, phosphates, bicarbonate and particular amino acids in the urine.Hypophosphatemic rickets refers to a group of conditions of proximal renal tubular dysfunction. They are identified by loss of phosphate and too low levels of the active form of vitamin D. Decreased intestinal absorption of calcium and skeletal problems occur in these conditions. Symptoms may include excessive removal of phosphate in the urine and low blood phosphate levels. Bone softening (osteomalacia) and pain, bowing of the legs, short stature, and/or other features are also seen. The condition can be inherited or develop due to certain cancers.
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Related disorders of Renal Glycosuria. Certain features of the following disorders may be similar to those connected to renal glycosuria. Comparisons may be useful for a making a correct diagnosis:Diabetes mellitus is a common disorder of high blood sugar (glucose) levels. It is due to a lack of insulin or an inability to use insulin. The hormone insulin helps with movement of glucose into cells for the body’s energy needs. Insulin may also go into liver and fat cells for storage. Too little insulin may lead to poor absorption of glucose leading to increased levels of glucose in the blood (hyperglycemia) and high levels of glucose in the urine (glycosuria). Not enough insulin may lead to reduced breakdown of fat (fat metabolism) and degeneration or loss of function of certain blood vessels. Symptoms may include excessive urination (polyuria) and increased thirst (polydipsia), and excessive hunger and eating (polyphagia). Other complications may arise without proper treatment. Although the exact causes of diabetes mellitus are not known, genetic factors are thought to play some role.Fanconi syndrome is renal (kidney) condition that may occur on its own or as part of a genetic condition, most often cystinosis. It can also develop due to environmental factors. Examples include drug toxicity, kidney transplantation, vitamin D deficiency or heavy metal exposure. Fanconi syndrome occurs when the first portion of the renal tubules (proximal renal tubules) is not working. Findings may include high acidity of the blood and increased levels of glucose, phosphates, bicarbonate and particular amino acids in the urine.Hypophosphatemic rickets refers to a group of conditions of proximal renal tubular dysfunction. They are identified by loss of phosphate and too low levels of the active form of vitamin D. Decreased intestinal absorption of calcium and skeletal problems occur in these conditions. Symptoms may include excessive removal of phosphate in the urine and low blood phosphate levels. Bone softening (osteomalacia) and pain, bowing of the legs, short stature, and/or other features are also seen. The condition can be inherited or develop due to certain cancers.
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Diagnosis of Renal Glycosuria
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Renal glycosuria is diagnosed based upon laboratory tests of urine and blood. They are looking for glucose in the urine and normal or low levels of glucose in the blood. (Usually, people cannot eat the night before the testing.) Once someone has this diagnosis, they may go on to have genetic testing for changes (mutations) in the SLC5A2 gene to determine risks for family members.
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Diagnosis of Renal Glycosuria. Renal glycosuria is diagnosed based upon laboratory tests of urine and blood. They are looking for glucose in the urine and normal or low levels of glucose in the blood. (Usually, people cannot eat the night before the testing.) Once someone has this diagnosis, they may go on to have genetic testing for changes (mutations) in the SLC5A2 gene to determine risks for family members.
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Therapies of Renal Glycosuria
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TreatmentTreatment is not needed for most people with this condition. However, some people with renal glycosuria may develop diabetes mellitus. (For more information, please see the “Related Disorders” section above.) so people with this condition should have testing to rule out diabetes. People with renal glycosuria should have routine medical care with a primary care provider and treatment is based on symptoms.Genetic counseling will help affected people and their families.
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Therapies of Renal Glycosuria. TreatmentTreatment is not needed for most people with this condition. However, some people with renal glycosuria may develop diabetes mellitus. (For more information, please see the “Related Disorders” section above.) so people with this condition should have testing to rule out diabetes. People with renal glycosuria should have routine medical care with a primary care provider and treatment is based on symptoms.Genetic counseling will help affected people and their families.
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Overview of Renal Medullary Carcinoma
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SummaryRenal medullary carcinoma, also known as RMC, is a rare cancer of the kidney that predominantly afflicts young people of African descent who carry the sickle cell trait, sickle cell disease or other sickle hemoglobinopathies that can cause sickling of the red blood cells. Renal cell carcinoma, unclassified with medullary phenotype (RCCU-MP) is a very rare subtype of RMC that occurs in people who do not carry any sickle hemoglobinopathies. All RMC and RCCU-MP tumors characteristically do not express a protein called INI1, also known as SMARCB1, hSNF5 or BAF47. Most patients with RMC are young and the cancer will most often have spread to the lymph nodes or other organs by the time it is diagnosed. RMC is twice more likely to occur in men than women, and in the right kidney compared with the left. The most common symptoms are blood in the urine and pain on the kidney side. RMC is treated with chemotherapy, surgery (when feasible) and sometimes radiation therapy. The exact cause of RMC is not fully understood.IntroductionRMC was originally described in 1995 and is one of the most aggressive kidney cancers. Half of the patients with RMC described in the original 1995 study did not survive longer than 4 months from diagnosis. With current therapies this has improved to 13 months and research is underway to find new and better treatments. RMC can be easier to treat if diagnosed early. Therefore, young black individuals (particularly those who are known to carry the sickle cell trait or sickle cell disease) should immediately contact their healthcare provider if they experience symptoms that can suggest RMC. By the time it is diagnosed, RMC will have spread to the lymph nodes or other organs in more than 90% of patients. If left untreated, RMC can quickly spread to the lymph nodes or other organs even in those patients who initially have RMC contained within the kidney. RMC most commonly spreads to the lymph nodes (85% of patients), lungs (46%), liver (15%) and bone (15%), but almost never spreads to the brain.
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Overview of Renal Medullary Carcinoma. SummaryRenal medullary carcinoma, also known as RMC, is a rare cancer of the kidney that predominantly afflicts young people of African descent who carry the sickle cell trait, sickle cell disease or other sickle hemoglobinopathies that can cause sickling of the red blood cells. Renal cell carcinoma, unclassified with medullary phenotype (RCCU-MP) is a very rare subtype of RMC that occurs in people who do not carry any sickle hemoglobinopathies. All RMC and RCCU-MP tumors characteristically do not express a protein called INI1, also known as SMARCB1, hSNF5 or BAF47. Most patients with RMC are young and the cancer will most often have spread to the lymph nodes or other organs by the time it is diagnosed. RMC is twice more likely to occur in men than women, and in the right kidney compared with the left. The most common symptoms are blood in the urine and pain on the kidney side. RMC is treated with chemotherapy, surgery (when feasible) and sometimes radiation therapy. The exact cause of RMC is not fully understood.IntroductionRMC was originally described in 1995 and is one of the most aggressive kidney cancers. Half of the patients with RMC described in the original 1995 study did not survive longer than 4 months from diagnosis. With current therapies this has improved to 13 months and research is underway to find new and better treatments. RMC can be easier to treat if diagnosed early. Therefore, young black individuals (particularly those who are known to carry the sickle cell trait or sickle cell disease) should immediately contact their healthcare provider if they experience symptoms that can suggest RMC. By the time it is diagnosed, RMC will have spread to the lymph nodes or other organs in more than 90% of patients. If left untreated, RMC can quickly spread to the lymph nodes or other organs even in those patients who initially have RMC contained within the kidney. RMC most commonly spreads to the lymph nodes (85% of patients), lungs (46%), liver (15%) and bone (15%), but almost never spreads to the brain.
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Symptoms of Renal Medullary Carcinoma
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The most common first sign of RMC is blood in the urine (hematuria) and patients may also feel pain in their flank around the kidney area or (less commonly) feel a mass in their abdomen, usually on the right side. About half of the patients with RMC will begin losing weight unintentionally and may develop fevers and night sweats.
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Symptoms of Renal Medullary Carcinoma. The most common first sign of RMC is blood in the urine (hematuria) and patients may also feel pain in their flank around the kidney area or (less commonly) feel a mass in their abdomen, usually on the right side. About half of the patients with RMC will begin losing weight unintentionally and may develop fevers and night sweats.
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Causes of Renal Medullary Carcinoma
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The exact reason why RMC develops is not fully understood but almost all patients have a blood disorder that can make their red blood cells sickle. These disorders are called “sickle hemoglobinopathies” and include sickle cell trait and sickle cell disease. Of note, most individuals with sickle cell trait are otherwise healthy and many are not aware that they have this blood disorder. Other than the presence of sickle hemoglobinopathy, there are no other known genetic predispositions that can explain why only certain individuals will develop RMC. There is currently no evidence to suggest that family members of a patient with RMC are at increased risk for developing RMC themselves. Although individuals with sickle hemoglobinopathies should take early signs and symptoms of possible RMC very seriously, there are currently no known effective strategies to screen for RMC in individuals without symptoms.Notably, all RMC tumors lack a protein called INI1, also known as SMARCB1, hSNF5 or BAF47. This protein is also often lost in other rare cancers such as malignant rhabdoid tumors (MRT), atypical teratoid rhabdoid tumors (ATRT) and epithelioid sarcomas. INI1 is a “tumor suppressor” that normally protects cells from turning into cancer.The red blood cells of individuals with sickle cell disease have changed into a sickle shape throughout the body and this can produce multiple health problems and symptoms unrelated to RMC. On the other hand, the red blood cells of individuals with sickle cell trait change into a sickle shape only in specific locations within the body, such as a part of the kidney called the “renal medulla”. This sickle shape makes red blood cells sticky, rigid and prone to blocking the blood supply of the renal medulla. It is thought that this process can sometimes damage the INI1 gene in cells within the renal medulla thus resulting in RMC. In rare cases, INI1 may be lost in the cells of the renal medulla in individuals without any sickle hemoglobinopathies, thus resulting in a subtype of RMC provisionally called “renal cell carcinoma, unclassified with medullary phenotype” (RCCU-MP).Recent evidence suggests that high-intensity exercise may be associated with RMC in individuals with sickle cell trait. High-intensity exercise can cause dehydration, low oxygenation and overheating that occasionally lead to serious complications in people with sickle cell trait, including damaging the kidneys in ways that may increase the risk for RMC. High-intensity exercise is defined as increasing your heart rate to 80% or more of your maximum heart rate. The maximum heart rate can be calculated by 220 minus your age. Thus, if you are 30 years old, then your maximum heart rate is 190 beats per minute, and 80% of your maximum heart rate is around 150 beat per minute. High-intensity exercise makes your breathing deep and rapid, you may sweat after just a few minutes of activity, and cannot say more than a few words without pausing for a breath. On the other hand, there is evidence that moderate-intensity exercise may decrease such kidney damage compared with having a sedentary lifestyle. Moderate-intensity exercise is defined as achieving between 50-70% of your maximum heart rate. Such exercise may quicken your breath, but you are not out of breath. Moderate-intensity exercise may make you develop a light sweat after 5-10 minutes of activity, and you can carry on a conversation but cannot sing. Individuals with sickle cell trait can participate in sports with no problems if they drink enough water, take breaks when needed and not overdo it, particularly when starting a new exercise program.
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Causes of Renal Medullary Carcinoma. The exact reason why RMC develops is not fully understood but almost all patients have a blood disorder that can make their red blood cells sickle. These disorders are called “sickle hemoglobinopathies” and include sickle cell trait and sickle cell disease. Of note, most individuals with sickle cell trait are otherwise healthy and many are not aware that they have this blood disorder. Other than the presence of sickle hemoglobinopathy, there are no other known genetic predispositions that can explain why only certain individuals will develop RMC. There is currently no evidence to suggest that family members of a patient with RMC are at increased risk for developing RMC themselves. Although individuals with sickle hemoglobinopathies should take early signs and symptoms of possible RMC very seriously, there are currently no known effective strategies to screen for RMC in individuals without symptoms.Notably, all RMC tumors lack a protein called INI1, also known as SMARCB1, hSNF5 or BAF47. This protein is also often lost in other rare cancers such as malignant rhabdoid tumors (MRT), atypical teratoid rhabdoid tumors (ATRT) and epithelioid sarcomas. INI1 is a “tumor suppressor” that normally protects cells from turning into cancer.The red blood cells of individuals with sickle cell disease have changed into a sickle shape throughout the body and this can produce multiple health problems and symptoms unrelated to RMC. On the other hand, the red blood cells of individuals with sickle cell trait change into a sickle shape only in specific locations within the body, such as a part of the kidney called the “renal medulla”. This sickle shape makes red blood cells sticky, rigid and prone to blocking the blood supply of the renal medulla. It is thought that this process can sometimes damage the INI1 gene in cells within the renal medulla thus resulting in RMC. In rare cases, INI1 may be lost in the cells of the renal medulla in individuals without any sickle hemoglobinopathies, thus resulting in a subtype of RMC provisionally called “renal cell carcinoma, unclassified with medullary phenotype” (RCCU-MP).Recent evidence suggests that high-intensity exercise may be associated with RMC in individuals with sickle cell trait. High-intensity exercise can cause dehydration, low oxygenation and overheating that occasionally lead to serious complications in people with sickle cell trait, including damaging the kidneys in ways that may increase the risk for RMC. High-intensity exercise is defined as increasing your heart rate to 80% or more of your maximum heart rate. The maximum heart rate can be calculated by 220 minus your age. Thus, if you are 30 years old, then your maximum heart rate is 190 beats per minute, and 80% of your maximum heart rate is around 150 beat per minute. High-intensity exercise makes your breathing deep and rapid, you may sweat after just a few minutes of activity, and cannot say more than a few words without pausing for a breath. On the other hand, there is evidence that moderate-intensity exercise may decrease such kidney damage compared with having a sedentary lifestyle. Moderate-intensity exercise is defined as achieving between 50-70% of your maximum heart rate. Such exercise may quicken your breath, but you are not out of breath. Moderate-intensity exercise may make you develop a light sweat after 5-10 minutes of activity, and you can carry on a conversation but cannot sing. Individuals with sickle cell trait can participate in sports with no problems if they drink enough water, take breaks when needed and not overdo it, particularly when starting a new exercise program.
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Affects of Renal Medullary Carcinoma
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RMC predominantly afflicts young adults and adolescents with sickle cell trait, sickle cell disease or other hemoglobinopathies that can cause red blood cells to change into a sickle shape. In the United States, such sickle hemoglobinopathies are mainly found in individuals of African descent. In other countries such as Greece, sickle hemoglobinopathies are found mainly in Caucasians. The presence of these sickle hemoglobinopathies increases the risk of RMC regardless of race or ethnicity. Men are twice as likely to be affected by RMC than women, and about 70% of RMC cases start from the right kidney. RMC is the third most common kidney cancer among children and young adults. Half of the patients diagnosed with RMC are 28 years old or younger with some being as young as 9 years old. Less commonly, patients can be 35 years old or older.Although all sickle hemoglobinopathies are risk factors for RMC, the vast majority of patients with RMC have sickle cell trait and only a handful have sickle cell disease or other sickle hemoglobinopathies such as hemoglobin SC disease or sickle beta thalassemia. This may in part be because sickle cell trait is 55 times more common than other sickle hemoglobinopathies. Pure thalassemias, such as alpha or beta thalassemia, are not risk factors for RMC.About 1 in 14 African Americans carry the sickle cell trait and between 1/20,000 to 1/39,000 of individuals with sickle cell trait will develop RMC. Sickle cell trait is found in approximately 300 million individuals worldwide. The frequency of sickle cell trait varies among different populations and can range from approximately 7% among African Americans, 23.5% in the Chalkidhiki peninsula of Greece, 10% in the Çukurova region of southern Turkey, up to 13% among certain populations in central India, 20% in the eastern province of Saudi Arabia and between 10%-40% across equatorial Africa, reaching up to 45% among the Baamba tribe in Uganda. However, most reports of RMC come from the United States or Europe. This is most likely because RMC is misdiagnosed in other countries, although it is possible that there may be environmental or other local regional risk factors for RMC in the United States and Europe.
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Affects of Renal Medullary Carcinoma. RMC predominantly afflicts young adults and adolescents with sickle cell trait, sickle cell disease or other hemoglobinopathies that can cause red blood cells to change into a sickle shape. In the United States, such sickle hemoglobinopathies are mainly found in individuals of African descent. In other countries such as Greece, sickle hemoglobinopathies are found mainly in Caucasians. The presence of these sickle hemoglobinopathies increases the risk of RMC regardless of race or ethnicity. Men are twice as likely to be affected by RMC than women, and about 70% of RMC cases start from the right kidney. RMC is the third most common kidney cancer among children and young adults. Half of the patients diagnosed with RMC are 28 years old or younger with some being as young as 9 years old. Less commonly, patients can be 35 years old or older.Although all sickle hemoglobinopathies are risk factors for RMC, the vast majority of patients with RMC have sickle cell trait and only a handful have sickle cell disease or other sickle hemoglobinopathies such as hemoglobin SC disease or sickle beta thalassemia. This may in part be because sickle cell trait is 55 times more common than other sickle hemoglobinopathies. Pure thalassemias, such as alpha or beta thalassemia, are not risk factors for RMC.About 1 in 14 African Americans carry the sickle cell trait and between 1/20,000 to 1/39,000 of individuals with sickle cell trait will develop RMC. Sickle cell trait is found in approximately 300 million individuals worldwide. The frequency of sickle cell trait varies among different populations and can range from approximately 7% among African Americans, 23.5% in the Chalkidhiki peninsula of Greece, 10% in the Çukurova region of southern Turkey, up to 13% among certain populations in central India, 20% in the eastern province of Saudi Arabia and between 10%-40% across equatorial Africa, reaching up to 45% among the Baamba tribe in Uganda. However, most reports of RMC come from the United States or Europe. This is most likely because RMC is misdiagnosed in other countries, although it is possible that there may be environmental or other local regional risk factors for RMC in the United States and Europe.
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Related disorders of Renal Medullary Carcinoma
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Young children (average age of 9 years old) with sickle cell trait are also at risk for developing another distinct cancer named “VCL-ALK renal cell carcinoma” (VCL-ALK RCC) also arising from the renal medulla. This cancer is characterized by the fusion of two genes called VCL and ALK. This VCL-ALK fusion is not found in RMC. Furthermore, VCL-ALK RCC expresses INI1 and is generally a much less aggressive cancer than RMC.RCCU-MP is a rare subtype of RMC that lacks INI1 and arises from the renal medulla but occurs in individuals without sickle hemoglobinopathies. It is generally diagnosed and managed similarly to typical RMC.
MRT of the kidney is a cancer that also lacks INI1 but is not associated with sickle hemoglobinopathies, and predominantly occurs in very young children (less than 3 years old). Although they share some biological similarities, MRT of the kidney has a very different appearance than RMC under the microscope and is managed differently. Collecting duct carcinoma (CDC) is an aggressive kidney cancer that looks very similar to RMC under the microscope and is often treated with similar therapies. CDC expresses INI1, occurs in older individuals and is not associated with sickle hemoglobinopathies. “CDC” tumors occurring in young individuals with sickle hemoglobinopathies should be tested for INI1 expression to ensure that this is not actually RMC instead of CDC.
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Related disorders of Renal Medullary Carcinoma. Young children (average age of 9 years old) with sickle cell trait are also at risk for developing another distinct cancer named “VCL-ALK renal cell carcinoma” (VCL-ALK RCC) also arising from the renal medulla. This cancer is characterized by the fusion of two genes called VCL and ALK. This VCL-ALK fusion is not found in RMC. Furthermore, VCL-ALK RCC expresses INI1 and is generally a much less aggressive cancer than RMC.RCCU-MP is a rare subtype of RMC that lacks INI1 and arises from the renal medulla but occurs in individuals without sickle hemoglobinopathies. It is generally diagnosed and managed similarly to typical RMC.
MRT of the kidney is a cancer that also lacks INI1 but is not associated with sickle hemoglobinopathies, and predominantly occurs in very young children (less than 3 years old). Although they share some biological similarities, MRT of the kidney has a very different appearance than RMC under the microscope and is managed differently. Collecting duct carcinoma (CDC) is an aggressive kidney cancer that looks very similar to RMC under the microscope and is often treated with similar therapies. CDC expresses INI1, occurs in older individuals and is not associated with sickle hemoglobinopathies. “CDC” tumors occurring in young individuals with sickle hemoglobinopathies should be tested for INI1 expression to ensure that this is not actually RMC instead of CDC.
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Diagnosis of Renal Medullary Carcinoma
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Because RMC does not cause symptoms early in the disease, getting an early diagnosis is difficult. Since treatment of RMC can be more effective the earlier the disease is identified, early diagnosis is important.The diagnosis of RMC should be suspected when a cancer arising from the kidney (most commonly from the right kidney) is found to look under the microscope like a “high-grade, poorly differentiated adenocarcinoma”, particularly if the patient is young and carries the sickle cell trait or other sickle hemoglobinopathies. The cancer tissue should be tested for expression of the INI1 protein using a method called “immunohistochemistry”. If the tissue is negative for INI1 then RMC is confirmed. If the tissue is positive for INI1 then the cancer is not RMC. If the tissue is negative for INI1 but the patient does not carry the sickle cell trait or other sickle hemoglobinopathies then this is the subtype of RMC provisionally called RCCU-MP.Clinical Testing and WorkupIndividuals with sickle cell trait or other sickle hemoglobinopathies who develop signs or symptoms (such as blood in the urine) suggestive of RMC can be evaluated using an ultrasound examination of their kidneys. During an ultrasound, reflected sound waves are used to create an image of the kidneys and other nearby structures. If a mass is found that is suspicious for cancer, then the doctors may recommend advanced imaging techniques such as computed tomography (CT) scan or magnetic resonance imaging (MRI) to further investigate whether this is indeed a cancer. CT and MRI scans use x-rays or magnetic waves, respectively, that are processed by a computer to create images of certain tissue structures, such as the kidneys, within the abdomen and other areas of the body.If the CT or MRI images show a mass in the kidney that is suspicious for cancer, then doctors may need to take a tiny sample of tissue from the kidney or from other areas that the cancer may have spread to. This is called “biopsy”. During a biopsy, a needle is passed through the skin to take a tiny sample of tumor tissue. The tissue is then studied under the microscope to confirm the diagnosis of RMC. The tissue needs to be tested for the presence or absence of INI1 (also known as SMARCB1, hSNF5 or BAF47) using a method called “immunohistochemistry”.
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Diagnosis of Renal Medullary Carcinoma. Because RMC does not cause symptoms early in the disease, getting an early diagnosis is difficult. Since treatment of RMC can be more effective the earlier the disease is identified, early diagnosis is important.The diagnosis of RMC should be suspected when a cancer arising from the kidney (most commonly from the right kidney) is found to look under the microscope like a “high-grade, poorly differentiated adenocarcinoma”, particularly if the patient is young and carries the sickle cell trait or other sickle hemoglobinopathies. The cancer tissue should be tested for expression of the INI1 protein using a method called “immunohistochemistry”. If the tissue is negative for INI1 then RMC is confirmed. If the tissue is positive for INI1 then the cancer is not RMC. If the tissue is negative for INI1 but the patient does not carry the sickle cell trait or other sickle hemoglobinopathies then this is the subtype of RMC provisionally called RCCU-MP.Clinical Testing and WorkupIndividuals with sickle cell trait or other sickle hemoglobinopathies who develop signs or symptoms (such as blood in the urine) suggestive of RMC can be evaluated using an ultrasound examination of their kidneys. During an ultrasound, reflected sound waves are used to create an image of the kidneys and other nearby structures. If a mass is found that is suspicious for cancer, then the doctors may recommend advanced imaging techniques such as computed tomography (CT) scan or magnetic resonance imaging (MRI) to further investigate whether this is indeed a cancer. CT and MRI scans use x-rays or magnetic waves, respectively, that are processed by a computer to create images of certain tissue structures, such as the kidneys, within the abdomen and other areas of the body.If the CT or MRI images show a mass in the kidney that is suspicious for cancer, then doctors may need to take a tiny sample of tissue from the kidney or from other areas that the cancer may have spread to. This is called “biopsy”. During a biopsy, a needle is passed through the skin to take a tiny sample of tumor tissue. The tissue is then studied under the microscope to confirm the diagnosis of RMC. The tissue needs to be tested for the presence or absence of INI1 (also known as SMARCB1, hSNF5 or BAF47) using a method called “immunohistochemistry”.
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Renal Medullary Carcinoma
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nord_1063_6
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Therapies of Renal Medullary Carcinoma
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Treatment
Treatment of RMC may require the coordinated efforts of a team of specialists who will need to plan an affected patient’s treatment systematically and comprehensively. This may include specialists who diagnose and treat cancer (medical oncologists), specialists who perform surgery on the kidney (urologists), specialists who use ionizing radiation to treat cancer (radiation oncologists), specialists who use minimally invasive, image-guide technologies to diagnose and treat cancer (interventional radiologists), as well as other healthcare professionals. Psychosocial support for the entire family is also essential.Specific therapeutic procedures and interventions may vary, depending upon many factors, such as disease stage (how extensive the disease is), the size of the tumor, the presence or absence of certain symptoms, whether the disease has spread (metastasized) to other areas of the body, an individual’s age and general health and/or other elements. Decisions concerning the use of surgery, radiation, specific drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case as well as a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects, patient preferences and other appropriate factors.RMC is often treated with chemotherapy. Many of the therapies that are used for other kidney cancers do not work against RMC. If CT or MRI imaging suggests that RMC is confined only to the kidney and has not spread to other areas, then surgery can be considered to remove the whole kidney and the cancer inside it. If the RMC tumor is large, for example larger than 4 cm, then doctors may decide to use chemotherapy first in order to shrink the tumor and perform the surgery afterwards, even if there is no evidence on CT or MRI that RMC has spread to other areas. This is because all imaging tests, including CT and MRI, are imperfect and may not detect very small RMC tumors in the lymph nodes or other organs. In these situations, it is hoped that the chemotherapy will treat these areas first, before they are allowed to become too big. Other specific therapeutic procedures may include radiation therapy or other therapies.
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Therapies of Renal Medullary Carcinoma. Treatment
Treatment of RMC may require the coordinated efforts of a team of specialists who will need to plan an affected patient’s treatment systematically and comprehensively. This may include specialists who diagnose and treat cancer (medical oncologists), specialists who perform surgery on the kidney (urologists), specialists who use ionizing radiation to treat cancer (radiation oncologists), specialists who use minimally invasive, image-guide technologies to diagnose and treat cancer (interventional radiologists), as well as other healthcare professionals. Psychosocial support for the entire family is also essential.Specific therapeutic procedures and interventions may vary, depending upon many factors, such as disease stage (how extensive the disease is), the size of the tumor, the presence or absence of certain symptoms, whether the disease has spread (metastasized) to other areas of the body, an individual’s age and general health and/or other elements. Decisions concerning the use of surgery, radiation, specific drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case as well as a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects, patient preferences and other appropriate factors.RMC is often treated with chemotherapy. Many of the therapies that are used for other kidney cancers do not work against RMC. If CT or MRI imaging suggests that RMC is confined only to the kidney and has not spread to other areas, then surgery can be considered to remove the whole kidney and the cancer inside it. If the RMC tumor is large, for example larger than 4 cm, then doctors may decide to use chemotherapy first in order to shrink the tumor and perform the surgery afterwards, even if there is no evidence on CT or MRI that RMC has spread to other areas. This is because all imaging tests, including CT and MRI, are imperfect and may not detect very small RMC tumors in the lymph nodes or other organs. In these situations, it is hoped that the chemotherapy will treat these areas first, before they are allowed to become too big. Other specific therapeutic procedures may include radiation therapy or other therapies.
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Renal Medullary Carcinoma
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nord_1064_0
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Overview of Renal Oncocytoma
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SummaryRenal oncocytoma, also known as oncocytoma of the kidney, is a rare type of benign kidney tumor. It is composed of oncocytes, which are cells that have an abnormally large number of mitochondria, the organelles that produce energy for the cell. Renal oncocytomas are usually slow-growing and do not spread beyond the kidney, but in rare cases they can become cancerous.Symptoms of renal oncocytoma may include abdominal pain, blood in the urine and a mass in the abdomen. These tumors are often discovered incidentally during imaging tests for other reasons. Diagnosis is typically confirmed through biopsy, which involves removing a small sample of tissue for examination under a microscope.Treatment of renal oncocytoma typically involves surgical removal of the tumor. In some cases, only the part of the kidney containing the tumor is removed, while in others the entire kidney may need to be removed. In cases where the tumor is large or has grown into nearby structures, additional treatments such as radiation, chemotherapy or immunotherapy may be necessary.Renal oncocytomas are rare, with an estimated incidence of 0.5-1.5 cases per million people per year, and they account for about 3-7% of all kidney tumors. They occur most commonly in middle-aged to older adults, with a peak incidence in the sixth and seventh decades of life. Men are more likely to develop renal oncocytoma than women.There is limited research on renal oncocytoma, as it is a rare condition. However, studies have shown that these tumors tend to have a good prognosis, with a low risk of recurrence after surgical removal. In most cases, patients can return to normal activities within a few weeks of surgery.
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Overview of Renal Oncocytoma. SummaryRenal oncocytoma, also known as oncocytoma of the kidney, is a rare type of benign kidney tumor. It is composed of oncocytes, which are cells that have an abnormally large number of mitochondria, the organelles that produce energy for the cell. Renal oncocytomas are usually slow-growing and do not spread beyond the kidney, but in rare cases they can become cancerous.Symptoms of renal oncocytoma may include abdominal pain, blood in the urine and a mass in the abdomen. These tumors are often discovered incidentally during imaging tests for other reasons. Diagnosis is typically confirmed through biopsy, which involves removing a small sample of tissue for examination under a microscope.Treatment of renal oncocytoma typically involves surgical removal of the tumor. In some cases, only the part of the kidney containing the tumor is removed, while in others the entire kidney may need to be removed. In cases where the tumor is large or has grown into nearby structures, additional treatments such as radiation, chemotherapy or immunotherapy may be necessary.Renal oncocytomas are rare, with an estimated incidence of 0.5-1.5 cases per million people per year, and they account for about 3-7% of all kidney tumors. They occur most commonly in middle-aged to older adults, with a peak incidence in the sixth and seventh decades of life. Men are more likely to develop renal oncocytoma than women.There is limited research on renal oncocytoma, as it is a rare condition. However, studies have shown that these tumors tend to have a good prognosis, with a low risk of recurrence after surgical removal. In most cases, patients can return to normal activities within a few weeks of surgery.
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Renal Oncocytoma
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Symptoms of Renal Oncocytoma
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Symptoms of Renal Oncocytoma.
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Renal Oncocytoma
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Causes of Renal Oncocytoma
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The exact cause of renal oncocytoma is not well understood, but there are several factors that may increase a person's risk of developing this condition. One possible cause of renal oncocytoma is genetic mutations. Some people may have inherited genetic mutations that increase their risk of developing this type of tumor. Other genetic mutations that may lead to the development of renal oncocytomas occur in tuberous sclerosis complex (TSC) and Birt-Hogg-Dubé syndrome.Another possible cause of renal oncocytoma is chronic kidney disease. People with chronic kidney disease may be more likely to develop renal oncocytoma due to the long-term damage to the kidneys.Obesity is also a potential risk factor for renal oncocytoma. People who are obese may be more likely to develop this type of tumor due to the extra strain on their kidneys.Other kidney cancers, particularly clear cell carcinoma and chromophobe renal cell carcinoma, may also be associated with renal oncocytomas, either growing alongside oncocytomas or appearing similar to them clinically. Part of the diagnostic and follow-up process may involve ruling out the possibility of these malignant growths from a benign diagnosis such as renal oncocytoma.Overall, the exact causes of renal oncocytoma are not well understood, and more research is needed to better understand this condition. However, genetic mutations, chronic kidney disease and obesity are all potential risk factors for renal oncocytoma.
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Causes of Renal Oncocytoma. The exact cause of renal oncocytoma is not well understood, but there are several factors that may increase a person's risk of developing this condition. One possible cause of renal oncocytoma is genetic mutations. Some people may have inherited genetic mutations that increase their risk of developing this type of tumor. Other genetic mutations that may lead to the development of renal oncocytomas occur in tuberous sclerosis complex (TSC) and Birt-Hogg-Dubé syndrome.Another possible cause of renal oncocytoma is chronic kidney disease. People with chronic kidney disease may be more likely to develop renal oncocytoma due to the long-term damage to the kidneys.Obesity is also a potential risk factor for renal oncocytoma. People who are obese may be more likely to develop this type of tumor due to the extra strain on their kidneys.Other kidney cancers, particularly clear cell carcinoma and chromophobe renal cell carcinoma, may also be associated with renal oncocytomas, either growing alongside oncocytomas or appearing similar to them clinically. Part of the diagnostic and follow-up process may involve ruling out the possibility of these malignant growths from a benign diagnosis such as renal oncocytoma.Overall, the exact causes of renal oncocytoma are not well understood, and more research is needed to better understand this condition. However, genetic mutations, chronic kidney disease and obesity are all potential risk factors for renal oncocytoma.
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Renal Oncocytoma
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Affects of Renal Oncocytoma
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In most cases, renal oncocytoma is found incidentally during imaging tests performed for other reasons. It is more common in older individuals, with the average age at diagnosis being around 60 years old. It is also more common in men than in women.Renal oncocytomas that are found as a single mass and on one side of the body tend to be sporadic or random in incidence. However, when multiple tumors are discovered or when both kidneys are affected, it may be a sign that there is an underlying disease process occurring. This situation has been described in diseases such as tuberous sclerosis complex and Birt-Hogg-Dubé syndrome.
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Affects of Renal Oncocytoma. In most cases, renal oncocytoma is found incidentally during imaging tests performed for other reasons. It is more common in older individuals, with the average age at diagnosis being around 60 years old. It is also more common in men than in women.Renal oncocytomas that are found as a single mass and on one side of the body tend to be sporadic or random in incidence. However, when multiple tumors are discovered or when both kidneys are affected, it may be a sign that there is an underlying disease process occurring. This situation has been described in diseases such as tuberous sclerosis complex and Birt-Hogg-Dubé syndrome.
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Renal Oncocytoma
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Related disorders of Renal Oncocytoma
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Related disorders of Renal Oncocytoma.
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Renal Oncocytoma
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nord_1064_5
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Diagnosis of Renal Oncocytoma
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The diagnosis of a renal oncocytoma typically begins with a physical examination, during which the doctor may feel a mass in the abdomen or flank area. The doctor may also order imaging tests, such as an ultrasound, CT scan, MRI or Sestamibi scan to confirm the presence of a tumor and to determine its size, location and activity.If the imaging tests suggest that the tumor may be a renal oncocytoma, the doctor will likely recommend a biopsy to confirm the diagnosis. Features on CT scan or MRI that may indicate the presence of an oncocytoma are a homogenous, well-circumscribed solid mass, sometimes with a central scar. During a biopsy, a small sample of tissue is removed from the tumor and examined under a microscope. The presence of oncocytes, which are abnormal cells with an unusually large number of mitochondria, can help confirm the diagnosis of a renal oncocytoma. When the tumor is removed, the overall appearance can further confirm the diagnosis. Renal oncocytomas are described as being “mahogany brown” or “dark red” in color due to the large quantity of mitochondria in the tumor cells.To provide a more detailed workup for the diagnosis of a renal oncocytoma, the doctor may also order blood and urine tests to assess the function of the kidneys and to look for any abnormalities. These tests may include a complete blood count (CBC), blood chemistry panel, urine analysis and creatinine clearance test.Once the diagnosis of a renal oncocytoma is confirmed, the doctor will discuss the treatment options with the patient. Surgical removal of the tumor is the most common treatment, but it may not be necessary if the tumor is small and not causing any symptoms. The type of surgery will depend on the size and location of the tumor and may include partial or total nephrectomy, removal of the kidney. If surgery is not an option, a clinician may instead use cryoablation.
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Diagnosis of Renal Oncocytoma. The diagnosis of a renal oncocytoma typically begins with a physical examination, during which the doctor may feel a mass in the abdomen or flank area. The doctor may also order imaging tests, such as an ultrasound, CT scan, MRI or Sestamibi scan to confirm the presence of a tumor and to determine its size, location and activity.If the imaging tests suggest that the tumor may be a renal oncocytoma, the doctor will likely recommend a biopsy to confirm the diagnosis. Features on CT scan or MRI that may indicate the presence of an oncocytoma are a homogenous, well-circumscribed solid mass, sometimes with a central scar. During a biopsy, a small sample of tissue is removed from the tumor and examined under a microscope. The presence of oncocytes, which are abnormal cells with an unusually large number of mitochondria, can help confirm the diagnosis of a renal oncocytoma. When the tumor is removed, the overall appearance can further confirm the diagnosis. Renal oncocytomas are described as being “mahogany brown” or “dark red” in color due to the large quantity of mitochondria in the tumor cells.To provide a more detailed workup for the diagnosis of a renal oncocytoma, the doctor may also order blood and urine tests to assess the function of the kidneys and to look for any abnormalities. These tests may include a complete blood count (CBC), blood chemistry panel, urine analysis and creatinine clearance test.Once the diagnosis of a renal oncocytoma is confirmed, the doctor will discuss the treatment options with the patient. Surgical removal of the tumor is the most common treatment, but it may not be necessary if the tumor is small and not causing any symptoms. The type of surgery will depend on the size and location of the tumor and may include partial or total nephrectomy, removal of the kidney. If surgery is not an option, a clinician may instead use cryoablation.
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Renal Oncocytoma
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Therapies of Renal Oncocytoma
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TreatmentTreatment for renal oncocytoma may include active surveillance or monitoring with imaging tests (CT, MRI or ultrasound) if the mass is very small, thermal ablation (applying heat or freezing the tumor) or surgery. The type of surgical procedure used will depend on the size and location of the tumor. In some cases, a partial nephrectomy, which involves removing the part of the kidney containing the tumor, may be performed. In other cases, a radical nephrectomy, which involves removing the entire affected kidney, may be necessary.After surgery, the patient will typically be monitored for any signs of recurrence or the development of other tumors. This may involve regular imaging tests such as CT or MRI scans, to check for any changes in the kidneys.It is important for patients with renal oncocytoma to receive regular follow-up care after their initial treatment. This can help ensure that any changes in the kidneys are detected and treated promptly. In addition, maintaining a healthy lifestyle, including following a healthy diet and exercising regularly, can help reduce the risk of recurrence and other health problems.
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Therapies of Renal Oncocytoma. TreatmentTreatment for renal oncocytoma may include active surveillance or monitoring with imaging tests (CT, MRI or ultrasound) if the mass is very small, thermal ablation (applying heat or freezing the tumor) or surgery. The type of surgical procedure used will depend on the size and location of the tumor. In some cases, a partial nephrectomy, which involves removing the part of the kidney containing the tumor, may be performed. In other cases, a radical nephrectomy, which involves removing the entire affected kidney, may be necessary.After surgery, the patient will typically be monitored for any signs of recurrence or the development of other tumors. This may involve regular imaging tests such as CT or MRI scans, to check for any changes in the kidneys.It is important for patients with renal oncocytoma to receive regular follow-up care after their initial treatment. This can help ensure that any changes in the kidneys are detected and treated promptly. In addition, maintaining a healthy lifestyle, including following a healthy diet and exercising regularly, can help reduce the risk of recurrence and other health problems.
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Renal Oncocytoma
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nord_1065_0
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Overview of Respiratory Distress Syndrome, Infant
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Infant respiratory distress syndrome is a lung disorder that tends to affect premature infants. Major symptoms include difficulty in breathing and collapsed lungs, potentially requiring mechanical ventilation or positive end-expiratory pressure (PEEP).
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Overview of Respiratory Distress Syndrome, Infant. Infant respiratory distress syndrome is a lung disorder that tends to affect premature infants. Major symptoms include difficulty in breathing and collapsed lungs, potentially requiring mechanical ventilation or positive end-expiratory pressure (PEEP).
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Respiratory Distress Syndrome, Infant
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Symptoms of Respiratory Distress Syndrome, Infant
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Infant respiratory distress syndrome is characterized by diminished oxygen intake in the premature newborn. A clear membrane is found lining the alveolar (air cell) ducts in the lungs and is associated with reduced amounts of lung wetting agents or emulsifier (surfactant). The surfactant is a lipoprotein based on lecithin that stabilizes alveolar membranes. When this surfactant is missing, breathing is difficult and may lead to collapse of a lung. The affected infant must be placed on some type of ventilation, either mechanical or physical, in order to continue breathing.
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Symptoms of Respiratory Distress Syndrome, Infant. Infant respiratory distress syndrome is characterized by diminished oxygen intake in the premature newborn. A clear membrane is found lining the alveolar (air cell) ducts in the lungs and is associated with reduced amounts of lung wetting agents or emulsifier (surfactant). The surfactant is a lipoprotein based on lecithin that stabilizes alveolar membranes. When this surfactant is missing, breathing is difficult and may lead to collapse of a lung. The affected infant must be placed on some type of ventilation, either mechanical or physical, in order to continue breathing.
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Respiratory Distress Syndrome, Infant
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nord_1065_2
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Causes of Respiratory Distress Syndrome, Infant
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Infant respiratory distress syndrome is caused by the absence of a natural lung wetting agent (surfactant) in the immature lungs of infants. Since surfactant normally develops late in prenatal life it usually is not present in the very premature infant of about 26-36 weeks of gestational age. This can result in improper functioning of the alveoli (air cells) of the lungs causing breathing difficulties and collapsed lungs.Surfactant protein-B (SP-B) deficiency is a rare type of infant respiratory distress syndrome caused by an abnormal pulmonary surfactant B gene. This type of infant respiratory distress syndrome follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
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Causes of Respiratory Distress Syndrome, Infant. Infant respiratory distress syndrome is caused by the absence of a natural lung wetting agent (surfactant) in the immature lungs of infants. Since surfactant normally develops late in prenatal life it usually is not present in the very premature infant of about 26-36 weeks of gestational age. This can result in improper functioning of the alveoli (air cells) of the lungs causing breathing difficulties and collapsed lungs.Surfactant protein-B (SP-B) deficiency is a rare type of infant respiratory distress syndrome caused by an abnormal pulmonary surfactant B gene. This type of infant respiratory distress syndrome follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
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Respiratory Distress Syndrome, Infant
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nord_1065_3
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Affects of Respiratory Distress Syndrome, Infant
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Infant respiratory distress syndrome affects male and female premature infants in equal numbers. Among approximately 250,000 infants born prematurely each year in the United States, up to 50,000 will have IRDS which will kill approximately 5,000 of them. Due in large part to the use of surfactants beginning in 1989, infant mortality rates in the United States have dropped from 9.7 per 1,000 births in 1989 to 8.9 per 1,000 births in 1991. Infants with surfactant protein-B deficiency do not respond to surfactant replacement therapy.
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Affects of Respiratory Distress Syndrome, Infant. Infant respiratory distress syndrome affects male and female premature infants in equal numbers. Among approximately 250,000 infants born prematurely each year in the United States, up to 50,000 will have IRDS which will kill approximately 5,000 of them. Due in large part to the use of surfactants beginning in 1989, infant mortality rates in the United States have dropped from 9.7 per 1,000 births in 1989 to 8.9 per 1,000 births in 1991. Infants with surfactant protein-B deficiency do not respond to surfactant replacement therapy.
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Respiratory Distress Syndrome, Infant
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nord_1065_4
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Related disorders of Respiratory Distress Syndrome, Infant
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Symptoms of the following disorders can be similar to those of infant respiratory distress syndrome, although they tend to affect older children or adults:Adult respiratory distress syndrome is a lung disorder caused by direct injury to the lungs or acute illness. It often occurs in conjunction with other illnesses and is characterized by the inability to breathe properly. Mechanical ventilation, surgical insertion of a breathing tube (tracheotomy) or positive end-expiratory pressure (PEEP) is usually necessary to aid in breathing. Secondary complications may occur resulting in pneumonia, blood poisoning (sepsis) or other infections. Chronic lung disease, multiple organ system failure and irreversible respiratory dysfunction may also occur. (For more information on this disorder, choose “adult respiratory distress syndrome” as your search term in the Rare Disease Database.)Pulmonary alveolar proteinosis is a rare lung disorder characterized by breathing difficulty that gradually becomes more severe, especially following exertion. The air sacs in the lungs (alveoli) are filled with a granular material (phospholipid) consisting mostly of protein and fat. Certain cells called macrophages, that usually swallow inhaled particles in the lung alveoli, can be found in the phospholipid material. This disorder may spread throughout the lungs or be confined to a small area. It may progress, remain stable, or spontaneously clear. (For more information on this disorder, choose “pulmonary alveolar proteinosis” as your search term in the Rare Disease Database.)Pneumonia is marked by excessive accumulation of fluid in the lungs due to an infection. Symptoms such as fever, cough, large amounts of mucous production (sputum), fluid in surrounding the lungs (pleurisy) and/or chills occur. Chest pain, headache, diarrhea, sore throat and fever blisters may also develop. Shortness of breath, difficulty in breathing, decreased exercise tolerance and night sweats are characteristic. Pneumonia occurs frequently in middle-aged to older adults with various underlying diseases. It can occur in persons of all ages, statistically most often in winter and early spring. Pneumonia can be caused by various bacteria, viruses, and fungi.Bronchial asthma is a common respiratory disease due to many different causes, airway irritability of unknown causes, and airway inflammation. Most of these problems are treatable. Asthma affects 2 to 6 percent of the U. S. population. It usually begins before the age of ten in about one-half of all patients and occurs twice as often in males as in females.Emphysema is characterized by abnormal difficulty in breathing upon exertion. As the disease advances it becomes more and more difficult for the patients to breathe. In advanced stages, breathing even at rest is difficult. The patient becomes thin and malnourished-appearing with a barrel-shaped chest, and appears to be in respiratory distress even during mild exertion as indicated by noisy expulsion of air. Lack of elasticity in lung tissue obstructs the airflow during exhalation. There is loss of lung tissue with abnormally enlarged air spaces. The causes of emphysema may include air pollution, smoking, occupational exposure to mineral dust, vegetable dusts and fibers. Regularly inhaled fumes and gases, infection and heredity may also play an important part in the development of emphysema. The disease may progress even with intensive treatment and after stopping smoking. However, one hereditary type of emphysema (alpha-1-antitrypsin deficiency) is treatable with the orphan drug Prolastin. (For more information on this disorder, choose “alpha-1-antitrypsin” as your search term in the Rare Disease Database.)
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Related disorders of Respiratory Distress Syndrome, Infant. Symptoms of the following disorders can be similar to those of infant respiratory distress syndrome, although they tend to affect older children or adults:Adult respiratory distress syndrome is a lung disorder caused by direct injury to the lungs or acute illness. It often occurs in conjunction with other illnesses and is characterized by the inability to breathe properly. Mechanical ventilation, surgical insertion of a breathing tube (tracheotomy) or positive end-expiratory pressure (PEEP) is usually necessary to aid in breathing. Secondary complications may occur resulting in pneumonia, blood poisoning (sepsis) or other infections. Chronic lung disease, multiple organ system failure and irreversible respiratory dysfunction may also occur. (For more information on this disorder, choose “adult respiratory distress syndrome” as your search term in the Rare Disease Database.)Pulmonary alveolar proteinosis is a rare lung disorder characterized by breathing difficulty that gradually becomes more severe, especially following exertion. The air sacs in the lungs (alveoli) are filled with a granular material (phospholipid) consisting mostly of protein and fat. Certain cells called macrophages, that usually swallow inhaled particles in the lung alveoli, can be found in the phospholipid material. This disorder may spread throughout the lungs or be confined to a small area. It may progress, remain stable, or spontaneously clear. (For more information on this disorder, choose “pulmonary alveolar proteinosis” as your search term in the Rare Disease Database.)Pneumonia is marked by excessive accumulation of fluid in the lungs due to an infection. Symptoms such as fever, cough, large amounts of mucous production (sputum), fluid in surrounding the lungs (pleurisy) and/or chills occur. Chest pain, headache, diarrhea, sore throat and fever blisters may also develop. Shortness of breath, difficulty in breathing, decreased exercise tolerance and night sweats are characteristic. Pneumonia occurs frequently in middle-aged to older adults with various underlying diseases. It can occur in persons of all ages, statistically most often in winter and early spring. Pneumonia can be caused by various bacteria, viruses, and fungi.Bronchial asthma is a common respiratory disease due to many different causes, airway irritability of unknown causes, and airway inflammation. Most of these problems are treatable. Asthma affects 2 to 6 percent of the U. S. population. It usually begins before the age of ten in about one-half of all patients and occurs twice as often in males as in females.Emphysema is characterized by abnormal difficulty in breathing upon exertion. As the disease advances it becomes more and more difficult for the patients to breathe. In advanced stages, breathing even at rest is difficult. The patient becomes thin and malnourished-appearing with a barrel-shaped chest, and appears to be in respiratory distress even during mild exertion as indicated by noisy expulsion of air. Lack of elasticity in lung tissue obstructs the airflow during exhalation. There is loss of lung tissue with abnormally enlarged air spaces. The causes of emphysema may include air pollution, smoking, occupational exposure to mineral dust, vegetable dusts and fibers. Regularly inhaled fumes and gases, infection and heredity may also play an important part in the development of emphysema. The disease may progress even with intensive treatment and after stopping smoking. However, one hereditary type of emphysema (alpha-1-antitrypsin deficiency) is treatable with the orphan drug Prolastin. (For more information on this disorder, choose “alpha-1-antitrypsin” as your search term in the Rare Disease Database.)
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Respiratory Distress Syndrome, Infant
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nord_1065_5
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Diagnosis of Respiratory Distress Syndrome, Infant
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Diagnosis of Respiratory Distress Syndrome, Infant.
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Respiratory Distress Syndrome, Infant
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nord_1065_6
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Therapies of Respiratory Distress Syndrome, Infant
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Treatment of infant respiratory distress syndrome consists of mechanical or physical breathing assistance such as positive end expiratory pressure (PEEP). Other treatment is symptomatic and supportive.Exosurf Neonatal (colfosceril palmitate) is a synthetic lung surfactant that was approved for use in August of 1990 by the Food and Drug Administration (FDA) for treatment of infant respiratory distress syndrome. The treatment consists of a single dose given 30 minutes after birth to high-risk infants. Surfactants are surface-cleaning agents that are used to wash out (lavage) the lungs and its air passages (bronchopulmonary area). This synthetic form of lung surfactant is manufactured by Burroughs Wellcome.Survanta (beractant) developed by Abbott Labs is another pediatric surfactant and is derived from bovine tissues. There is also great improvement in the infants treated with this product.Surfactant TA and Human Surf have both been approved by the FDA for treatment of infant respiratory distress syndrome.The FDA has also approved Dey Lab's lung surfactant, Curosurf Intratracheal Suspension (poractant alpha) for the treatment of infant respiratory distress syndrome.
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Therapies of Respiratory Distress Syndrome, Infant. Treatment of infant respiratory distress syndrome consists of mechanical or physical breathing assistance such as positive end expiratory pressure (PEEP). Other treatment is symptomatic and supportive.Exosurf Neonatal (colfosceril palmitate) is a synthetic lung surfactant that was approved for use in August of 1990 by the Food and Drug Administration (FDA) for treatment of infant respiratory distress syndrome. The treatment consists of a single dose given 30 minutes after birth to high-risk infants. Surfactants are surface-cleaning agents that are used to wash out (lavage) the lungs and its air passages (bronchopulmonary area). This synthetic form of lung surfactant is manufactured by Burroughs Wellcome.Survanta (beractant) developed by Abbott Labs is another pediatric surfactant and is derived from bovine tissues. There is also great improvement in the infants treated with this product.Surfactant TA and Human Surf have both been approved by the FDA for treatment of infant respiratory distress syndrome.The FDA has also approved Dey Lab's lung surfactant, Curosurf Intratracheal Suspension (poractant alpha) for the treatment of infant respiratory distress syndrome.
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Respiratory Distress Syndrome, Infant
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Overview of Restless Legs Syndrome
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Restless legs syndrome (RLS) is a neurologic and sleep related movement disorder characterized by an irresistible urge to move in the legs that typically occurs or worsens at rest. It is usually accompanied by abnormal, uncomfortable sensations, known as paresthesias or dysesthesias, that are often likened to crawling, cramping, aching, burning, itching, or prickling deep within the affected areas. Although the legs are usually involved, an urge to move with paresthesias or dysesthesias may also sometimes affect the arms or other areas of the body. Those with RLS may vigorously move the affected area, engage in pacing, or perform other, often repetitive movements, such as stretching, bending, or rocking. Symptoms typically worsen in the evening or at night, often resulting in sleep disturbances. Some individuals with RLS may also develop symptoms during other extended periods of inactivity, such as while sitting in a movie theater or traveling in a car. RLS may occur as a primary condition or due to another underlying disorder, certain medications, or other factors (secondary or symptomatic RLS). In primary RLS, the disorder is often genetic in origin or occurs for unknown reasons (idiopathic). Secondary RLS may occur in association with certain conditions, such as iron deficiency, low levels of the oxygen-carrying component of red blood cells (anemia), kidney failure, or pregnancy.
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Overview of Restless Legs Syndrome. Restless legs syndrome (RLS) is a neurologic and sleep related movement disorder characterized by an irresistible urge to move in the legs that typically occurs or worsens at rest. It is usually accompanied by abnormal, uncomfortable sensations, known as paresthesias or dysesthesias, that are often likened to crawling, cramping, aching, burning, itching, or prickling deep within the affected areas. Although the legs are usually involved, an urge to move with paresthesias or dysesthesias may also sometimes affect the arms or other areas of the body. Those with RLS may vigorously move the affected area, engage in pacing, or perform other, often repetitive movements, such as stretching, bending, or rocking. Symptoms typically worsen in the evening or at night, often resulting in sleep disturbances. Some individuals with RLS may also develop symptoms during other extended periods of inactivity, such as while sitting in a movie theater or traveling in a car. RLS may occur as a primary condition or due to another underlying disorder, certain medications, or other factors (secondary or symptomatic RLS). In primary RLS, the disorder is often genetic in origin or occurs for unknown reasons (idiopathic). Secondary RLS may occur in association with certain conditions, such as iron deficiency, low levels of the oxygen-carrying component of red blood cells (anemia), kidney failure, or pregnancy.
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Restless Legs Syndrome
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Symptoms of Restless Legs Syndrome
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In individuals with restless legs syndrome (RLS), symptoms may become apparent at any age, including childhood. In most cases, the disorder is chronic in nature, sometimes becoming more severe with increasing age. However, in some affected individuals, RLS symptoms may periodically subside and recur with varying levels of severity.Because RLS symptoms typically occur upon relaxation and inactivity, many with the disorder may have problems falling asleep and/or may often be awakened by symptoms. In addition, the irresistible urge to move often causes affected individuals to get out of bed and walk around or perform other movements, further disrupting the opportunity for restful (restorative) sleep. In some cases, those with severe symptoms may only be able to obtain a few hours of sleep on a nightly basis, resulting in excessive daytime sleepiness.In many cases, individuals with RLS may also experience repetitive movements of the legs during sleep (periodic limb movements in sleep [PLMS]) in which there is bending of the ankle (i.e., dorsiflexion), extension of the big toe, and, often, associated bending (flexion) of the knee or hip. PLMS tends to occur during non-dreaming periods of sleep (non-REM sleep) and is defined as five or more periodic limb movements per hour. In those with RLS, PLMS may contribute to sleep difficulties.Some individuals with severe RLS may also experience abnormal, involuntary (dyskinetic) movements while awake that may be characterized by sudden, rapid muscle jerks or more prolonged uncontrolled movements of certain muscles or muscle groups. Although the legs are usually affected, the arms may also be involved in some cases. These involuntary movements, which may appear similar to PLMS, typically cease upon the performance of voluntary movements.
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Symptoms of Restless Legs Syndrome. In individuals with restless legs syndrome (RLS), symptoms may become apparent at any age, including childhood. In most cases, the disorder is chronic in nature, sometimes becoming more severe with increasing age. However, in some affected individuals, RLS symptoms may periodically subside and recur with varying levels of severity.Because RLS symptoms typically occur upon relaxation and inactivity, many with the disorder may have problems falling asleep and/or may often be awakened by symptoms. In addition, the irresistible urge to move often causes affected individuals to get out of bed and walk around or perform other movements, further disrupting the opportunity for restful (restorative) sleep. In some cases, those with severe symptoms may only be able to obtain a few hours of sleep on a nightly basis, resulting in excessive daytime sleepiness.In many cases, individuals with RLS may also experience repetitive movements of the legs during sleep (periodic limb movements in sleep [PLMS]) in which there is bending of the ankle (i.e., dorsiflexion), extension of the big toe, and, often, associated bending (flexion) of the knee or hip. PLMS tends to occur during non-dreaming periods of sleep (non-REM sleep) and is defined as five or more periodic limb movements per hour. In those with RLS, PLMS may contribute to sleep difficulties.Some individuals with severe RLS may also experience abnormal, involuntary (dyskinetic) movements while awake that may be characterized by sudden, rapid muscle jerks or more prolonged uncontrolled movements of certain muscles or muscle groups. Although the legs are usually affected, the arms may also be involved in some cases. These involuntary movements, which may appear similar to PLMS, typically cease upon the performance of voluntary movements.
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Restless Legs Syndrome
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Causes of Restless Legs Syndrome
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RLS may occur as a primary disorder for unknown reasons (primary or idiopathic RLS) or in association with certain underlying conditions or other factors (secondary or symptomatic RLS).Many individuals with primary RLS report a family history of the disorder that may appear to suggest autosomal dominant inheritance. In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disease gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. RLS has been linked to sites on several chromosomes and several genes, but the exact genetic basis of the disorder has not been clearly defined.Secondary RLS may be associated with other conditions, such as iron deficiency, anemia, kidney failure, or peripheral neuropathy. RLS may also occur or become more severe in women who are pregnant. In addition, some medications may appear to cause or aggravate RLS symptoms, such as certain antipsychotic, antidepressant or antinausea drugs.The exact underlying cause of RLS symptoms is unknown. However, many researchers suggest that abnormalities in a certain neurotransmitter (dopamine) in the brain and spinal cord (central nervous system) plays some causative role. Neurotransmitters, including dopamine, are chemicals that regulate the transmission of nerve impulses. Low iron stores in the brain may also play a role.
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Causes of Restless Legs Syndrome. RLS may occur as a primary disorder for unknown reasons (primary or idiopathic RLS) or in association with certain underlying conditions or other factors (secondary or symptomatic RLS).Many individuals with primary RLS report a family history of the disorder that may appear to suggest autosomal dominant inheritance. In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disease gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. RLS has been linked to sites on several chromosomes and several genes, but the exact genetic basis of the disorder has not been clearly defined.Secondary RLS may be associated with other conditions, such as iron deficiency, anemia, kidney failure, or peripheral neuropathy. RLS may also occur or become more severe in women who are pregnant. In addition, some medications may appear to cause or aggravate RLS symptoms, such as certain antipsychotic, antidepressant or antinausea drugs.The exact underlying cause of RLS symptoms is unknown. However, many researchers suggest that abnormalities in a certain neurotransmitter (dopamine) in the brain and spinal cord (central nervous system) plays some causative role. Neurotransmitters, including dopamine, are chemicals that regulate the transmission of nerve impulses. Low iron stores in the brain may also play a role.
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Restless Legs Syndrome
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Affects of Restless Legs Syndrome
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Restless legs syndrome appears to be about twice as common in women than men. Associated symptoms may become apparent at any age, and the disorder is usually chronic, often becoming more severe with increasing age. However, in some affected individuals, RLS symptoms may periodically subside and recur with varying levels of severity. According to some reports, although most individuals do not bring their symptoms to the attention of physicians until middle age, up to 40 percent may initially experience symptoms before age 20.
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Affects of Restless Legs Syndrome. Restless legs syndrome appears to be about twice as common in women than men. Associated symptoms may become apparent at any age, and the disorder is usually chronic, often becoming more severe with increasing age. However, in some affected individuals, RLS symptoms may periodically subside and recur with varying levels of severity. According to some reports, although most individuals do not bring their symptoms to the attention of physicians until middle age, up to 40 percent may initially experience symptoms before age 20.
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Related disorders of Restless Legs Syndrome
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Symptoms of the following disorders may be similar to those of RLS. Comparisons may be useful for a differential diagnosis:Myoclonus is a neurological movement disorder characterized by sudden, involuntary, shock-like contractions of skeletal muscles. It may be classified based on affected bodily regions, triggering factors, underlying cause, and/or other factors. (For more information on myoclonus, choose “myoclonus” as your search term in the Rare Disease Database.)Nocturnal muscle cramps are very painful contractions of leg, especially calf, muscles which can wake a patient from sleep. In contrast to restless legs, the affected muscles are tight and tender. Relief is obtained by stretching and massaging the affected muscles, not by walking.
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Related disorders of Restless Legs Syndrome. Symptoms of the following disorders may be similar to those of RLS. Comparisons may be useful for a differential diagnosis:Myoclonus is a neurological movement disorder characterized by sudden, involuntary, shock-like contractions of skeletal muscles. It may be classified based on affected bodily regions, triggering factors, underlying cause, and/or other factors. (For more information on myoclonus, choose “myoclonus” as your search term in the Rare Disease Database.)Nocturnal muscle cramps are very painful contractions of leg, especially calf, muscles which can wake a patient from sleep. In contrast to restless legs, the affected muscles are tight and tender. Relief is obtained by stretching and massaging the affected muscles, not by walking.
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Diagnosis of Restless Legs Syndrome
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The diagnosis of RLS is based upon a thorough clinical evaluation; a complete patient history, including current medications; family history; and specialized tests. In addition, a clinical assessment scale may be used to help evaluate severity of the disorder. Various laboratory studies may be conducted to help detect or rule out possible associated conditions, including tests to measure iron and ferritin levels in the blood to assess iron stores in the body. In addition, a neurological examination may be conducted if associated neurological abnormalities are suspected (e.g., peripheral neuropathy). In addition, some physicians may recommend specialized sleep studies to evaluate sleep disturbances and possible PLMS, but sleep studies are not needed to diagnose uncomplicated RLS.
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Diagnosis of Restless Legs Syndrome. The diagnosis of RLS is based upon a thorough clinical evaluation; a complete patient history, including current medications; family history; and specialized tests. In addition, a clinical assessment scale may be used to help evaluate severity of the disorder. Various laboratory studies may be conducted to help detect or rule out possible associated conditions, including tests to measure iron and ferritin levels in the blood to assess iron stores in the body. In addition, a neurological examination may be conducted if associated neurological abnormalities are suspected (e.g., peripheral neuropathy). In addition, some physicians may recommend specialized sleep studies to evaluate sleep disturbances and possible PLMS, but sleep studies are not needed to diagnose uncomplicated RLS.
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Therapies of Restless Legs Syndrome
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TreatmentBecause making certain adjustments in lifestyle may help to alleviate RLS symptoms, physicians may recommend that patients follow a regular sleep routine, regularly engage in moderate exercise, yet avoid excessive exercise that may aggravate symptoms. Physicians may also stress that individuals with RLS should refrain from using caffeine, and, if possible, using certain antidepressant, antinausea, or other medications that may aggravate RLS symptoms.In individuals with secondary RLS, disease management includes appropriate treatment of the underlying disorder or condition, such as iron therapy. Depending on individual circumstances, iron can be given by mouth or by intravenous infusion. Iron should only be used under supervision of a physician as too much iron can sometimes be harmful. Such treatment may alleviate or eliminate symptoms of RLS in some patients. If such treatment does not effectively manage symptoms, certain drug therapies may be prescribed specifically to treat RLS.Drug therapy may also be considered for many individuals with primary RLS. The main drug classes used for RLS include drugs binding to calcium channels, dopamine precursors or agonists, opioids and benzodiazepines. The specific medication(s) recommended may depend upon various factors, including disease severity, specific symptoms present and response to therapy.Drugs binding to calcium channels including gabapentin, pregabalin and gabapentin enacarbil (Horizant) are first-line therapies for RLS. Gabapentin enacarbil is a precursor of gabapentin and has been approved by the FDA for the treatment of RLS as a once daily treatment. These drugs are all effective in RLS treatment but may cause sleepiness, dizziness, unsteadiness, a sense of mental fog, depression and weight gain.Dopamine precursors and dopamine agonists are medications that enhance levels or mimic the effects of the neurotransmitter dopamine. Certain of these medications may be recommended as therapies that may be beneficial in improving RLS if drugs binding to calcium channels are contraindicated, unhelpful or result in undesirable side effects.Dopamine agonists act like dopamine by stimulating molecules on the surface of certain cells that bind with dopamine (dopamine receptors). Dopamine agonists used to treat RLS include ropinirole, pramipexole and the rotigotine patch, all approved by the FDA for the treatment of RLS. With time, RLS may worsen in 40 to 80% of patients using these medications, including symptoms developing earlier in the day, spreading to the arms or reoccurring during the night, a phenomenon known as “augmentation”. Other potentially serious side-effects include the development of impulse control disorders (compulsive shopping, pathologic gambling, increased sexuality and compulsive eating) in 6-17% of patients and increased sleepiness during the day. These potential side-effects should be discussed with the treating physician before starting therapy.Levodopa, also known as L-dopa, is a dopamine precursor that increases concentrations of dopamine in the brain. Because certain enzymes immediately begin to break down available dopamine, a medication (carbidopa) that blocks the activity of such enzymes is often combined with L-dopa (e.g., as a combination drug known as carbidopa/levodopa). Augmentation is even more common with levodopa than the dopamine agonists and therefore the drug should never be used long-term but should be restricted to intermittent use, not more frequently than twice a week.In some cases, recommended treatment may include the use of other medications. Low dose opioids (e.g., oxycodone) are highly effective but are usually restricted to patients with RLS refractory to other drugs because of the potential for dependence and other side-effects. Certain benzodiazepine sleeping medications (e.g., clonazepam, temazepam); may be used to enhance sleep.
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Therapies of Restless Legs Syndrome. TreatmentBecause making certain adjustments in lifestyle may help to alleviate RLS symptoms, physicians may recommend that patients follow a regular sleep routine, regularly engage in moderate exercise, yet avoid excessive exercise that may aggravate symptoms. Physicians may also stress that individuals with RLS should refrain from using caffeine, and, if possible, using certain antidepressant, antinausea, or other medications that may aggravate RLS symptoms.In individuals with secondary RLS, disease management includes appropriate treatment of the underlying disorder or condition, such as iron therapy. Depending on individual circumstances, iron can be given by mouth or by intravenous infusion. Iron should only be used under supervision of a physician as too much iron can sometimes be harmful. Such treatment may alleviate or eliminate symptoms of RLS in some patients. If such treatment does not effectively manage symptoms, certain drug therapies may be prescribed specifically to treat RLS.Drug therapy may also be considered for many individuals with primary RLS. The main drug classes used for RLS include drugs binding to calcium channels, dopamine precursors or agonists, opioids and benzodiazepines. The specific medication(s) recommended may depend upon various factors, including disease severity, specific symptoms present and response to therapy.Drugs binding to calcium channels including gabapentin, pregabalin and gabapentin enacarbil (Horizant) are first-line therapies for RLS. Gabapentin enacarbil is a precursor of gabapentin and has been approved by the FDA for the treatment of RLS as a once daily treatment. These drugs are all effective in RLS treatment but may cause sleepiness, dizziness, unsteadiness, a sense of mental fog, depression and weight gain.Dopamine precursors and dopamine agonists are medications that enhance levels or mimic the effects of the neurotransmitter dopamine. Certain of these medications may be recommended as therapies that may be beneficial in improving RLS if drugs binding to calcium channels are contraindicated, unhelpful or result in undesirable side effects.Dopamine agonists act like dopamine by stimulating molecules on the surface of certain cells that bind with dopamine (dopamine receptors). Dopamine agonists used to treat RLS include ropinirole, pramipexole and the rotigotine patch, all approved by the FDA for the treatment of RLS. With time, RLS may worsen in 40 to 80% of patients using these medications, including symptoms developing earlier in the day, spreading to the arms or reoccurring during the night, a phenomenon known as “augmentation”. Other potentially serious side-effects include the development of impulse control disorders (compulsive shopping, pathologic gambling, increased sexuality and compulsive eating) in 6-17% of patients and increased sleepiness during the day. These potential side-effects should be discussed with the treating physician before starting therapy.Levodopa, also known as L-dopa, is a dopamine precursor that increases concentrations of dopamine in the brain. Because certain enzymes immediately begin to break down available dopamine, a medication (carbidopa) that blocks the activity of such enzymes is often combined with L-dopa (e.g., as a combination drug known as carbidopa/levodopa). Augmentation is even more common with levodopa than the dopamine agonists and therefore the drug should never be used long-term but should be restricted to intermittent use, not more frequently than twice a week.In some cases, recommended treatment may include the use of other medications. Low dose opioids (e.g., oxycodone) are highly effective but are usually restricted to patients with RLS refractory to other drugs because of the potential for dependence and other side-effects. Certain benzodiazepine sleeping medications (e.g., clonazepam, temazepam); may be used to enhance sleep.
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Restless Legs Syndrome
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Overview of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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SummaryRetinal vasculopathy with cerebral leukoencephalopathy (pronounced: looko-encefa-LA-pathee) and systemic manifestations (RVCL-S) is a rare genetic disease that causes progressive loss of tiny blood vessels, ultimately resulting in visual deterioration and a series of mini-strokes in the brain. The initial symptoms of visual disturbance often begin in middle age years (35 to 50 years of age). Usually there also are mild clinical changes seen in the liver and kidneys. Patients with RVCL have a shortened lifespan and usually have a life expectancy in the range of 5-20 years after onset of symptoms. The gene responsible for causing RVCL-S, called TREX1, codes for the protein of the same name whose two primary functions are to repair DNA and to control a specific kind of sugar machinery within cells. A mutation in ~25% of the TREX1 gene produces a shortened version of the protein that mislocalizes inside cells and in middle age leads to development of RVCL-S. The disease is an autosomal dominant disorder, so one copy of an abnormal TREX1 gene leads to the disease even though the other copy is normal. Diagnosis can be conclusively established by genetic testing of the TREX1 gene. Because of its rarity, this disease is often misdiagnosed as a brain tumor, multiple sclerosis, vasculitis or disease of unknown origin. This may lead to unnecessary and often hazardous diagnostic procedures such as multiple biopsies of the brain. Currently, there is no established preventative therapy. Nevertheless, a phase II clinical trial is currently underway using an antibody drug that is already FDA-approved for another rare disease that affects small blood vessels.IntroductionIn 1988, physicians at Washington University School of Medicine in Saint Louis, Missouri described a large family having a unique type of genetic disorder that particularly damaged parts of the brain including the eyes during adult middle years. They called this syndrome cerebroretinal vasculopathy (CRV) [1]. In particular, deterioration of small blood vessels (the microvasculature) in the retina (back of the eye) was the predominant cause of the vision loss. Additionally, brain magnetic resonance imaging (MRI) revealed the family suffered from mini strokes in a part of the brain called the “white matter.” In this American-Caucasian family of Northern European extraction, eight afflicted patients spanning three generations were identified. An unrelated Ashkenazi-Jewish family with the same set of symptoms and pathologic findings was reported a year later [1,2]. Since then, a total of approximately 43 unrelated families have been identified with 17 (~ 40%) of these unrelated families having the same mutation (called V235Gfs*6) [3,4, and Liszewski M.K. and Atkinson, J.P., unpublished].In 1997, Dr. Joanna Jen (currently at Mount Sinai Hospital, New York, NY) described a family of Chinese descent (Taiwan) that could trace similar disease symptoms back three generations [5]. She named the disease HERNS (hereditary endotheliopathy with retinopathy, nephropathy and stroke). In 1990 and 1998 Dutch researchers published a report of a family with a similar disease, but with a history of migraine headaches [6]. They called the disease HVR (hereditary vascular retinopathy).In 2007, these researchers entered a collaboration that conclusively proved through modern day genetics that CRV, HERNS and HVR are the same disease. The name was changed to RVCL [7]. All affected members of RVCL families had mutations in the one region of the gene TREX1. Since then, several additional scientific reports have described other patients with mutations that all localize to the same region of TREX1 [4,8-10].It is important to note that there are several different diseases that are caused by mutations in other areas of the TREX1 gene [9]. However, the mutations that cause RVCL originate only in one specific segment of TREX1.TREX1 is an important protein in the body. It serves as both a DNA repair enzyme and also metabolizes damaged DNA. As a DNA-degrading enzyme, it cleans up and digests DNA debris that is generated when tissue is damaged, or cells die and regenerate. TREX1 is also important for eliminating DNA derived from viruses that invade and infect human cells.In 2016, collaborators from around the world prepared a comprehensive report analyzing clinical features on 78 patients from 11 unrelated families and renamed the disease to RVCL-S [3].In 2018, researchers focused on identifying and characterizing TREX1 protein in the brain [11]. They found that TREX1 was localized to a specialized subset of cells (called microglia) and that TREX1 levels increased in brain areas affected by loss of blood vessels. TREX1 is also expressed in many other cell types, but at lower levels that are important, but more difficult to detect. Future studies clarifying the relationship of TREX1, its role in specific cell types and how TREX1 regulates the health of small blood, vessels may lead to new treatment strategies.Studies of the natural history of this disease, which help to characterize the typical disease course, have been a critical step to improve the design of clinical trials [12]. Understanding the natural progression of RVCL-S helps physicians and researchers design better studies to test whether medications are effective at slowing disease progression.
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Overview of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. SummaryRetinal vasculopathy with cerebral leukoencephalopathy (pronounced: looko-encefa-LA-pathee) and systemic manifestations (RVCL-S) is a rare genetic disease that causes progressive loss of tiny blood vessels, ultimately resulting in visual deterioration and a series of mini-strokes in the brain. The initial symptoms of visual disturbance often begin in middle age years (35 to 50 years of age). Usually there also are mild clinical changes seen in the liver and kidneys. Patients with RVCL have a shortened lifespan and usually have a life expectancy in the range of 5-20 years after onset of symptoms. The gene responsible for causing RVCL-S, called TREX1, codes for the protein of the same name whose two primary functions are to repair DNA and to control a specific kind of sugar machinery within cells. A mutation in ~25% of the TREX1 gene produces a shortened version of the protein that mislocalizes inside cells and in middle age leads to development of RVCL-S. The disease is an autosomal dominant disorder, so one copy of an abnormal TREX1 gene leads to the disease even though the other copy is normal. Diagnosis can be conclusively established by genetic testing of the TREX1 gene. Because of its rarity, this disease is often misdiagnosed as a brain tumor, multiple sclerosis, vasculitis or disease of unknown origin. This may lead to unnecessary and often hazardous diagnostic procedures such as multiple biopsies of the brain. Currently, there is no established preventative therapy. Nevertheless, a phase II clinical trial is currently underway using an antibody drug that is already FDA-approved for another rare disease that affects small blood vessels.IntroductionIn 1988, physicians at Washington University School of Medicine in Saint Louis, Missouri described a large family having a unique type of genetic disorder that particularly damaged parts of the brain including the eyes during adult middle years. They called this syndrome cerebroretinal vasculopathy (CRV) [1]. In particular, deterioration of small blood vessels (the microvasculature) in the retina (back of the eye) was the predominant cause of the vision loss. Additionally, brain magnetic resonance imaging (MRI) revealed the family suffered from mini strokes in a part of the brain called the “white matter.” In this American-Caucasian family of Northern European extraction, eight afflicted patients spanning three generations were identified. An unrelated Ashkenazi-Jewish family with the same set of symptoms and pathologic findings was reported a year later [1,2]. Since then, a total of approximately 43 unrelated families have been identified with 17 (~ 40%) of these unrelated families having the same mutation (called V235Gfs*6) [3,4, and Liszewski M.K. and Atkinson, J.P., unpublished].In 1997, Dr. Joanna Jen (currently at Mount Sinai Hospital, New York, NY) described a family of Chinese descent (Taiwan) that could trace similar disease symptoms back three generations [5]. She named the disease HERNS (hereditary endotheliopathy with retinopathy, nephropathy and stroke). In 1990 and 1998 Dutch researchers published a report of a family with a similar disease, but with a history of migraine headaches [6]. They called the disease HVR (hereditary vascular retinopathy).In 2007, these researchers entered a collaboration that conclusively proved through modern day genetics that CRV, HERNS and HVR are the same disease. The name was changed to RVCL [7]. All affected members of RVCL families had mutations in the one region of the gene TREX1. Since then, several additional scientific reports have described other patients with mutations that all localize to the same region of TREX1 [4,8-10].It is important to note that there are several different diseases that are caused by mutations in other areas of the TREX1 gene [9]. However, the mutations that cause RVCL originate only in one specific segment of TREX1.TREX1 is an important protein in the body. It serves as both a DNA repair enzyme and also metabolizes damaged DNA. As a DNA-degrading enzyme, it cleans up and digests DNA debris that is generated when tissue is damaged, or cells die and regenerate. TREX1 is also important for eliminating DNA derived from viruses that invade and infect human cells.In 2016, collaborators from around the world prepared a comprehensive report analyzing clinical features on 78 patients from 11 unrelated families and renamed the disease to RVCL-S [3].In 2018, researchers focused on identifying and characterizing TREX1 protein in the brain [11]. They found that TREX1 was localized to a specialized subset of cells (called microglia) and that TREX1 levels increased in brain areas affected by loss of blood vessels. TREX1 is also expressed in many other cell types, but at lower levels that are important, but more difficult to detect. Future studies clarifying the relationship of TREX1, its role in specific cell types and how TREX1 regulates the health of small blood, vessels may lead to new treatment strategies.Studies of the natural history of this disease, which help to characterize the typical disease course, have been a critical step to improve the design of clinical trials [12]. Understanding the natural progression of RVCL-S helps physicians and researchers design better studies to test whether medications are effective at slowing disease progression.
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Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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Symptoms of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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Hallmark symptoms of RVCL-S usually begin in middle age (~35-50 years) with eye issues such as an increasing number of “floaters” and “blind spots.” The main pathologic process of RVCL-S is that small blood vessels prematurely drop out; that is, deteriorate and disappear [3]. This leads to mini strokes (or “micro-infarcts”) in tissues. The loss of blood supply affects both the eye (retina) and the brain (white matter) since these organs serve key functions and are sensitive to even small disruptions in blood flow. As more vessels drop out, there is development of increased vision loss and larger brain infarcts (or tumor-like lesions), especially if the mini-strokes are clustered.Another study found systemic manifestations of the disease as well [3]. In a report detailing 11 unrelated families, five different mutations in the TREX1 gene were identified. Disease-related findings were similar across all mutations and families including visual loss, brain disease producing stroke-like symptoms, mental impairment, migraine, psychiatric disturbances and seizures. Additional systemic features included liver and kidney disease, anemia, high blood pressure and, less commonly, Raynaud’s phenomenon and intestinal bleeding. These features likely arise primarily because small blood vessels progressively deteriorate in the organs (e.g., liver, kidney, skin, intestine). Some RVCL-S patients also develop thyroid disease (hypothyroidism) or bone problems caused by loss of small blood vessels (osteonecrosis).Because RVCL-S is so rare and only recently recognized, it is often misdiagnosed as a severe type of multiple sclerosis, diabetic retinopathy, brain tumor or vasculitis (inflammation of blood vessels).The correct diagnosis can be definitively made to conclusively establish if the patient has the disease by genetic testing for mutations in the TREX1 gene on a small blood sample. However, prior to obtaining genetic testing, consultation with a genetic counselor who is familiar with RVCL-S is recommended.Research studies are currently being conducted at the RVCL Research Centers at Washington University School of Medicine in St. Louis and the University of Pennsylvania Perelman School of Medicine in Philadelphia. These are open to adults who have been genetically tested and shown to have a RVCL-S mutation.
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Symptoms of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. Hallmark symptoms of RVCL-S usually begin in middle age (~35-50 years) with eye issues such as an increasing number of “floaters” and “blind spots.” The main pathologic process of RVCL-S is that small blood vessels prematurely drop out; that is, deteriorate and disappear [3]. This leads to mini strokes (or “micro-infarcts”) in tissues. The loss of blood supply affects both the eye (retina) and the brain (white matter) since these organs serve key functions and are sensitive to even small disruptions in blood flow. As more vessels drop out, there is development of increased vision loss and larger brain infarcts (or tumor-like lesions), especially if the mini-strokes are clustered.Another study found systemic manifestations of the disease as well [3]. In a report detailing 11 unrelated families, five different mutations in the TREX1 gene were identified. Disease-related findings were similar across all mutations and families including visual loss, brain disease producing stroke-like symptoms, mental impairment, migraine, psychiatric disturbances and seizures. Additional systemic features included liver and kidney disease, anemia, high blood pressure and, less commonly, Raynaud’s phenomenon and intestinal bleeding. These features likely arise primarily because small blood vessels progressively deteriorate in the organs (e.g., liver, kidney, skin, intestine). Some RVCL-S patients also develop thyroid disease (hypothyroidism) or bone problems caused by loss of small blood vessels (osteonecrosis).Because RVCL-S is so rare and only recently recognized, it is often misdiagnosed as a severe type of multiple sclerosis, diabetic retinopathy, brain tumor or vasculitis (inflammation of blood vessels).The correct diagnosis can be definitively made to conclusively establish if the patient has the disease by genetic testing for mutations in the TREX1 gene on a small blood sample. However, prior to obtaining genetic testing, consultation with a genetic counselor who is familiar with RVCL-S is recommended.Research studies are currently being conducted at the RVCL Research Centers at Washington University School of Medicine in St. Louis and the University of Pennsylvania Perelman School of Medicine in Philadelphia. These are open to adults who have been genetically tested and shown to have a RVCL-S mutation.
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Causes of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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A mutation in the TREX1 gene causes RVCL-S. The abnormal gene results in production of a truncated form of TREX1 protein.Normal TREX1 protein is located inside cells in a network of ‘sacks’ or membranes called the endoplasmic reticulum (ER). The ER is attached to the nucleus of each cell and serves important roles in manufacturing and releasing proteins needed by the body. In RVCL-S, one copy of the TREX1 gene is normal, but one is mutated. These TREX1 mutations occur in the last one-fourth of the gene. This region codes for a part of the protein that is important for keeping it localized to the ER compartment. Mutations in this area allow the protein to drift out of the ER and mislocalize throughout the cell. In an unknown way, mislocalized TREX1 protein particularly affects and ultimately damages the lining of blood vessels and thereby disrupts brain and eye function.RVCL-S is an autosomal dominant genetic disorder. 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. Autosomal refers to the gene being a non-sex chromosome. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, a dominant disorder could be due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Causes of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. A mutation in the TREX1 gene causes RVCL-S. The abnormal gene results in production of a truncated form of TREX1 protein.Normal TREX1 protein is located inside cells in a network of ‘sacks’ or membranes called the endoplasmic reticulum (ER). The ER is attached to the nucleus of each cell and serves important roles in manufacturing and releasing proteins needed by the body. In RVCL-S, one copy of the TREX1 gene is normal, but one is mutated. These TREX1 mutations occur in the last one-fourth of the gene. This region codes for a part of the protein that is important for keeping it localized to the ER compartment. Mutations in this area allow the protein to drift out of the ER and mislocalize throughout the cell. In an unknown way, mislocalized TREX1 protein particularly affects and ultimately damages the lining of blood vessels and thereby disrupts brain and eye function.RVCL-S is an autosomal dominant genetic disorder. 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. Autosomal refers to the gene being a non-sex chromosome. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, a dominant disorder could be due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Affects of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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RVCL-S affects males and females with equivalent frequency and commonly begins in middle age (35-50 years). It is commonly first noticed as eye symptoms (increased ‘floaters’ or ‘blind spots’). Patients have been identified in several countries including the USA, UK, Australia, China, France, Germany, Italy, Japan, Mexico, the Netherlands, Spain, Switzerland, Taiwan and Turkey.
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Affects of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. RVCL-S affects males and females with equivalent frequency and commonly begins in middle age (35-50 years). It is commonly first noticed as eye symptoms (increased ‘floaters’ or ‘blind spots’). Patients have been identified in several countries including the USA, UK, Australia, China, France, Germany, Italy, Japan, Mexico, the Netherlands, Spain, Switzerland, Taiwan and Turkey.
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Related disorders of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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RVCL-S is frequently misdiagnosed. This may lead to unnecessary and invasive diagnostic procedures such as biopsies of brain, liver or kidney. Symptoms of the following disorders can be similar to those of RVCL-S:
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Related disorders of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. RVCL-S is frequently misdiagnosed. This may lead to unnecessary and invasive diagnostic procedures such as biopsies of brain, liver or kidney. Symptoms of the following disorders can be similar to those of RVCL-S:
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Diagnosis of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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RVCL-S should be considered when a middle-aged individual has retinal and microvascular abnormalities, in addition to a family history of similar symptoms. The definitive work up is genetic testing for mutations in the TREX1 gene from a small blood sample. Mutations on just one allele, in a specific region distal to the enzyme region, conclusively establish if the patient has the disease. Additional testing may include a retinal exam and a brain MRI. Genetic counseling, as well as consultation with a physician familiar with RVCL, is strongly recommended prior to genetic testing.
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Diagnosis of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. RVCL-S should be considered when a middle-aged individual has retinal and microvascular abnormalities, in addition to a family history of similar symptoms. The definitive work up is genetic testing for mutations in the TREX1 gene from a small blood sample. Mutations on just one allele, in a specific region distal to the enzyme region, conclusively establish if the patient has the disease. Additional testing may include a retinal exam and a brain MRI. Genetic counseling, as well as consultation with a physician familiar with RVCL, is strongly recommended prior to genetic testing.
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Therapies of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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Treatment
There currently is no approved treatment for RVCL-S. Sometimes substantial brain edema may lead to a larger lesion and cause pressure on other parts of the brain. This edema has been reduced by steroid treatment. Additionally, the use of statins may be indicated upon consultation with a physician familiar with RVCL-S.
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Therapies of Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. Treatment
There currently is no approved treatment for RVCL-S. Sometimes substantial brain edema may lead to a larger lesion and cause pressure on other parts of the brain. This edema has been reduced by steroid treatment. Additionally, the use of statins may be indicated upon consultation with a physician familiar with RVCL-S.
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Overview of Retinitis Pigmentosa
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Retinitis pigmentosa (RP) comprises a large group of inherited vision disorders that cause progressive degeneration of the retina (the so-called inherited retinal diseases, or IRDs), the light sensitive membrane that coats the inside of the eyes. Peripheral (or side) vision gradually decreases and eventually is lost in most patients. Central vision is usually preserved until late in these conditions. Some forms of RP can be associated with deafness, obesity, kidney disease and various other general health problems, including central nervous system and metabolic disorders and occasionally chromosomal abnormalities.
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Overview of Retinitis Pigmentosa. Retinitis pigmentosa (RP) comprises a large group of inherited vision disorders that cause progressive degeneration of the retina (the so-called inherited retinal diseases, or IRDs), the light sensitive membrane that coats the inside of the eyes. Peripheral (or side) vision gradually decreases and eventually is lost in most patients. Central vision is usually preserved until late in these conditions. Some forms of RP can be associated with deafness, obesity, kidney disease and various other general health problems, including central nervous system and metabolic disorders and occasionally chromosomal abnormalities.
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Symptoms of Retinitis Pigmentosa
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RP usually begins as night or dim light visual impairment (that is, difficulty seeing in dimly lit environments or at dusk, or adapting to, or recovering function in, dim light after being in bright light for any length of time). Typically, this is followed by the affected individual’s growing awareness of a loss of peripheral vision. Symptoms are more often noticed between the age 10 and 40, but earlier and later onset forms of RP exist. Characteristically, symptoms develop gradually over time. The sudden onset of these same symptoms should point to a different cause, such as an autoimmune process. Older people with sudden onset of these symptoms are especially at risk for experiencing them as the result of having cancer (so called paraneoplastic retinopathy, which often co-occurs with an optic nerve involvement as well).The rate and extent of progression of visual loss in RP can vary. The way that peripheral vision is lost in RP has been especially well characterized by various authors. It has been reported in various studies that the most variable aspect is the age of onset of the symptoms. This can vary not only between families and between subtypes of RP, but also within families. However, after that, the rate and modality of progression tends to follow a fairly predictable and stereotyped exponential pattern. This pattern signifies that, during the first decade of symptomatic disease patients experience a slower rate of disease progression, which then accelerates during the subsequent two decades, to slow again during the remainder of life. When other members of a family are affected, the rates of progression are often similar within that family, but some degree of variability exists in this aspect of RP too.Some patients with RP or related disorders present with complex manifestations affecting other organs, termed “syndromes”. The most common associations of RP with general health (so called “systemic”) problems causing these more complex syndromes are hearing loss and obesity, and are reviewed under the “Related Syndromes” section of this review.
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Symptoms of Retinitis Pigmentosa. RP usually begins as night or dim light visual impairment (that is, difficulty seeing in dimly lit environments or at dusk, or adapting to, or recovering function in, dim light after being in bright light for any length of time). Typically, this is followed by the affected individual’s growing awareness of a loss of peripheral vision. Symptoms are more often noticed between the age 10 and 40, but earlier and later onset forms of RP exist. Characteristically, symptoms develop gradually over time. The sudden onset of these same symptoms should point to a different cause, such as an autoimmune process. Older people with sudden onset of these symptoms are especially at risk for experiencing them as the result of having cancer (so called paraneoplastic retinopathy, which often co-occurs with an optic nerve involvement as well).The rate and extent of progression of visual loss in RP can vary. The way that peripheral vision is lost in RP has been especially well characterized by various authors. It has been reported in various studies that the most variable aspect is the age of onset of the symptoms. This can vary not only between families and between subtypes of RP, but also within families. However, after that, the rate and modality of progression tends to follow a fairly predictable and stereotyped exponential pattern. This pattern signifies that, during the first decade of symptomatic disease patients experience a slower rate of disease progression, which then accelerates during the subsequent two decades, to slow again during the remainder of life. When other members of a family are affected, the rates of progression are often similar within that family, but some degree of variability exists in this aspect of RP too.Some patients with RP or related disorders present with complex manifestations affecting other organs, termed “syndromes”. The most common associations of RP with general health (so called “systemic”) problems causing these more complex syndromes are hearing loss and obesity, and are reviewed under the “Related Syndromes” section of this review.
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Retinitis Pigmentosa
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Causes of Retinitis Pigmentosa
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Retinitis pigmentosa is a group of hereditary progressive disorders that may be inherited in an autosomal recessive, autosomal dominant or X-linked recessive pattern. Maternally inherited variants of RP transmitted via the mitochondrial DNA also exist.About half of all RP cases are isolated (these patients have no family history of the condition). This does not mean that the condition is not genetic (see below). RP may appear alone or in conjunction with one of several other rare disorders. Over 60 systemic disorders show some type of retinal involvement similar to RP.Autosomal dominant disorders occur when only a single copy of a gene carries a variant (mutation) that, alone, is sufficient and necessary for the appearance of the disease. In dominant disorders, the abnormal gene can be inherited from either parent, or can be the result of a new mutation (termed a “de novo” mutation) in the affected individual. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy, regardless of the sex of the parent or of the child. However, in some forms of dominant diseases including some types of dominant RP, patients who inherit the mutated gene will not develop the disease, or will develop a very mild form of it, due to a phenomenon called “incomplete penetrance”. Regardless of the severity, if any, of the disease expression in these patients, they remain capable of passing the genetic mutation to their own children, who can be fully affected. Examples of this scenario are the RP11 gene (PRPF31) and other genes of this family (e.g., PRPF8), which cause autosomal dominant RP and are especially prone to experiencing the “incomplete penetrance” phenomenon, which poses a significant diagnostic, prognostic and reproductive risk assessment challenge. However, children who did not inherit the gene variant that causes the autosomal dominant disorder in question, even if born of affected patients, cannot develop the disease and cannot pass it on.Autosomal recessive disorders occur when an individual inherits mutations in the same gene from each parent. If an individual receives one normal gene and one gene for the disease, he or she will be a carrier of the disease, but usually will not show symptoms. The risk of two carrier parents both passing the altered gene and having an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance of having a child who receives normal genes for that particular trait from both parents is also 25%. The risk is the same for males and females. All children born to a person affected with an autosomal recessive condition will receive one copy of the altered gene from the affected parent. Therefore, they will be healthy carriers like the parents of the affected patient. A child born to a patient affected with an autosomal recessive condition can be affected only if the affected parent mates with someone who is also a carrier of mutations in the same gene causing disease in the patient. If this happens, then the risk of having an affected child becomes 50%. If an affected person mates with another affected person with a disorder caused by mutations in the same gene, then their risk of having a child affected with that same genetic condition will be 100%, as long as the gene causing the disease in the two parents is the same.Since most individuals carry a few abnormalities in their genes, parents who are close blood relatives (consanguineous) have a higher chance than do unrelated parents of both carrying the same abnormality in any given gene, which increases the risk of having children with an autosomal recessive genetic disorder. These children will typically carry the same exact change in both copies of their genes (homozygous). However, in most instances, autosomal recessive conditions arise by the serendipitous mating between two unaware healthy carriers, each typically carrying a distinct mutation in the same gene (compound heterozygous).X-linked recessive genetic disorders are conditions caused by an abnormality in a gene on the X chromosome. Females have two X chromosomes; however, one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization”, and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are carriers of that disorder. As the result of the lyonization process, most carrier females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then female carriers can be completely asymptomatic. If the mutant copy prevails, then carrier females can be affected as severely as males. At times, the pattern and ratio of inactivation of the X chromosome will vary between eyes, whereby carriers can present with significantly asymmetric disease (for example, one eye affected severely, and the other much less so). This is not at all uncommon in X-linked RP carriers.Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be carriers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female carrier of an X-linked disorder has a 25% chance with each pregnancy of having a carrier daughter, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected with the disease, and a 25% chance of having an unaffected son.In recent years, molecular genetics advances have impacted the understanding and the classification of hereditary retinal diseases perhaps more than any other group of eye diseases, with more than 316 distinct genes mapped (that is, their approximate location on one of the chromosomes has been identified) and over 280 cloned (that is, precisely identified, located, and mutation(s) that cause forms of RP found in them).
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Causes of Retinitis Pigmentosa. Retinitis pigmentosa is a group of hereditary progressive disorders that may be inherited in an autosomal recessive, autosomal dominant or X-linked recessive pattern. Maternally inherited variants of RP transmitted via the mitochondrial DNA also exist.About half of all RP cases are isolated (these patients have no family history of the condition). This does not mean that the condition is not genetic (see below). RP may appear alone or in conjunction with one of several other rare disorders. Over 60 systemic disorders show some type of retinal involvement similar to RP.Autosomal dominant disorders occur when only a single copy of a gene carries a variant (mutation) that, alone, is sufficient and necessary for the appearance of the disease. In dominant disorders, the abnormal gene can be inherited from either parent, or can be the result of a new mutation (termed a “de novo” mutation) in the affected individual. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy, regardless of the sex of the parent or of the child. However, in some forms of dominant diseases including some types of dominant RP, patients who inherit the mutated gene will not develop the disease, or will develop a very mild form of it, due to a phenomenon called “incomplete penetrance”. Regardless of the severity, if any, of the disease expression in these patients, they remain capable of passing the genetic mutation to their own children, who can be fully affected. Examples of this scenario are the RP11 gene (PRPF31) and other genes of this family (e.g., PRPF8), which cause autosomal dominant RP and are especially prone to experiencing the “incomplete penetrance” phenomenon, which poses a significant diagnostic, prognostic and reproductive risk assessment challenge. However, children who did not inherit the gene variant that causes the autosomal dominant disorder in question, even if born of affected patients, cannot develop the disease and cannot pass it on.Autosomal recessive disorders occur when an individual inherits mutations in the same gene from each parent. If an individual receives one normal gene and one gene for the disease, he or she will be a carrier of the disease, but usually will not show symptoms. The risk of two carrier parents both passing the altered gene and having an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance of having a child who receives normal genes for that particular trait from both parents is also 25%. The risk is the same for males and females. All children born to a person affected with an autosomal recessive condition will receive one copy of the altered gene from the affected parent. Therefore, they will be healthy carriers like the parents of the affected patient. A child born to a patient affected with an autosomal recessive condition can be affected only if the affected parent mates with someone who is also a carrier of mutations in the same gene causing disease in the patient. If this happens, then the risk of having an affected child becomes 50%. If an affected person mates with another affected person with a disorder caused by mutations in the same gene, then their risk of having a child affected with that same genetic condition will be 100%, as long as the gene causing the disease in the two parents is the same.Since most individuals carry a few abnormalities in their genes, parents who are close blood relatives (consanguineous) have a higher chance than do unrelated parents of both carrying the same abnormality in any given gene, which increases the risk of having children with an autosomal recessive genetic disorder. These children will typically carry the same exact change in both copies of their genes (homozygous). However, in most instances, autosomal recessive conditions arise by the serendipitous mating between two unaware healthy carriers, each typically carrying a distinct mutation in the same gene (compound heterozygous).X-linked recessive genetic disorders are conditions caused by an abnormality in a gene on the X chromosome. Females have two X chromosomes; however, one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization”, and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are carriers of that disorder. As the result of the lyonization process, most carrier females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then female carriers can be completely asymptomatic. If the mutant copy prevails, then carrier females can be affected as severely as males. At times, the pattern and ratio of inactivation of the X chromosome will vary between eyes, whereby carriers can present with significantly asymmetric disease (for example, one eye affected severely, and the other much less so). This is not at all uncommon in X-linked RP carriers.Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be carriers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female carrier of an X-linked disorder has a 25% chance with each pregnancy of having a carrier daughter, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected with the disease, and a 25% chance of having an unaffected son.In recent years, molecular genetics advances have impacted the understanding and the classification of hereditary retinal diseases perhaps more than any other group of eye diseases, with more than 316 distinct genes mapped (that is, their approximate location on one of the chromosomes has been identified) and over 280 cloned (that is, precisely identified, located, and mutation(s) that cause forms of RP found in them).
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Retinitis Pigmentosa
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Affects of Retinitis Pigmentosa
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RP as a group of vision disorders affects about 1 in 3,000 to 1 in 4,000 people in the world. This means that, with a population of about 330 million in the United States in February 2021 (see http://www.census.gov for continuous updates), about 82,500 to 110,000 people in the United States have RP or a related disorder. With a worldwide population presently estimated at over 7.74 billion, it can be estimated that approximately 1.94 to 2.58 million people around the world have one of these disorders. Excluding age-related macular degeneration and glaucoma, the genetic causes of which are complex and linked simultaneously to more than one gene (so called “polygenic” disorders), RP is the most common cause of inherited visual loss.
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Affects of Retinitis Pigmentosa. RP as a group of vision disorders affects about 1 in 3,000 to 1 in 4,000 people in the world. This means that, with a population of about 330 million in the United States in February 2021 (see http://www.census.gov for continuous updates), about 82,500 to 110,000 people in the United States have RP or a related disorder. With a worldwide population presently estimated at over 7.74 billion, it can be estimated that approximately 1.94 to 2.58 million people around the world have one of these disorders. Excluding age-related macular degeneration and glaucoma, the genetic causes of which are complex and linked simultaneously to more than one gene (so called “polygenic” disorders), RP is the most common cause of inherited visual loss.
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Related disorders of Retinitis Pigmentosa
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Signs of the following disorders can be similar to RP. Comparisons may be useful for a differential diagnosis:Leber congenital amaurosis (LCA), severe early childhood-onset retinal dystrophy (SECORD), and early-onset RP (EORP) are special forms of RP characterized by the presence of severe symptoms from birth or shortly thereafter, respectively. This sub-group of RP forms is inherited in an autosomal recessive fashion, although X-linked RP also tends to have a significantly earlier onset than other forms of RP. When present from birth as in LCA, the visual deficit of affected children is typically recognized because of the coexistence of unsteadiness of the eyes known as nystagmus. Nystagmus is characterized by either fast-beating movements or by wandering movements of the eyeballs. The appearance of the back of the eye can be normal or near normal for several years, but testing of retinal function in response to flashes of light (the electroretinogram, or ERG) will invariably reveal the disease status in these patients. LCA patients often develop a deformation of the cornea causing high astigmatism up to a frank cone-shaped deformation of the cornea known as keratoconus. Prompt recognition of, and molecular genetic diagnostic testing for LCA has become increasingly important, since an FDA-approved gene therapy called Luxturna has become commercially available in 2017 as a treatment for one form of LCA linked to the RPE65 gene (see below). There are many different genes responsible for LCA and for recessive EORP. (For more information on this condition, choose “Leber congenital amaurosis” as your search term in the Rare Disease Database)Pericentral RP is a clinical subtype of RP that is characterized by loss of side vision right around the center of a patient’s vision in the shape of a donut. This form of RP can be inherited in various ways (recessive, dominant, and sporadic, that is, without an uncertain mode of inheritance). Pericentral RP tends to have later onset than typical RP, causes far less loss of peripheral vision (in fact, the farthest portions of the field of vision in pericentral RP are rarely affected), it has been reported to have an overall slower progression rate than typical RP but, once it becomes symptomatic to patients, pericentral RP tends to encroach the center of the patients’ vision more rapidly and more severely than typical RP. As a result of this feature of the disease, patients with pericentral RP tend to experience a greater loss in visual acuity and central vision than peripheral vision, which is opposite of what is seen in typical RP, and is more similar to what is observed in what was once termed “RP inversa”, more properly referred to nowadays as cone-rod dystrophy (CORD). By ERG criteria, pericentral RP tends to equally compromise rod and cone cells (the primary vision cells of the retina) or, at times, cone cells (the daytime ones) more than rod cells (the nighttime ones). On the genetic level, many forms of pericentral RP share mutations in the same genes as those involved in other RP conditions. Thus, it does not appear to be a distinct entity, but may rather represent the mild end of the RP disease spectrum. Specific genes responsible for pericentral RP, if any, have not been identified yet, but research is ongoing to discover them.A group of disorders that is often confused with RP but is distinct from RP is that linked to mutations, to date, to a single gene, known as NR2E3. This gene affects the development of progenitor retinal cells. Mutations in this gene lead to disorders that can present with clinically distinct pictures, known respectively as Goldmann-Favre vitreoretinal dystrophy, enhanced S-cone syndrome (ESCS), and clumped pigmentary retinal degeneration. These three conditions, all inherited in an autosomal recessive pattern, share the feature of congenital night blindness and better than normal (or selectively better preserved) vision of the short wavelength-sensitive (blue, or S) cones, due to the erroneous development of rods into S-cones in the retina of affected patients. Unlike RP, these patients have slower disease progression rates, but are also prone to complications that RP patients do not typically incur, such as splitting of the retina at the macular and peripheral level (retinoschisis) and retinal detachments. The changes visible on fundus exam affecting patients with this group of disorders are typically located along the vascular arcades of the retina, and vary in appearance primarily from whitish flecks to coin-shaped (“nummular”) areas of confluent pigmentation that is typically located underneath the retina and not within it, as seen instead in RP. Recent investigations have shed further light on these unique changes seen at the vascular arcades.Cone-rod dystrophy (CORD) is a term that identifies a group of disorders that can be inherited as autosomal recessive, autosomal dominant, X-linked recessive or mitochondrial (maternally inherited) traits. As noted above, opposite from RP, CORD typically affects central and daytime vision much more severely than peripheral and night vision, hence the classical term “RP inversa”, with which this family of conditions was originally known. CORDs are, at least in part, genetically distinct from RP. However, depending on the mutations, certain genes expressed in both rods and cones can cause either RP or CORD (for example, the RDS/peripherin gene in dominant forms, the ABCA4 gene in recessive forms, and the RPGR gene in X-linked forms).Choroideremia is a vision disorder inherited in an X-linked recessive pattern characterized by extensive defects (atrophy) in the pigmented layer of cells underneath the retina, the retinal pigment epithelium (RPE) and of the capillary blood vessels of the underlying vascular layer, the choroid, which is called the choriocapillaris. Much like RP, the major symptoms of this disorder include a progressive loss of the peripheral field of vision and night blindness, which can start as early as during childhood and as late as young adulthood. It has been shown that, despite the extensive RPE and choriocapillaris loss that can occur early on in the disease, the neuroretina above areas of atrophy of these other tissues can remain at least partially intact and, therefore, partially functioning for an extended period of time. This explains why, often times, the changes seen at the back of the eye of affected males appear more severe than the actual degree of visual loss experienced by the patients. Unlike RP, patients with choroideremia do not typically develop bone spicule-like pigmentary deposits in the retina, but rather scattered patches of irregularly shaped hyperpigmentation underneath the retina. The overall prognosis of choroideremia appears to be, on average, better than that of RP and X-linked RP in particular, but severe vision loss has been reported in choroideremia as well.With very few exceptions, choroideremia affects only males. Unlike female carriers of X-linked RP, who commonly experience some sign of the disease, however mild or late-onset they may be, female carriers of choroideremia only sometimes have symptoms, although a few will complain about dim light or night vision issues late in life. Despite the relative lack of symptoms experienced by female carriers, they can usually be identified as such by characteristic pigment mottling under the retina at the RPE level after the pupils of the eye has been dilated. Even more so in the case of the female carriers, the fundus appearance is usually much more abnormal in appearance than the degree of functional compromise that carriers can experience – in other words, the fundus exam usually has very prominent changes of little to no functional impact on the vision of female carriers. These findings can often lead to the incorrect diagnosis of RP or the suspicion of another, more severe form of IRD, in a carrier of choroideremia who may have no known family history thereof. Despite the fact that the functional outcome of this condition is for the most part benign, female carriers of choroideremia are at risk for macular complications that include neovascular membranes, as seen in the “wet” form of age-related macular degeneration. These complications can occur in relatively young age (as early as the 3rd or 4th decade of life) and are treatable with injections administered directly in the eyeball of drugs that block the main factor implicated in the growth of these membranes, termed vascular endothelial growth factor (VEGF).Related SyndromesThe most common associations of RP with general health (so called “systemic”) problems causing more complex disorders known as “syndromes” are hearing loss and obesity.Some individuals with RP can be born deaf (Usher syndrome type I or infantile-onset Refsum disease), or hearing-impaired (Usher syndrome type II), or can become hearing impaired (Usher syndrome type III or adult-onset Refsum disease). A rarer form of hearing-related syndrome that can present also with an RP-like retinopathy is Wolfram syndrome, but optic atrophy (not RP) and diabetes mellitus are by far the most common manifestations of this disorder. Hearing impairment of various degrees of severity and type can also be present in RP variants caused by changes in mitochondrial DNA. The most common form of this rarer association is termed NARP, an acronym for the peripheral neuropathy, ataxia, and retinitis pigmentosa syndrome, which includes also (and more commonly) progressive neurological problems resulting in abnormal gait and late-onset stutter. The type of deafness/hearing loss presented by patients with all these conditions is termed “sensorineural” that is, linked to congenital malfunction and/or progressive degeneration of the hearing nerves and nervous structures, which are much like the type of visual loss that occurs at the level of the retina.Usher syndrome is a group of inherited disorders characterized by RP and hearing impairment. Usher syndrome accounts for about 50% of all deaf-blinding disorders. The exact prevalence (frequency) of Usher syndrome in the population is not precisely known, but it has been estimated to affect 1:10,000 to 1:20,000 people. Usher syndrome is, for the most part, genetically distinct from non-syndromic forms of RP, although some cases of simple RP (that is, without hearing loss) in association with mutations in the USH2A gene have been reported. A major multicenter international collaborative natural history study of USH2A-related RP, termed RUSH2A, is presently in progress. There are three major types of Usher syndrome, distinguished by the severity and the age of onset of the hearing features. Type I is characterized by congenital, non-progressive, profound hearing loss. Type II is characterized by congenital, non-progressive, mild to moderate hearing loss, whereby speech is much less affected. Type III, which is rarer, is characterized by progressive, later-onset (post-verbal) hearing loss; speech is typically not affected. All three types of Usher syndrome are inherited in an autosomal recessive pattern. Although three main types of Usher syndrome are recognized clinically, many more genes accounting for these clinical subtypes exist. To date, 18 genes have been mapped (six for Usher syndrome type I, USH1B-G, three for type II, USH2A-C, and one for type III, (USH3A), fifteen of which have been cloned. A type IV Usher syndrome with X-linked recessive inheritance was suspected to exist in the past, but this has now been shown to be a pseudo-Usher syndrome linked to mutations affecting the RRC1-like domain of the RPGR gene, a common cause of X-linked RP (and X-linked CORD), which we showed is also expressed in the epithelial lining of the respiratory tract and in the inner ear. This disease variant is also associated with recurrent upper respiratory tract infections (especially otitis and sinusitis) and immotile cilia-like symptoms.Refsum syndrome is a slowly progressive disorder of fat (lipid) metabolism inherited in an autosomal recessive pattern that is characterized by the accumulation of phytanic acid in the blood and tissues. The main features of this disorder in its more common, adult-onset form are RP, peripheral neuropathy (typically numbness and weakness), impaired ability to coordinate movement (ataxia) and late-onset, progressive hearing loss. As such, unlike Usher syndrome type I and II but similar to Usher syndrome type III, speech is typically not affected in Refsum disease. Infantile-onset forms, though, are more severe, and include other features such as congenital deafness and failure to thrive. Prompt recognition of this disorder is important because it can be either kept from worsening or reversed with a high-calorie diet devoid of foods rich in phytanic acid (such as butter and animal fat) combined with plasmapheresis. Demonstration of elevated levels of circulating phytanic acid is diagnostic. To date, there are fifteen distinct genes that can cause Refsum disease, two causing the adult-onset form and thirteen that cause the infantile-onset form, which are all linked to defective function of peroxisomes.Obesity syndromes are rarer than the ones associated with hearing loss. Of them, the most common form of obesity syndrome is Bardet-Biedl syndrome (BBS). In addition to RP, the BBS spectrum of clinical manifestations includes obesity, abnormality of the extremities such as more than the normal number of fingers and/or toes (polydactyly), fused digits (syndactyly), or shorter than normal digits (brachydactyly) and underdevelopment of the testes and small external genitalia (the latter more apparent in males), kidney anomalies at times as severe as kidney failure, impairment of smell function (typically revealed only by formal testing), dental abnormalities, vertebral anomalies, behavioral abnormalities (including forms within the autistic spectrum) and in some people intellectual disability. Some individuals also have asthma, diabetes and elevated lipid profiles. Cardiovascular and liver function problems are also possible, albeit rarer.BBS is estimated to affect fewer than 1:100,000 people, although this estimate likely reflects an under-ascertainment bias. In populations with high degree of consanguinity (inbreeding) the incidence can be significantly higher (e.g., certain Bedouin tribes in which the first few BBS genes were mapped). Despite its rarity, BBS is markedly heterogeneous from a genetic point of view, with at least 22 distinct genes implicated in causing this disorder to date. Most BBS genes share a role in the function of cilia, which are present, for example, in the retina and kidneys, or that of functioning as chaperonins (e.g., BBS6, BBS10, and BBS12). BBS1 accounts for the majority of cases of BBS, followed by BBS10. The genetic overlap between BBS and other conditions has recently emerged, with mutations in CEP290 (also known as or NPHP6), which is the cause of LCA, Senior-Loken syndrome, Joubert syndrome, and Meckel syndrome type 4, being associated also with BBS (BBS14 gene). It has also been suggested that, unlike most other conditions, more than two mutations in more than one gene may be necessary to cause BBS (triallelic or polyallelic inheritance). However, this phenomenon has not been verified as necessary in all studies. Most certainly, though, the convergence of the BBS genes at certain subcellular levels, such as the cilia, creates the premises for significant epistatic effects, i.e., an increase (or decrease) in severity of the disease, caused by the main mutations (inherited in a classical Mendelian autosomal recessive mode), exerted on these mutations by mutations (or polymorphisms) in either other BBS genes or in additional genes relevant to the function of the subcellular structure in question in the case of BBS, the cilium.Despite the similarity in symptoms between RP and BBS, BBS patients often have late-onset clinical retinal changes, whereby the diagnosis of BBS is often delayed until an ERG is performed, showing invariably evidence of retinal disease. While to date it appears that retinal disease is a constant and inevitable outcome of carrying BBS gene mutations, it must be noted that the retinopathy of BBS is not always present since birth or childhood, even by ERG criteria, but will ultimately develop. Patients who have BBS gene mutations and yet exhibit only RP and minimal to no systemic features of BBS have also been reported. Similar to LCA, development of nystagmus and high astigmatism are also common in BBS.Alström syndrome (ALMS) is another rare obesity syndrome inherited in an autosomal recessive pattern, characterized not by RP but by CORD, obesity, dilated cardiomyopathy (typically infantile in onset) and subsequent development of diabetes mellitus, sensorineural, post-verbal hearing loss and kidney disease. Unlike RP patients and most BBS patients, but similar to LCA, ALMS patients are typically born with nystagmus. However, ALMS patients also complain primarily of light aversion and far less so of night blindness. ALMS patients do not usually have polydactyly, syndactyly or brachydactyly as seen in BBS. The gene responsible for ALMS is ALMS1. Although distinct from the BBS genes, ALMS1 is also involved in ciliary function, explaining the similarity between BBS and ALMS and establishing an additional link between ciliary dysfunction and syndromes characterized by obesity and kidney dysfunction. Consistent with this, partial overlap in the manifestations of the two syndromes has been reported, with BBS patients with documented BBS gene mutations exhibiting ALMS-like features such as hearing loss and diabetes.A rarer obesity syndrome variant abridging BBS and ALMS is linked to the TUB gene. This gene has been known to cause such a complex syndrome in mice for many years, but only in recent years two families with hybrid features of BBS and ALMS (not expressing dystrophic extremities, but exhibiting a variety of the other possible manifestations, including dilated cardiomyopathy and olfaction deficits) have been reported. The TUB-related retinopathy thus far appears to be of the RP type but with atypical characteristics.Senior-Loken syndrome (SLSN) is a variant of LCA inherited in an autosomal recessive pattern in which, similar to BBS and ALMS, there is multi-cystic involvement of the kidneys that can evolve in serious damage to kidney function (nephronophthisis) and failure, which carries marked morbidity. Unlike BBS and ALMS, though, SLSN patients are not obese and do not have abnormalities of the digits. Additional features that can often be observed in SLSN patients are sensorineural hearing loss and cone-shaped deformity of long bone epiphyses. Less commonly, SLSN patients can also present with liver fibrosis, cerebellar ataxia, diabetes insipidus and, at the ocular level, with congenital cataracts and keratoconus. Although SLSN is rarer than LCA and BBS, due to the severity of the renal involvement, prompt recognition of this disorder has important diagnostic and prognostic implications.Ten distinct genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, SDCCAG8, WDR19, TRAF3IP1, and CEP164) responsible for SLSN have been cloned to date, all of which are part of the family of the nephrocystins, important proteins expressed in the kidney as well as in the retina and other organs and tissues characterized by the presence of cilia. Therefore, also SLSN is a member of the emerging group of ciliopathies. As noted above in the BBS section, CEP290 (also known as NPHP6), which is responsible for a form of LCA, is also one of the genes responsible for one type of SLSN, as well as BBS and other clinically distinct but clearly allelic conditions.Lastly, a rare RP syndrome is abetalipoproteinemia, or Bassen-Kornzweig syndrome, a disorder inherited in an autosomal recessive pattern characterized by the presence of misshapen red blood cells (acanthocytosis) in the circulating blood. This disorder usually begins in the first year of life and is characterized by a progressive inability to coordinate movement (ataxia), RP, the malabsorption of fat in the digestive system with fatty, greasy stools (steatorrhea) and low serum cholesterol since childhood (celiac syndrome). Serum beta lipoprotein is absent as a result of defective function in the microsomal triglyceride transfer protein, encoded for by the MTP gene. The aforementioned clinical and laboratory features allow for differentiation of this condition from Refsum disease. Despite its rarity, awareness of the characteristics abetalipoproteinemia is very important because the syndrome is responsive to vitamin A, E and K supplementation. Therefore, as in Refsum disease, early diagnosis of abetalipoproteinemia is crucial.
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Related disorders of Retinitis Pigmentosa. Signs of the following disorders can be similar to RP. Comparisons may be useful for a differential diagnosis:Leber congenital amaurosis (LCA), severe early childhood-onset retinal dystrophy (SECORD), and early-onset RP (EORP) are special forms of RP characterized by the presence of severe symptoms from birth or shortly thereafter, respectively. This sub-group of RP forms is inherited in an autosomal recessive fashion, although X-linked RP also tends to have a significantly earlier onset than other forms of RP. When present from birth as in LCA, the visual deficit of affected children is typically recognized because of the coexistence of unsteadiness of the eyes known as nystagmus. Nystagmus is characterized by either fast-beating movements or by wandering movements of the eyeballs. The appearance of the back of the eye can be normal or near normal for several years, but testing of retinal function in response to flashes of light (the electroretinogram, or ERG) will invariably reveal the disease status in these patients. LCA patients often develop a deformation of the cornea causing high astigmatism up to a frank cone-shaped deformation of the cornea known as keratoconus. Prompt recognition of, and molecular genetic diagnostic testing for LCA has become increasingly important, since an FDA-approved gene therapy called Luxturna has become commercially available in 2017 as a treatment for one form of LCA linked to the RPE65 gene (see below). There are many different genes responsible for LCA and for recessive EORP. (For more information on this condition, choose “Leber congenital amaurosis” as your search term in the Rare Disease Database)Pericentral RP is a clinical subtype of RP that is characterized by loss of side vision right around the center of a patient’s vision in the shape of a donut. This form of RP can be inherited in various ways (recessive, dominant, and sporadic, that is, without an uncertain mode of inheritance). Pericentral RP tends to have later onset than typical RP, causes far less loss of peripheral vision (in fact, the farthest portions of the field of vision in pericentral RP are rarely affected), it has been reported to have an overall slower progression rate than typical RP but, once it becomes symptomatic to patients, pericentral RP tends to encroach the center of the patients’ vision more rapidly and more severely than typical RP. As a result of this feature of the disease, patients with pericentral RP tend to experience a greater loss in visual acuity and central vision than peripheral vision, which is opposite of what is seen in typical RP, and is more similar to what is observed in what was once termed “RP inversa”, more properly referred to nowadays as cone-rod dystrophy (CORD). By ERG criteria, pericentral RP tends to equally compromise rod and cone cells (the primary vision cells of the retina) or, at times, cone cells (the daytime ones) more than rod cells (the nighttime ones). On the genetic level, many forms of pericentral RP share mutations in the same genes as those involved in other RP conditions. Thus, it does not appear to be a distinct entity, but may rather represent the mild end of the RP disease spectrum. Specific genes responsible for pericentral RP, if any, have not been identified yet, but research is ongoing to discover them.A group of disorders that is often confused with RP but is distinct from RP is that linked to mutations, to date, to a single gene, known as NR2E3. This gene affects the development of progenitor retinal cells. Mutations in this gene lead to disorders that can present with clinically distinct pictures, known respectively as Goldmann-Favre vitreoretinal dystrophy, enhanced S-cone syndrome (ESCS), and clumped pigmentary retinal degeneration. These three conditions, all inherited in an autosomal recessive pattern, share the feature of congenital night blindness and better than normal (or selectively better preserved) vision of the short wavelength-sensitive (blue, or S) cones, due to the erroneous development of rods into S-cones in the retina of affected patients. Unlike RP, these patients have slower disease progression rates, but are also prone to complications that RP patients do not typically incur, such as splitting of the retina at the macular and peripheral level (retinoschisis) and retinal detachments. The changes visible on fundus exam affecting patients with this group of disorders are typically located along the vascular arcades of the retina, and vary in appearance primarily from whitish flecks to coin-shaped (“nummular”) areas of confluent pigmentation that is typically located underneath the retina and not within it, as seen instead in RP. Recent investigations have shed further light on these unique changes seen at the vascular arcades.Cone-rod dystrophy (CORD) is a term that identifies a group of disorders that can be inherited as autosomal recessive, autosomal dominant, X-linked recessive or mitochondrial (maternally inherited) traits. As noted above, opposite from RP, CORD typically affects central and daytime vision much more severely than peripheral and night vision, hence the classical term “RP inversa”, with which this family of conditions was originally known. CORDs are, at least in part, genetically distinct from RP. However, depending on the mutations, certain genes expressed in both rods and cones can cause either RP or CORD (for example, the RDS/peripherin gene in dominant forms, the ABCA4 gene in recessive forms, and the RPGR gene in X-linked forms).Choroideremia is a vision disorder inherited in an X-linked recessive pattern characterized by extensive defects (atrophy) in the pigmented layer of cells underneath the retina, the retinal pigment epithelium (RPE) and of the capillary blood vessels of the underlying vascular layer, the choroid, which is called the choriocapillaris. Much like RP, the major symptoms of this disorder include a progressive loss of the peripheral field of vision and night blindness, which can start as early as during childhood and as late as young adulthood. It has been shown that, despite the extensive RPE and choriocapillaris loss that can occur early on in the disease, the neuroretina above areas of atrophy of these other tissues can remain at least partially intact and, therefore, partially functioning for an extended period of time. This explains why, often times, the changes seen at the back of the eye of affected males appear more severe than the actual degree of visual loss experienced by the patients. Unlike RP, patients with choroideremia do not typically develop bone spicule-like pigmentary deposits in the retina, but rather scattered patches of irregularly shaped hyperpigmentation underneath the retina. The overall prognosis of choroideremia appears to be, on average, better than that of RP and X-linked RP in particular, but severe vision loss has been reported in choroideremia as well.With very few exceptions, choroideremia affects only males. Unlike female carriers of X-linked RP, who commonly experience some sign of the disease, however mild or late-onset they may be, female carriers of choroideremia only sometimes have symptoms, although a few will complain about dim light or night vision issues late in life. Despite the relative lack of symptoms experienced by female carriers, they can usually be identified as such by characteristic pigment mottling under the retina at the RPE level after the pupils of the eye has been dilated. Even more so in the case of the female carriers, the fundus appearance is usually much more abnormal in appearance than the degree of functional compromise that carriers can experience – in other words, the fundus exam usually has very prominent changes of little to no functional impact on the vision of female carriers. These findings can often lead to the incorrect diagnosis of RP or the suspicion of another, more severe form of IRD, in a carrier of choroideremia who may have no known family history thereof. Despite the fact that the functional outcome of this condition is for the most part benign, female carriers of choroideremia are at risk for macular complications that include neovascular membranes, as seen in the “wet” form of age-related macular degeneration. These complications can occur in relatively young age (as early as the 3rd or 4th decade of life) and are treatable with injections administered directly in the eyeball of drugs that block the main factor implicated in the growth of these membranes, termed vascular endothelial growth factor (VEGF).Related SyndromesThe most common associations of RP with general health (so called “systemic”) problems causing more complex disorders known as “syndromes” are hearing loss and obesity.Some individuals with RP can be born deaf (Usher syndrome type I or infantile-onset Refsum disease), or hearing-impaired (Usher syndrome type II), or can become hearing impaired (Usher syndrome type III or adult-onset Refsum disease). A rarer form of hearing-related syndrome that can present also with an RP-like retinopathy is Wolfram syndrome, but optic atrophy (not RP) and diabetes mellitus are by far the most common manifestations of this disorder. Hearing impairment of various degrees of severity and type can also be present in RP variants caused by changes in mitochondrial DNA. The most common form of this rarer association is termed NARP, an acronym for the peripheral neuropathy, ataxia, and retinitis pigmentosa syndrome, which includes also (and more commonly) progressive neurological problems resulting in abnormal gait and late-onset stutter. The type of deafness/hearing loss presented by patients with all these conditions is termed “sensorineural” that is, linked to congenital malfunction and/or progressive degeneration of the hearing nerves and nervous structures, which are much like the type of visual loss that occurs at the level of the retina.Usher syndrome is a group of inherited disorders characterized by RP and hearing impairment. Usher syndrome accounts for about 50% of all deaf-blinding disorders. The exact prevalence (frequency) of Usher syndrome in the population is not precisely known, but it has been estimated to affect 1:10,000 to 1:20,000 people. Usher syndrome is, for the most part, genetically distinct from non-syndromic forms of RP, although some cases of simple RP (that is, without hearing loss) in association with mutations in the USH2A gene have been reported. A major multicenter international collaborative natural history study of USH2A-related RP, termed RUSH2A, is presently in progress. There are three major types of Usher syndrome, distinguished by the severity and the age of onset of the hearing features. Type I is characterized by congenital, non-progressive, profound hearing loss. Type II is characterized by congenital, non-progressive, mild to moderate hearing loss, whereby speech is much less affected. Type III, which is rarer, is characterized by progressive, later-onset (post-verbal) hearing loss; speech is typically not affected. All three types of Usher syndrome are inherited in an autosomal recessive pattern. Although three main types of Usher syndrome are recognized clinically, many more genes accounting for these clinical subtypes exist. To date, 18 genes have been mapped (six for Usher syndrome type I, USH1B-G, three for type II, USH2A-C, and one for type III, (USH3A), fifteen of which have been cloned. A type IV Usher syndrome with X-linked recessive inheritance was suspected to exist in the past, but this has now been shown to be a pseudo-Usher syndrome linked to mutations affecting the RRC1-like domain of the RPGR gene, a common cause of X-linked RP (and X-linked CORD), which we showed is also expressed in the epithelial lining of the respiratory tract and in the inner ear. This disease variant is also associated with recurrent upper respiratory tract infections (especially otitis and sinusitis) and immotile cilia-like symptoms.Refsum syndrome is a slowly progressive disorder of fat (lipid) metabolism inherited in an autosomal recessive pattern that is characterized by the accumulation of phytanic acid in the blood and tissues. The main features of this disorder in its more common, adult-onset form are RP, peripheral neuropathy (typically numbness and weakness), impaired ability to coordinate movement (ataxia) and late-onset, progressive hearing loss. As such, unlike Usher syndrome type I and II but similar to Usher syndrome type III, speech is typically not affected in Refsum disease. Infantile-onset forms, though, are more severe, and include other features such as congenital deafness and failure to thrive. Prompt recognition of this disorder is important because it can be either kept from worsening or reversed with a high-calorie diet devoid of foods rich in phytanic acid (such as butter and animal fat) combined with plasmapheresis. Demonstration of elevated levels of circulating phytanic acid is diagnostic. To date, there are fifteen distinct genes that can cause Refsum disease, two causing the adult-onset form and thirteen that cause the infantile-onset form, which are all linked to defective function of peroxisomes.Obesity syndromes are rarer than the ones associated with hearing loss. Of them, the most common form of obesity syndrome is Bardet-Biedl syndrome (BBS). In addition to RP, the BBS spectrum of clinical manifestations includes obesity, abnormality of the extremities such as more than the normal number of fingers and/or toes (polydactyly), fused digits (syndactyly), or shorter than normal digits (brachydactyly) and underdevelopment of the testes and small external genitalia (the latter more apparent in males), kidney anomalies at times as severe as kidney failure, impairment of smell function (typically revealed only by formal testing), dental abnormalities, vertebral anomalies, behavioral abnormalities (including forms within the autistic spectrum) and in some people intellectual disability. Some individuals also have asthma, diabetes and elevated lipid profiles. Cardiovascular and liver function problems are also possible, albeit rarer.BBS is estimated to affect fewer than 1:100,000 people, although this estimate likely reflects an under-ascertainment bias. In populations with high degree of consanguinity (inbreeding) the incidence can be significantly higher (e.g., certain Bedouin tribes in which the first few BBS genes were mapped). Despite its rarity, BBS is markedly heterogeneous from a genetic point of view, with at least 22 distinct genes implicated in causing this disorder to date. Most BBS genes share a role in the function of cilia, which are present, for example, in the retina and kidneys, or that of functioning as chaperonins (e.g., BBS6, BBS10, and BBS12). BBS1 accounts for the majority of cases of BBS, followed by BBS10. The genetic overlap between BBS and other conditions has recently emerged, with mutations in CEP290 (also known as or NPHP6), which is the cause of LCA, Senior-Loken syndrome, Joubert syndrome, and Meckel syndrome type 4, being associated also with BBS (BBS14 gene). It has also been suggested that, unlike most other conditions, more than two mutations in more than one gene may be necessary to cause BBS (triallelic or polyallelic inheritance). However, this phenomenon has not been verified as necessary in all studies. Most certainly, though, the convergence of the BBS genes at certain subcellular levels, such as the cilia, creates the premises for significant epistatic effects, i.e., an increase (or decrease) in severity of the disease, caused by the main mutations (inherited in a classical Mendelian autosomal recessive mode), exerted on these mutations by mutations (or polymorphisms) in either other BBS genes or in additional genes relevant to the function of the subcellular structure in question in the case of BBS, the cilium.Despite the similarity in symptoms between RP and BBS, BBS patients often have late-onset clinical retinal changes, whereby the diagnosis of BBS is often delayed until an ERG is performed, showing invariably evidence of retinal disease. While to date it appears that retinal disease is a constant and inevitable outcome of carrying BBS gene mutations, it must be noted that the retinopathy of BBS is not always present since birth or childhood, even by ERG criteria, but will ultimately develop. Patients who have BBS gene mutations and yet exhibit only RP and minimal to no systemic features of BBS have also been reported. Similar to LCA, development of nystagmus and high astigmatism are also common in BBS.Alström syndrome (ALMS) is another rare obesity syndrome inherited in an autosomal recessive pattern, characterized not by RP but by CORD, obesity, dilated cardiomyopathy (typically infantile in onset) and subsequent development of diabetes mellitus, sensorineural, post-verbal hearing loss and kidney disease. Unlike RP patients and most BBS patients, but similar to LCA, ALMS patients are typically born with nystagmus. However, ALMS patients also complain primarily of light aversion and far less so of night blindness. ALMS patients do not usually have polydactyly, syndactyly or brachydactyly as seen in BBS. The gene responsible for ALMS is ALMS1. Although distinct from the BBS genes, ALMS1 is also involved in ciliary function, explaining the similarity between BBS and ALMS and establishing an additional link between ciliary dysfunction and syndromes characterized by obesity and kidney dysfunction. Consistent with this, partial overlap in the manifestations of the two syndromes has been reported, with BBS patients with documented BBS gene mutations exhibiting ALMS-like features such as hearing loss and diabetes.A rarer obesity syndrome variant abridging BBS and ALMS is linked to the TUB gene. This gene has been known to cause such a complex syndrome in mice for many years, but only in recent years two families with hybrid features of BBS and ALMS (not expressing dystrophic extremities, but exhibiting a variety of the other possible manifestations, including dilated cardiomyopathy and olfaction deficits) have been reported. The TUB-related retinopathy thus far appears to be of the RP type but with atypical characteristics.Senior-Loken syndrome (SLSN) is a variant of LCA inherited in an autosomal recessive pattern in which, similar to BBS and ALMS, there is multi-cystic involvement of the kidneys that can evolve in serious damage to kidney function (nephronophthisis) and failure, which carries marked morbidity. Unlike BBS and ALMS, though, SLSN patients are not obese and do not have abnormalities of the digits. Additional features that can often be observed in SLSN patients are sensorineural hearing loss and cone-shaped deformity of long bone epiphyses. Less commonly, SLSN patients can also present with liver fibrosis, cerebellar ataxia, diabetes insipidus and, at the ocular level, with congenital cataracts and keratoconus. Although SLSN is rarer than LCA and BBS, due to the severity of the renal involvement, prompt recognition of this disorder has important diagnostic and prognostic implications.Ten distinct genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, SDCCAG8, WDR19, TRAF3IP1, and CEP164) responsible for SLSN have been cloned to date, all of which are part of the family of the nephrocystins, important proteins expressed in the kidney as well as in the retina and other organs and tissues characterized by the presence of cilia. Therefore, also SLSN is a member of the emerging group of ciliopathies. As noted above in the BBS section, CEP290 (also known as NPHP6), which is responsible for a form of LCA, is also one of the genes responsible for one type of SLSN, as well as BBS and other clinically distinct but clearly allelic conditions.Lastly, a rare RP syndrome is abetalipoproteinemia, or Bassen-Kornzweig syndrome, a disorder inherited in an autosomal recessive pattern characterized by the presence of misshapen red blood cells (acanthocytosis) in the circulating blood. This disorder usually begins in the first year of life and is characterized by a progressive inability to coordinate movement (ataxia), RP, the malabsorption of fat in the digestive system with fatty, greasy stools (steatorrhea) and low serum cholesterol since childhood (celiac syndrome). Serum beta lipoprotein is absent as a result of defective function in the microsomal triglyceride transfer protein, encoded for by the MTP gene. The aforementioned clinical and laboratory features allow for differentiation of this condition from Refsum disease. Despite its rarity, awareness of the characteristics abetalipoproteinemia is very important because the syndrome is responsive to vitamin A, E and K supplementation. Therefore, as in Refsum disease, early diagnosis of abetalipoproteinemia is crucial.
| 1,068 |
Retinitis Pigmentosa
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nord_1068_5
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Diagnosis of Retinitis Pigmentosa
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RP is diagnosed by full-field flash electroretinography (ffERG) showing progressive loss in photoreceptor function, visual field testing, and retinal imaging [mainly by optical coherence tomography (OCT) and fundus auto-fluorescence (FAF) that show detailed microanatomical features that cannot be resolved by naked eye]. Molecular genetic testing for mutations in many of the genes associated with RP is available and is essential to confirm the diagnosis.
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Diagnosis of Retinitis Pigmentosa. RP is diagnosed by full-field flash electroretinography (ffERG) showing progressive loss in photoreceptor function, visual field testing, and retinal imaging [mainly by optical coherence tomography (OCT) and fundus auto-fluorescence (FAF) that show detailed microanatomical features that cannot be resolved by naked eye]. Molecular genetic testing for mutations in many of the genes associated with RP is available and is essential to confirm the diagnosis.
| 1,068 |
Retinitis Pigmentosa
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nord_1068_6
|
Therapies of Retinitis Pigmentosa
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TreatmentsDietary SupplementsThe treatment regimen for patients with RP has evolved during the last two decades. A six-year study of patients aged 18 through 49 years conducted at Harvard Medical School with the support of the National Eye Institute and the Foundation Fighting Blindness, showed that those who supplemented their regular diets with 15,000 IU (international units) daily of vitamin A palmitate had a slower decline of retinal function than those who received only trace amounts. It must be noted that vitamin A palmitate is the specific form of vitamin A that was used in this trial. Beta-carotene needs to be metabolized by the liver and broken down into vitamin A before it can be utilized by the body. The rate of absorption and metabolism of beta-carotene varies greatly between individuals and also within the same individual depending on other factors. Beta-carotene, therefore, although a precursor of vitamin A, is not necessarily a substitute for vitamin A palmitate. The study results also indicated that taking 400 IU daily of vitamin E supplementation did not delay retinal disease progression but in fact hastened it, whereby RP patients are generally recommended against taking vitamin E supplements in addition to what is provided by a regular, balanced diet. This means that virtually all RP patients should not be on generic multivitamins, which are rich in both beta-carotene (but not vitamin A palmitate) and vitamin E, as well as a number of other supplements the effects of which on RP progression are not presently known.Long-term supplementation with these regimens of vitamin A palmitate appears to be safe, although older patients should be aware that there is some evidence (although not univocal) that vitamin A supplements may promote further bone density loss, worsen osteoporosis and, therefore, increase the risk of hip or other bone fractures. In these patients, it may be wise to obtain a baseline bone density scan and, in the presence of existing osteoporosis, treat the underlying disorder appropriately before starting vitamin A supplements and monitor closely the bone density profiles thereafter. In addition, adverse interaction between smoking and beta-carotene has been documented. A 2010 meta-analysis by Druesne et al. that included 9 randomized control trials on β-carotone supplementation confirmed the increased risk of cancer among smokers and asbestos workers taking more than 20 mg/day of β-carotene. Thus, since smokers using such supplements have an increased risk of lung cancer, smokers should not be on vitamin A- or beta-carotene-containing supplements, and smokers with RP should not start vitamin A palmitate supplements until successful completion of a smoking cessation program. Monitoring liver function every 1-2 years while on vitamin A palmitate supplements is advisable even in the absence of liver disease. RP patients with liver disease may not be able to tolerate the full dose of recommended vitamin A supplement, and decision on use and dosage should be made individually by treating physicians.It should also be noted that more is not better. Because long-term high-dose vitamin A supplementation (e.g., exceeding 20,000 IU) may cause certain adverse effects such as liver disease, patients should not undertake such high supplementation regimens unless so recommended by their treating physician and unless regularly monitored for liver function status when taking such supplementation.Supplementation has recently been formally studied retrospectively also in children followed by at the Massachusetts Eye and Ear Infirmary. The study included 55 children with different genetic types of RP taking vitamin A palmitate and 25 not taking vitamin A. Age-adjusted dosage supplementation were given to the children (5,000 IU/day for ages 6-10 years old, 10,000 IU/day for ages 10-15 years old, and 15,000 IU/d for ages ≥15 years old, provided that the children had normal serum liver function test results at baseline). Parents were advised that their children taking vitamin A should eat a regular diet, avoid a high-dose vitamin E supplement, monitor their serum liver function annually and return to clinic for follow-up assessment and possible dose adjustment every 2 years. No adverse effects were reported in any of the children on these vitamin A palmitate dose ranges. While this was a retrospective investigation, and not a formal, randomized prospective trial, similar to what reported previously in adults, the cone ERG responses of children on these supplementation regimens on average declined less than those who were not, supporting further the notion that this supplementation regimen may be beneficial in reducing the overall rates of disease progression also in children. Thus, this evidence of supplement efficacy and safety suggests that also children with RP should consider oral supplementation of vitamin A palmitate with age-adjusted dosage under the care of their pediatrician.Furthermore, it should be noted that vitamin A use can cause malformations of the fetus during pregnancy. The highest risks have been identified in women taking more than 10,000 IUs of vitamin A daily (identified as a threshold level) and especially those taking high supplements during the first 7 weeks of gestation. Above this dosage, the risk for certain specific malformations was estimated at about 1 in 57 (hence, about 1.8%). Therefore, women of childbearing age should be careful while on vitamin A supplements and either avoid becoming pregnant while on the 15,000 IU daily supplements, or monitor the frequency of their menstrual cycles while on supplementation and interrupt or reduce promptly vitamin A supplements as soon as they become aware of being pregnant. Women intending to become pregnant should consider reducing supplementation to less than 10,000 IUs daily, or perhaps discontinuing altogether the vitamin A supplements during period of active attempts to conceive. However, it does not appear that vitamin A use during pregnancy should be completely avoided. The use, and dose, of any supplements during or around pregnancy should be carefully discussed by individual patients with their doctors.Further studies by the same group at Harvard have shown that additional, short-term benefits can be obtained by treating naive RP patients with 15,000 IU of daily vitamin A palmitate in combination with 1,200 mg of docosahexaenoic acid (DHA), an omega-3 fatty acid that is a key component of fish oil. In addition, current treatment recommendations include an omega-3 rich fish diet for those already on vitamin A supplements, since subgroup analyses suggest potentially harmful effects of initiating DHA supplementation while already on the vitamin A supplements. Also, long term use of DHA supplements was not associated with benefits. Therefore, DHA supplementation beyond 2 years from its onset according to the criteria summarized above is not recommended, except for X-linked RP (see below).Additional studies from the same group have subsequently reported further reduction in the rate of visual field sensitivity loss in RP patients who took 12 mg of daily lutein added to the previously studied 15,000 IU vitamin A palmitate supplementation regimen compared to those on vitamin A alone.Another relevant trial was a specific one focused of DHA supplementation in children and young adults with X-linked RP, which was conducted at the Retina Foundation of the Southwest (ClinicalTrials.gov identifier: NCT00100230). This trial, which was based on preexisting evidence that there is an abnormality in fatty acid metabolism in XLRP patients leading up to an impaired DHA synthesis, tested the potential benefits of a higher dose of DHA than that previously tested on this specific type of RP. The results did not show a statistically significant reduction in loss of electroretinographic function as compared with placebo. However there was a significant reduction in the rates of visual field loss in the DHA treated group. Therefore, high-dose DHA supplementation is recommended in patients with X-linked RP.A review by Brito-Garcia et al. that includes 7 studies on the effectiveness of nutritional supplementation in retinitis pigmentosa found that vitamin A, lutein, and β-carotene showed a small protective effect on the progression of RP. Supplementation with DHA was not shown to have strong evidence of efficacy in RP. None of the studies reported any severe adverse effects of supplementation.Patients with less common disorders that may be associated with RP were not evaluated in these supplementation studies. In addition, certain patients were not included, such as patients with severely advanced RP. Thus, based on the results of these studies, precise recommendations cannot be made regarding vitamin A supplementation for these patients.Tauroursodeoxycholic acid (TUDCA), a major component of bear bile, is another supplement that has come to light as a photoreceptor-protective agent for use in RP. Interestingly, an alternate version of the bile acid pathway has now been demonstrated to be important for cholesterol metabolism in the retina. Bile acids appear to activate several types of molecular signaling receptors within the retina. In several different animal models of RP, TUDCA was demonstrated to significantly slow down the rate of disease progression, as evidenced by preserved retinal anatomy and electrophysiological function. Systemic administration of TUDCA was shown to reduce cellular stress and preserve photoreceptors in several models of RP, including Leber congenital amaurosis and RP associated with RPGR and PDE6B mutations, as well in animal models of the syndromic form of RP, known as Bardet-Biedl syndrome. Furthermore, in these models, TUDCA also prevented/reduced obesity, a disease feature that is otherwise notoriously challenging to address. TUDCA is available as an over-the-counter supplement. Human trials in conditions other than RP have utilized safely a 500 mg daily dosage. It is not exactly known whether this oral dosage would be effective in RP. Of note, there is now an FDA approved drug to reduce obesity in Bardet-Biedl syndrome and other related ciliopathies, called setmelatonide that tackles a specific mechanism that is at play in these forms of syndromic obesity.Interestingly, saffron, a spice derived from the flower of Crocus sativus, has gained interest in recent years as well, after animal studies demonstrated beneficial effects in neurodegenerative diseases and RP. Safranal (which contains crocin and crocetin) is thought to be the active chemical component of saffron that is responsible for this neuroprotective effect. A human trial of a highly purified 20 mg saffron supplement in macular degeneration indicated beneficial effects on macular function, and a trial of a macular dystrophy, Stargardt disease, suggested similar benefits. To our knowledge, to date no formal RP trial of saffron supplementation has been conducted. However, the neuroprotective potential of saffron appears to be gene- and disease type-independent, and therefore it is likely to apply also to RP.Another emerging supplement for use by RP patients is N-acetylcysteine (NAC), discussed in the “Antioxidants” section below.Treatment of Cystoid Macular EdemaA common complication of RP is the formation of small pockets of fluid in the centermost part of the retina, called cystoid macular edema, or CME. CME can cause significant reduction in central visual acuity, as well as blurred vision, and glare. If untreated, further degenerative changes in the retinal tissue will ultimately occur, and the development of a macular hole by rupture of a central larger cyst can also occur. With the current imaging techniques available to ophthalmologists in the clinical setting, detection of CME changes has become much easier and much more precise. A study with such techniques estimated the frequency of cystic macular changes consistent with CME to be 38% in at least one eye and 27% in both eyes of RP patients. This complication can be successfully treated with oral (tablets) or topical (eye drops) medications in the family of the so-called carbonic anhydrase inhibitors (CAIs), such as acetazolamide or metazolamide (tablets) and dorzalamide or brinzolamide (topical eye drops). While not all patients will respond to these treatments, these medications have been shown to diminish and often eliminate the cystic changes in the retina of RP patients, improving visual acuity in the short term and improving the overall functional prognosis over the long term. Some side effects can result from use of these medications, but most of them can be managed. Patients allergic to sulfonamides should not be taking CAIs. CAIs have been shown to be effective in reducing or resolving cystic changes also in patients with similar findings due a different problem, called macular retinoschisis, as it is seen in patients with ESCS or another hereditary vitreo-retinal disorder, called X-linked retinoschisis.Since an inflammatory component to CME is also likely, and an increased frequency of certain antibodies in the bloodstream of RP patients with CME has been reported, corticosteroids utilized off-label and injected around (that is, periocularly) or directly inside the eye ball (that is, intravitreally) of RP patients with CME have also been tried in some patients that do not respond to CAIs, and variable success has been reported. However, the intravitreal use of these medications increases the risk of other complications, such as glaucoma or cataract, and a very small but serious risk of infection inside the eye ball (endophthalmitis) exists with all intravitreal injections. Periocular injections pose a much lower risk of glaucoma and cataracts, and do not normally pose a risk of endophthalmitis. A newer formulation of triamcinolone acetonide specifically designed for intravitreal injection has become available in more recent years. Implantable slow-release steroid-laden (dexamethasone and fluocinolone acetonide) devices have also become available. For example, intravitreal dexamethasone implants have been shown to improve anatomic and functional outcomes in refractory CME associated with RP. Initial reports show repeated injections of the implant may be needed to prevent recurrence.A National Eye Institute sponsored pilot study of 5 participants (ClinicalTrials.gov identifier: NCT02140164) suggested that 100 mg twice a day of minocycline, a tetracycline antibiotic, reduced CME associated with RP. This too appears due to anti-inflammatory properties of minocycline.Supportive MeasuresFor individuals with RP, low-vision aids and other assistive devices may be of benefit as vision worsens (see below). Although a study of light deprivation in RP was conducted many years ago without benefit, the concern that light damage may play a role in worsening retinal degeneration in some forms of RP remains. This concern is in part supported by recent evidence that, in a dog naturally affected with RP resulting from a mutation in the rhodopsin (RHO) gene, evidence for light-induced worsening of the disease has been obtained. Therefore, to err on the side of caution, use of sunglasses in the outdoors and avoiding undue and unnecessary exposure to excessive amounts of light is generally recommended to all RP patients. Most modern smart phone devices have the “dark mode” feature that limits the total light exposure of the retina while maintaining good contrast level.Genetic counseling is also recommended for affected individuals and their families.Assistive DevicesThe Canadian company eSight has created a portable headset visual aid which uses a high-resolution camera along with patented processing algorithms to send high speed video to two screens positioned in front of the user’s eyes. The screens can be adjusted and placed in a position that provides the best view for the individual. The high-speed camera and processing algorithms provide a clear picture with minimal latency to reduce nausea and balance disturbance that can be experienced with immersive technologies. This technology may allow individuals to become more independent by increasing ability to perform activities of daily living. The newest eSight3 device is currently available for purchase. The company does provide assistance with the cost by various public and private funding sources.A similar technology that is also available for purchase is the MyEye device, made available by Orcam – a small assistive device that fits unobtrusively on any eye glass frame. This technology allows the user to point at objects, surfaces or labels and read written text on them, recognize familiar faces or identify products by simply pointing at them or looking in that direction. For example, up to 100 faces and 150 commonly used products can be stored in the device for automated recognition.There is no such thing as a one-size-fits-all device. Each patient may have different needs, issues and abilities. Thus, it is highly recommended that patients interested in trying any of these assistive devices reach out to local low vision and occupational therapy (LV/OT) specialists to try them out first and obtain direct, unbiased counseling about them from these providers. In the absence of such options locally and should patients be unable to arrange for travel to go see a LV/OT specialist, patients can contact the manufacturers directly via their websites and make arrangements to try the devices directly with them.
|
Therapies of Retinitis Pigmentosa. TreatmentsDietary SupplementsThe treatment regimen for patients with RP has evolved during the last two decades. A six-year study of patients aged 18 through 49 years conducted at Harvard Medical School with the support of the National Eye Institute and the Foundation Fighting Blindness, showed that those who supplemented their regular diets with 15,000 IU (international units) daily of vitamin A palmitate had a slower decline of retinal function than those who received only trace amounts. It must be noted that vitamin A palmitate is the specific form of vitamin A that was used in this trial. Beta-carotene needs to be metabolized by the liver and broken down into vitamin A before it can be utilized by the body. The rate of absorption and metabolism of beta-carotene varies greatly between individuals and also within the same individual depending on other factors. Beta-carotene, therefore, although a precursor of vitamin A, is not necessarily a substitute for vitamin A palmitate. The study results also indicated that taking 400 IU daily of vitamin E supplementation did not delay retinal disease progression but in fact hastened it, whereby RP patients are generally recommended against taking vitamin E supplements in addition to what is provided by a regular, balanced diet. This means that virtually all RP patients should not be on generic multivitamins, which are rich in both beta-carotene (but not vitamin A palmitate) and vitamin E, as well as a number of other supplements the effects of which on RP progression are not presently known.Long-term supplementation with these regimens of vitamin A palmitate appears to be safe, although older patients should be aware that there is some evidence (although not univocal) that vitamin A supplements may promote further bone density loss, worsen osteoporosis and, therefore, increase the risk of hip or other bone fractures. In these patients, it may be wise to obtain a baseline bone density scan and, in the presence of existing osteoporosis, treat the underlying disorder appropriately before starting vitamin A supplements and monitor closely the bone density profiles thereafter. In addition, adverse interaction between smoking and beta-carotene has been documented. A 2010 meta-analysis by Druesne et al. that included 9 randomized control trials on β-carotone supplementation confirmed the increased risk of cancer among smokers and asbestos workers taking more than 20 mg/day of β-carotene. Thus, since smokers using such supplements have an increased risk of lung cancer, smokers should not be on vitamin A- or beta-carotene-containing supplements, and smokers with RP should not start vitamin A palmitate supplements until successful completion of a smoking cessation program. Monitoring liver function every 1-2 years while on vitamin A palmitate supplements is advisable even in the absence of liver disease. RP patients with liver disease may not be able to tolerate the full dose of recommended vitamin A supplement, and decision on use and dosage should be made individually by treating physicians.It should also be noted that more is not better. Because long-term high-dose vitamin A supplementation (e.g., exceeding 20,000 IU) may cause certain adverse effects such as liver disease, patients should not undertake such high supplementation regimens unless so recommended by their treating physician and unless regularly monitored for liver function status when taking such supplementation.Supplementation has recently been formally studied retrospectively also in children followed by at the Massachusetts Eye and Ear Infirmary. The study included 55 children with different genetic types of RP taking vitamin A palmitate and 25 not taking vitamin A. Age-adjusted dosage supplementation were given to the children (5,000 IU/day for ages 6-10 years old, 10,000 IU/day for ages 10-15 years old, and 15,000 IU/d for ages ≥15 years old, provided that the children had normal serum liver function test results at baseline). Parents were advised that their children taking vitamin A should eat a regular diet, avoid a high-dose vitamin E supplement, monitor their serum liver function annually and return to clinic for follow-up assessment and possible dose adjustment every 2 years. No adverse effects were reported in any of the children on these vitamin A palmitate dose ranges. While this was a retrospective investigation, and not a formal, randomized prospective trial, similar to what reported previously in adults, the cone ERG responses of children on these supplementation regimens on average declined less than those who were not, supporting further the notion that this supplementation regimen may be beneficial in reducing the overall rates of disease progression also in children. Thus, this evidence of supplement efficacy and safety suggests that also children with RP should consider oral supplementation of vitamin A palmitate with age-adjusted dosage under the care of their pediatrician.Furthermore, it should be noted that vitamin A use can cause malformations of the fetus during pregnancy. The highest risks have been identified in women taking more than 10,000 IUs of vitamin A daily (identified as a threshold level) and especially those taking high supplements during the first 7 weeks of gestation. Above this dosage, the risk for certain specific malformations was estimated at about 1 in 57 (hence, about 1.8%). Therefore, women of childbearing age should be careful while on vitamin A supplements and either avoid becoming pregnant while on the 15,000 IU daily supplements, or monitor the frequency of their menstrual cycles while on supplementation and interrupt or reduce promptly vitamin A supplements as soon as they become aware of being pregnant. Women intending to become pregnant should consider reducing supplementation to less than 10,000 IUs daily, or perhaps discontinuing altogether the vitamin A supplements during period of active attempts to conceive. However, it does not appear that vitamin A use during pregnancy should be completely avoided. The use, and dose, of any supplements during or around pregnancy should be carefully discussed by individual patients with their doctors.Further studies by the same group at Harvard have shown that additional, short-term benefits can be obtained by treating naive RP patients with 15,000 IU of daily vitamin A palmitate in combination with 1,200 mg of docosahexaenoic acid (DHA), an omega-3 fatty acid that is a key component of fish oil. In addition, current treatment recommendations include an omega-3 rich fish diet for those already on vitamin A supplements, since subgroup analyses suggest potentially harmful effects of initiating DHA supplementation while already on the vitamin A supplements. Also, long term use of DHA supplements was not associated with benefits. Therefore, DHA supplementation beyond 2 years from its onset according to the criteria summarized above is not recommended, except for X-linked RP (see below).Additional studies from the same group have subsequently reported further reduction in the rate of visual field sensitivity loss in RP patients who took 12 mg of daily lutein added to the previously studied 15,000 IU vitamin A palmitate supplementation regimen compared to those on vitamin A alone.Another relevant trial was a specific one focused of DHA supplementation in children and young adults with X-linked RP, which was conducted at the Retina Foundation of the Southwest (ClinicalTrials.gov identifier: NCT00100230). This trial, which was based on preexisting evidence that there is an abnormality in fatty acid metabolism in XLRP patients leading up to an impaired DHA synthesis, tested the potential benefits of a higher dose of DHA than that previously tested on this specific type of RP. The results did not show a statistically significant reduction in loss of electroretinographic function as compared with placebo. However there was a significant reduction in the rates of visual field loss in the DHA treated group. Therefore, high-dose DHA supplementation is recommended in patients with X-linked RP.A review by Brito-Garcia et al. that includes 7 studies on the effectiveness of nutritional supplementation in retinitis pigmentosa found that vitamin A, lutein, and β-carotene showed a small protective effect on the progression of RP. Supplementation with DHA was not shown to have strong evidence of efficacy in RP. None of the studies reported any severe adverse effects of supplementation.Patients with less common disorders that may be associated with RP were not evaluated in these supplementation studies. In addition, certain patients were not included, such as patients with severely advanced RP. Thus, based on the results of these studies, precise recommendations cannot be made regarding vitamin A supplementation for these patients.Tauroursodeoxycholic acid (TUDCA), a major component of bear bile, is another supplement that has come to light as a photoreceptor-protective agent for use in RP. Interestingly, an alternate version of the bile acid pathway has now been demonstrated to be important for cholesterol metabolism in the retina. Bile acids appear to activate several types of molecular signaling receptors within the retina. In several different animal models of RP, TUDCA was demonstrated to significantly slow down the rate of disease progression, as evidenced by preserved retinal anatomy and electrophysiological function. Systemic administration of TUDCA was shown to reduce cellular stress and preserve photoreceptors in several models of RP, including Leber congenital amaurosis and RP associated with RPGR and PDE6B mutations, as well in animal models of the syndromic form of RP, known as Bardet-Biedl syndrome. Furthermore, in these models, TUDCA also prevented/reduced obesity, a disease feature that is otherwise notoriously challenging to address. TUDCA is available as an over-the-counter supplement. Human trials in conditions other than RP have utilized safely a 500 mg daily dosage. It is not exactly known whether this oral dosage would be effective in RP. Of note, there is now an FDA approved drug to reduce obesity in Bardet-Biedl syndrome and other related ciliopathies, called setmelatonide that tackles a specific mechanism that is at play in these forms of syndromic obesity.Interestingly, saffron, a spice derived from the flower of Crocus sativus, has gained interest in recent years as well, after animal studies demonstrated beneficial effects in neurodegenerative diseases and RP. Safranal (which contains crocin and crocetin) is thought to be the active chemical component of saffron that is responsible for this neuroprotective effect. A human trial of a highly purified 20 mg saffron supplement in macular degeneration indicated beneficial effects on macular function, and a trial of a macular dystrophy, Stargardt disease, suggested similar benefits. To our knowledge, to date no formal RP trial of saffron supplementation has been conducted. However, the neuroprotective potential of saffron appears to be gene- and disease type-independent, and therefore it is likely to apply also to RP.Another emerging supplement for use by RP patients is N-acetylcysteine (NAC), discussed in the “Antioxidants” section below.Treatment of Cystoid Macular EdemaA common complication of RP is the formation of small pockets of fluid in the centermost part of the retina, called cystoid macular edema, or CME. CME can cause significant reduction in central visual acuity, as well as blurred vision, and glare. If untreated, further degenerative changes in the retinal tissue will ultimately occur, and the development of a macular hole by rupture of a central larger cyst can also occur. With the current imaging techniques available to ophthalmologists in the clinical setting, detection of CME changes has become much easier and much more precise. A study with such techniques estimated the frequency of cystic macular changes consistent with CME to be 38% in at least one eye and 27% in both eyes of RP patients. This complication can be successfully treated with oral (tablets) or topical (eye drops) medications in the family of the so-called carbonic anhydrase inhibitors (CAIs), such as acetazolamide or metazolamide (tablets) and dorzalamide or brinzolamide (topical eye drops). While not all patients will respond to these treatments, these medications have been shown to diminish and often eliminate the cystic changes in the retina of RP patients, improving visual acuity in the short term and improving the overall functional prognosis over the long term. Some side effects can result from use of these medications, but most of them can be managed. Patients allergic to sulfonamides should not be taking CAIs. CAIs have been shown to be effective in reducing or resolving cystic changes also in patients with similar findings due a different problem, called macular retinoschisis, as it is seen in patients with ESCS or another hereditary vitreo-retinal disorder, called X-linked retinoschisis.Since an inflammatory component to CME is also likely, and an increased frequency of certain antibodies in the bloodstream of RP patients with CME has been reported, corticosteroids utilized off-label and injected around (that is, periocularly) or directly inside the eye ball (that is, intravitreally) of RP patients with CME have also been tried in some patients that do not respond to CAIs, and variable success has been reported. However, the intravitreal use of these medications increases the risk of other complications, such as glaucoma or cataract, and a very small but serious risk of infection inside the eye ball (endophthalmitis) exists with all intravitreal injections. Periocular injections pose a much lower risk of glaucoma and cataracts, and do not normally pose a risk of endophthalmitis. A newer formulation of triamcinolone acetonide specifically designed for intravitreal injection has become available in more recent years. Implantable slow-release steroid-laden (dexamethasone and fluocinolone acetonide) devices have also become available. For example, intravitreal dexamethasone implants have been shown to improve anatomic and functional outcomes in refractory CME associated with RP. Initial reports show repeated injections of the implant may be needed to prevent recurrence.A National Eye Institute sponsored pilot study of 5 participants (ClinicalTrials.gov identifier: NCT02140164) suggested that 100 mg twice a day of minocycline, a tetracycline antibiotic, reduced CME associated with RP. This too appears due to anti-inflammatory properties of minocycline.Supportive MeasuresFor individuals with RP, low-vision aids and other assistive devices may be of benefit as vision worsens (see below). Although a study of light deprivation in RP was conducted many years ago without benefit, the concern that light damage may play a role in worsening retinal degeneration in some forms of RP remains. This concern is in part supported by recent evidence that, in a dog naturally affected with RP resulting from a mutation in the rhodopsin (RHO) gene, evidence for light-induced worsening of the disease has been obtained. Therefore, to err on the side of caution, use of sunglasses in the outdoors and avoiding undue and unnecessary exposure to excessive amounts of light is generally recommended to all RP patients. Most modern smart phone devices have the “dark mode” feature that limits the total light exposure of the retina while maintaining good contrast level.Genetic counseling is also recommended for affected individuals and their families.Assistive DevicesThe Canadian company eSight has created a portable headset visual aid which uses a high-resolution camera along with patented processing algorithms to send high speed video to two screens positioned in front of the user’s eyes. The screens can be adjusted and placed in a position that provides the best view for the individual. The high-speed camera and processing algorithms provide a clear picture with minimal latency to reduce nausea and balance disturbance that can be experienced with immersive technologies. This technology may allow individuals to become more independent by increasing ability to perform activities of daily living. The newest eSight3 device is currently available for purchase. The company does provide assistance with the cost by various public and private funding sources.A similar technology that is also available for purchase is the MyEye device, made available by Orcam – a small assistive device that fits unobtrusively on any eye glass frame. This technology allows the user to point at objects, surfaces or labels and read written text on them, recognize familiar faces or identify products by simply pointing at them or looking in that direction. For example, up to 100 faces and 150 commonly used products can be stored in the device for automated recognition.There is no such thing as a one-size-fits-all device. Each patient may have different needs, issues and abilities. Thus, it is highly recommended that patients interested in trying any of these assistive devices reach out to local low vision and occupational therapy (LV/OT) specialists to try them out first and obtain direct, unbiased counseling about them from these providers. In the absence of such options locally and should patients be unable to arrange for travel to go see a LV/OT specialist, patients can contact the manufacturers directly via their websites and make arrangements to try the devices directly with them.
| 1,068 |
Retinitis Pigmentosa
|
nord_1069_0
|
Overview of Retinoblastoma
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Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). The retina is a thin layer of nerve cells that senses light and converts it into nerve signals, which are then relayed to the brain through the optic nerve. Retinoblastoma is most commonly diagnosed in children under the age of three. The most typical finding associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so-called “cat’s eye reflex” (leukocoria). In addition, the eyes may be misaligned so that they appear crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause glaucoma, a condition marked by a rise in the pressure within the eyeball that prevents the normal drainage of fluid from the eye and potentially causes characteristic damage to the optic nerve. Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). Retinoblastomas occur in two forms – heritable and non-heritable. Bilateral forms are heritable and usually diagnosed at a younger age. In most affected children, retinoblastoma is non-heritable; it occurs spontaneously for no apparent reason.
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Overview of Retinoblastoma. Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). The retina is a thin layer of nerve cells that senses light and converts it into nerve signals, which are then relayed to the brain through the optic nerve. Retinoblastoma is most commonly diagnosed in children under the age of three. The most typical finding associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so-called “cat’s eye reflex” (leukocoria). In addition, the eyes may be misaligned so that they appear crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause glaucoma, a condition marked by a rise in the pressure within the eyeball that prevents the normal drainage of fluid from the eye and potentially causes characteristic damage to the optic nerve. Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). Retinoblastomas occur in two forms – heritable and non-heritable. Bilateral forms are heritable and usually diagnosed at a younger age. In most affected children, retinoblastoma is non-heritable; it occurs spontaneously for no apparent reason.
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Symptoms of Retinoblastoma
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In approximately 60 percent of children, the presenting sign of retinoblastoma is leukocoria. Initially, leukocoria may only be detectable at certain angles or under certain light conditions. Leukocoria is often seen on flash photography. Leukocoria can be caused by conditions other than retinoblastoma. The detection of leukocoria warrants an immediate evaluation by an eye specialist (ophthalmologist). Another common initial sign of a retinoblastoma is misalignment of the eyes in which they often appear crossed (strabismus). Strabismus may develop before or at the same time as leukocoria. Other signs are a red, inflamed eye(s) or repetitive, uncontrolled movements of the eyes (nystagmus). Less often, symptoms may include differences in pupil size (anisocoria), differences in pupil color (heterochromia), enlargement of the eyeball (buphthalmos), protrusion or ‘bulging’ of the eyeball (exophthalmos), decreased vision, inflammation of the soft tissues of the eye socket (orbital cellulitis), or ocular inflammation (uveitis), an inflammation of the middle layer of the eye called the uvea. Some infants may have vitreous hemorrhage, which is a leakage of blood near the vitreous of the eye. The vitreous is a clear, jelly-like fluid that fills the middle of the eye. Vitreous hemorrhage can cause vision loss. Some affected children may exhibit pooling or accumulation of blood in the space between the cornea and the iris of the eyes. This is called hyphema and the blood can cover most or all of the iris and the pupil, partially or completely blocking an infant’s vision. Hyphema is painful. Additional symptoms include clouding of the lenses of the eyes (cataract) or elevated fluid pressure within the eye preventing the normal outflow of fluid from the eye and potentially causing damage to the optic nerve (glaucoma). Pain in the eye can also occur, especially when glaucoma is present. In two-thirds of children, only one eye is affected (unilateral). When both eyes are affected, the tumors usually develop simultaneously. In some instances, children with a tumor in one eye will develop a tumor in the unaffected eye later in life. In most children, retinoblastoma only affects the eye and does not spread to surrounding tissue. However, if a retinoblastoma is not detected early, the tumor may spread to affect the tissue surrounding the eye or other parts of the body such as the central nervous system, lymph nodes, skeleton, or lung. This is known as extraocular or metastatic retinoblastoma. Signs and symptoms of metastatic disease include unintended weight loss, vomiting, headaches, and neurological impairment.Some infants and children develop retinoblastoma in the brain as well as the eye. The most common additional tumor, a pinealoblastoma, may form in the pineal gland. This condition is called trilateral retinoblastoma. Trilateral retinoblastoma develops in less than 5% of individuals with bilateral or heritable retinoblastoma. It is even rarer in unilateral or non-heritable retinoblastoma.
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Symptoms of Retinoblastoma. In approximately 60 percent of children, the presenting sign of retinoblastoma is leukocoria. Initially, leukocoria may only be detectable at certain angles or under certain light conditions. Leukocoria is often seen on flash photography. Leukocoria can be caused by conditions other than retinoblastoma. The detection of leukocoria warrants an immediate evaluation by an eye specialist (ophthalmologist). Another common initial sign of a retinoblastoma is misalignment of the eyes in which they often appear crossed (strabismus). Strabismus may develop before or at the same time as leukocoria. Other signs are a red, inflamed eye(s) or repetitive, uncontrolled movements of the eyes (nystagmus). Less often, symptoms may include differences in pupil size (anisocoria), differences in pupil color (heterochromia), enlargement of the eyeball (buphthalmos), protrusion or ‘bulging’ of the eyeball (exophthalmos), decreased vision, inflammation of the soft tissues of the eye socket (orbital cellulitis), or ocular inflammation (uveitis), an inflammation of the middle layer of the eye called the uvea. Some infants may have vitreous hemorrhage, which is a leakage of blood near the vitreous of the eye. The vitreous is a clear, jelly-like fluid that fills the middle of the eye. Vitreous hemorrhage can cause vision loss. Some affected children may exhibit pooling or accumulation of blood in the space between the cornea and the iris of the eyes. This is called hyphema and the blood can cover most or all of the iris and the pupil, partially or completely blocking an infant’s vision. Hyphema is painful. Additional symptoms include clouding of the lenses of the eyes (cataract) or elevated fluid pressure within the eye preventing the normal outflow of fluid from the eye and potentially causing damage to the optic nerve (glaucoma). Pain in the eye can also occur, especially when glaucoma is present. In two-thirds of children, only one eye is affected (unilateral). When both eyes are affected, the tumors usually develop simultaneously. In some instances, children with a tumor in one eye will develop a tumor in the unaffected eye later in life. In most children, retinoblastoma only affects the eye and does not spread to surrounding tissue. However, if a retinoblastoma is not detected early, the tumor may spread to affect the tissue surrounding the eye or other parts of the body such as the central nervous system, lymph nodes, skeleton, or lung. This is known as extraocular or metastatic retinoblastoma. Signs and symptoms of metastatic disease include unintended weight loss, vomiting, headaches, and neurological impairment.Some infants and children develop retinoblastoma in the brain as well as the eye. The most common additional tumor, a pinealoblastoma, may form in the pineal gland. This condition is called trilateral retinoblastoma. Trilateral retinoblastoma develops in less than 5% of individuals with bilateral or heritable retinoblastoma. It is even rarer in unilateral or non-heritable retinoblastoma.
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Causes of Retinoblastoma
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Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes, 23 of which are inherited from the mother and 23 of which are inherited from the father. 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 sub-divided into many bands that are numbered. For example, “chromosome 13q14.1-q41.2” refers to bands 14.1-14.2 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The retinoblastoma gene RB1 is located on the long arm (q) of chromosome 13 (13q14.1-q14.2). A retinoblastoma forms when both copies of the RB1 gene are affected by a gene alteration (mutation). 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. There are two kinds of genes that can cause cancer: those that cause cancer by their presence (oncogenes), and those that cause cancer by their absence (tumor suppressor genes). Both types are altered or incomplete versions of ordinary genes that normally regulate cell growth. The oncogenes tend to be dominant and cause out-of-control growth (cancer) when either one of the paired copies (alleles) is defective. Tumor suppressor genes like the RB1 gene normally limit or stop the growth of cells. They are recessive genes because both alleles have to be defective to cause disease. When the tumor suppressor genes are mutated, cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing. Inheriting an alteration in one copy of the RB1 gene is not enough to cause a retinoblastoma to form. Cancer development in children with retinoblastoma is believed to follow the “two-hit” hypothesis first described by the Nobel laureate Dr. Albert Knudsen. This hypothesis states that a second hit that damages the remaining normal copy of the RB1 gene is required for cancer development. The second hit occurs in a retinal precursor cell at any point after conception (somatically). Researchers do not know what causes this second hit but it almost always occurs since most children who have a heritable mutation develop retinoblastoma. Geneticists would describe this as a genetically recessive, dominantly inherited disease with high penetrance. Dr. Knudsen’s concept of retinoblastoma contributed to the understanding of the cause all cancers.Approximately 60 percent of cases of retinoblastoma are non-heritable and 40 percent are heritable. All of the non-heritable cases affect only one eye (unilateral). Of the 40 percent of cases that are heritable, approximately 85 percent of patients will develop multiple tumors affecting both eyes (bilateral). The remaining 15 percent of heritable cases affect only one eye. Some individuals with retinoblastoma, especially those with tumors affecting both eyes, may be at a greater risk than the general population of developing other types of cancer such as osteogenic sarcoma (a form of bone cancer) later in life. Genetic testing can identify whether a patient has non-heritable or heritable retinoblastoma and is critical for counseling families especially if they plan to have more children.Most instances of retinoblastoma are caused by sequential mutations in both RB1 genes. Non-heritable cases of retinoblastoma are the result of somatic mutations that occur after fertilization and are not passed down from the parents. These types of mutations occur randomly for no apparent reason. A mutation occurs in one of the two RB1 genes. A second event occurs either by a mutation in the second gene or by loss of the second gene. This loss, termed “loss of heterozygosity”, leads to unchecked cellular growth and the formation of a tumor in one eye (unilateral). In about 25 percent of heritable retinoblastoma cases, the first mutation in the RB1 gene is passed down from one parent. These patients may have a family history of the disease but sometimes, a parent will be a carrier of the altered RB1 gene but not have any symptoms (asymptomatic). The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In the other 75% of instances of heritable retinoblastoma, the first RB1 mutation occurs as a random (spontaneous) genetic change in a germ line cell. In these instances, a retinoblastoma is not inherited and the risk of another child in the same family developing the tumor is extremely low. The affected individual, however, can potentially pass along the altered gene. In extremely rare instances, children develop a retinoblastoma because they are missing genetic material (known as a deletion or monosomy) on the long arm of chromosome 13. The missing genetic material includes the RB1 gene as well as several other nearby genes. Consequently, additional symptoms are present. These children are classified as having partial monosomy 13q. (For more information on this disorder, choose “partial monosomy 13q” as your search term in the NORD Rare Disease Database.)
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Causes of Retinoblastoma. Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes, 23 of which are inherited from the mother and 23 of which are inherited from the father. 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 sub-divided into many bands that are numbered. For example, “chromosome 13q14.1-q41.2” refers to bands 14.1-14.2 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The retinoblastoma gene RB1 is located on the long arm (q) of chromosome 13 (13q14.1-q14.2). A retinoblastoma forms when both copies of the RB1 gene are affected by a gene alteration (mutation). 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. There are two kinds of genes that can cause cancer: those that cause cancer by their presence (oncogenes), and those that cause cancer by their absence (tumor suppressor genes). Both types are altered or incomplete versions of ordinary genes that normally regulate cell growth. The oncogenes tend to be dominant and cause out-of-control growth (cancer) when either one of the paired copies (alleles) is defective. Tumor suppressor genes like the RB1 gene normally limit or stop the growth of cells. They are recessive genes because both alleles have to be defective to cause disease. When the tumor suppressor genes are mutated, cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing. Inheriting an alteration in one copy of the RB1 gene is not enough to cause a retinoblastoma to form. Cancer development in children with retinoblastoma is believed to follow the “two-hit” hypothesis first described by the Nobel laureate Dr. Albert Knudsen. This hypothesis states that a second hit that damages the remaining normal copy of the RB1 gene is required for cancer development. The second hit occurs in a retinal precursor cell at any point after conception (somatically). Researchers do not know what causes this second hit but it almost always occurs since most children who have a heritable mutation develop retinoblastoma. Geneticists would describe this as a genetically recessive, dominantly inherited disease with high penetrance. Dr. Knudsen’s concept of retinoblastoma contributed to the understanding of the cause all cancers.Approximately 60 percent of cases of retinoblastoma are non-heritable and 40 percent are heritable. All of the non-heritable cases affect only one eye (unilateral). Of the 40 percent of cases that are heritable, approximately 85 percent of patients will develop multiple tumors affecting both eyes (bilateral). The remaining 15 percent of heritable cases affect only one eye. Some individuals with retinoblastoma, especially those with tumors affecting both eyes, may be at a greater risk than the general population of developing other types of cancer such as osteogenic sarcoma (a form of bone cancer) later in life. Genetic testing can identify whether a patient has non-heritable or heritable retinoblastoma and is critical for counseling families especially if they plan to have more children.Most instances of retinoblastoma are caused by sequential mutations in both RB1 genes. Non-heritable cases of retinoblastoma are the result of somatic mutations that occur after fertilization and are not passed down from the parents. These types of mutations occur randomly for no apparent reason. A mutation occurs in one of the two RB1 genes. A second event occurs either by a mutation in the second gene or by loss of the second gene. This loss, termed “loss of heterozygosity”, leads to unchecked cellular growth and the formation of a tumor in one eye (unilateral). In about 25 percent of heritable retinoblastoma cases, the first mutation in the RB1 gene is passed down from one parent. These patients may have a family history of the disease but sometimes, a parent will be a carrier of the altered RB1 gene but not have any symptoms (asymptomatic). The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In the other 75% of instances of heritable retinoblastoma, the first RB1 mutation occurs as a random (spontaneous) genetic change in a germ line cell. In these instances, a retinoblastoma is not inherited and the risk of another child in the same family developing the tumor is extremely low. The affected individual, however, can potentially pass along the altered gene. In extremely rare instances, children develop a retinoblastoma because they are missing genetic material (known as a deletion or monosomy) on the long arm of chromosome 13. The missing genetic material includes the RB1 gene as well as several other nearby genes. Consequently, additional symptoms are present. These children are classified as having partial monosomy 13q. (For more information on this disorder, choose “partial monosomy 13q” as your search term in the NORD Rare Disease Database.)
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Affects of Retinoblastoma
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Although retinoblastoma is a rare disorder, it is the most common cancer of the eye in children, accounting for about 3% of all childhood malignancies. Retinoblastoma affects males slightly more often than females. The incidence in the United States and Europe is estimated to be 2-5 children per 1,000,000 people in the general population. The age-adjusted annual incidence for children aged 0-4 in the United States is 10-14 children per 1,000,000. This equates to about 1 in 14,000-18,000 live births. Incidence is the number of newly diagnosed people with a disorder identified in a given year. Two-thirds of children are affected before the age of 2 and more than 90% of retinoblastomas become apparent before the age of five years.
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Affects of Retinoblastoma. Although retinoblastoma is a rare disorder, it is the most common cancer of the eye in children, accounting for about 3% of all childhood malignancies. Retinoblastoma affects males slightly more often than females. The incidence in the United States and Europe is estimated to be 2-5 children per 1,000,000 people in the general population. The age-adjusted annual incidence for children aged 0-4 in the United States is 10-14 children per 1,000,000. This equates to about 1 in 14,000-18,000 live births. Incidence is the number of newly diagnosed people with a disorder identified in a given year. Two-thirds of children are affected before the age of 2 and more than 90% of retinoblastomas become apparent before the age of five years.
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Related disorders of Retinoblastoma
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Symptoms of the following disorders can be similar to those of retinoblastoma. Comparisons may be useful for a differential diagnosis: Ocular toxocariasis is an infectious disease caused by the parasite Toxocara, a worm of dogs and cats. Infection occurs when there is purposeful or incidental ingestion of soil from hand to mouth through such activities as biting fingernails or inserting recently contaminated objects such as toys into the mouth. Consequently, the disorder is found disproportionately among children. Once ingested, the eggs hatch into larvae and burrow into body tissue of all types. When the larvae affect the eye, the disorder is known as ocular toxocariasis. Symptoms may include a brief redness of the sclera (white of the eye) without pain, a “whitish” appearance of the pupil, visual acuity changes, or blindness of one eye. (For more information on this disorder, choose “Toxocariasis” as your search term in the NORD Rare Disease Database.)Coats disease was first described in 1908 and is a rare disorder characterized by abnormal development of the blood vessels in the retina. The retina is a nerve-rich tissue lining the back of the eye that transmits light images to the brain, which allows a person to see. Therefore, affected individuals may experience loss of vision due to changes in the retina and, in severe cases, retinal detachment. In almost all cases of Coats disease, only one eye is affected. Rarely, both eyes may exhibit symptoms however one eye is often affected more than the other. The specific cause of Coats disease is not known. (For more information on this disorder, choose “Coats” as your search terms in the NORD Rare Disease Database.)Persistent hyperplastic primary vitreous (PHPV) is a developmental disorder affecting the eye that is present at birth (congenital). The disorder is characterized by abnormalities of certain eye structures and loss of vision. Specific symptoms include abnormally small eyes (microphthalmia), cataracts, and/or the formation of a white membrane or mass in the pupil area behind the lens of the eyes (leukocoria) that causes the pupil to appear white when light reflects off it.Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. In infants born prematurely, the blood vessels that supply the retinas are not yet completely developed. Although blood vessel growth continues after birth, these vessels may develop in an abnormal, disorganized pattern, known as ROP. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness, misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery. (For more information, choose “retinopathy of prematurity” as your search term in the NORD Rare Disease Database.)Primary retinal dysplasia is a rare inherited condition characterized by an elevated retinal fold arising from the optic disc covering the macular area inside the eye, and widening toward the temporal fundus, which may cause blindness. This condition is thought to be inherited as an X-linked trait. There are a variety of tumors that can affect the eye that should be included in a differential diagnosis. These tumors may include retinal astrocytoma, glioneuroma, and retinal hamartoma. (For more information on these disorders, choose the specific tumor name as your search term in the NORD Rare Disease Database.)
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Related disorders of Retinoblastoma. Symptoms of the following disorders can be similar to those of retinoblastoma. Comparisons may be useful for a differential diagnosis: Ocular toxocariasis is an infectious disease caused by the parasite Toxocara, a worm of dogs and cats. Infection occurs when there is purposeful or incidental ingestion of soil from hand to mouth through such activities as biting fingernails or inserting recently contaminated objects such as toys into the mouth. Consequently, the disorder is found disproportionately among children. Once ingested, the eggs hatch into larvae and burrow into body tissue of all types. When the larvae affect the eye, the disorder is known as ocular toxocariasis. Symptoms may include a brief redness of the sclera (white of the eye) without pain, a “whitish” appearance of the pupil, visual acuity changes, or blindness of one eye. (For more information on this disorder, choose “Toxocariasis” as your search term in the NORD Rare Disease Database.)Coats disease was first described in 1908 and is a rare disorder characterized by abnormal development of the blood vessels in the retina. The retina is a nerve-rich tissue lining the back of the eye that transmits light images to the brain, which allows a person to see. Therefore, affected individuals may experience loss of vision due to changes in the retina and, in severe cases, retinal detachment. In almost all cases of Coats disease, only one eye is affected. Rarely, both eyes may exhibit symptoms however one eye is often affected more than the other. The specific cause of Coats disease is not known. (For more information on this disorder, choose “Coats” as your search terms in the NORD Rare Disease Database.)Persistent hyperplastic primary vitreous (PHPV) is a developmental disorder affecting the eye that is present at birth (congenital). The disorder is characterized by abnormalities of certain eye structures and loss of vision. Specific symptoms include abnormally small eyes (microphthalmia), cataracts, and/or the formation of a white membrane or mass in the pupil area behind the lens of the eyes (leukocoria) that causes the pupil to appear white when light reflects off it.Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. In infants born prematurely, the blood vessels that supply the retinas are not yet completely developed. Although blood vessel growth continues after birth, these vessels may develop in an abnormal, disorganized pattern, known as ROP. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness, misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery. (For more information, choose “retinopathy of prematurity” as your search term in the NORD Rare Disease Database.)Primary retinal dysplasia is a rare inherited condition characterized by an elevated retinal fold arising from the optic disc covering the macular area inside the eye, and widening toward the temporal fundus, which may cause blindness. This condition is thought to be inherited as an X-linked trait. There are a variety of tumors that can affect the eye that should be included in a differential diagnosis. These tumors may include retinal astrocytoma, glioneuroma, and retinal hamartoma. (For more information on these disorders, choose the specific tumor name as your search term in the NORD Rare Disease Database.)
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Diagnosis of Retinoblastoma
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The diagnosis of retinoblastoma is made based upon a thorough clinical evaluation, detailed patient history, the identification of characteristic symptoms, and a variety of specialized tests. The presenting symptom is usually leukocoria. A complete examination of the interior of the eye (fundoscopic examination under anesthesia – EUA) may be performed to locate the presence of a tumor or tumors. Magnetic resonance imaging (MRIs) may be used to determine the extent of the tumor(s) and determine if the tumor has spread to surrounding structures or tissue. Ultrasonography may be used to rule out other conditions. Computed tomography (CT) scans are generally avoided because of the potential risk of additional radiation-induced tumors if the child has hereditary retinoblastoma.
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Diagnosis of Retinoblastoma. The diagnosis of retinoblastoma is made based upon a thorough clinical evaluation, detailed patient history, the identification of characteristic symptoms, and a variety of specialized tests. The presenting symptom is usually leukocoria. A complete examination of the interior of the eye (fundoscopic examination under anesthesia – EUA) may be performed to locate the presence of a tumor or tumors. Magnetic resonance imaging (MRIs) may be used to determine the extent of the tumor(s) and determine if the tumor has spread to surrounding structures or tissue. Ultrasonography may be used to rule out other conditions. Computed tomography (CT) scans are generally avoided because of the potential risk of additional radiation-induced tumors if the child has hereditary retinoblastoma.
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Therapies of Retinoblastoma
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TreatmentThe treatment of retinoblastoma is directed first toward preserving life and then preserving vision in the affected eye(s). Treatment is highly personalized, which means one affected individual may receive significantly different treatment than another individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or primary care physicians, surgeons, specialists who assess and treat eye problems (ophthalmologists or pediatric ophthalmologists), specialists who assess and treat cancer (oncologists or pediatric oncologists), specialists in the use of ionizing radiation to treat cancer (radiation oncologists), clinical social workers and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is of benefit for affected individuals and their families with inherited forms of retinoblastoma. Psychosocial support is essential for the entire family as well.Specific treatment methods depend upon several factors including the size of the tumor(s), the exact location of the tumor(s), whether one or both eyes are affected, the extent of the primary tumor (stage), the degree of malignancy (grade), whether the tumor has spread (metastasized), an individual’s age and general health, and the associated likelihood of retaining adequate vision. Decisions concerning the appropriate therapeutic interventions to use should be made by physicians and other members of the healthcare team in careful consultation with the patient’s family, and based upon the specifics of his or her case with a thorough discussion of the potential benefits and risks, patient preference, and other appropriate factors. Several different therapeutic methods are available to treat retinoblastoma including local and systemic chemotherapy, cryotherapy, laser photoablation, thermotherapy, radiotherapy, and surgical removal of the affected eye (enucleation). During the last few decades, the rate of enucleation as a treatment for retinoblastoma has dropped considerably and is usually reserved for individuals with disease that recurs after treatment or is resistant to treatment and who have no useful vision left in the affected eye. Doctors also try to limit systemic exposure to chemotherapy drugs and avoid using radiotherapy because of the increased risk of developing a second cancer later in life. Individuals with smaller tumors may be treated with less invasive methods directed at preserving the vision of the affected eye. These methods include local chemotherapy, a procedure that uses extreme cold to destroy tissue and cancer cells (cryotherapy), a procedure that uses intense, focused light (e.g., laser therapy) to heat and destroy tissue and cancer cells (photocoagulation), the use of a different type of laser to heat and kill tumor cells (thermotherapy), or procedures that use local radiation to destroy tissue and cancer cells (radiotherapy) such as brachytherapy or external beam radiotherapy.Local chemotherapy can include injecting anti-cancer medications directly into the vitreous (intravitreal) or into the arteries (intra-arterial) of the eyes and is often used in conjunction with treatments such as cryotherapy, thermotherapy, and photocoagulation. Common chemotherapy medications for retinoblastoma include melphalan, carboplatin, etoposide, vincristine, and topotecan. Local chemotherapy is usually used when retinoblastoma affects one eye (unilateral) and sometimes when retinoblastomas affect both eyes (bilateral). Brachytherapy is also known as internal radiation therapy or radioactive plaque therapy. During brachytherapy, radioactive material (implant) is placed within the eye socket usually near the base of a tumor. The implant is left there for several days. This procedure is used only for individuals with small tumors.With external beam radiotherapy, laser beams are directed by a machine to the retina to destroy cancer cells. This form of radiotherapy can also be used to treat disease that has spread outside of the eye (extraocular disease) but is still within the eye socket, central nervous system involvement, and/or cancer that has spread to other sites in the body (metastatic disease). External beam radiotherapy can affect nearby healthy tissue and may increase the risk of developing a second cancer later during life. External beam radiotherapy is rarely used and is generally reserved for people who have failed to respond to other treatment options. For individuals in whom only one eye is affected and when the prospects of retaining adequate vision are unlikely, enucleation of the affected eye may be performed. This is curative for about 90% of children who undergo this procedure. Individuals with multiple or large tumors may be treated by a combination of certain anticancer drugs (chemotherapy) or surgical removal of the affected eye (enucleation) and part of the optic nerve. Sometimes, chemotherapy drugs are given to shrink the size of the retinoblastoma (chemoreduction) before the tumor is treated surgically or with radiotherapy.In most children in whom both eyes are affected, the more severely affected eye is treated with enucleation. The remaining eye is treated with cryotherapy, radiation therapy, or photocoagulation to preserve vision. Children who present with extraocular disease such as those with metastatic disease or trilateral retinoblastoma may be treated with systemic chemotherapy in combination with external beam radiotherapy. Systemic chemotherapy is the use of anti-cancer mediations that are delivered through the mouth or directly injected into the vein. For individuals with central nervous system involvement, chemotherapy may be delivered directly into the fluid surrounding the brain and spinal cord (intrathecally). These medications travel throughout the body. Late Effects of Retinoblastoma Therapy
Late effects of cancer therapy refer to the risk that survivors of childhood cancer may develop problems years later in life as a consequence of treatment during childhood. Children treated with radiotherapy for retinoblastoma have a risk of developing a second, different cancer later in life. The most common cancer developed is osteogenic sarcoma (a form of bone cancer). Decreased clarity of vision (visual acuity) may develop in children treated with systemic chemotherapy or local ophthalmologic therapy. Hearing loss has been reported in some children treated with systemic carboplatin.
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Therapies of Retinoblastoma. TreatmentThe treatment of retinoblastoma is directed first toward preserving life and then preserving vision in the affected eye(s). Treatment is highly personalized, which means one affected individual may receive significantly different treatment than another individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or primary care physicians, surgeons, specialists who assess and treat eye problems (ophthalmologists or pediatric ophthalmologists), specialists who assess and treat cancer (oncologists or pediatric oncologists), specialists in the use of ionizing radiation to treat cancer (radiation oncologists), clinical social workers and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is of benefit for affected individuals and their families with inherited forms of retinoblastoma. Psychosocial support is essential for the entire family as well.Specific treatment methods depend upon several factors including the size of the tumor(s), the exact location of the tumor(s), whether one or both eyes are affected, the extent of the primary tumor (stage), the degree of malignancy (grade), whether the tumor has spread (metastasized), an individual’s age and general health, and the associated likelihood of retaining adequate vision. Decisions concerning the appropriate therapeutic interventions to use should be made by physicians and other members of the healthcare team in careful consultation with the patient’s family, and based upon the specifics of his or her case with a thorough discussion of the potential benefits and risks, patient preference, and other appropriate factors. Several different therapeutic methods are available to treat retinoblastoma including local and systemic chemotherapy, cryotherapy, laser photoablation, thermotherapy, radiotherapy, and surgical removal of the affected eye (enucleation). During the last few decades, the rate of enucleation as a treatment for retinoblastoma has dropped considerably and is usually reserved for individuals with disease that recurs after treatment or is resistant to treatment and who have no useful vision left in the affected eye. Doctors also try to limit systemic exposure to chemotherapy drugs and avoid using radiotherapy because of the increased risk of developing a second cancer later in life. Individuals with smaller tumors may be treated with less invasive methods directed at preserving the vision of the affected eye. These methods include local chemotherapy, a procedure that uses extreme cold to destroy tissue and cancer cells (cryotherapy), a procedure that uses intense, focused light (e.g., laser therapy) to heat and destroy tissue and cancer cells (photocoagulation), the use of a different type of laser to heat and kill tumor cells (thermotherapy), or procedures that use local radiation to destroy tissue and cancer cells (radiotherapy) such as brachytherapy or external beam radiotherapy.Local chemotherapy can include injecting anti-cancer medications directly into the vitreous (intravitreal) or into the arteries (intra-arterial) of the eyes and is often used in conjunction with treatments such as cryotherapy, thermotherapy, and photocoagulation. Common chemotherapy medications for retinoblastoma include melphalan, carboplatin, etoposide, vincristine, and topotecan. Local chemotherapy is usually used when retinoblastoma affects one eye (unilateral) and sometimes when retinoblastomas affect both eyes (bilateral). Brachytherapy is also known as internal radiation therapy or radioactive plaque therapy. During brachytherapy, radioactive material (implant) is placed within the eye socket usually near the base of a tumor. The implant is left there for several days. This procedure is used only for individuals with small tumors.With external beam radiotherapy, laser beams are directed by a machine to the retina to destroy cancer cells. This form of radiotherapy can also be used to treat disease that has spread outside of the eye (extraocular disease) but is still within the eye socket, central nervous system involvement, and/or cancer that has spread to other sites in the body (metastatic disease). External beam radiotherapy can affect nearby healthy tissue and may increase the risk of developing a second cancer later during life. External beam radiotherapy is rarely used and is generally reserved for people who have failed to respond to other treatment options. For individuals in whom only one eye is affected and when the prospects of retaining adequate vision are unlikely, enucleation of the affected eye may be performed. This is curative for about 90% of children who undergo this procedure. Individuals with multiple or large tumors may be treated by a combination of certain anticancer drugs (chemotherapy) or surgical removal of the affected eye (enucleation) and part of the optic nerve. Sometimes, chemotherapy drugs are given to shrink the size of the retinoblastoma (chemoreduction) before the tumor is treated surgically or with radiotherapy.In most children in whom both eyes are affected, the more severely affected eye is treated with enucleation. The remaining eye is treated with cryotherapy, radiation therapy, or photocoagulation to preserve vision. Children who present with extraocular disease such as those with metastatic disease or trilateral retinoblastoma may be treated with systemic chemotherapy in combination with external beam radiotherapy. Systemic chemotherapy is the use of anti-cancer mediations that are delivered through the mouth or directly injected into the vein. For individuals with central nervous system involvement, chemotherapy may be delivered directly into the fluid surrounding the brain and spinal cord (intrathecally). These medications travel throughout the body. Late Effects of Retinoblastoma Therapy
Late effects of cancer therapy refer to the risk that survivors of childhood cancer may develop problems years later in life as a consequence of treatment during childhood. Children treated with radiotherapy for retinoblastoma have a risk of developing a second, different cancer later in life. The most common cancer developed is osteogenic sarcoma (a form of bone cancer). Decreased clarity of vision (visual acuity) may develop in children treated with systemic chemotherapy or local ophthalmologic therapy. Hearing loss has been reported in some children treated with systemic carboplatin.
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Overview of Retinopathy of Prematurity
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Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. The retinas are the light-sensitive linings of the insides of the eyes. In infants born prematurely, the blood vessels that supply the retinas are not yet completely developed. Although blood vessel growth continues after birth, these vessels may develop in an abnormal, disorganized pattern, known as ROP. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness, misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery.
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Overview of Retinopathy of Prematurity. Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. The retinas are the light-sensitive linings of the insides of the eyes. In infants born prematurely, the blood vessels that supply the retinas are not yet completely developed. Although blood vessel growth continues after birth, these vessels may develop in an abnormal, disorganized pattern, known as ROP. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness, misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery.
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Symptoms of Retinopathy of Prematurity
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Retinopathy of prematurity (ROP) is characterized by abnormal and uncontrolled development of blood vessels in the back of the eye (i.e., the retina) in premature infants. The retina is the innermost tissue layer in which images are focused at the back of the eye; it contains light-responding nerve cells (rods and cones) that convert light images into nerve impulses, which are conveyed via the optic nerve to the brain. During fetal development–at about 16 weeks' gestation*–blood vessels that supply the retina begin to bud from the center of the retina (i.e., near the optic nerve), gradually reaching the front edges (periphery) of the retina at about the time of normal delivery. Thus, when infants are born prematurely, this process is incomplete. (*Gestation is the period of time from fertilization to birth. Full term is the normal period of human gestation from about 38 to 42 weeks.) ROP occurs when the blood vessel development is abnormal, with disorganized branching of retinal vessels and anomalous interconnections. ROP is descriptively localized within the eye according to three anatomic “zones”, based on the specific areas of the retina that are malformed (i.e., posterior (rear-most), middle, and anterior (most forward in the eye) zones). It is also classified into five sequential stages, based on the severity of the disease. In infants with early-stage ROP, the normal growth of blood vessels ends abruptly (stage 1), marked by a flat, whitish, “demarcation” line separating retinal regions that are and are not supplied with blood vessels (vascularized and avascular retina); multiple, abnormal, wide-branching blood vessels often lead into the line. In some cases, this line may then grow into a “ridge” that is higher and wider, extends inward above the plane of the retina, and may change in color from white to pink (if the central core fills with blood) (stage 2). Stages 1 and 2 may improve without treatment (spontaneous involution). In stage 3, the ridge increases in dimension, and new, abnormal blood vessels extend internally toward the vitreous humor gel that fills the large rear cavity of the eye between the retina and the lens., or on and along the retinal surface (stage 3). ) Stage 3 often requires treatment intervention. (For information on treatment, see the Standard Therapies section below.) The overgrowth of these abnormal blood vessels in the wrong locations may lead to development of scar tissue. The scars may then contract and tug on the retina, causing its separation from underlying, supporting tissue (retinal detachment). Stage 4 is characterized by partial detachment of the retina, potentially resulting in loss of vision. This stage is further categorized into two phases, based on whether the macula (the center vision area) is or is not involved. Macular detachment results in a marked deterioration of vision. Stage 5 indicates complete and total retinal detachment, sometimes leading to a white mass behind the pupil, cataract, and blindness. (Note: The term “retrolental fibroplasia” was used formerly as the name for ROP; however, it is used currently only to refer to advanced stages of ROP). In some affected infants, unusual blood vessel appearance may suggest a rapidly progressive course of disease. These cases have abnormal growth, widening (dilation), and twisting (tortuosity) of blood vessels near the optic nerve in the back of the eye and on the surface of the colored region surrounding the pupil of the eye (iris); rigidity of the pupil (meaning that it is difficult to dilate); and haziness of the vitreous humor. This situation is labeled “Plus Disease”, and this is a marker of poor prognosis unless treatment is performed. According to medical literature, the disease process ceases and returns to its original condition (involutes) spontaneously in approximately 90 percent of affected infants. In the birth weight category under 2 lb. 2 oz. (1250 g), fewer than 10 percent of cases progress to severe ROP, characterized by proliferation of blood vessels outside the retina, retinal detachment, and visual loss. In those affected by end-stage disease, the eyes may be unusually small and sunken (phthisis bulbi), when the retina appears as a whitish mass pressing against the lens (leukokoria). Some may also develop increased fluid pressure within the eye (glaucoma), loss of transparency of the lens of the eye (cataract), signs of inflammation, and/or other changes. Even after the disease subsides, affected children may have an increased risk of certain eye (ocular) abnormalities. In some instances, arrested or regressed ROP may leave demarcation lines or changes of the underlying pigment layer of the retina, retinal scarring and displacement of the macula, and may increase the risk of retinal detachment later in life. Affected children also have an increased incidence of nearsightedness (myopia); decreased clearness of vision (visual acuity) due to lack of a clear image falling on the retina (amblyopia); misalignment of the eyes (strabismus); unequal focusing ability of the two eyes (anisometropia); and/or other abnormalities. Regular ophthalmological monitoring is important for infants and children diagnosed with ROP to assess retinal blood vessel development and to ensure prompt detection and appropriate treatment of associated ocular abnormalities. (For more information, see the Standard Therapies: Diagnosis section below.) Certain signs should be brought to the attention of a physician immediately. These abnormalities include “crossing”, squinting, or misalignment of one eye in relation to the other; an apparent reluctance to use one eye; holding objects close to the eyes; apparent difficulty seeing distant objects; rubbing of the eyes, abnormally jerky eye movements, and/or other similar findings.
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Symptoms of Retinopathy of Prematurity. Retinopathy of prematurity (ROP) is characterized by abnormal and uncontrolled development of blood vessels in the back of the eye (i.e., the retina) in premature infants. The retina is the innermost tissue layer in which images are focused at the back of the eye; it contains light-responding nerve cells (rods and cones) that convert light images into nerve impulses, which are conveyed via the optic nerve to the brain. During fetal development–at about 16 weeks' gestation*–blood vessels that supply the retina begin to bud from the center of the retina (i.e., near the optic nerve), gradually reaching the front edges (periphery) of the retina at about the time of normal delivery. Thus, when infants are born prematurely, this process is incomplete. (*Gestation is the period of time from fertilization to birth. Full term is the normal period of human gestation from about 38 to 42 weeks.) ROP occurs when the blood vessel development is abnormal, with disorganized branching of retinal vessels and anomalous interconnections. ROP is descriptively localized within the eye according to three anatomic “zones”, based on the specific areas of the retina that are malformed (i.e., posterior (rear-most), middle, and anterior (most forward in the eye) zones). It is also classified into five sequential stages, based on the severity of the disease. In infants with early-stage ROP, the normal growth of blood vessels ends abruptly (stage 1), marked by a flat, whitish, “demarcation” line separating retinal regions that are and are not supplied with blood vessels (vascularized and avascular retina); multiple, abnormal, wide-branching blood vessels often lead into the line. In some cases, this line may then grow into a “ridge” that is higher and wider, extends inward above the plane of the retina, and may change in color from white to pink (if the central core fills with blood) (stage 2). Stages 1 and 2 may improve without treatment (spontaneous involution). In stage 3, the ridge increases in dimension, and new, abnormal blood vessels extend internally toward the vitreous humor gel that fills the large rear cavity of the eye between the retina and the lens., or on and along the retinal surface (stage 3). ) Stage 3 often requires treatment intervention. (For information on treatment, see the Standard Therapies section below.) The overgrowth of these abnormal blood vessels in the wrong locations may lead to development of scar tissue. The scars may then contract and tug on the retina, causing its separation from underlying, supporting tissue (retinal detachment). Stage 4 is characterized by partial detachment of the retina, potentially resulting in loss of vision. This stage is further categorized into two phases, based on whether the macula (the center vision area) is or is not involved. Macular detachment results in a marked deterioration of vision. Stage 5 indicates complete and total retinal detachment, sometimes leading to a white mass behind the pupil, cataract, and blindness. (Note: The term “retrolental fibroplasia” was used formerly as the name for ROP; however, it is used currently only to refer to advanced stages of ROP). In some affected infants, unusual blood vessel appearance may suggest a rapidly progressive course of disease. These cases have abnormal growth, widening (dilation), and twisting (tortuosity) of blood vessels near the optic nerve in the back of the eye and on the surface of the colored region surrounding the pupil of the eye (iris); rigidity of the pupil (meaning that it is difficult to dilate); and haziness of the vitreous humor. This situation is labeled “Plus Disease”, and this is a marker of poor prognosis unless treatment is performed. According to medical literature, the disease process ceases and returns to its original condition (involutes) spontaneously in approximately 90 percent of affected infants. In the birth weight category under 2 lb. 2 oz. (1250 g), fewer than 10 percent of cases progress to severe ROP, characterized by proliferation of blood vessels outside the retina, retinal detachment, and visual loss. In those affected by end-stage disease, the eyes may be unusually small and sunken (phthisis bulbi), when the retina appears as a whitish mass pressing against the lens (leukokoria). Some may also develop increased fluid pressure within the eye (glaucoma), loss of transparency of the lens of the eye (cataract), signs of inflammation, and/or other changes. Even after the disease subsides, affected children may have an increased risk of certain eye (ocular) abnormalities. In some instances, arrested or regressed ROP may leave demarcation lines or changes of the underlying pigment layer of the retina, retinal scarring and displacement of the macula, and may increase the risk of retinal detachment later in life. Affected children also have an increased incidence of nearsightedness (myopia); decreased clearness of vision (visual acuity) due to lack of a clear image falling on the retina (amblyopia); misalignment of the eyes (strabismus); unequal focusing ability of the two eyes (anisometropia); and/or other abnormalities. Regular ophthalmological monitoring is important for infants and children diagnosed with ROP to assess retinal blood vessel development and to ensure prompt detection and appropriate treatment of associated ocular abnormalities. (For more information, see the Standard Therapies: Diagnosis section below.) Certain signs should be brought to the attention of a physician immediately. These abnormalities include “crossing”, squinting, or misalignment of one eye in relation to the other; an apparent reluctance to use one eye; holding objects close to the eyes; apparent difficulty seeing distant objects; rubbing of the eyes, abnormally jerky eye movements, and/or other similar findings.
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Causes of Retinopathy of Prematurity
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The risk factors for ROP are not completely understood. However, ROP occurs exclusively in premature infants, particularly those who weigh less than 3 pounds, 5 ounces (1,500 grams) at birth and those born before 28 weeks' gestation. In countries with less developed newborn care practices, severe ROP can occur in larger premature infants. Exposure to high oxygen concentrations (hyperoxia) during the newborn period, regrettably necessary to keep the infant alive due to immature lung development and inability of the premature lungs to exchange oxygen properly, seems to increase the risk of ROP. In the 1940s and 1950s, the major predisposing factor for ROP was the use of high levels of supplemental oxygen in premature newborns to treat breathing problems or other conditions associated with insufficient oxygen supply to body tissues (hypoxia). With improved, modern techniques, the use of supplemental oxygen can be monitored more precisely to provide amounts sufficient to avoid or treat hypoxia, and minimize the risk of related tissue damage including ROP. Nevertheless, ROP continues to occur in some extremely low-birth weight, high-risk infants. Evidence suggests that supplementary oxygen alone is not sufficient or required to cause ROP; in addition, no “safe” threshold of oxygen has been determined. Some data suggest that other factors increase the risk of ROP in premature infants, such as multiple episodes of an abnormally slow heart rate (bradycardia); sudden episodes of uncontrolled electrical activity in the brain (seizures); infection; reduced levels of the oxygen-carrying component of red blood cells (anemia); or blood transfusions. These factors might affect the risk of ROP or may be seen in more premature, smaller, “sicker” infants who are more likely to have numerous complications of prematurity, including ROP. In general, evidence suggests that the lower an infant's birth weight and the greater the medical complications, the higher the probability of developing ROP. The specific underlying mechanisms responsible for ROP remain unclear. Oxygen “free radical” activity may contribute to the risk. Free radicals are reactive compounds that are produced during chemical reactions in the body. Their increasing accumulation may cause cellular damage to and impaired functioning of many cells. Certain substances known as “antioxidants” may protect against or promote the elimination of damaging free radicals. (For further information, please see “Investigational Therapies” below.)
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Causes of Retinopathy of Prematurity. The risk factors for ROP are not completely understood. However, ROP occurs exclusively in premature infants, particularly those who weigh less than 3 pounds, 5 ounces (1,500 grams) at birth and those born before 28 weeks' gestation. In countries with less developed newborn care practices, severe ROP can occur in larger premature infants. Exposure to high oxygen concentrations (hyperoxia) during the newborn period, regrettably necessary to keep the infant alive due to immature lung development and inability of the premature lungs to exchange oxygen properly, seems to increase the risk of ROP. In the 1940s and 1950s, the major predisposing factor for ROP was the use of high levels of supplemental oxygen in premature newborns to treat breathing problems or other conditions associated with insufficient oxygen supply to body tissues (hypoxia). With improved, modern techniques, the use of supplemental oxygen can be monitored more precisely to provide amounts sufficient to avoid or treat hypoxia, and minimize the risk of related tissue damage including ROP. Nevertheless, ROP continues to occur in some extremely low-birth weight, high-risk infants. Evidence suggests that supplementary oxygen alone is not sufficient or required to cause ROP; in addition, no “safe” threshold of oxygen has been determined. Some data suggest that other factors increase the risk of ROP in premature infants, such as multiple episodes of an abnormally slow heart rate (bradycardia); sudden episodes of uncontrolled electrical activity in the brain (seizures); infection; reduced levels of the oxygen-carrying component of red blood cells (anemia); or blood transfusions. These factors might affect the risk of ROP or may be seen in more premature, smaller, “sicker” infants who are more likely to have numerous complications of prematurity, including ROP. In general, evidence suggests that the lower an infant's birth weight and the greater the medical complications, the higher the probability of developing ROP. The specific underlying mechanisms responsible for ROP remain unclear. Oxygen “free radical” activity may contribute to the risk. Free radicals are reactive compounds that are produced during chemical reactions in the body. Their increasing accumulation may cause cellular damage to and impaired functioning of many cells. Certain substances known as “antioxidants” may protect against or promote the elimination of damaging free radicals. (For further information, please see “Investigational Therapies” below.)
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Affects of Retinopathy of Prematurity
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ROP is a leading cause of visual impairment and blindness in infants in many industrialized and “middle-income” countries. As noted above, an increased incidence of ROP in the 1940s and 1950s was shown to be due to the use of high concentrations of supplemental oxygen in premature infants. The number of cases decreased with measures to monitor oxygen blood levels carefully. However, with modern advances in care and technology in neonatal intensive care units (NICUs), the incidence of ROP has increased as more premature infants of lower birth weights survive. Careful control of blood oxygen levels reduces the risk of ROP without compromising measures necessary to sustain life. Again, supplementary oxygen alone does not appear to be sufficient for the development of ROP. (For more, see “Causes” above.)
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Affects of Retinopathy of Prematurity. ROP is a leading cause of visual impairment and blindness in infants in many industrialized and “middle-income” countries. As noted above, an increased incidence of ROP in the 1940s and 1950s was shown to be due to the use of high concentrations of supplemental oxygen in premature infants. The number of cases decreased with measures to monitor oxygen blood levels carefully. However, with modern advances in care and technology in neonatal intensive care units (NICUs), the incidence of ROP has increased as more premature infants of lower birth weights survive. Careful control of blood oxygen levels reduces the risk of ROP without compromising measures necessary to sustain life. Again, supplementary oxygen alone does not appear to be sufficient for the development of ROP. (For more, see “Causes” above.)
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Related disorders of Retinopathy of Prematurity
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Symptoms of the following disorders can be similar to those of ROP. Comparisons may be useful for a differential diagnosis: Norrie disease is a rare disorder that affected males and causes loss of vision and eventually blindness present at birth or shortly after birth. Additional symptoms may occur in some cases, although this varies even among individuals in the same family. Some affected individuals may develop hearing (auditory) loss and exhibit cognitive abnormalities such as developmental delays or behavioral issues. Mental retardation may occur in some cases. Norrie disease is inherited as an X-linked recessive trait and occurs due to errors or disruption (mutations) of the NDP gene. Several disorders occur due to mutation of the NDP gene including persistent hyperplastic primary vitreous, X-linked familial exudative vitreoretinopathy (XL-FEVR), and some cases of retinopathy of prematurity (ROP) and Coats disease. These disorders represent a spectrum of disease associated with the NPD gene. Norrie disease is the severe end of the spectrum. (For additional information, use Norrie Disease as your search term in the Rare Disease Database). Familial exudative vitreoretinopathy is a genetic disorder involving retinal detachments caused by retinal dysfunction or dysfunction of the blood vessel bearing tissue of the eye (choroids). These conditions disturb the outer blood-retinal barrier (retinal pigment epithelium [RPE] or inner blood-retinal barrier, allowing fluid to build up in the subretinal space. Under normal conditions, water flows from the vitreous cavity to the choroids. The direction of flow is influenced by the relative concentration of the choroids with respect to the vitreous and the RPE that actively pumps ions and water from the vitreous into the choroids. When there is an increase in the inflow of fluid or a decrease in the outflow of fluid from the vitreous cavity that overwhelms the normal compensatory mechanisms, fluid accumulates in the subretinal space leading to an exudative retinal detachment. Damage to the RPE prevents the pumping action of fluid. Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). The retina is a thin layer of nerve cells that sense light and convert it into nerve signals, which are then relayed to brain through the optic nerve. Retinoblastoma occurs most commonly in children under the age of three. The most typical finding associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so called “cat's eye reflex” (leukokoria). In addition, the eyes may be misaligned so that they appear crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause glaucoma, a condition marked by a rise in the pressure within the eyeball preventing the normal drainage of fluid from the eye and potentially causing characteristic damage to the optic nerve. Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). Bilateral forms of retinoblastoma are hereditary. In most cases, retinoblastoma occurs spontaneously for no apparent reason (sporadic). (For additional information, use Norrie Disease as your search term in the Rare Disease Database.)
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Related disorders of Retinopathy of Prematurity. Symptoms of the following disorders can be similar to those of ROP. Comparisons may be useful for a differential diagnosis: Norrie disease is a rare disorder that affected males and causes loss of vision and eventually blindness present at birth or shortly after birth. Additional symptoms may occur in some cases, although this varies even among individuals in the same family. Some affected individuals may develop hearing (auditory) loss and exhibit cognitive abnormalities such as developmental delays or behavioral issues. Mental retardation may occur in some cases. Norrie disease is inherited as an X-linked recessive trait and occurs due to errors or disruption (mutations) of the NDP gene. Several disorders occur due to mutation of the NDP gene including persistent hyperplastic primary vitreous, X-linked familial exudative vitreoretinopathy (XL-FEVR), and some cases of retinopathy of prematurity (ROP) and Coats disease. These disorders represent a spectrum of disease associated with the NPD gene. Norrie disease is the severe end of the spectrum. (For additional information, use Norrie Disease as your search term in the Rare Disease Database). Familial exudative vitreoretinopathy is a genetic disorder involving retinal detachments caused by retinal dysfunction or dysfunction of the blood vessel bearing tissue of the eye (choroids). These conditions disturb the outer blood-retinal barrier (retinal pigment epithelium [RPE] or inner blood-retinal barrier, allowing fluid to build up in the subretinal space. Under normal conditions, water flows from the vitreous cavity to the choroids. The direction of flow is influenced by the relative concentration of the choroids with respect to the vitreous and the RPE that actively pumps ions and water from the vitreous into the choroids. When there is an increase in the inflow of fluid or a decrease in the outflow of fluid from the vitreous cavity that overwhelms the normal compensatory mechanisms, fluid accumulates in the subretinal space leading to an exudative retinal detachment. Damage to the RPE prevents the pumping action of fluid. Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). The retina is a thin layer of nerve cells that sense light and convert it into nerve signals, which are then relayed to brain through the optic nerve. Retinoblastoma occurs most commonly in children under the age of three. The most typical finding associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so called “cat's eye reflex” (leukokoria). In addition, the eyes may be misaligned so that they appear crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause glaucoma, a condition marked by a rise in the pressure within the eyeball preventing the normal drainage of fluid from the eye and potentially causing characteristic damage to the optic nerve. Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). Bilateral forms of retinoblastoma are hereditary. In most cases, retinoblastoma occurs spontaneously for no apparent reason (sporadic). (For additional information, use Norrie Disease as your search term in the Rare Disease Database.)
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Diagnosis of Retinopathy of Prematurity
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The eyes of premature infants at risk for ROP should be examined thoroughly approximately four to six weeks after birth and regularly reexamined as required until retinal blood vessel growth is complete. Although specific guidelines vary, at-risk infants typically include those who are born before 30 weeks' gestation and those who weigh less than 1,500 grams at birth–or weigh more than 1,500 grams but are in unstable health with a high risk for ROP. Parents of premature infants should speak with their children's health care team by the time the infant is five weeks old about guidelines concerning at-risk infants and evaluations for evidence of ROP.The diagnostic evaluation involves the use of drops to dilate the pupil of each eye, followed by examination of the inside of the eyes (including the retina, retinal blood vessels, optic nerve, and vitreous humor) with a special viewing instrument called an indirect ophthalmoscope. For infants with ROP, regular surveillance is necessary, regardless of whether treatment is required initially, to assess whether ROP changes have ceased or regressed, or to determine whether intervention is necessary. If retinal scarring occurs, experts indicate that affected individuals should receive regular monitoring throughout life to prevent, detect, and/or ensure prompt treatment of related ocular conditions before progression (e.g., refractive errors, amblyopia, glaucoma, retinal detachment).
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Diagnosis of Retinopathy of Prematurity. The eyes of premature infants at risk for ROP should be examined thoroughly approximately four to six weeks after birth and regularly reexamined as required until retinal blood vessel growth is complete. Although specific guidelines vary, at-risk infants typically include those who are born before 30 weeks' gestation and those who weigh less than 1,500 grams at birth–or weigh more than 1,500 grams but are in unstable health with a high risk for ROP. Parents of premature infants should speak with their children's health care team by the time the infant is five weeks old about guidelines concerning at-risk infants and evaluations for evidence of ROP.The diagnostic evaluation involves the use of drops to dilate the pupil of each eye, followed by examination of the inside of the eyes (including the retina, retinal blood vessels, optic nerve, and vitreous humor) with a special viewing instrument called an indirect ophthalmoscope. For infants with ROP, regular surveillance is necessary, regardless of whether treatment is required initially, to assess whether ROP changes have ceased or regressed, or to determine whether intervention is necessary. If retinal scarring occurs, experts indicate that affected individuals should receive regular monitoring throughout life to prevent, detect, and/or ensure prompt treatment of related ocular conditions before progression (e.g., refractive errors, amblyopia, glaucoma, retinal detachment).
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Therapies of Retinopathy of Prematurity
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TreatmentThe treatment of ROP requires the coordinated efforts of a team of medical professionals, including neonatologists, pediatricians, ophthalmologists, and other health care professionals.Most children with stages 1 or 2 eventually improve without treatment. Treatment needs to be considered once the ROP develops signs of Plus Disease. Areas of the retina may be frozen (cryotherapy) or treated with an intense beam of light (laser therapy) to prevent or reverse the growth (proliferation) of abnormal retinal vessels and thereby reduce complications (e.g., retinal detachment) and preserve central vision. Laser therapy and cryotherapy destroy the outer (peripheral) areas of the retina and can potentially cause some loss of side (peripheral) vision, but this is a relatively minor impediment compared to the major loss of formed vision that untreated ROP can yield. Pharmacological therapies with intravitral injections of anti-vascular endothelial growth factor (VEGF) agents are a promising new treatment, particular for infants with severe ROP.Treatment is usually performed before the retina starts detaching. If retinal detachment occurs during infancy, incisional surgical repairs may reattach the retina. These include techniques in which indentations are made in the outermost membrane of the eye (sclera) over the regions of retinal detachment to promote the retina's re-attachment (scleral buckling), surgical removal of the contents of the vitreous humor to relax the tissues and scar pulling the retina inward (vitrectomy), and, often, removal of the lens (cataract extraction or lensectomy). However, it is important to recognize that treatment of serious retinal detachment in newborns generally has limited benefit in terms of restoring vision.In some cases, additional interventions may be recommended, including the use of corrective glasses, surgery, and/or other ophthalmologic measures. Other treatment for this disorder is symptomatic and supportive.For infants who weigh less than 750g (1 lb. 10 oz.) at birth, 16-20 percent will require treatment and approximately 5 percent will be blind despite the best treatment.
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Therapies of Retinopathy of Prematurity. TreatmentThe treatment of ROP requires the coordinated efforts of a team of medical professionals, including neonatologists, pediatricians, ophthalmologists, and other health care professionals.Most children with stages 1 or 2 eventually improve without treatment. Treatment needs to be considered once the ROP develops signs of Plus Disease. Areas of the retina may be frozen (cryotherapy) or treated with an intense beam of light (laser therapy) to prevent or reverse the growth (proliferation) of abnormal retinal vessels and thereby reduce complications (e.g., retinal detachment) and preserve central vision. Laser therapy and cryotherapy destroy the outer (peripheral) areas of the retina and can potentially cause some loss of side (peripheral) vision, but this is a relatively minor impediment compared to the major loss of formed vision that untreated ROP can yield. Pharmacological therapies with intravitral injections of anti-vascular endothelial growth factor (VEGF) agents are a promising new treatment, particular for infants with severe ROP.Treatment is usually performed before the retina starts detaching. If retinal detachment occurs during infancy, incisional surgical repairs may reattach the retina. These include techniques in which indentations are made in the outermost membrane of the eye (sclera) over the regions of retinal detachment to promote the retina's re-attachment (scleral buckling), surgical removal of the contents of the vitreous humor to relax the tissues and scar pulling the retina inward (vitrectomy), and, often, removal of the lens (cataract extraction or lensectomy). However, it is important to recognize that treatment of serious retinal detachment in newborns generally has limited benefit in terms of restoring vision.In some cases, additional interventions may be recommended, including the use of corrective glasses, surgery, and/or other ophthalmologic measures. Other treatment for this disorder is symptomatic and supportive.For infants who weigh less than 750g (1 lb. 10 oz.) at birth, 16-20 percent will require treatment and approximately 5 percent will be blind despite the best treatment.
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Retinopathy of Prematurity
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nord_1071_0
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Overview of Retinoschisis
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Retinoschisis means splitting of the eye's retina into two layers. There are two forms of this disorder. The most common is an acquired form that affects both men and women. It usually occurs in middle age or beyond, although it can occur earlier, and it is sometimes known as senile retinoschisis. The other form is present at birth (congenital) and affects mostly boys and young men. It is known as juvenile, X-linked retinoschisis.The disorder is characterized by a slow, progressive loss of parts of the field of vision corresponding to the areas of the retina that have become split. Either form may be associated with the development of saclike blisters (cysts) in the retina.
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Overview of Retinoschisis. Retinoschisis means splitting of the eye's retina into two layers. There are two forms of this disorder. The most common is an acquired form that affects both men and women. It usually occurs in middle age or beyond, although it can occur earlier, and it is sometimes known as senile retinoschisis. The other form is present at birth (congenital) and affects mostly boys and young men. It is known as juvenile, X-linked retinoschisis.The disorder is characterized by a slow, progressive loss of parts of the field of vision corresponding to the areas of the retina that have become split. Either form may be associated with the development of saclike blisters (cysts) in the retina.
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Retinoschisis
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nord_1071_1
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Symptoms of Retinoschisis
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Retinoschisis is characterized by a reduction in visual acuity. There may also be a loss of peripheral vision. Very few people become totally blind from either form of the disorder, but some men with the juvenile form may ultimately have very poor vision. Decreased visual acuity is directly linked to the formation of small cysts that damage the nerves in the retina. Prescribing eyeglasses cannot correct for the vision loss caused by such nerve damage. Peripheral vision is affected by the split of the retina into two layers, an inner layer of nerve cells and an outer layer of other cells.Usually, and almost always with the juvenile form, both eyes are affected (bilateral). The juvenile form is the more serious form of retinoschisis. The acquired form may occur without symptoms (asymptomatic).This disorder may lead to retinal detachment. The retinal split often extends back over the area near the center of the visual field (macula). If a break develops in both the front and the back layers of the retina, a true retinal detachment may occur causing loss of parts of the field of vision. A completely blind area (scotoma) with a sharp edge in the area where splitting (schisis) occurs is evident in the patient's visual field.
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Symptoms of Retinoschisis. Retinoschisis is characterized by a reduction in visual acuity. There may also be a loss of peripheral vision. Very few people become totally blind from either form of the disorder, but some men with the juvenile form may ultimately have very poor vision. Decreased visual acuity is directly linked to the formation of small cysts that damage the nerves in the retina. Prescribing eyeglasses cannot correct for the vision loss caused by such nerve damage. Peripheral vision is affected by the split of the retina into two layers, an inner layer of nerve cells and an outer layer of other cells.Usually, and almost always with the juvenile form, both eyes are affected (bilateral). The juvenile form is the more serious form of retinoschisis. The acquired form may occur without symptoms (asymptomatic).This disorder may lead to retinal detachment. The retinal split often extends back over the area near the center of the visual field (macula). If a break develops in both the front and the back layers of the retina, a true retinal detachment may occur causing loss of parts of the field of vision. A completely blind area (scotoma) with a sharp edge in the area where splitting (schisis) occurs is evident in the patient's visual field.
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Retinoschisis
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nord_1071_2
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Causes of Retinoschisis
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The cause of acquired retinoschisis is not known. Although it often occurs in middle age or beyond, it may appear in individuals as young as 20.Juvenile retinoschisis is transmitted genetically as an X-linked recessive trait. The mutated gene responsible is located on the short arm of the X chromosome (Xp22.2-p22.1).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, chromosome Xp22.2-p22.1 refers to the region between bands 22.2 and 22.1 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
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Causes of Retinoschisis. The cause of acquired retinoschisis is not known. Although it often occurs in middle age or beyond, it may appear in individuals as young as 20.Juvenile retinoschisis is transmitted genetically as an X-linked recessive trait. The mutated gene responsible is located on the short arm of the X chromosome (Xp22.2-p22.1).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, chromosome Xp22.2-p22.1 refers to the region between bands 22.2 and 22.1 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
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Retinoschisis
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