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Causes of Proctitis
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Proctitis can be caused by the pus-producing bacteria gonococci and by the herpes simplex virus, primary and secondary syphilis, chlamydia trachomatis and the human papilloma viruses. Gonococcal Proctitis usually results from passive anal intercourse with men who have infection in the canal that empties urine from the bladder (urethra).Ulcerative Proctitis may be caused by radiation injury, trauma from a foreign body, constriction or obstruction of a blood vessel (ischemia), infection or the cause may be unknown (idiopathic).The effects of irritating enemas or laxatives may be confused with Ulcerative Proctitis. This disorder may also mimic the symptoms of long-term trauma.
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Causes of Proctitis. Proctitis can be caused by the pus-producing bacteria gonococci and by the herpes simplex virus, primary and secondary syphilis, chlamydia trachomatis and the human papilloma viruses. Gonococcal Proctitis usually results from passive anal intercourse with men who have infection in the canal that empties urine from the bladder (urethra).Ulcerative Proctitis may be caused by radiation injury, trauma from a foreign body, constriction or obstruction of a blood vessel (ischemia), infection or the cause may be unknown (idiopathic).The effects of irritating enemas or laxatives may be confused with Ulcerative Proctitis. This disorder may also mimic the symptoms of long-term trauma.
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Affects of Proctitis
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Proctitis is increasing in incidence. Gonococcal Proctitis is most frequently found in women and homosexual men who practice anal-receptive intercourse.
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Affects of Proctitis. Proctitis is increasing in incidence. Gonococcal Proctitis is most frequently found in women and homosexual men who practice anal-receptive intercourse.
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Related disorders of Proctitis
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Symptoms of the following disorders can be similar to those of Proctitis. Comparisons may be useful for a differential diagnosis:Ulcerative Colitis is an acute inflammation of the large intestine (colon) characterized by multiple, irregular, superficial ulcerations. The inflammation results in thickening of the wall of the colon with scar tissue and polyp-like growths. The primary symptom of Ulcerative Colitis is bloody diarrhea. The disease may involve only one side of the colon or it may eventually spread throughout the entire large intestine. (For more information on this disorder, choose “Ulcerative Colitis” as your search term in the Rare Disease Database.)Crohn's Disease is a form of inflammatory bowel disease and is characterized by chronic diarrhea, abdominal pain, fever, weight loss and a solid mass in the abdomen. The intestine gradually becomes thickened and leathery. Complications may appear in the joints, skin and eyes. (For more information on this disorder, choose “Crohn's Disease” as your search term in the Rare Disease Database.)
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Related disorders of Proctitis. Symptoms of the following disorders can be similar to those of Proctitis. Comparisons may be useful for a differential diagnosis:Ulcerative Colitis is an acute inflammation of the large intestine (colon) characterized by multiple, irregular, superficial ulcerations. The inflammation results in thickening of the wall of the colon with scar tissue and polyp-like growths. The primary symptom of Ulcerative Colitis is bloody diarrhea. The disease may involve only one side of the colon or it may eventually spread throughout the entire large intestine. (For more information on this disorder, choose “Ulcerative Colitis” as your search term in the Rare Disease Database.)Crohn's Disease is a form of inflammatory bowel disease and is characterized by chronic diarrhea, abdominal pain, fever, weight loss and a solid mass in the abdomen. The intestine gradually becomes thickened and leathery. Complications may appear in the joints, skin and eyes. (For more information on this disorder, choose “Crohn's Disease” as your search term in the Rare Disease Database.)
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Diagnosis of Proctitis
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Diagnosis of proctitis is made when sigmoidoscopy reveals inflammation of the mucus lining of the rectum with a clearly demarcated upper border above which the lining is normal. The remainder of the colon and small intestine is found to be normal by barium x-rays, while colonoscopy and rectal biopsy may show changes which are indistinguishable from those of chronic ulcerative colitis. (For more information on chronic ulcerative colitis, see the related disorder section of this report.)
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Diagnosis of Proctitis. Diagnosis of proctitis is made when sigmoidoscopy reveals inflammation of the mucus lining of the rectum with a clearly demarcated upper border above which the lining is normal. The remainder of the colon and small intestine is found to be normal by barium x-rays, while colonoscopy and rectal biopsy may show changes which are indistinguishable from those of chronic ulcerative colitis. (For more information on chronic ulcerative colitis, see the related disorder section of this report.)
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Therapies of Proctitis
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TreatmentThe treatment of proctitis is determined by cause. Gonococcal proctitis responds to standard intramuscular injection with procaine penicillin or spectinomycin, but less consistently to oral treatment with penicillin or tetracycline. Primary herpetic proctitis responds well to acyclovir. Chlamydial proctitis responds to tetracycline. Treatment of idiopathic (unknown cause) ulcerative proctitis is very similar to that of ulcerative colitis and Crohn's disease, and includes a nonlaxative diet, the administration of antidiarrheal drugs such as diphenoxylate hydrochloride with atropine sulfate (Lomotil) or loperamide. Topical corticosteroids may be applied in the form of suppositories, steroid enemas or steroid foam. Enemas or suppositories should be administered at bedtime to maximize their retention. Other symptoms may be treated by pain-killing and antispasmodic drugs. Hospitalization may be necessary for a thorough physical examination.Although proctitis may persist for many years, it is not associated with an increased incidence of cancer of the rectum or colon. With treatment, proctitis usually runs a course with periodic mild to severe episodes of symptoms. The inflammation spreads beyond the rectum in only 10 to 30% of individuals affected with proctitis. Less than 15% of individuals with ulcerative proctitis will develop chronic ulcerative colitis.Approximately 40% of homosexual males with proctitis also have anorectal gonorrhea. It is not unusual to discover multiple disease producing organisms in patients with proctitis. Men who have had passive rectal intercourse with sex partners who have gonococcal infection of the ureter should have cultures performed for gonorrhea, regardless of an apparent lack of symptoms.
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Therapies of Proctitis. TreatmentThe treatment of proctitis is determined by cause. Gonococcal proctitis responds to standard intramuscular injection with procaine penicillin or spectinomycin, but less consistently to oral treatment with penicillin or tetracycline. Primary herpetic proctitis responds well to acyclovir. Chlamydial proctitis responds to tetracycline. Treatment of idiopathic (unknown cause) ulcerative proctitis is very similar to that of ulcerative colitis and Crohn's disease, and includes a nonlaxative diet, the administration of antidiarrheal drugs such as diphenoxylate hydrochloride with atropine sulfate (Lomotil) or loperamide. Topical corticosteroids may be applied in the form of suppositories, steroid enemas or steroid foam. Enemas or suppositories should be administered at bedtime to maximize their retention. Other symptoms may be treated by pain-killing and antispasmodic drugs. Hospitalization may be necessary for a thorough physical examination.Although proctitis may persist for many years, it is not associated with an increased incidence of cancer of the rectum or colon. With treatment, proctitis usually runs a course with periodic mild to severe episodes of symptoms. The inflammation spreads beyond the rectum in only 10 to 30% of individuals affected with proctitis. Less than 15% of individuals with ulcerative proctitis will develop chronic ulcerative colitis.Approximately 40% of homosexual males with proctitis also have anorectal gonorrhea. It is not unusual to discover multiple disease producing organisms in patients with proctitis. Men who have had passive rectal intercourse with sex partners who have gonococcal infection of the ureter should have cultures performed for gonorrhea, regardless of an apparent lack of symptoms.
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nord_1015_0
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Overview of Progressive Multifocal Leukoencephalopathy
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Progressive multifocal leukoencephalopathy (PML) (1) is a neurological disorder characterized by destruction of cells that produce myelin, an oily substance that helps protect nerve cells in the brain and spinal cord, also known as central nervous system (CNS) white matter. It is caused by a virus called JC virus (JCV), named after the initials of the patient in whom it was first discovered. The virus is widespread, found in up to 85% of the general adult population. It remains inactive in healthy individuals and causes disease only when the immune system has been severely weakened, such as in people with HIV/AIDS, hematological malignancies and those receiving certain immunosuppressant medications. Altogether, PML occurs in approximately one in 200,000 people. Each year, it is estimated that 4,000 people develop PML in the United States and Europe combined. The term “progressive” in PML means that the disease continues to get worse and often leads to serious brain damage. The term “multifocal” means that JCV causes disease in multiple parts of the brain. However, it is possible for an individual with PML to have only one brain lesion instead of several lesions. The term “leukoencephalopathy” means that the disease affects mainly the white matter of the brain or myelin, although in some patients the gray matter neurons are also involved.
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Overview of Progressive Multifocal Leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) (1) is a neurological disorder characterized by destruction of cells that produce myelin, an oily substance that helps protect nerve cells in the brain and spinal cord, also known as central nervous system (CNS) white matter. It is caused by a virus called JC virus (JCV), named after the initials of the patient in whom it was first discovered. The virus is widespread, found in up to 85% of the general adult population. It remains inactive in healthy individuals and causes disease only when the immune system has been severely weakened, such as in people with HIV/AIDS, hematological malignancies and those receiving certain immunosuppressant medications. Altogether, PML occurs in approximately one in 200,000 people. Each year, it is estimated that 4,000 people develop PML in the United States and Europe combined. The term “progressive” in PML means that the disease continues to get worse and often leads to serious brain damage. The term “multifocal” means that JCV causes disease in multiple parts of the brain. However, it is possible for an individual with PML to have only one brain lesion instead of several lesions. The term “leukoencephalopathy” means that the disease affects mainly the white matter of the brain or myelin, although in some patients the gray matter neurons are also involved.
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Symptoms of Progressive Multifocal Leukoencephalopathy
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Symptoms of PML vary from person to person because lesions may occur anywhere in the central nervous system. Most patients present with subacute neurological damage, which may include some degree of mental impairment and a variety of other symptoms such as vision loss, speech disturbances, facial drooping, weakness, problems with coordination, gait and sensory loss. In addition, approximately one third of PML patients can present with seizures during the course of their disease.The disease course of PML used to be considered invariably progressive, with most non-HIV-related cases leading to a fatal outcome within months after the diagnosis. However, it is now known that there are a small number of HIV-positive patients who, having developed PML, will experience disease stabilization and prolonged survival.(2)CD4+ and CD8+ T lymphocytes are types of immune cells that are of major importance to the health of the immune system. They help to mediate the immune response against many infectious organisms. In a patient with an active HIV infection, the levels of these lymphocytes are greatly decreased. However, antiretroviral medications, which are now a standard part of HIV treatment, have enabled the crucial CD4 and CD8 lymphocytes to rise to within normal levels.Before the availability of medications used to fight HIV (antiretrovirals), only 10% of HIV-positive patients with PML lived for more than a year. With the advent of antiretroviral therapy (ART), one-year survival has increased to 50% on average.(3) ART increases the crucial lymphocyte levels, thus enabling the immune system, under certain circumstances, to fight off the JC virus. However, among these patients, those who are able to mount a strong immune response mediated by T lymphocytes which are directed specifically against JCV have a better outcome. Those patients have a one year survival of 73% compared to 46% for those who do not have T cells capable of recognizing JCV.Because formation of new white matter by CNS cells (remyelination) does not occur in affected areas, 80% of PML survivors do not experience much regression of their symptoms. They may be left with permanent neurological dysfunction, similar to patients who have suffered a stroke. Nevertheless, PML patients may have extended survival up to 15 years and beyond if the initial cause of immunosuppression is under control, for example in HIV-infected patients treated by ART or in cancer patients successfully treated with chemotherapy. In these patients, the disease is not active anymore and they have burnt-out PML.
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Symptoms of Progressive Multifocal Leukoencephalopathy. Symptoms of PML vary from person to person because lesions may occur anywhere in the central nervous system. Most patients present with subacute neurological damage, which may include some degree of mental impairment and a variety of other symptoms such as vision loss, speech disturbances, facial drooping, weakness, problems with coordination, gait and sensory loss. In addition, approximately one third of PML patients can present with seizures during the course of their disease.The disease course of PML used to be considered invariably progressive, with most non-HIV-related cases leading to a fatal outcome within months after the diagnosis. However, it is now known that there are a small number of HIV-positive patients who, having developed PML, will experience disease stabilization and prolonged survival.(2)CD4+ and CD8+ T lymphocytes are types of immune cells that are of major importance to the health of the immune system. They help to mediate the immune response against many infectious organisms. In a patient with an active HIV infection, the levels of these lymphocytes are greatly decreased. However, antiretroviral medications, which are now a standard part of HIV treatment, have enabled the crucial CD4 and CD8 lymphocytes to rise to within normal levels.Before the availability of medications used to fight HIV (antiretrovirals), only 10% of HIV-positive patients with PML lived for more than a year. With the advent of antiretroviral therapy (ART), one-year survival has increased to 50% on average.(3) ART increases the crucial lymphocyte levels, thus enabling the immune system, under certain circumstances, to fight off the JC virus. However, among these patients, those who are able to mount a strong immune response mediated by T lymphocytes which are directed specifically against JCV have a better outcome. Those patients have a one year survival of 73% compared to 46% for those who do not have T cells capable of recognizing JCV.Because formation of new white matter by CNS cells (remyelination) does not occur in affected areas, 80% of PML survivors do not experience much regression of their symptoms. They may be left with permanent neurological dysfunction, similar to patients who have suffered a stroke. Nevertheless, PML patients may have extended survival up to 15 years and beyond if the initial cause of immunosuppression is under control, for example in HIV-infected patients treated by ART or in cancer patients successfully treated with chemotherapy. In these patients, the disease is not active anymore and they have burnt-out PML.
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Causes of Progressive Multifocal Leukoencephalopathy
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The JC virus usually enters the bloodstream during childhood. It can be found via blood tests in healthy children with no symptoms of PML. Because the virus is also frequently found in the urine of healthy individuals, it is possible that the initial infection may occur through urine-oral contamination.After primary infection, the virus remains inactive in the kidneys and lymphoid organs. Indeed, JCV can be found in the urine samples of approximately 30% of people, regardless of their immune status.(4) JCV also has been detected in bone marrow samples, including patients with PML, HIV, leukemia, and bone marrow transplant recipients, but also in bone marrow of some HIV-negative patients without immunosuppression.(5) Other studies have suggested that JCV is also latent in the normal digestive system and tonsils, and there is growing evidence that JCV can also remain latent in the brain.(6)The exact mechanisms that lead to JCV activation and the development of PML have not been entirely elucidated, but as explained above, most cases occur in the setting of profound cellular immune dysfunction. Studies of the type of blood cells that carries JCV have shown an association with B lymphocytes blood cells that mainly produce antibodies as well as other types of leukocytes including T lymphocytes, monocytes, polymorphonuclear leukocytes and cell-free plasma.(7)Despite the possible participation of the blood cells in transporting the JC virus throughout the body, the virus is rarely detected in routine blood tests of healthy individuals. While it is believed that PML is usually caused by activation of a dormant JC virus, it may also occur as a new infection in adults who have become severely immune-compromised.
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Causes of Progressive Multifocal Leukoencephalopathy. The JC virus usually enters the bloodstream during childhood. It can be found via blood tests in healthy children with no symptoms of PML. Because the virus is also frequently found in the urine of healthy individuals, it is possible that the initial infection may occur through urine-oral contamination.After primary infection, the virus remains inactive in the kidneys and lymphoid organs. Indeed, JCV can be found in the urine samples of approximately 30% of people, regardless of their immune status.(4) JCV also has been detected in bone marrow samples, including patients with PML, HIV, leukemia, and bone marrow transplant recipients, but also in bone marrow of some HIV-negative patients without immunosuppression.(5) Other studies have suggested that JCV is also latent in the normal digestive system and tonsils, and there is growing evidence that JCV can also remain latent in the brain.(6)The exact mechanisms that lead to JCV activation and the development of PML have not been entirely elucidated, but as explained above, most cases occur in the setting of profound cellular immune dysfunction. Studies of the type of blood cells that carries JCV have shown an association with B lymphocytes blood cells that mainly produce antibodies as well as other types of leukocytes including T lymphocytes, monocytes, polymorphonuclear leukocytes and cell-free plasma.(7)Despite the possible participation of the blood cells in transporting the JC virus throughout the body, the virus is rarely detected in routine blood tests of healthy individuals. While it is believed that PML is usually caused by activation of a dormant JC virus, it may also occur as a new infection in adults who have become severely immune-compromised.
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Affects of Progressive Multifocal Leukoencephalopathy
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In the advent of the human immunodeficiency virus (HIV) epidemic, PML was soon recognized as a major opportunistic infection of acquired immunodeficiency syndrome (AIDS) occurring in up to 5% of patients.(8) Based on a study of 91 cases of PML from 1994 to 2019, 49% of PML patients have HIV infection, 31% have hematological malignancies, 30% have exposure to chemotherapeutic medications and 19% have exposure to monoclonal antibody therapies.(9)Among patients with lymphoproliferative disorders, such as chronic lymphocytic leukemia, it has been found that those treated with certain medications that interfere with life cycles of blood cells (i.e. fludarabine) might be at increased risk for developing PML. Studies have shown a 3% incidence of PML in patients receiving these types of medications.(10) In addition, rare cases of PML have been diagnosed in HIV-negative patients with other types of drug-induced or idiopathic CD4 and CD8 T cell suppression, as well as in patients with no obvious source of immunosuppression.(11)In February, 2005, two biotechnology companies, Biogen Idec and Elan, voluntarily withdrew a promising new drug for treatment for relapsing/remitting multiple sclerosis (MS) and Crohn’s disease called Tysabri (natalizumab). This drug was taken off the market after the discovery of two people with MS who developed PML after taking Tysabri.(12)However, after a review of the data by an independent adjudication committee, the “Peripheral and Central Nervous System Drug Advisory Committee of the US Food and Drug Administration”, Tysabri was allowed back on the market. It has become available again as of August 2006 for MS patients. The risk of PML increases with duration of treatment, with the greatest increase in risk occurring after 2 years of therapy (13) Improved risk stratification (14) and clinical monitoring including the mandatory TOUCH® Prescribing Program Database has led to a decline in PML cases associated with Tysabri.(15) As of February 2021, there have been 853 cases of Tysabri-associated PML in MS (850) and Crohn’s (3) patients in the world. The risk of PML can be determined by anti-JCV antibody serostatus. In patients who are negative for anti-JCV antibody, the risk of PML is 1/10,000. However, if patients are JCV seropositive and have received immunosuppressant medications prior to Tysabri, the risk of PML goes up to 6/1,000 after 24 months of continuous therapy.(16)Other disease modifying therapies have been associated with PML. Tecfidera (dimethyl fumarate) poses a risk of 0.02/1000 (1/50,000), of which the majority were associated with an absolute lymphocyte count (ALC) < 800.(17, 18) As of February 2020, Gilenya (fingolimod) has been associated with 54 cases (37 monotherapy, 17 Tysabri carry over) and has a risk of 0.13/1000 (1/8000). Ocrevus (ocrelizumab) has been associated with 10 cases as of December 2020, 8 from Tysabri carry over, 1 from Gilenya carry over and 1 in a 78-year-old man with lymphopenia.(19, 20)
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Affects of Progressive Multifocal Leukoencephalopathy. In the advent of the human immunodeficiency virus (HIV) epidemic, PML was soon recognized as a major opportunistic infection of acquired immunodeficiency syndrome (AIDS) occurring in up to 5% of patients.(8) Based on a study of 91 cases of PML from 1994 to 2019, 49% of PML patients have HIV infection, 31% have hematological malignancies, 30% have exposure to chemotherapeutic medications and 19% have exposure to monoclonal antibody therapies.(9)Among patients with lymphoproliferative disorders, such as chronic lymphocytic leukemia, it has been found that those treated with certain medications that interfere with life cycles of blood cells (i.e. fludarabine) might be at increased risk for developing PML. Studies have shown a 3% incidence of PML in patients receiving these types of medications.(10) In addition, rare cases of PML have been diagnosed in HIV-negative patients with other types of drug-induced or idiopathic CD4 and CD8 T cell suppression, as well as in patients with no obvious source of immunosuppression.(11)In February, 2005, two biotechnology companies, Biogen Idec and Elan, voluntarily withdrew a promising new drug for treatment for relapsing/remitting multiple sclerosis (MS) and Crohn’s disease called Tysabri (natalizumab). This drug was taken off the market after the discovery of two people with MS who developed PML after taking Tysabri.(12)However, after a review of the data by an independent adjudication committee, the “Peripheral and Central Nervous System Drug Advisory Committee of the US Food and Drug Administration”, Tysabri was allowed back on the market. It has become available again as of August 2006 for MS patients. The risk of PML increases with duration of treatment, with the greatest increase in risk occurring after 2 years of therapy (13) Improved risk stratification (14) and clinical monitoring including the mandatory TOUCH® Prescribing Program Database has led to a decline in PML cases associated with Tysabri.(15) As of February 2021, there have been 853 cases of Tysabri-associated PML in MS (850) and Crohn’s (3) patients in the world. The risk of PML can be determined by anti-JCV antibody serostatus. In patients who are negative for anti-JCV antibody, the risk of PML is 1/10,000. However, if patients are JCV seropositive and have received immunosuppressant medications prior to Tysabri, the risk of PML goes up to 6/1,000 after 24 months of continuous therapy.(16)Other disease modifying therapies have been associated with PML. Tecfidera (dimethyl fumarate) poses a risk of 0.02/1000 (1/50,000), of which the majority were associated with an absolute lymphocyte count (ALC) < 800.(17, 18) As of February 2020, Gilenya (fingolimod) has been associated with 54 cases (37 monotherapy, 17 Tysabri carry over) and has a risk of 0.13/1000 (1/8000). Ocrevus (ocrelizumab) has been associated with 10 cases as of December 2020, 8 from Tysabri carry over, 1 from Gilenya carry over and 1 in a 78-year-old man with lymphopenia.(19, 20)
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Related disorders of Progressive Multifocal Leukoencephalopathy
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Inflammatory Progressive Multifocal LeukoencephalopathyAlthough antiretroviral medications may help recover from PML, new onset or clinical worsening has been described shortly after initiation of ART in HIV-infected people. This occurs in the setting of a recovery of the immune system marked by an increase in CD4 +T-cell count and a decrease in HIV plasma viral load, the amount of HIV in human serum. This paradoxical development of PML is usually associated with an inflammatory reaction in brain lesions and it has been called “immune reconstitution inflammatory syndrome” (IRIS).(21) Despite transient worsening, the outcome is usually favorable, and resolution of the inflammatory phase results in clinical improvement, with subsequent imaging studies showing only the classic residual atrophy, loss of brain tissue secondary to previous infection. Nevertheless, fatal cases of PML/IRIS have been described. Magnetic resonance spectroscopy (MRS) allows the study the metabolism of the brain and has proven helpful in diagnosing PML/IRIS.(22)JC virus granule cell neuronopathy (JCV GCN)Demyelination of the central nervous system leading to PML is not the only CNS disease caused by the JC virus. Although dysfunction of the cerebellum (a portion of the brain located toward the back of the brain) is frequently found in PML, recent studies have found that problems with coordination, along with cerebellar atrophy, can occur in HIV-infected patients who do not have PML lesions in the cerebellum. Areas of cell loss have been observed in the internal cell layer of the cerebellum. This novel syndrome has been named JCV granule cell neuronopathy (JCV GCN).(23, 24) It appears that a specific mutation of JC virus is necessary for infection of granule cell neurons within the cerebellum.(25) More recently, JCV GCN was also described in two patients with MS treated with Tysabri.(26, 27, 28)JC virus encephalopathy (JCVE)Another novel syndrome associated with JCV has been characterized, distinct for PML and JCV GCN, caused by infection of pyramidal neurons of the cortical gray matter of the brain itself. This syndrome is associated with subacute and global cognitive dysfunction, and brain lesions can be seen on MRI in the cortex of the cerebral hemispheres. This condition was named JCV encephalopathy (JCVE) and it is caused by a different JCV variant.(29, 30)JC virus meningitis (JCVM)JC virus has also been shown to infect the membranes that surround the brain, causing meningitis in a previously healthy person who presented with headaches and accumulation of cerebrospinal fluid in the brain (hydrocephalus). In this patient, no other causes were found, but direct JC virus infection of choroid plexus cells, which produces the CSF in the brain, was documented.(31, 32)
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Related disorders of Progressive Multifocal Leukoencephalopathy. Inflammatory Progressive Multifocal LeukoencephalopathyAlthough antiretroviral medications may help recover from PML, new onset or clinical worsening has been described shortly after initiation of ART in HIV-infected people. This occurs in the setting of a recovery of the immune system marked by an increase in CD4 +T-cell count and a decrease in HIV plasma viral load, the amount of HIV in human serum. This paradoxical development of PML is usually associated with an inflammatory reaction in brain lesions and it has been called “immune reconstitution inflammatory syndrome” (IRIS).(21) Despite transient worsening, the outcome is usually favorable, and resolution of the inflammatory phase results in clinical improvement, with subsequent imaging studies showing only the classic residual atrophy, loss of brain tissue secondary to previous infection. Nevertheless, fatal cases of PML/IRIS have been described. Magnetic resonance spectroscopy (MRS) allows the study the metabolism of the brain and has proven helpful in diagnosing PML/IRIS.(22)JC virus granule cell neuronopathy (JCV GCN)Demyelination of the central nervous system leading to PML is not the only CNS disease caused by the JC virus. Although dysfunction of the cerebellum (a portion of the brain located toward the back of the brain) is frequently found in PML, recent studies have found that problems with coordination, along with cerebellar atrophy, can occur in HIV-infected patients who do not have PML lesions in the cerebellum. Areas of cell loss have been observed in the internal cell layer of the cerebellum. This novel syndrome has been named JCV granule cell neuronopathy (JCV GCN).(23, 24) It appears that a specific mutation of JC virus is necessary for infection of granule cell neurons within the cerebellum.(25) More recently, JCV GCN was also described in two patients with MS treated with Tysabri.(26, 27, 28)JC virus encephalopathy (JCVE)Another novel syndrome associated with JCV has been characterized, distinct for PML and JCV GCN, caused by infection of pyramidal neurons of the cortical gray matter of the brain itself. This syndrome is associated with subacute and global cognitive dysfunction, and brain lesions can be seen on MRI in the cortex of the cerebral hemispheres. This condition was named JCV encephalopathy (JCVE) and it is caused by a different JCV variant.(29, 30)JC virus meningitis (JCVM)JC virus has also been shown to infect the membranes that surround the brain, causing meningitis in a previously healthy person who presented with headaches and accumulation of cerebrospinal fluid in the brain (hydrocephalus). In this patient, no other causes were found, but direct JC virus infection of choroid plexus cells, which produces the CSF in the brain, was documented.(31, 32)
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Diagnosis of Progressive Multifocal Leukoencephalopathy
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The brain MRI is the first step in diagnosing PML. Cerebrospinal fluid, collected via a spinal tap, is also a dependable way to diagnose PML. Based on the 2013 consensus criteria, the diagnosis of PML can be made by the presence of positive CSF JC virus PCR in conjunction with typical clinical and imaging findings. Alternatively, brain biopsy may be necessary in some patients to confirm the diagnosis.(33) Due to the expanded population of individuals at risk for PML, early diagnosis has become of critical importance.
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Diagnosis of Progressive Multifocal Leukoencephalopathy. The brain MRI is the first step in diagnosing PML. Cerebrospinal fluid, collected via a spinal tap, is also a dependable way to diagnose PML. Based on the 2013 consensus criteria, the diagnosis of PML can be made by the presence of positive CSF JC virus PCR in conjunction with typical clinical and imaging findings. Alternatively, brain biopsy may be necessary in some patients to confirm the diagnosis.(33) Due to the expanded population of individuals at risk for PML, early diagnosis has become of critical importance.
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Therapies of Progressive Multifocal Leukoencephalopathy
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TreatmentThere is no specific treatment for JCV. In HIV-positive patients with PML, optimization of ART is the best therapeutic option, and in HIV-negative patients, removal or decrease of any potential source of immunosuppression is recommended.(34) Because PML has a high mortality rate, numerous drugs have been tried empirically. Mefloquine inhibits JCV replication in vitro, and few case reports have shown a beneficial effect in PML (35); however, this medication did not benefit PML patients in a randomized controlled trial (clinicaltrials.gov number NCT00746941). A single study showed benefit of treatment with filgrastim (also known as granulocyte‐colony stimulating factor G‐CSF) in 17 natalizumab-induced PML patients.(36) Targeted cytokine therapy with interleukin-7 (IL7) has been shown to improve cell-mediated immunity and enhance immune reconstitution for PML in several patients.(37, 38, 39) Moreover, two immune checkpoint inhibitors, pembrolizumab and nivolumab, have been recently reported to improve outcomes in patients with PML from various etiologies in three small cohorts,(40, 41, 42) although clinical trials are warranted.(43) Additionally, a few centers have reported results of case reports or small series with adoptive transfer of T cells programmed to detect and kill cells infected with the JC virus.(44, 45, 46) Every patient may have a different presentation, and require personalized management. This can be best determined through an office visit, or if this is not practical, through a “cyberconsult”.(47)For information or to schedule a cyberconsult, contact:Igor J. Koralnik, M.D. FAAN, FANA
Archibald Church Professor of Neurology
Chief, Division of Neuro-Infectious Diseases & Global Neurology
Davee Department of Neurology
Director, Global Neurology Program
Global Health Institute
Morton 7-615, 320E Superior St.
Chicago, IL 60611
T: (312) 503 1345 F: (312) 503 3950
Appt line: (312) 695-7950
Clinic Fax: (312) 695-5747
Email: [email protected]
https://www.neurology.northwestern.edu/divisions/neuroinfectious-disease/index.html
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Therapies of Progressive Multifocal Leukoencephalopathy. TreatmentThere is no specific treatment for JCV. In HIV-positive patients with PML, optimization of ART is the best therapeutic option, and in HIV-negative patients, removal or decrease of any potential source of immunosuppression is recommended.(34) Because PML has a high mortality rate, numerous drugs have been tried empirically. Mefloquine inhibits JCV replication in vitro, and few case reports have shown a beneficial effect in PML (35); however, this medication did not benefit PML patients in a randomized controlled trial (clinicaltrials.gov number NCT00746941). A single study showed benefit of treatment with filgrastim (also known as granulocyte‐colony stimulating factor G‐CSF) in 17 natalizumab-induced PML patients.(36) Targeted cytokine therapy with interleukin-7 (IL7) has been shown to improve cell-mediated immunity and enhance immune reconstitution for PML in several patients.(37, 38, 39) Moreover, two immune checkpoint inhibitors, pembrolizumab and nivolumab, have been recently reported to improve outcomes in patients with PML from various etiologies in three small cohorts,(40, 41, 42) although clinical trials are warranted.(43) Additionally, a few centers have reported results of case reports or small series with adoptive transfer of T cells programmed to detect and kill cells infected with the JC virus.(44, 45, 46) Every patient may have a different presentation, and require personalized management. This can be best determined through an office visit, or if this is not practical, through a “cyberconsult”.(47)For information or to schedule a cyberconsult, contact:Igor J. Koralnik, M.D. FAAN, FANA
Archibald Church Professor of Neurology
Chief, Division of Neuro-Infectious Diseases & Global Neurology
Davee Department of Neurology
Director, Global Neurology Program
Global Health Institute
Morton 7-615, 320E Superior St.
Chicago, IL 60611
T: (312) 503 1345 F: (312) 503 3950
Appt line: (312) 695-7950
Clinic Fax: (312) 695-5747
Email: [email protected]
https://www.neurology.northwestern.edu/divisions/neuroinfectious-disease/index.html
| 1,015 |
Progressive Multifocal Leukoencephalopathy
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nord_1016_0
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Overview of Progressive Myoclonus Epilepsy
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Progressive myoclonus epilepsy (PME) is a group of conditions involving the central nervous system and representing more than a dozen different diseases. These diseases share certain features, including a worsening of symptoms over time and the presence of both muscle contractions (myoclonus) and seizures (epilepsy). Patients may have more than one type of seizure, such as petit mal or grand mal. PME is progressive, but the rate of progression may be quick or slow, depending on the underlying disease.Progressive myoclonus epilepsy (PME) is different from myoclonic epilepsy. In myoclonic epilepsy, the myoclonic jerking motions occur as part of the seizure. In PME, myoclonus occurs separately from seizures, the two respond differently to the same drugs, they evolve differently during the natural history of the disease, and they cause different problems for the patient. Some drugs that are good for seizures, e.g. phenytoin and carbamazepine, may tend to make the myoclonus worse.
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Overview of Progressive Myoclonus Epilepsy. Progressive myoclonus epilepsy (PME) is a group of conditions involving the central nervous system and representing more than a dozen different diseases. These diseases share certain features, including a worsening of symptoms over time and the presence of both muscle contractions (myoclonus) and seizures (epilepsy). Patients may have more than one type of seizure, such as petit mal or grand mal. PME is progressive, but the rate of progression may be quick or slow, depending on the underlying disease.Progressive myoclonus epilepsy (PME) is different from myoclonic epilepsy. In myoclonic epilepsy, the myoclonic jerking motions occur as part of the seizure. In PME, myoclonus occurs separately from seizures, the two respond differently to the same drugs, they evolve differently during the natural history of the disease, and they cause different problems for the patient. Some drugs that are good for seizures, e.g. phenytoin and carbamazepine, may tend to make the myoclonus worse.
| 1,016 |
Progressive Myoclonus Epilepsy
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nord_1016_1
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Symptoms of Progressive Myoclonus Epilepsy
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Myoclonus is usually a greater problem than seizures for patients with PME because it is not helped much by the anticonvulsants that do help to control the seizures. The twitching occurs more frequently in the early part of the day or when the patient is under stress of various sorts. Positive myoclonus alludes to jerking of the hands and arms. Negative myoclonus refers to the sudden onset of loss of control of the muscles of the legs that leads to falls and injuries. As the frequency of myoclonic jerks increases, it may build to a “crescendo myoclonus” or a convulsion, after which the condition improves for a few days.Lack of motor coordination may occur along with myoclonus, even in the absence of seizures. Mental function may be impaired, leading especially to problems with memory. Depression is not uncommon. It can become severe and should not be left untreated.Other problems may include a bladder abnormality that may be associated with urinary tract infection. Depending on the type of PME, patients may also experience gastrointestinal and thyroid problems, as well as vision or hearing impairment. Weight control may be a problem for inactive patients. There are many different types of PME, each with a different underlying cause. The types of PME include the following:Mitochondrial myopathies EPM1 (epilepsy, progressive myoclonus 1) or myoclonic epilepsy of Unverricht and LundborgEPM2A (epilepsy, progressive myoclonus 2) or myoclonic epilepsy of LaforaBatten disease (neuronal ceroid lipofuscinosis)Cerebral storage and degenerative disordersBiotin-responsive encephalopathy(For more information on these disorders, choose the disorder name as your search term in the Rare Disease Database.)EPM1 (Unverricht-Lundborg disease) usually presents between the ages of six and thirteen with the advent of convulsions. Myoclonus begins one to five years later when muscle spasms of the limbs and minor twitching motions become obvious. Later, these spasms may become so violent that the patient falls. Mental deterioration accompanies the disease progression. However, the progression of the disease in EPM1 is slower than in most other forms of the syndrome. The duration and seriousness of EPM1 are variable. In advanced cases, inability to coordinate voluntary muscle movements (cerebellar ataxia) occurs. Very rarely, deafness may occur, especially when cerebellar ataxia is present. Emotional instability is common. In EPM1, there are no particles in brain or other tissue cells as in Lafora's disease. However the area of the brain concerned with muscle coordination and balance shows a loss of nerve cells. Changes in the environment like flashing lights or the flickering of sunlight may cause the worst symptoms (stimulus-sensitive myoclonus). Other features are generalized tonic-clonic seizures that are sometimes combined with absence attacks (petit mal). These types of seizures may be documented by EEG readings. EPM1 is an autosomal recessive genetic disease caused by mutations in the CSTB gene.EPM2A (Lafora disease) presents in the form of grand mal seizures and/or myoclonus, usually during the teen years. It is characterized by the presence of carbohydrate particles (Lafora bodies) in cells of the nervous system (brain, spinal cord, or nerves), muscle (or muscle fibers), and/or skin. The presence of Lafora bodies in biopsied tissue is diagnostic. Over time, mental deterioration may occur and grand mal seizures become more frequent. EPM2A is one of the more severe forms of PME. EPM2A is an autosomal recessive genetic disorder caused by mutations in the EPM2A gene or NHLRC1 gene.Mitochondrial myopathies are a group of neurological and neuromuscular disorders that arise from genetic mutations affecting the function of intracellular (within the cell capsule) energy-producing particles (mitochondria). Since mitochondria are found in the cells of most tissues, diagnosis of these disorders is made though the use of blood chemistry tests or through muscle biopsies. Batten Disease refers to a family of about seven disorders called the neuronal ceroid lipofuscinoses.Cerebral storage and degenerative disorders often are accompanied by PME. Among these are several disorders that result from the storage of inappropriate intermediate metabolites in the lysosomes of cells. The accumulation (storage) of these metabolites occurs because an essential enzyme, needed to further metabolize the accumulated chemicals, is not present or is present in insufficient concentration. Gene mutations are the cause of these metabolic disorders. Tay-Sachs disease and Gaucher’s disease are examples of this group of conditions.Biotin-responsive disorders often present with PME that, in these cases, is frequently reversible. Biotin is essential for several enzymes to keep brain metabolism proceeding smoothly. Normally, biotin is recycled and levels are sustained. If the enzymes required for recycling the biotin are not available, then the condition is called biotinidase deficiency. The condition can be diagnosed through blood chemistry to measure the levels of biotin, biotinidase and biotin-dependent enzymes.
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Symptoms of Progressive Myoclonus Epilepsy. Myoclonus is usually a greater problem than seizures for patients with PME because it is not helped much by the anticonvulsants that do help to control the seizures. The twitching occurs more frequently in the early part of the day or when the patient is under stress of various sorts. Positive myoclonus alludes to jerking of the hands and arms. Negative myoclonus refers to the sudden onset of loss of control of the muscles of the legs that leads to falls and injuries. As the frequency of myoclonic jerks increases, it may build to a “crescendo myoclonus” or a convulsion, after which the condition improves for a few days.Lack of motor coordination may occur along with myoclonus, even in the absence of seizures. Mental function may be impaired, leading especially to problems with memory. Depression is not uncommon. It can become severe and should not be left untreated.Other problems may include a bladder abnormality that may be associated with urinary tract infection. Depending on the type of PME, patients may also experience gastrointestinal and thyroid problems, as well as vision or hearing impairment. Weight control may be a problem for inactive patients. There are many different types of PME, each with a different underlying cause. The types of PME include the following:Mitochondrial myopathies EPM1 (epilepsy, progressive myoclonus 1) or myoclonic epilepsy of Unverricht and LundborgEPM2A (epilepsy, progressive myoclonus 2) or myoclonic epilepsy of LaforaBatten disease (neuronal ceroid lipofuscinosis)Cerebral storage and degenerative disordersBiotin-responsive encephalopathy(For more information on these disorders, choose the disorder name as your search term in the Rare Disease Database.)EPM1 (Unverricht-Lundborg disease) usually presents between the ages of six and thirteen with the advent of convulsions. Myoclonus begins one to five years later when muscle spasms of the limbs and minor twitching motions become obvious. Later, these spasms may become so violent that the patient falls. Mental deterioration accompanies the disease progression. However, the progression of the disease in EPM1 is slower than in most other forms of the syndrome. The duration and seriousness of EPM1 are variable. In advanced cases, inability to coordinate voluntary muscle movements (cerebellar ataxia) occurs. Very rarely, deafness may occur, especially when cerebellar ataxia is present. Emotional instability is common. In EPM1, there are no particles in brain or other tissue cells as in Lafora's disease. However the area of the brain concerned with muscle coordination and balance shows a loss of nerve cells. Changes in the environment like flashing lights or the flickering of sunlight may cause the worst symptoms (stimulus-sensitive myoclonus). Other features are generalized tonic-clonic seizures that are sometimes combined with absence attacks (petit mal). These types of seizures may be documented by EEG readings. EPM1 is an autosomal recessive genetic disease caused by mutations in the CSTB gene.EPM2A (Lafora disease) presents in the form of grand mal seizures and/or myoclonus, usually during the teen years. It is characterized by the presence of carbohydrate particles (Lafora bodies) in cells of the nervous system (brain, spinal cord, or nerves), muscle (or muscle fibers), and/or skin. The presence of Lafora bodies in biopsied tissue is diagnostic. Over time, mental deterioration may occur and grand mal seizures become more frequent. EPM2A is one of the more severe forms of PME. EPM2A is an autosomal recessive genetic disorder caused by mutations in the EPM2A gene or NHLRC1 gene.Mitochondrial myopathies are a group of neurological and neuromuscular disorders that arise from genetic mutations affecting the function of intracellular (within the cell capsule) energy-producing particles (mitochondria). Since mitochondria are found in the cells of most tissues, diagnosis of these disorders is made though the use of blood chemistry tests or through muscle biopsies. Batten Disease refers to a family of about seven disorders called the neuronal ceroid lipofuscinoses.Cerebral storage and degenerative disorders often are accompanied by PME. Among these are several disorders that result from the storage of inappropriate intermediate metabolites in the lysosomes of cells. The accumulation (storage) of these metabolites occurs because an essential enzyme, needed to further metabolize the accumulated chemicals, is not present or is present in insufficient concentration. Gene mutations are the cause of these metabolic disorders. Tay-Sachs disease and Gaucher’s disease are examples of this group of conditions.Biotin-responsive disorders often present with PME that, in these cases, is frequently reversible. Biotin is essential for several enzymes to keep brain metabolism proceeding smoothly. Normally, biotin is recycled and levels are sustained. If the enzymes required for recycling the biotin are not available, then the condition is called biotinidase deficiency. The condition can be diagnosed through blood chemistry to measure the levels of biotin, biotinidase and biotin-dependent enzymes.
| 1,016 |
Progressive Myoclonus Epilepsy
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nord_1016_2
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Causes of Progressive Myoclonus Epilepsy
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There are many different types of PME, each with a different underlying cause.EPM1 is an autosomal recessive genetic disease caused by mutations in the CSTB gene.EPM2A is an autosomal recessive genetic disorder caused by mutations in the EPM2A gene or NHLRC1 gene.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Mitochondrial disorders may be caused by defects of nuclear DNA or mitochondrial DNA. Nuclear gene defects may be inherited in an autosomal recessive manner or an autosomal dominant manner. Mitochondrial DNA defects are transmitted by maternal inheritance. Genes have ben identified that are associated with some mitochondrial myopathies.Gene mutations have been discovered for some of the forms of Batten disease.
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Causes of Progressive Myoclonus Epilepsy. There are many different types of PME, each with a different underlying cause.EPM1 is an autosomal recessive genetic disease caused by mutations in the CSTB gene.EPM2A is an autosomal recessive genetic disorder caused by mutations in the EPM2A gene or NHLRC1 gene.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Mitochondrial disorders may be caused by defects of nuclear DNA or mitochondrial DNA. Nuclear gene defects may be inherited in an autosomal recessive manner or an autosomal dominant manner. Mitochondrial DNA defects are transmitted by maternal inheritance. Genes have ben identified that are associated with some mitochondrial myopathies.Gene mutations have been discovered for some of the forms of Batten disease.
| 1,016 |
Progressive Myoclonus Epilepsy
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nord_1016_3
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Affects of Progressive Myoclonus Epilepsy
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EPM1 occurs throughout the world but the prevalence is highest in the North African countries of Tunisia, Algeria and Morocco and also in Finland. The prevalence in Finland is approximately 1/20,000 births.EPM2A occurs worldwide but estimates of prevalence are not available. This condition is known to occur more often in the Mediterranean basin of Spain, France and Italy and in some areas of central Asia, India, Pakistan, northern Africa and the Middle East where marriage within families is common.
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Affects of Progressive Myoclonus Epilepsy. EPM1 occurs throughout the world but the prevalence is highest in the North African countries of Tunisia, Algeria and Morocco and also in Finland. The prevalence in Finland is approximately 1/20,000 births.EPM2A occurs worldwide but estimates of prevalence are not available. This condition is known to occur more often in the Mediterranean basin of Spain, France and Italy and in some areas of central Asia, India, Pakistan, northern Africa and the Middle East where marriage within families is common.
| 1,016 |
Progressive Myoclonus Epilepsy
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nord_1016_4
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Related disorders of Progressive Myoclonus Epilepsy
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Symptoms of the following disorders can be similar to those of Progressive Myoclonus Epilepsy. Comparisons may be useful for a differential diagnosis:In general, myoclonus is a group of movement disorders characterized by sudden, involuntary contractions of a skeletal muscle or group of muscles. It may be divided into two groups, rhythmical and arrhythmic myoclonus. Myoclonus may accompany a number of neurological diseases including seizure disorders, brain injuries, hereditary brain disorders, viral infections, and brain tumors. Hereditary, and idiopathic forms also exist. In Postanoxic Myoclonus the disorder begins after the brain is deprived of oxygen. (For more information about other types of myoclonus, choose “myoclonus” as your search term in the Rare Disease Database.)In Juvenile Myoclonic Epilepsy, the age of onset is early. It is characterized by the presence of isolated myoclonic jerks that do not necessarily lead to major seizures. These symptoms usually occur in the morning. There may be a record of epilepsy in the family history. In some cases there is evidence that this form of epilepsy is inherited through autosomal recessive genes. Juvenile Myoclonic Epilepsy is often diagnosed through use of electroencephalography (EEG) which demonstrates evidence of the illness even when no seizures are present. Occasionally, some family members who show no outward symptoms of the disorder will show the same EEG characteristics. This disorder is chronic but not progressive.Huntington's Disease (also known as Huntington's Chorea) is an inherited, progressively degenerative neurological illness. Those affected experience abnormal involuntary movements (chorea), loss of motor control, changes in gait, loss of memory, and eventual loss of both mental capacity and physical control. In general, onset of HD occurs in adults between thirty and fifty years of age and runs a progressive course, severely weakening patients usually over a ten to twenty year period. (For more information on this disorder, choose “Huntington's Disease” as your search term in the Rare Disease Database.)Tourette Syndrome is a neurological movement disorder that begins in childhood between the ages of 2 and 16. The disease is characterized by involuntary, abrupt, muscular movements called ” tics”, and uncontrollable vocal sounds. Sometimes inappropriate words may occur. Tourette Syndrome is not a degenerative disorder and those affected can expect to live a normal life span. (For more information on this disorder, choose “Tourette Syndrome” as your search term in the Rare Disease Database.)Wilson's Disease is a rare genetic disorder characterized by excess storage of copper in the body tissues, particularly in the liver, brain, and corneas of the eyes. It eventually leads to liver disease, neurological abnormalities such as seizures, and a characteristic rusty-brown colored ring in the cornea of the eyes known as Kayser-Fleischer rings. Involuntary abnormal movements, particularly tremor and chorea, and behavioral changes are early symptoms of this disorder. (For more information on this disorder, choose “Wilson” as your search term in the Rare Disease Database.)The following disorders may be associated with Progressive Myoclonus Epilepsy. They are not necessary for a differential diagnosis:Kufs Disease is a very rare disorder of the central nervous system marked initially by progressive weakness with diminished muscle coordination, seizures, rapid involuntary jerky movements and rarely blindness. This disorder can be inherited as either a dominant or recessive trait and is usually slowly progressive. (For more information on this disorder, choose “Kufs Disease” as your search term in the Rare Disease Database.)Ramsay-Hunt Syndrome is an autosomal dominant disorder in which epilepsy and myoclonus accompany significant spinocerebellar degeneration and other progressive neurological abnormalities. (For more information on this disorder, choose “Ramsay” as your search term in the Rare Disease Database.)
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Related disorders of Progressive Myoclonus Epilepsy. Symptoms of the following disorders can be similar to those of Progressive Myoclonus Epilepsy. Comparisons may be useful for a differential diagnosis:In general, myoclonus is a group of movement disorders characterized by sudden, involuntary contractions of a skeletal muscle or group of muscles. It may be divided into two groups, rhythmical and arrhythmic myoclonus. Myoclonus may accompany a number of neurological diseases including seizure disorders, brain injuries, hereditary brain disorders, viral infections, and brain tumors. Hereditary, and idiopathic forms also exist. In Postanoxic Myoclonus the disorder begins after the brain is deprived of oxygen. (For more information about other types of myoclonus, choose “myoclonus” as your search term in the Rare Disease Database.)In Juvenile Myoclonic Epilepsy, the age of onset is early. It is characterized by the presence of isolated myoclonic jerks that do not necessarily lead to major seizures. These symptoms usually occur in the morning. There may be a record of epilepsy in the family history. In some cases there is evidence that this form of epilepsy is inherited through autosomal recessive genes. Juvenile Myoclonic Epilepsy is often diagnosed through use of electroencephalography (EEG) which demonstrates evidence of the illness even when no seizures are present. Occasionally, some family members who show no outward symptoms of the disorder will show the same EEG characteristics. This disorder is chronic but not progressive.Huntington's Disease (also known as Huntington's Chorea) is an inherited, progressively degenerative neurological illness. Those affected experience abnormal involuntary movements (chorea), loss of motor control, changes in gait, loss of memory, and eventual loss of both mental capacity and physical control. In general, onset of HD occurs in adults between thirty and fifty years of age and runs a progressive course, severely weakening patients usually over a ten to twenty year period. (For more information on this disorder, choose “Huntington's Disease” as your search term in the Rare Disease Database.)Tourette Syndrome is a neurological movement disorder that begins in childhood between the ages of 2 and 16. The disease is characterized by involuntary, abrupt, muscular movements called ” tics”, and uncontrollable vocal sounds. Sometimes inappropriate words may occur. Tourette Syndrome is not a degenerative disorder and those affected can expect to live a normal life span. (For more information on this disorder, choose “Tourette Syndrome” as your search term in the Rare Disease Database.)Wilson's Disease is a rare genetic disorder characterized by excess storage of copper in the body tissues, particularly in the liver, brain, and corneas of the eyes. It eventually leads to liver disease, neurological abnormalities such as seizures, and a characteristic rusty-brown colored ring in the cornea of the eyes known as Kayser-Fleischer rings. Involuntary abnormal movements, particularly tremor and chorea, and behavioral changes are early symptoms of this disorder. (For more information on this disorder, choose “Wilson” as your search term in the Rare Disease Database.)The following disorders may be associated with Progressive Myoclonus Epilepsy. They are not necessary for a differential diagnosis:Kufs Disease is a very rare disorder of the central nervous system marked initially by progressive weakness with diminished muscle coordination, seizures, rapid involuntary jerky movements and rarely blindness. This disorder can be inherited as either a dominant or recessive trait and is usually slowly progressive. (For more information on this disorder, choose “Kufs Disease” as your search term in the Rare Disease Database.)Ramsay-Hunt Syndrome is an autosomal dominant disorder in which epilepsy and myoclonus accompany significant spinocerebellar degeneration and other progressive neurological abnormalities. (For more information on this disorder, choose “Ramsay” as your search term in the Rare Disease Database.)
| 1,016 |
Progressive Myoclonus Epilepsy
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nord_1016_5
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Diagnosis of Progressive Myoclonus Epilepsy
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Progressive myoclonus epilepsy is diagnosed by clinical findings and Electroencephalogram (EEG) results. Molecular genetic testing is available for genes associated with EPM1, EPM2A, and for some of the genes associated with other types of PME.
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Diagnosis of Progressive Myoclonus Epilepsy. Progressive myoclonus epilepsy is diagnosed by clinical findings and Electroencephalogram (EEG) results. Molecular genetic testing is available for genes associated with EPM1, EPM2A, and for some of the genes associated with other types of PME.
| 1,016 |
Progressive Myoclonus Epilepsy
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nord_1016_6
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Therapies of Progressive Myoclonus Epilepsy
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TreatmentTreatment of progressive myoclonus epilepsy includes the anticonvulsant drugs clonazepam, divalproex, and primidone in much the same dosages used to treat epilepsy. In all cases, the better advice is to start with low doses and work upwards. The diets of patients taking divalproex chronically should be supplemented with carnitine.Low dose oral contraceptives may be of help to women who experience heightened myoclonus or seizures during menstruation.Phenytoin, carbamazepine, and lamotrigine are drugs to be avoided since they may make the myoclonus worse and/or damage parts of the cerebellum even further.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Progressive Myoclonus Epilepsy. TreatmentTreatment of progressive myoclonus epilepsy includes the anticonvulsant drugs clonazepam, divalproex, and primidone in much the same dosages used to treat epilepsy. In all cases, the better advice is to start with low doses and work upwards. The diets of patients taking divalproex chronically should be supplemented with carnitine.Low dose oral contraceptives may be of help to women who experience heightened myoclonus or seizures during menstruation.Phenytoin, carbamazepine, and lamotrigine are drugs to be avoided since they may make the myoclonus worse and/or damage parts of the cerebellum even further.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
| 1,016 |
Progressive Myoclonus Epilepsy
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nord_1017_0
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Overview of Progressive Osseous Heteroplasia
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SummaryProgressive osseous heteroplasia (POH) is an extremely rare disorder characterized by abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification). The disorder first appears as areas of patchy bone formation (ossification) in the skin during infancy; heterotopic ossification progresses to involve superficial and deep connective tissues, including areas of fat beneath the skin (subcutaneous fat), muscles, tendons, ligaments, and the sheets of fibrous tissue that envelop muscle (fascia). This abnormal formation of bone may restrict the movement of affected joints and/or hinder the growth of affected limbs. The course of the disease is unpredictable; some areas of the body may become severely affected while others may remain unaffected. A diagnosis of POH is made only if the bone formation progresses to the deeper connective tissues. Otherwise, the bone formation is classified as osteoma cutis.
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Overview of Progressive Osseous Heteroplasia. SummaryProgressive osseous heteroplasia (POH) is an extremely rare disorder characterized by abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification). The disorder first appears as areas of patchy bone formation (ossification) in the skin during infancy; heterotopic ossification progresses to involve superficial and deep connective tissues, including areas of fat beneath the skin (subcutaneous fat), muscles, tendons, ligaments, and the sheets of fibrous tissue that envelop muscle (fascia). This abnormal formation of bone may restrict the movement of affected joints and/or hinder the growth of affected limbs. The course of the disease is unpredictable; some areas of the body may become severely affected while others may remain unaffected. A diagnosis of POH is made only if the bone formation progresses to the deeper connective tissues. Otherwise, the bone formation is classified as osteoma cutis.
| 1,017 |
Progressive Osseous Heteroplasia
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nord_1017_1
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Symptoms of Progressive Osseous Heteroplasia
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The symptoms of POH are usually present at birth (congenital) or within the first few weeks of life, and they tend to progress slowly and asymmetrically as an affected individual grows older. Infants with POH typically have a maculopapular rash (with patchy areas of bone within the dermis). Initially, affected skin may feel abnormally rough. The major finding in infants with POH is the development of extra-skeletal bone (heterotopic ossification). Initially, bone growth may develop within the skin (osseous nodules or plaques called osteoma cutis). These areas may become progressively widespread and may grow together (coalesce) to form even larger areas of hardened and thickened skin (dermal ossification). As the disease progresses, these bony growths may extend into the deeper layers of the skin (subcutaneous layers). Eventually, abnormal bony growths occur in various connective tissues of the body such as fascia and skeletal muscle. Children with osteoma cutis or POH may also have sharp, needle-like projections of bone (spicules) that break through the surface of the skin, causing irritation or superficial infection. As the abnormal development of bone progresses, it may restrict movement of joints and eventually lock the joints (ankylosis). POH may also restrict movement in any area of the body. Affected arms and legs may become malformed and not grow to full length. This can occur on one side of the body and lead to unequal growth; one leg or one arm may become shorter than the other, for example. Some areas of the body may be severely affected, while other areas may remain unaffected. In some patients, lesion formation occurs predominantly or exclusively on one side (either left or right) of the body (hemimelic progressive osseous heteroplasia). In addition, when bone growth occurs around the spine, some affected individuals may develop an abnormal sideways curvature of the spine (scoliosis). The progression of POH is highly variable even among members of the same family. In some individuals, it may progress extremely slowly; in others it may progress more rapidly. Most individuals experience a gradual progression of the condition. Heterotopic bone formation in POH may be more intramembranous than endochondral in nature, and no inflammatory component has been identified. Histologically, bone can be seen to arise directly within adipose stromal tissue although the exact cell(s) of origin remain unknown. In addition to induction of extra-skeletal bone formation, inactivating mutations in the GNAS gene have been associated with altered skeletal bone quality in mouse models. Detailed studies of skeletal bone quality in POH remain to be thoroughly investigated.
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Symptoms of Progressive Osseous Heteroplasia. The symptoms of POH are usually present at birth (congenital) or within the first few weeks of life, and they tend to progress slowly and asymmetrically as an affected individual grows older. Infants with POH typically have a maculopapular rash (with patchy areas of bone within the dermis). Initially, affected skin may feel abnormally rough. The major finding in infants with POH is the development of extra-skeletal bone (heterotopic ossification). Initially, bone growth may develop within the skin (osseous nodules or plaques called osteoma cutis). These areas may become progressively widespread and may grow together (coalesce) to form even larger areas of hardened and thickened skin (dermal ossification). As the disease progresses, these bony growths may extend into the deeper layers of the skin (subcutaneous layers). Eventually, abnormal bony growths occur in various connective tissues of the body such as fascia and skeletal muscle. Children with osteoma cutis or POH may also have sharp, needle-like projections of bone (spicules) that break through the surface of the skin, causing irritation or superficial infection. As the abnormal development of bone progresses, it may restrict movement of joints and eventually lock the joints (ankylosis). POH may also restrict movement in any area of the body. Affected arms and legs may become malformed and not grow to full length. This can occur on one side of the body and lead to unequal growth; one leg or one arm may become shorter than the other, for example. Some areas of the body may be severely affected, while other areas may remain unaffected. In some patients, lesion formation occurs predominantly or exclusively on one side (either left or right) of the body (hemimelic progressive osseous heteroplasia). In addition, when bone growth occurs around the spine, some affected individuals may develop an abnormal sideways curvature of the spine (scoliosis). The progression of POH is highly variable even among members of the same family. In some individuals, it may progress extremely slowly; in others it may progress more rapidly. Most individuals experience a gradual progression of the condition. Heterotopic bone formation in POH may be more intramembranous than endochondral in nature, and no inflammatory component has been identified. Histologically, bone can be seen to arise directly within adipose stromal tissue although the exact cell(s) of origin remain unknown. In addition to induction of extra-skeletal bone formation, inactivating mutations in the GNAS gene have been associated with altered skeletal bone quality in mouse models. Detailed studies of skeletal bone quality in POH remain to be thoroughly investigated.
| 1,017 |
Progressive Osseous Heteroplasia
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nord_1017_2
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Causes of Progressive Osseous Heteroplasia
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Some cases of POH may be caused by disruption or changes (mutations) of the GNAS gene. About three-fourths of examined POH patients have inactivating GNAS gene mutations. The GNAS (guanine nucleotide-binding protein, alpha-stimulating polypeptide) gene contains instructions for producing (encoding) a protein that researchers believe may be involved in regulating the activity of proteins (produced by other genes) that promote bone growth and direct cell fate decisions. In POH, mutation of the GNAS gene results in deficiency or dysfunction of the Gsα protein. The exact manner in which mutations of the GNAS gene bring about the symptoms of POH is not yet known, however evidence implicates activation of the “hedgehog” signaling pathway in this process. Most cases of POH occur randomly as the result of a spontaneous (sporadic) genetic change (new mutation) of the GNAS gene. However, this mutation can also be inherited from a parent and follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. A specific gene regulation process associated with POH is known as genetic imprinting. Everyone has two copies of every gene (except for genes on X and Y chromosomes) – one received from the father and one received from the mother. In most cases, both gene copies can be “turned on” and are active. However, some genes are maintained as preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical regulation through a process called DNA methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several human diseases including POH. In individuals with POH, the defective copy of the GNAS gene is inherited from the father. If a defective GNAS gene is inherited from the mother, individuals typically develop related, yet clinically distinct, disorders known as Albright hereditary osteodystrophy (AHO) and/or pseudohypoparathyrodism type 1a (PHP1a).
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Causes of Progressive Osseous Heteroplasia. Some cases of POH may be caused by disruption or changes (mutations) of the GNAS gene. About three-fourths of examined POH patients have inactivating GNAS gene mutations. The GNAS (guanine nucleotide-binding protein, alpha-stimulating polypeptide) gene contains instructions for producing (encoding) a protein that researchers believe may be involved in regulating the activity of proteins (produced by other genes) that promote bone growth and direct cell fate decisions. In POH, mutation of the GNAS gene results in deficiency or dysfunction of the Gsα protein. The exact manner in which mutations of the GNAS gene bring about the symptoms of POH is not yet known, however evidence implicates activation of the “hedgehog” signaling pathway in this process. Most cases of POH occur randomly as the result of a spontaneous (sporadic) genetic change (new mutation) of the GNAS gene. However, this mutation can also be inherited from a parent and follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. A specific gene regulation process associated with POH is known as genetic imprinting. Everyone has two copies of every gene (except for genes on X and Y chromosomes) – one received from the father and one received from the mother. In most cases, both gene copies can be “turned on” and are active. However, some genes are maintained as preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical regulation through a process called DNA methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several human diseases including POH. In individuals with POH, the defective copy of the GNAS gene is inherited from the father. If a defective GNAS gene is inherited from the mother, individuals typically develop related, yet clinically distinct, disorders known as Albright hereditary osteodystrophy (AHO) and/or pseudohypoparathyrodism type 1a (PHP1a).
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Affects of Progressive Osseous Heteroplasia
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More than 50 affected individuals with POH have been identified around the world. Although the majority of the cases initially reported occurred in females, the disorder appears to affect males and females in similar numbers. Because POH often goes unrecognized or misdiagnosed, determining the true frequency of the disorder in the general population is difficult. In the most severe cases, symptoms are usually apparent at birth or within the first few weeks of life. Symptoms usually progress as affected individual’s age. POH was first described in 1994.
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Affects of Progressive Osseous Heteroplasia. More than 50 affected individuals with POH have been identified around the world. Although the majority of the cases initially reported occurred in females, the disorder appears to affect males and females in similar numbers. Because POH often goes unrecognized or misdiagnosed, determining the true frequency of the disorder in the general population is difficult. In the most severe cases, symptoms are usually apparent at birth or within the first few weeks of life. Symptoms usually progress as affected individual’s age. POH was first described in 1994.
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Related disorders of Progressive Osseous Heteroplasia
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Symptoms of the following diseases may be similar to those of progressive osseous heteroplasia. Comparisons may be useful for differential diagnosis: Fibrodysplasia ossificans progressiva (FOP) is a very rare inherited connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification), such as the ligaments, tendons, and muscles. Specifically, this disorder causes the body’s skeletal muscles and soft connective tissue to undergo a transformation into bone, progressively locking joints in place and making movement difficult or impossible. FOP is characterized by malformation of the big toe that is present at birth (congenital). Other skeletal malformations variably occur. As the disease progresses, there may be abnormal formation of bone in soft tissues that may lead to stiffness in affected areas and limited movement in affected joints (e.g., knees, wrists, shoulders, spine, and/or neck). FOP usually begins during early childhood and progresses throughout life. Most cases of FOP occur randomly (sporadic). The genetic mutation that results in this disorder has been identified. FOP is caused by the mutation of a gene (ACVR1/ALK2) in the “BMP pathway” which is associated with the formation of the skeleton in the embryo and the repair of the skeleton following birth. (For more information on this disorder, choose “FOP” as your search term in the Rare Disease Database.) Albright hereditary osteodystrophy (AHO) is a rare disorder characterized by short stature, an unusually round face, abnormally short fingers (brachydactyly), and/or the development of bony growths (osseous plaques) on the surface of the skin but not in the deep connective tissue. These growths may spread to the lower level of the skin as well (subcutaneous ossification). Other symptoms may include mild intellectual disability, abnormally low levels of calcium in the blood (hypocalcemia), and/or the clinical features of pseudohypoparathyroidism. Pseudohypoparathyroidism type 1a (PHP1a) is caused by defective G-proteins that are needed to properly respond to parathyroid hormone and other hormones. In addition to hormone resistance, symptoms of pseudohypoparathyroidism include weakness, muscle cramps, excessive nervousness, headaches, and/or abnormal sensations such as tingling, burning, and numbness of the hands. AHO and PHP1a are caused by mutations of the same gene (GNAS) that causes POH. Both conditions can be inherited in an autosomal dominant pattern. While POH occurs only when the mutant gene is inherited from fathers, AHO features are associated with GNAS gene mutations that are inherited either from mothers or fathers. PHP1a and/or AHO-associated obesity occur when the mutant gene is inherited from mothers. (For more information on this disorder, choose “AHO” as your search term in the Rare Disease Database.)
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Related disorders of Progressive Osseous Heteroplasia. Symptoms of the following diseases may be similar to those of progressive osseous heteroplasia. Comparisons may be useful for differential diagnosis: Fibrodysplasia ossificans progressiva (FOP) is a very rare inherited connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification), such as the ligaments, tendons, and muscles. Specifically, this disorder causes the body’s skeletal muscles and soft connective tissue to undergo a transformation into bone, progressively locking joints in place and making movement difficult or impossible. FOP is characterized by malformation of the big toe that is present at birth (congenital). Other skeletal malformations variably occur. As the disease progresses, there may be abnormal formation of bone in soft tissues that may lead to stiffness in affected areas and limited movement in affected joints (e.g., knees, wrists, shoulders, spine, and/or neck). FOP usually begins during early childhood and progresses throughout life. Most cases of FOP occur randomly (sporadic). The genetic mutation that results in this disorder has been identified. FOP is caused by the mutation of a gene (ACVR1/ALK2) in the “BMP pathway” which is associated with the formation of the skeleton in the embryo and the repair of the skeleton following birth. (For more information on this disorder, choose “FOP” as your search term in the Rare Disease Database.) Albright hereditary osteodystrophy (AHO) is a rare disorder characterized by short stature, an unusually round face, abnormally short fingers (brachydactyly), and/or the development of bony growths (osseous plaques) on the surface of the skin but not in the deep connective tissue. These growths may spread to the lower level of the skin as well (subcutaneous ossification). Other symptoms may include mild intellectual disability, abnormally low levels of calcium in the blood (hypocalcemia), and/or the clinical features of pseudohypoparathyroidism. Pseudohypoparathyroidism type 1a (PHP1a) is caused by defective G-proteins that are needed to properly respond to parathyroid hormone and other hormones. In addition to hormone resistance, symptoms of pseudohypoparathyroidism include weakness, muscle cramps, excessive nervousness, headaches, and/or abnormal sensations such as tingling, burning, and numbness of the hands. AHO and PHP1a are caused by mutations of the same gene (GNAS) that causes POH. Both conditions can be inherited in an autosomal dominant pattern. While POH occurs only when the mutant gene is inherited from fathers, AHO features are associated with GNAS gene mutations that are inherited either from mothers or fathers. PHP1a and/or AHO-associated obesity occur when the mutant gene is inherited from mothers. (For more information on this disorder, choose “AHO” as your search term in the Rare Disease Database.)
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Diagnosis of Progressive Osseous Heteroplasia
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The diagnosis of POH may be confirmed by a thorough clinical evaluation, characteristic physical findings, and tests that demonstrate the presence of heterotopic ossification (e.g., x-ray or roentgenograms and CT scans) with characteristic appearance for POH in the deep connective of the fascia, muscles, tendons, muscles and/or ligaments.
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Diagnosis of Progressive Osseous Heteroplasia. The diagnosis of POH may be confirmed by a thorough clinical evaluation, characteristic physical findings, and tests that demonstrate the presence of heterotopic ossification (e.g., x-ray or roentgenograms and CT scans) with characteristic appearance for POH in the deep connective of the fascia, muscles, tendons, muscles and/or ligaments.
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Therapies of Progressive Osseous Heteroplasia
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TreatmentSpecial shoes, braces, and other devices to assist in walking and weight-bearing have been used to help people with POH involving the lower limbs. Occupational therapy evaluations and appropriate assistive devices for activities of daily living may be helpful for those in whom POH involves the upper limbs. Immunizations should be given on areas of the skin that are unaffected by the bony growths that are prevalent with this disorder. Other treatment is symptomatic and supportive. A team approach for infants with this disorder will be of benefit and may include special social, educational, and medical services. Genetic counseling is recommended for affected individuals and their families.
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Therapies of Progressive Osseous Heteroplasia. TreatmentSpecial shoes, braces, and other devices to assist in walking and weight-bearing have been used to help people with POH involving the lower limbs. Occupational therapy evaluations and appropriate assistive devices for activities of daily living may be helpful for those in whom POH involves the upper limbs. Immunizations should be given on areas of the skin that are unaffected by the bony growths that are prevalent with this disorder. Other treatment is symptomatic and supportive. A team approach for infants with this disorder will be of benefit and may include special social, educational, and medical services. Genetic counseling is recommended for affected individuals and their families.
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Overview of Progressive Supranuclear Palsy
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SummaryProgressive supranuclear palsy (PSP) is an uncommon degenerative neurological disorder that causes progressive impairment of balance and walking; impaired eye movement, especially in the downward direction; abnormal muscle tone (rigidity); speech difficulties (dysarthria); and problems related to swallowing and eating (dysphagia). Affected individuals frequently experience personality changes and cognitive impairment. Symptoms typically begin after age 60 but can begin earlier. The exact cause of PSP is unknown. PSP is often misdiagnosed as Parkinson disease, Alzheimer disease, corticobasal degeneration and other neurodegenerative disorders.IntroductionDrs. John C. Steele, J.C. Richardson and J. Olszewski identified progressive supranuclear palsy as a distinct neurological disorder in 1963.
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Overview of Progressive Supranuclear Palsy. SummaryProgressive supranuclear palsy (PSP) is an uncommon degenerative neurological disorder that causes progressive impairment of balance and walking; impaired eye movement, especially in the downward direction; abnormal muscle tone (rigidity); speech difficulties (dysarthria); and problems related to swallowing and eating (dysphagia). Affected individuals frequently experience personality changes and cognitive impairment. Symptoms typically begin after age 60 but can begin earlier. The exact cause of PSP is unknown. PSP is often misdiagnosed as Parkinson disease, Alzheimer disease, corticobasal degeneration and other neurodegenerative disorders.IntroductionDrs. John C. Steele, J.C. Richardson and J. Olszewski identified progressive supranuclear palsy as a distinct neurological disorder in 1963.
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Symptoms of Progressive Supranuclear Palsy
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The signs and symptoms of PSP vary from person to person, but patients generally fall into one of four clinical syndromes (phenotypes): Richardson syndrome, atypical Parkinsonism, corticobasal syndrome, and pure akinesia and gait freezing. Less commonly, patients present with cognitive loss and no motor signs.The most common presentation is the Richardson syndrome, consisting of gait and balance impairment, a wide-eyed staring facial expression, abnormal speech, memory and cognitive impairment and a slowing or loss of voluntary eye movement, particularly in the downward direction (supranuclear ophthalmoplegia). Cognitive symptoms include forgetfulness and personality changes, such as loss of interest in formerly pleasurable activities (apathy), impaired attention and concentration, depression, and increased irritability.Fewer than half of all PSP patients are initially diagnosed correctly because many patients do not present with the classic Richardson syndrome. Many of these patients are initially slow and have muscle rigidity and occasionally tremor, resembling Parkinson disease, and they may initially respond somewhat to levodopa. Other patients present with bizarre stiffening (rigidity and dystonia) and loss of voluntary function in one upper limb, as is seen in corticobasal degeneration.Some patients exhibit a syndrome of progressive gait freezing. These patients exhibit hesitant initiation of gait and a tendency to freeze or stop when turning and when crossing thresholds (doorways). Their eye movements and cognition are normal. Small handwriting and low-volume rapid, mumbling speech (tachyphemia or cluttered speech) are typical and are similar to that which occurs in Parkinson disease, but in contrast to Parkinson disease, there is no slowness (bradykinesia) or muscle stiffness (rigidity). Finally, some patients with PSP present with cognitive impairment and personality change (frontotemporal dementia), progressive speech and language impairment, generalized ataxia, or generalized spasticity. Most patients with these atypical presentations ultimately develop abnormalities of eye movement, speech, swallowing and gait (Richardson syndrome) in a few years. Thus, the diagnosis of PSP typically becomes more certain as the disease progresses. The challenge is to diagnose the disease in the very early stages, and this is very difficult in patients that do not have the classic Richardson syndrome. There is no diagnostic laboratory or radiologic test for PSP. Therefore, most patients are diagnosed fairly late in the course of the illness. PSP culminates in death at a median of 6 to 9 years after diagnosis, and those with the Richardson syndrome and dementia progress most rapidly. Death from PSP is most often caused by pneumonia or other infections.Impaired eye movements eventually make reading, driving, and interpersonal eye contact difficult or impossible. Abnormal eyelid control causes the eyes to close involuntarily (blepharospasm) for seconds or more, and some affected individuals may have difficulty opening their eyes after closure (eye opening apraxia), even though the muscles around the eyes appear relaxed. Patients often blink less than normal, causing the eyes to become dry and red.Muscles of the body may contract involuntarily, causing the affected body part (e.g., the upper or lower limbs) to assume bizarre postures. This is called dystonia. Blepharospasm is a form of dystonia affecting the muscles around the eyes.A mild or moderate degree of mental impairment eventually occurs in most patients, and this may be misdiagnosed as Alzheimer disease when it occurs early in the illness, before significant difficulties with speech, balance and eye movements appear. Some patients experience sleep disturbances such as frequent awakenings and changes in sleeping patterns. Sleep disturbances may be a sign of depression or may be a side effect of a medication. REM (rapid eye movement) sleep behavior disorder is not a characteristic of PSP but is a characteristic of dementia with Lewy bodies, Parkinson disease and multiple system atrophy. In REM sleep behavior disorder, patients talk and move during dream sleep, and the movement can result in personal injury or injury to a bed partner.
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Symptoms of Progressive Supranuclear Palsy. The signs and symptoms of PSP vary from person to person, but patients generally fall into one of four clinical syndromes (phenotypes): Richardson syndrome, atypical Parkinsonism, corticobasal syndrome, and pure akinesia and gait freezing. Less commonly, patients present with cognitive loss and no motor signs.The most common presentation is the Richardson syndrome, consisting of gait and balance impairment, a wide-eyed staring facial expression, abnormal speech, memory and cognitive impairment and a slowing or loss of voluntary eye movement, particularly in the downward direction (supranuclear ophthalmoplegia). Cognitive symptoms include forgetfulness and personality changes, such as loss of interest in formerly pleasurable activities (apathy), impaired attention and concentration, depression, and increased irritability.Fewer than half of all PSP patients are initially diagnosed correctly because many patients do not present with the classic Richardson syndrome. Many of these patients are initially slow and have muscle rigidity and occasionally tremor, resembling Parkinson disease, and they may initially respond somewhat to levodopa. Other patients present with bizarre stiffening (rigidity and dystonia) and loss of voluntary function in one upper limb, as is seen in corticobasal degeneration.Some patients exhibit a syndrome of progressive gait freezing. These patients exhibit hesitant initiation of gait and a tendency to freeze or stop when turning and when crossing thresholds (doorways). Their eye movements and cognition are normal. Small handwriting and low-volume rapid, mumbling speech (tachyphemia or cluttered speech) are typical and are similar to that which occurs in Parkinson disease, but in contrast to Parkinson disease, there is no slowness (bradykinesia) or muscle stiffness (rigidity). Finally, some patients with PSP present with cognitive impairment and personality change (frontotemporal dementia), progressive speech and language impairment, generalized ataxia, or generalized spasticity. Most patients with these atypical presentations ultimately develop abnormalities of eye movement, speech, swallowing and gait (Richardson syndrome) in a few years. Thus, the diagnosis of PSP typically becomes more certain as the disease progresses. The challenge is to diagnose the disease in the very early stages, and this is very difficult in patients that do not have the classic Richardson syndrome. There is no diagnostic laboratory or radiologic test for PSP. Therefore, most patients are diagnosed fairly late in the course of the illness. PSP culminates in death at a median of 6 to 9 years after diagnosis, and those with the Richardson syndrome and dementia progress most rapidly. Death from PSP is most often caused by pneumonia or other infections.Impaired eye movements eventually make reading, driving, and interpersonal eye contact difficult or impossible. Abnormal eyelid control causes the eyes to close involuntarily (blepharospasm) for seconds or more, and some affected individuals may have difficulty opening their eyes after closure (eye opening apraxia), even though the muscles around the eyes appear relaxed. Patients often blink less than normal, causing the eyes to become dry and red.Muscles of the body may contract involuntarily, causing the affected body part (e.g., the upper or lower limbs) to assume bizarre postures. This is called dystonia. Blepharospasm is a form of dystonia affecting the muscles around the eyes.A mild or moderate degree of mental impairment eventually occurs in most patients, and this may be misdiagnosed as Alzheimer disease when it occurs early in the illness, before significant difficulties with speech, balance and eye movements appear. Some patients experience sleep disturbances such as frequent awakenings and changes in sleeping patterns. Sleep disturbances may be a sign of depression or may be a side effect of a medication. REM (rapid eye movement) sleep behavior disorder is not a characteristic of PSP but is a characteristic of dementia with Lewy bodies, Parkinson disease and multiple system atrophy. In REM sleep behavior disorder, patients talk and move during dream sleep, and the movement can result in personal injury or injury to a bed partner.
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Causes of Progressive Supranuclear Palsy
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The cause of PSP is not known, but it is a form of tauopathy, in which abnormal phosphorylation of the protein tau is associated with destruction of vital protein filaments in nerve cells. This “neurofibrillary” degeneration is hypothesized to cause the death of nerve cells, and most experimental treatments are aimed at preventing tau pathology. The signs and symptoms of PSP are determined by the distribution of tau pathology in the brain. Recent work suggests that the disease is at least partly genetic. Many researchers now believe that various genetic and environmental factors interact to produce this disorder.In the medical literature, the word “tauopathy” is used to refer to several neurodegenerative disorders including PSP, in which tau are mishandled. Other neurodegenerative disorders classified as tauopathies include corticobasal degeneration and Pick disease. Alzheimer disease also produces tau pathology.Genetics plays an important role in PSP even though most patients have no family history of PSP. Rare mutations in the gene for the microtubule-associated protein tau (MAPT) appear to cause PSP in rare patients, and risk of PSP is determined to some extent by genetic variation in this gene. Variants of least three other genes (STX6, EIF2AK3, and MOBP) are also associated with an increased the risk of developing PSP. The study of genetic mechanisms should eventually lead to effective medical therapies.
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Causes of Progressive Supranuclear Palsy. The cause of PSP is not known, but it is a form of tauopathy, in which abnormal phosphorylation of the protein tau is associated with destruction of vital protein filaments in nerve cells. This “neurofibrillary” degeneration is hypothesized to cause the death of nerve cells, and most experimental treatments are aimed at preventing tau pathology. The signs and symptoms of PSP are determined by the distribution of tau pathology in the brain. Recent work suggests that the disease is at least partly genetic. Many researchers now believe that various genetic and environmental factors interact to produce this disorder.In the medical literature, the word “tauopathy” is used to refer to several neurodegenerative disorders including PSP, in which tau are mishandled. Other neurodegenerative disorders classified as tauopathies include corticobasal degeneration and Pick disease. Alzheimer disease also produces tau pathology.Genetics plays an important role in PSP even though most patients have no family history of PSP. Rare mutations in the gene for the microtubule-associated protein tau (MAPT) appear to cause PSP in rare patients, and risk of PSP is determined to some extent by genetic variation in this gene. Variants of least three other genes (STX6, EIF2AK3, and MOBP) are also associated with an increased the risk of developing PSP. The study of genetic mechanisms should eventually lead to effective medical therapies.
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Affects of Progressive Supranuclear Palsy
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PSP is under-diagnosed, so it is difficult to know how many people are affected. This disorder is believed to affect at least 20,000 people in the United States. According to some reports, PSP is estimated to affect as many as 5-17 in 100,000 people, but recent autopsy studies found PSP pathology in 2-6% of elderly people that had no diagnosis of PSP before death. The onset of this disorder occurs between 45 and 75 years of age, with the average age of onset at about 63 years. Men and women are affected more or less equally.
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Affects of Progressive Supranuclear Palsy. PSP is under-diagnosed, so it is difficult to know how many people are affected. This disorder is believed to affect at least 20,000 people in the United States. According to some reports, PSP is estimated to affect as many as 5-17 in 100,000 people, but recent autopsy studies found PSP pathology in 2-6% of elderly people that had no diagnosis of PSP before death. The onset of this disorder occurs between 45 and 75 years of age, with the average age of onset at about 63 years. Men and women are affected more or less equally.
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Related disorders of Progressive Supranuclear Palsy
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Symptoms of the following disorders can resemble those of progressive supranuclear palsy. Comparisons may be useful for a differential diagnosis.Corticobasal degeneration (CBD) is a rare progressive neurological disorder characterized by cell loss and shrinkage (atrophy) in certain areas of the brain (cerebral cortex and basal ganglia). The symptoms and signs of this disease resemble some patients with PSP, and some experts believe that CBD and PSP are variations of the same disease. Both are tauopathies. (For more information, choose “corticobasal degeneration” as your search term in the Rare Disease Database.)Multiple system atrophy (MSA) is a rare progressive neurological disorder characterized by a varying combination of Parkinsonism and cerebellar ataxia (poorly coordinated limb movement, unsteady gait and dysarthria). Many patients with MSA also develop impaired function of the autonomic nervous system, which controls blood pressure, heart rate, sweating, the bowels and the urinary bladder. The exact cause of multiple system atrophy is unknown. (For more information, choose “multiple system atrophy” as your search term in the Rare Disease Database.)Shy-Drager syndrome is multiple system atrophy with autonomic failure. Most experts no longer use this term Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (rest tremor), muscular stiffness or inflexibility (rigidity), slowness of movement (bradykinesia) and difficulty carrying out voluntary movements (akinesia). Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal from one nerve cell to another in the brain. Parkinson disease progresses much more slowly than PSP and usually is not incapacitating for a decade or more.
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Related disorders of Progressive Supranuclear Palsy. Symptoms of the following disorders can resemble those of progressive supranuclear palsy. Comparisons may be useful for a differential diagnosis.Corticobasal degeneration (CBD) is a rare progressive neurological disorder characterized by cell loss and shrinkage (atrophy) in certain areas of the brain (cerebral cortex and basal ganglia). The symptoms and signs of this disease resemble some patients with PSP, and some experts believe that CBD and PSP are variations of the same disease. Both are tauopathies. (For more information, choose “corticobasal degeneration” as your search term in the Rare Disease Database.)Multiple system atrophy (MSA) is a rare progressive neurological disorder characterized by a varying combination of Parkinsonism and cerebellar ataxia (poorly coordinated limb movement, unsteady gait and dysarthria). Many patients with MSA also develop impaired function of the autonomic nervous system, which controls blood pressure, heart rate, sweating, the bowels and the urinary bladder. The exact cause of multiple system atrophy is unknown. (For more information, choose “multiple system atrophy” as your search term in the Rare Disease Database.)Shy-Drager syndrome is multiple system atrophy with autonomic failure. Most experts no longer use this term Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (rest tremor), muscular stiffness or inflexibility (rigidity), slowness of movement (bradykinesia) and difficulty carrying out voluntary movements (akinesia). Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal from one nerve cell to another in the brain. Parkinson disease progresses much more slowly than PSP and usually is not incapacitating for a decade or more.
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Diagnosis of Progressive Supranuclear Palsy
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The diagnosis of progressive supranuclear palsy may be suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings.
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Diagnosis of Progressive Supranuclear Palsy. The diagnosis of progressive supranuclear palsy may be suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings.
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Therapies of Progressive Supranuclear Palsy
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Treatment
Treatment of progressive supranuclear palsy is symptomatic and supportive. There is no cure at the present time. In some cases, drugs used to treat Parkinson disease (antiparkinsonian agents), such as levodopa, are beneficial in relieving symptoms of slowness, but the effect is usually limited and temporary. Antidepressant medications are of some benefit in some cases. The use of these drugs should be monitored carefully by a neurologist experienced in their administration.Walking aids such as a walker weighted in front and wearing shoes with built-up heels may help in preventing affected individuals from falling backwards. Periodic evaluations by physical therapy, occupational therapy and speech therapy are helpful in maximizing quality of life. Bifocals or special glasses with prisms may be prescribed for some individuals with PSP to treat certain difficulties in eyesight (i.e., difficulty looking down). Botulinum toxin injections are helpful in treating blepharospasm.When a patient can no longer swallow, a surgical procedure known as percutaneous gastrostomy can be performed, depending upon the patient’s wishes and quality of life. In this procedure, a tube is placed through the skin of the abdomen into the stomach to allow sufficient feeding.
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Therapies of Progressive Supranuclear Palsy. Treatment
Treatment of progressive supranuclear palsy is symptomatic and supportive. There is no cure at the present time. In some cases, drugs used to treat Parkinson disease (antiparkinsonian agents), such as levodopa, are beneficial in relieving symptoms of slowness, but the effect is usually limited and temporary. Antidepressant medications are of some benefit in some cases. The use of these drugs should be monitored carefully by a neurologist experienced in their administration.Walking aids such as a walker weighted in front and wearing shoes with built-up heels may help in preventing affected individuals from falling backwards. Periodic evaluations by physical therapy, occupational therapy and speech therapy are helpful in maximizing quality of life. Bifocals or special glasses with prisms may be prescribed for some individuals with PSP to treat certain difficulties in eyesight (i.e., difficulty looking down). Botulinum toxin injections are helpful in treating blepharospasm.When a patient can no longer swallow, a surgical procedure known as percutaneous gastrostomy can be performed, depending upon the patient’s wishes and quality of life. In this procedure, a tube is placed through the skin of the abdomen into the stomach to allow sufficient feeding.
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Overview of Prolactinoma
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A prolactinoma is a benign tumor of the pituitary gland (adenoma) that produces an excessive amount of the hormone prolactin. In women, hyperprolactinemia is characterized by irregular menstrual periods or even absence of periods, infertility and production of breast milk in women who are not pregnant (galactorrhea). The most common symptom in men is impotence.
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Overview of Prolactinoma. A prolactinoma is a benign tumor of the pituitary gland (adenoma) that produces an excessive amount of the hormone prolactin. In women, hyperprolactinemia is characterized by irregular menstrual periods or even absence of periods, infertility and production of breast milk in women who are not pregnant (galactorrhea). The most common symptom in men is impotence.
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Symptoms of Prolactinoma
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Many of the symptoms of prolactinoma are caused by an excessive amount of prolactin in the blood (hyperprolactinemia) which decreases the ovarian and testicular function. In women, prolactinoma is characterized by irregular menstrual periods, infertility and production of breast milk in women who are not pregnant (galactorrhea). Some women experience diminished sexual desire or painful intercourse. The most common symptom in men is impotence, with Infertility and decreased muscle power being of concern. Both genders can develop low bone mass (osteopenia to osteoporosis).Some symptoms such as headaches and vision abnormalities are caused by pressure from the pituitary tumor on other tissues and the optic chiasm.
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Symptoms of Prolactinoma. Many of the symptoms of prolactinoma are caused by an excessive amount of prolactin in the blood (hyperprolactinemia) which decreases the ovarian and testicular function. In women, prolactinoma is characterized by irregular menstrual periods, infertility and production of breast milk in women who are not pregnant (galactorrhea). Some women experience diminished sexual desire or painful intercourse. The most common symptom in men is impotence, with Infertility and decreased muscle power being of concern. Both genders can develop low bone mass (osteopenia to osteoporosis).Some symptoms such as headaches and vision abnormalities are caused by pressure from the pituitary tumor on other tissues and the optic chiasm.
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Causes of Prolactinoma
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The cause of pituitary tumors is unknown. Most pituitary tumors are sporadic and not associated with genetic factors that are inherited or can be passed on to children.
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Causes of Prolactinoma. The cause of pituitary tumors is unknown. Most pituitary tumors are sporadic and not associated with genetic factors that are inherited or can be passed on to children.
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Affects of Prolactinoma
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Pituitary tumors that produce enough prolactin to affect health occur in approximately 14 out of 100,000 people.
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Affects of Prolactinoma. Pituitary tumors that produce enough prolactin to affect health occur in approximately 14 out of 100,000 people.
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Related disorders of Prolactinoma
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Comparisons with the following conditions may be useful for a differential diagnosis: Chiari-Frommel syndrome is a rare endocrine disorder that affects women who have recently had a child (postpartum) and is characterized by the production of breast milk (lactation), lack of ovulation (anovulation), and the absence of regular menstrual periods (amenorrhea). These symptoms persist long after childbirth. The absence of normal hormonal cycles may result in a reduction in the size of the uterus (atrophy). Other symptoms may include emotional distress, anxiety, headaches, backaches, abdominal pain, and occasionally obesity. (For more information on this disorder, choose “Chiari Frommel” as your search term in the Rare Disease Database.) Hypothyroidism is a condition characterized by abnormally decreased activity of the thyroid gland and deficient production of thyroid hormones. The thyroid gland secretes hormones that play an essential role in regulating growth, maturation, and the rate of metabolism. Specific symptoms and findings associated with hypothyroidism may be variable, depending upon the age at symptom onset, the degree of thyroid hormone deficiency, and/or other factors. In many adults with hypothyroidism, the condition may be characterized by generalized fatigue and lack of energy (lethargy), muscle weakness and cramping, dryness of the skin and hair, incomplete or infrequent passing of stools (constipation), sensitivity to cold, and other symptoms. Individuals with hypothyroidism sometimes have hyperprolactinemia that can cause reproductive disorders. Many drugs are known to cause hyperprolactinemia, including dopamine-receptor antagonists (phenothiazines, butyrophenones, thioxanthenes, risperidone, metoclopramide, sulpiride, pimozide), dopamine-depleting agents (methyldopa, reserpine) and others such as isoniazid, danazol, tricyclic antidepressants, monoamine antihypertensives, verapamil, estrogen, antiandrogens, cyproheptadine, opiates, H2-blockers and cocaine.
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Related disorders of Prolactinoma. Comparisons with the following conditions may be useful for a differential diagnosis: Chiari-Frommel syndrome is a rare endocrine disorder that affects women who have recently had a child (postpartum) and is characterized by the production of breast milk (lactation), lack of ovulation (anovulation), and the absence of regular menstrual periods (amenorrhea). These symptoms persist long after childbirth. The absence of normal hormonal cycles may result in a reduction in the size of the uterus (atrophy). Other symptoms may include emotional distress, anxiety, headaches, backaches, abdominal pain, and occasionally obesity. (For more information on this disorder, choose “Chiari Frommel” as your search term in the Rare Disease Database.) Hypothyroidism is a condition characterized by abnormally decreased activity of the thyroid gland and deficient production of thyroid hormones. The thyroid gland secretes hormones that play an essential role in regulating growth, maturation, and the rate of metabolism. Specific symptoms and findings associated with hypothyroidism may be variable, depending upon the age at symptom onset, the degree of thyroid hormone deficiency, and/or other factors. In many adults with hypothyroidism, the condition may be characterized by generalized fatigue and lack of energy (lethargy), muscle weakness and cramping, dryness of the skin and hair, incomplete or infrequent passing of stools (constipation), sensitivity to cold, and other symptoms. Individuals with hypothyroidism sometimes have hyperprolactinemia that can cause reproductive disorders. Many drugs are known to cause hyperprolactinemia, including dopamine-receptor antagonists (phenothiazines, butyrophenones, thioxanthenes, risperidone, metoclopramide, sulpiride, pimozide), dopamine-depleting agents (methyldopa, reserpine) and others such as isoniazid, danazol, tricyclic antidepressants, monoamine antihypertensives, verapamil, estrogen, antiandrogens, cyproheptadine, opiates, H2-blockers and cocaine.
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Prolactinoma
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Diagnosis of Prolactinoma
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All patients who are shown to have a pituitary adenoma on MRI or CT imaging should have a serum prolactin level checked and if their prolactin level is >150-200 ng/ml the patient likely harbors a prolactin secreting tumor which should be treated with a dopamine agonist medication rather than surgery. If the level is less, this could be due to a tumor <10 mm or lack of normal inhibition by hypothalamic dopamine which then permits the normal prolactin secreting cells to hypersecrete (stalk effect). The effect of certain medications, recreational drugs, macroprolactin (big prolactin molecule with no effect on the body), other medical conditions (like low thyroid function, hepatic or renal insufficiency) should be evaluated for these lower levels. A specialist consultation should be considered for such patients by an experienced endocrinologist.
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Diagnosis of Prolactinoma. All patients who are shown to have a pituitary adenoma on MRI or CT imaging should have a serum prolactin level checked and if their prolactin level is >150-200 ng/ml the patient likely harbors a prolactin secreting tumor which should be treated with a dopamine agonist medication rather than surgery. If the level is less, this could be due to a tumor <10 mm or lack of normal inhibition by hypothalamic dopamine which then permits the normal prolactin secreting cells to hypersecrete (stalk effect). The effect of certain medications, recreational drugs, macroprolactin (big prolactin molecule with no effect on the body), other medical conditions (like low thyroid function, hepatic or renal insufficiency) should be evaluated for these lower levels. A specialist consultation should be considered for such patients by an experienced endocrinologist.
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Prolactinoma
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Therapies of Prolactinoma
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Prolactinoma is treated with medications that act like dopamine (dopamine agonists) such as bromocriptine, quinagolide and cabergoline because dopamine inhibits prolactin secretion. These medications reduce the size of the tumor and reduce the amount of prolactin secretion in approximately 80-90% of patients. Surgery may be recommended if medical therapy is not effective or bothersome side effects (dizziness, mental fogginess, nausea, vomiting). For both medical therapy and surgery, cure rates depend on the size and location of the tumor and the prolactinoma can recur in some affected individuals. Radiation therapy is sometimes used to control growth of a prolactinoma if no response to medications and not amenable to surgery.
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Therapies of Prolactinoma. Prolactinoma is treated with medications that act like dopamine (dopamine agonists) such as bromocriptine, quinagolide and cabergoline because dopamine inhibits prolactin secretion. These medications reduce the size of the tumor and reduce the amount of prolactin secretion in approximately 80-90% of patients. Surgery may be recommended if medical therapy is not effective or bothersome side effects (dizziness, mental fogginess, nausea, vomiting). For both medical therapy and surgery, cure rates depend on the size and location of the tumor and the prolactinoma can recur in some affected individuals. Radiation therapy is sometimes used to control growth of a prolactinoma if no response to medications and not amenable to surgery.
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Overview of Propionic Acidemia
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SummaryPropionic acidemia is a rare metabolic disorder affecting from 1/20,000 to 1/250,000 individuals in various regions of the world. It is characterized by deficiency of propionyl-CoA carboxylase, an enzyme involved in the breakdown (catabolism) of the chemical “building blocks” (amino acids) of proteins. Symptoms most commonly become apparent during the first weeks of life and may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, listlessness (lethargy), dehydration and seizures. Without appropriate treatment, coma and death may result. Rarely, the condition may become apparent later in life and may be associated with less severe symptoms and findings. Propionic acidemia is inherited in an autosomal recessive pattern. Individuals with this condition have to follow a specific diet including a low protein intake and specific food formulas (medical foods). Liver transplant is a surgical option that can help decrease the frequency of acute metabolic episodes (decompensation).
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Overview of Propionic Acidemia. SummaryPropionic acidemia is a rare metabolic disorder affecting from 1/20,000 to 1/250,000 individuals in various regions of the world. It is characterized by deficiency of propionyl-CoA carboxylase, an enzyme involved in the breakdown (catabolism) of the chemical “building blocks” (amino acids) of proteins. Symptoms most commonly become apparent during the first weeks of life and may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, listlessness (lethargy), dehydration and seizures. Without appropriate treatment, coma and death may result. Rarely, the condition may become apparent later in life and may be associated with less severe symptoms and findings. Propionic acidemia is inherited in an autosomal recessive pattern. Individuals with this condition have to follow a specific diet including a low protein intake and specific food formulas (medical foods). Liver transplant is a surgical option that can help decrease the frequency of acute metabolic episodes (decompensation).
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Symptoms of Propionic Acidemia
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Symptoms most commonly develop during the first weeks of life and may include vomiting, listlessness (lethargy), low muscle tone (hypotonia), failure to grow and gain weight at the expected rate (failure to thrive), and dehydration. Approximately 30% of affected infants may also develop seizures. The recurrence or worsening of symptoms may be associated with an infection, constipation, or consumption of high amounts of protein. In some affected infants, episodes of symptoms may alternate with periods of apparently normal health and development.Without appropriate treatment, episodes of vomiting, lethargy, dehydration, and accumulation of excessive levels of acids in the blood and bodily tissues (acidosis) may lead to coma and death [1-4].As patients age, they can experience various symptoms affecting nearly all organ systems. These symptoms include brain damage (encephalopathy), hypotonia, intellectual disability, severe vision problems, inflammation of the pancreas (pancreatitis), recurrent vomiting, chronic renal failure, heart failure (cardiomyopathy), heart rhythm problems (prolonged QTc interval) , and osteoporosis which can lead to fractures. Affected individuals can also have a reduced number of cells in their blood, such as reduced red blood cells (anemia), reduced white blood cells (leukopenia), reduced platelets (thrombocytopenia), or a reduced number of all cell types (pancytopenia). These blood abnormalities can cause various symptoms, such as immune deficiency or bleeding problems. Individuals with propionic acidemia are also at an increased risk of having a stroke as early as a few weeks of age [4-10].Less commonly, propionic acidemia may become apparent in childhood or later in life [11-13]. These affected individuals may not experience sudden, acute episodes of acidosis and tend to come to medical attention due to neurological symptoms such as intellectual disability or cardiomyopathy.
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Symptoms of Propionic Acidemia. Symptoms most commonly develop during the first weeks of life and may include vomiting, listlessness (lethargy), low muscle tone (hypotonia), failure to grow and gain weight at the expected rate (failure to thrive), and dehydration. Approximately 30% of affected infants may also develop seizures. The recurrence or worsening of symptoms may be associated with an infection, constipation, or consumption of high amounts of protein. In some affected infants, episodes of symptoms may alternate with periods of apparently normal health and development.Without appropriate treatment, episodes of vomiting, lethargy, dehydration, and accumulation of excessive levels of acids in the blood and bodily tissues (acidosis) may lead to coma and death [1-4].As patients age, they can experience various symptoms affecting nearly all organ systems. These symptoms include brain damage (encephalopathy), hypotonia, intellectual disability, severe vision problems, inflammation of the pancreas (pancreatitis), recurrent vomiting, chronic renal failure, heart failure (cardiomyopathy), heart rhythm problems (prolonged QTc interval) , and osteoporosis which can lead to fractures. Affected individuals can also have a reduced number of cells in their blood, such as reduced red blood cells (anemia), reduced white blood cells (leukopenia), reduced platelets (thrombocytopenia), or a reduced number of all cell types (pancytopenia). These blood abnormalities can cause various symptoms, such as immune deficiency or bleeding problems. Individuals with propionic acidemia are also at an increased risk of having a stroke as early as a few weeks of age [4-10].Less commonly, propionic acidemia may become apparent in childhood or later in life [11-13]. These affected individuals may not experience sudden, acute episodes of acidosis and tend to come to medical attention due to neurological symptoms such as intellectual disability or cardiomyopathy.
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Causes of Propionic Acidemia
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Propionic acidemia is caused by changes (mutations) in the PCCA and PCCB genes resulting in a deficiency of the enzyme propionyl-CoA carboxylase. This enzyme is required for the proper breakdown of the amino acids isoleucine, valine, threonine, and methionine. These amino acids are needed for proper growth and development. Propionyl-CoA carboxylase is also involved in the breakdown of cholesterol, certain fatty acids, and other substances (metabolites) necessary for metabolic actions or processes. Propionyl-CoA carboxylase deficiency leads to accumulation of toxic chemicals (metabolites). Some of these accumulated chemicals harm the mitochondria (power houses inside cells responsible for energy production). [16-20].Propionic acidemia is inherited in an autosomal recessive pattern.Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Causes of Propionic Acidemia. Propionic acidemia is caused by changes (mutations) in the PCCA and PCCB genes resulting in a deficiency of the enzyme propionyl-CoA carboxylase. This enzyme is required for the proper breakdown of the amino acids isoleucine, valine, threonine, and methionine. These amino acids are needed for proper growth and development. Propionyl-CoA carboxylase is also involved in the breakdown of cholesterol, certain fatty acids, and other substances (metabolites) necessary for metabolic actions or processes. Propionyl-CoA carboxylase deficiency leads to accumulation of toxic chemicals (metabolites). Some of these accumulated chemicals harm the mitochondria (power houses inside cells responsible for energy production). [16-20].Propionic acidemia is inherited in an autosomal recessive pattern.Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Affects of Propionic Acidemia
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Propionic acidemia affects males and females in equal numbers. The prevalence varies among different populations and regions. It affects around 1/100,000 to 1/250,000 individuals in most regions of the world. In the Middle East, where there is a high rate of marriage between blood relatives (consanguineous), around 1/20,000 to 1/45,000 individuals are affected. There are around 1/5,000 to ½,000 individuals with this disease in some Saudi tribes. The highest reported rate of propionic acidemia, with 1/1,000 people, has been reported in Greenlandic Inuits [21-29].
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Affects of Propionic Acidemia. Propionic acidemia affects males and females in equal numbers. The prevalence varies among different populations and regions. It affects around 1/100,000 to 1/250,000 individuals in most regions of the world. In the Middle East, where there is a high rate of marriage between blood relatives (consanguineous), around 1/20,000 to 1/45,000 individuals are affected. There are around 1/5,000 to ½,000 individuals with this disease in some Saudi tribes. The highest reported rate of propionic acidemia, with 1/1,000 people, has been reported in Greenlandic Inuits [21-29].
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Related disorders of Propionic Acidemia
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Symptoms of the following disorders may be similar to those of propionic acidemia. Comparisons may be useful for a differential diagnosis: isolated methylmalonic academia; maple syrup urine disease; non-ketotic hyperglycinemia; biotinidase deficiency; urea cycle disorders; pyruvate dehydrogenase complex deficiency; and pyruvate carboxylase deficiency. (For more information on these disorders, search for them in the Rare Disease Database.)
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Related disorders of Propionic Acidemia. Symptoms of the following disorders may be similar to those of propionic acidemia. Comparisons may be useful for a differential diagnosis: isolated methylmalonic academia; maple syrup urine disease; non-ketotic hyperglycinemia; biotinidase deficiency; urea cycle disorders; pyruvate dehydrogenase complex deficiency; and pyruvate carboxylase deficiency. (For more information on these disorders, search for them in the Rare Disease Database.)
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Diagnosis of Propionic Acidemia
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Propionic acidemia can be identified at birth through expanded newborn screening by measuring levels of certain metabolites such a propionylcarnitine and methionine in a blood sample. [9, 30]. Most infants with propionic acidemia are diagnosed in the first weeks of life based upon a thorough clinical evaluation, a detailed patient and family history, and molecular genetic testing. Propionic acidemia may be diagnosed before birth (prenatally) by screening fetal DNA for disease-causing (pathogenic) mutations in the PCCA and PCCB genes. The diagnosis can also be made by measuring the concentration of characteristic metabolites in amniotic fluid or the activity of the propionyl-CoA carboxylase enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS]). During amniocentesis, a sample of fluid surrounding the developing fetus is removed and analyzed. CVS involves the removal and examination of tissue from a portion of the placenta.
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Diagnosis of Propionic Acidemia. Propionic acidemia can be identified at birth through expanded newborn screening by measuring levels of certain metabolites such a propionylcarnitine and methionine in a blood sample. [9, 30]. Most infants with propionic acidemia are diagnosed in the first weeks of life based upon a thorough clinical evaluation, a detailed patient and family history, and molecular genetic testing. Propionic acidemia may be diagnosed before birth (prenatally) by screening fetal DNA for disease-causing (pathogenic) mutations in the PCCA and PCCB genes. The diagnosis can also be made by measuring the concentration of characteristic metabolites in amniotic fluid or the activity of the propionyl-CoA carboxylase enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS]). During amniocentesis, a sample of fluid surrounding the developing fetus is removed and analyzed. CVS involves the removal and examination of tissue from a portion of the placenta.
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Propionic Acidemia
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Therapies of Propionic Acidemia
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Treatment
During acute episodes, the treatment of infants with propionic acidemia may require fluid therapy; measures to provide appropriate nutritional intake (e.g., intravenous glucose, with and without intravenous lipids); administration of certain medications to prevent or treat bacterial infection; and other supportive measures as required. In infants with severe disease (e.g., severe acidosis, hyperammonemia), treatment may require procedures that remove excess waste products from the blood (hemodialysis). During hemodialysis, waste products are removed by filtering the blood through an artificial kidney machine. Peritoneal dialysis is a technique during which the peritoneum is used as a natural filtering membrane. (The peritoneum is the two-layered membrane that lines the abdominal wall and covers abdominal organs.). Injection of intravenous bicarbonate can also help reduce the acid load in the body. In addition, until the diagnosis is confirmed, physicians may completely eliminate protein from the newborn’s diet and may also administer biotin, a B complex vitamin that plays a role in the metabolism of certain fatty acids and amino acids.Long-term treatment includes administration of a low-protein diet, possibly in combination with medical formula (medical foods) that are low in certain amino acids (i.e., amino acids which give rise to propionate, e.g., isoleucine, valine, threonine, and methionine). Infants and children with the disorder may develop secondary deficiency of carnitine, a substance that plays a role in metabolism and the proper use of fatty acids. In such cases, therapy includes administration of L-carnitine (carnitine or levocarnitine). Antibiotic therapy with metronidazole can reduce the burden of propionyl-CoA in the body, as this chemical is produced by some bacteria during fermentation of carbohydrates in our gut.) [4,9,31].Liver transplant is a potential surgical option for individuals with severe symptoms and frequent recurrent acute episodes (decompensation). Liver recipients generally have a lower risk of decompensation and hospitalization. However, lifelong immunosuppressive therapy is necessary to prevent organ rejection [32-34].
All patients with propionic academia must be followed by dieticians with experience in providing care to metabolic patients. Some children might need to be in special education classes, as intellectual disability is common with propionic academia.Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Propionic Acidemia. Treatment
During acute episodes, the treatment of infants with propionic acidemia may require fluid therapy; measures to provide appropriate nutritional intake (e.g., intravenous glucose, with and without intravenous lipids); administration of certain medications to prevent or treat bacterial infection; and other supportive measures as required. In infants with severe disease (e.g., severe acidosis, hyperammonemia), treatment may require procedures that remove excess waste products from the blood (hemodialysis). During hemodialysis, waste products are removed by filtering the blood through an artificial kidney machine. Peritoneal dialysis is a technique during which the peritoneum is used as a natural filtering membrane. (The peritoneum is the two-layered membrane that lines the abdominal wall and covers abdominal organs.). Injection of intravenous bicarbonate can also help reduce the acid load in the body. In addition, until the diagnosis is confirmed, physicians may completely eliminate protein from the newborn’s diet and may also administer biotin, a B complex vitamin that plays a role in the metabolism of certain fatty acids and amino acids.Long-term treatment includes administration of a low-protein diet, possibly in combination with medical formula (medical foods) that are low in certain amino acids (i.e., amino acids which give rise to propionate, e.g., isoleucine, valine, threonine, and methionine). Infants and children with the disorder may develop secondary deficiency of carnitine, a substance that plays a role in metabolism and the proper use of fatty acids. In such cases, therapy includes administration of L-carnitine (carnitine or levocarnitine). Antibiotic therapy with metronidazole can reduce the burden of propionyl-CoA in the body, as this chemical is produced by some bacteria during fermentation of carbohydrates in our gut.) [4,9,31].Liver transplant is a potential surgical option for individuals with severe symptoms and frequent recurrent acute episodes (decompensation). Liver recipients generally have a lower risk of decompensation and hospitalization. However, lifelong immunosuppressive therapy is necessary to prevent organ rejection [32-34].
All patients with propionic academia must be followed by dieticians with experience in providing care to metabolic patients. Some children might need to be in special education classes, as intellectual disability is common with propionic academia.Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families.
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Propionic Acidemia
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Overview of Protein C Deficiency
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SummaryProtein C deficiency is a rare genetic disorder characterized by a deficiency of protein C, which is a natural anticoagulant. This means it helps to prevent the blood from clumping together (clotting) too much. There is a mild form in which affected individuals are at risk for developing blood clots, particularly a type of blood clot called deep vein thrombosis. This is a clot that forms in the legs. Although very rare, there is a severe form that is present at birth (congenital) and can potentially cause widespread small clots in the body and life-threatening complications in infancy. Protein C deficiency is caused by alterations (mutations) in the PROC gene. The milder form is caused by an alteration in one PROC gene and is inherited in an autosomal dominant manner. The severe form is caused by an alteration in both PROC genes and is inherited in an autosomal recessive manner.
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Overview of Protein C Deficiency. SummaryProtein C deficiency is a rare genetic disorder characterized by a deficiency of protein C, which is a natural anticoagulant. This means it helps to prevent the blood from clumping together (clotting) too much. There is a mild form in which affected individuals are at risk for developing blood clots, particularly a type of blood clot called deep vein thrombosis. This is a clot that forms in the legs. Although very rare, there is a severe form that is present at birth (congenital) and can potentially cause widespread small clots in the body and life-threatening complications in infancy. Protein C deficiency is caused by alterations (mutations) in the PROC gene. The milder form is caused by an alteration in one PROC gene and is inherited in an autosomal dominant manner. The severe form is caused by an alteration in both PROC genes and is inherited in an autosomal recessive manner.
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Protein C Deficiency
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Symptoms of Protein C Deficiency
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Individuals with the mild form of protein C deficiency are at risk for developing blood clots, particularly in the veins (venous thromboembolisms). They are also at risk for a skin disease following treatment with a blood thinner called warfarin (warfarin-induced skin necrosis). Whether protein C deficiency increases the risk of blood clots in the arteries (arterial thrombosis) is not fully understood. Infants with the severe forms of protein C deficiency (homozygous or compound heterozygous forms) can develop symptoms within hours to a few days after birth. They develop a potentially life-threatening condition called purpura fulminans. This condition is characterized by the formation of blood clots in blood vessels throughout the body. Blood clots affect the arms and legs most often, but can become widespread throughout the body (disseminated intravascular coagulation). Blood clots can block the normal flow of blood and lead to death (necrosis) of the surrounding tissue. Infants experience abnormal bleeding in affected areas and the formation of large, purple patches or spots on the skin and necrosis of the affected skin. Bruising and discoloration of the skin can be widespread over the body. Episodes of purpura fulminans may recur. Without treatment, purpura fulminans can be fatal. People with the milder form of protein C deficiency may not show any symptoms (asymptomatic) until they reach adulthood. Others may remain asymptomatic. The most common symptom is deep vein thrombosis. This is a clot that forms in the deep veins of the legs. This can be painful and can cause the leg to swell, but the clots can form without pain or swelling too. A potential complication of this blood clot is that a piece of it can break off, travel through the bloodstream, and become lodged in the lungs. This can block the flow of blood to the lungs, a condition called pulmonary embolism. Blood clots can also form in the blood vessels that drain blood from the large and small intestines (mesenteric veins). Less often, blood clots may form in the cerebral veins, the main vein of the liver (portal vein), and other areas. Episodes of blood clots are often “triggered” or provoked by other risk factors such as surgery, pregnancy or immobilization or inactivity. Blood clots are more likely to develop as people with the milder form protein C deficiency get older. Individuals with protein C deficiency are at risk of developing a condition called Warfarin-induced skin necrosis. The use of warfarin in affected individuals can lead to widespread skin lesions. The arms and legs, breasts and trunk are the most commonly affected areas. The lesions may be reddish or purple and, without treatment, will worsen until the affected skin breaks down. Doctors do not know for sure whether people with protein C deficiency have an increased risk of developing blood clots in the arteries. This would increase their risk of having a cardiovascular issue such as a stroke.
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Symptoms of Protein C Deficiency. Individuals with the mild form of protein C deficiency are at risk for developing blood clots, particularly in the veins (venous thromboembolisms). They are also at risk for a skin disease following treatment with a blood thinner called warfarin (warfarin-induced skin necrosis). Whether protein C deficiency increases the risk of blood clots in the arteries (arterial thrombosis) is not fully understood. Infants with the severe forms of protein C deficiency (homozygous or compound heterozygous forms) can develop symptoms within hours to a few days after birth. They develop a potentially life-threatening condition called purpura fulminans. This condition is characterized by the formation of blood clots in blood vessels throughout the body. Blood clots affect the arms and legs most often, but can become widespread throughout the body (disseminated intravascular coagulation). Blood clots can block the normal flow of blood and lead to death (necrosis) of the surrounding tissue. Infants experience abnormal bleeding in affected areas and the formation of large, purple patches or spots on the skin and necrosis of the affected skin. Bruising and discoloration of the skin can be widespread over the body. Episodes of purpura fulminans may recur. Without treatment, purpura fulminans can be fatal. People with the milder form of protein C deficiency may not show any symptoms (asymptomatic) until they reach adulthood. Others may remain asymptomatic. The most common symptom is deep vein thrombosis. This is a clot that forms in the deep veins of the legs. This can be painful and can cause the leg to swell, but the clots can form without pain or swelling too. A potential complication of this blood clot is that a piece of it can break off, travel through the bloodstream, and become lodged in the lungs. This can block the flow of blood to the lungs, a condition called pulmonary embolism. Blood clots can also form in the blood vessels that drain blood from the large and small intestines (mesenteric veins). Less often, blood clots may form in the cerebral veins, the main vein of the liver (portal vein), and other areas. Episodes of blood clots are often “triggered” or provoked by other risk factors such as surgery, pregnancy or immobilization or inactivity. Blood clots are more likely to develop as people with the milder form protein C deficiency get older. Individuals with protein C deficiency are at risk of developing a condition called Warfarin-induced skin necrosis. The use of warfarin in affected individuals can lead to widespread skin lesions. The arms and legs, breasts and trunk are the most commonly affected areas. The lesions may be reddish or purple and, without treatment, will worsen until the affected skin breaks down. Doctors do not know for sure whether people with protein C deficiency have an increased risk of developing blood clots in the arteries. This would increase their risk of having a cardiovascular issue such as a stroke.
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Protein C Deficiency
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Causes of Protein C Deficiency
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Protein C deficiency is caused by an alteration (mutation) in the PROC gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The PROC gene contains instructions for creating protein C. This protein is an anticoagulant; it works to keep the blood from clotting more than is needed. It also works to counteract inflammation. People with the milder forms of protein C deficiency may have abnormally low levels of protein C, or they may have normal levels, but the protein does not function as well as it’s supposed to. People with the severe forms have a severe deficiency of protein C in the body. 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. The milder form of protein C deficiency is inherited in an autosomal dominant manner, which means that people inherit one altered copy of the PROC gene and one unaltered copy (heterozygous). The severe forms are inherited in an autosomal recessive manner, which means that people inherited two altered copies of the PROC gene. They may inherit the same alteration in both genes (homozygous), or they may inherit different alterations in each gene (compound heterozygotes). 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.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 Protein C Deficiency. Protein C deficiency is caused by an alteration (mutation) in the PROC gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The PROC gene contains instructions for creating protein C. This protein is an anticoagulant; it works to keep the blood from clotting more than is needed. It also works to counteract inflammation. People with the milder forms of protein C deficiency may have abnormally low levels of protein C, or they may have normal levels, but the protein does not function as well as it’s supposed to. People with the severe forms have a severe deficiency of protein C in the body. 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. The milder form of protein C deficiency is inherited in an autosomal dominant manner, which means that people inherit one altered copy of the PROC gene and one unaltered copy (heterozygous). The severe forms are inherited in an autosomal recessive manner, which means that people inherited two altered copies of the PROC gene. They may inherit the same alteration in both genes (homozygous), or they may inherit different alterations in each gene (compound heterozygotes). 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.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.
| 1,021 |
Protein C Deficiency
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nord_1021_3
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Affects of Protein C Deficiency
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Protein C deficiency affects men and women in equal numbers. The prevalence of the milder form is about 1 in 200-500 people in the general population. Prevalence is the number of people in a population that have a disorder at a given time. The prevalence of severe protein C deficiency is about 1 in 500,000-750,000 people in the general population.
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Affects of Protein C Deficiency. Protein C deficiency affects men and women in equal numbers. The prevalence of the milder form is about 1 in 200-500 people in the general population. Prevalence is the number of people in a population that have a disorder at a given time. The prevalence of severe protein C deficiency is about 1 in 500,000-750,000 people in the general population.
| 1,021 |
Protein C Deficiency
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nord_1021_4
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Related disorders of Protein C Deficiency
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Symptoms of the following disorders can be similar to those of protein C deficiency. Comparisons may be useful for a differential diagnosis.Acquired protein C deficiency refers to people who have protein C deficiency that is not because of a genetic cause (i.e., altered gene). These people ‘acquire’ the disease at some point in their lives due to a specific cause. Various conditions have been shown to cause acquired protein C deficiency. These conditions include vitamin K deficiency, warfarin therapy, severe liver disease, disseminated intravascular coagulation (DIC), severe bacterial infections in the young, and some chemotherapy drugs. Antithrombin deficiency is a blood disorder characterized by the tendency to form clots in the veins (thrombosis). An inherited tendency to thrombosis is known as thrombophilia. Antithrombin is a substance in the blood that limits the blood's ability to clot (coagulation) and the primary inhibitor of thrombin, which is required for the development of blood clots. In people with congenital antithrombin deficiency, there is a reduced amount of this substance in the blood due to a genetic abnormality. Antithrombin deficiency may also be acquired; in such cases, the disorder may be reversible with treatment. (For more information on this disorder, choose “antithrombin deficiency” as your search term in the Rare Disease Database.)Protein S deficiency is a rare inherited disorder characterized by the formation of recurrent blood clots and emboli. Affected individuals are particularly at risk for developing deep vein thrombosis. In severe cases of protein S deficiency, infants may develop a potentially life-threatening complication called purpura fulminans. Occasionally protein S deficiency may be acquired as a result of kidney disease (i.e., nephrotic syndrome). Protein S deficiency is caused by alterations in the PROS1 gene.
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Related disorders of Protein C Deficiency. Symptoms of the following disorders can be similar to those of protein C deficiency. Comparisons may be useful for a differential diagnosis.Acquired protein C deficiency refers to people who have protein C deficiency that is not because of a genetic cause (i.e., altered gene). These people ‘acquire’ the disease at some point in their lives due to a specific cause. Various conditions have been shown to cause acquired protein C deficiency. These conditions include vitamin K deficiency, warfarin therapy, severe liver disease, disseminated intravascular coagulation (DIC), severe bacterial infections in the young, and some chemotherapy drugs. Antithrombin deficiency is a blood disorder characterized by the tendency to form clots in the veins (thrombosis). An inherited tendency to thrombosis is known as thrombophilia. Antithrombin is a substance in the blood that limits the blood's ability to clot (coagulation) and the primary inhibitor of thrombin, which is required for the development of blood clots. In people with congenital antithrombin deficiency, there is a reduced amount of this substance in the blood due to a genetic abnormality. Antithrombin deficiency may also be acquired; in such cases, the disorder may be reversible with treatment. (For more information on this disorder, choose “antithrombin deficiency” as your search term in the Rare Disease Database.)Protein S deficiency is a rare inherited disorder characterized by the formation of recurrent blood clots and emboli. Affected individuals are particularly at risk for developing deep vein thrombosis. In severe cases of protein S deficiency, infants may develop a potentially life-threatening complication called purpura fulminans. Occasionally protein S deficiency may be acquired as a result of kidney disease (i.e., nephrotic syndrome). Protein S deficiency is caused by alterations in the PROS1 gene.
| 1,021 |
Protein C Deficiency
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nord_1021_5
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Diagnosis of Protein C Deficiency
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A diagnosis of protein C deficiency is based upon identification of characteristic symptoms (e.g. repeated blood clot formation), a detailed patient and familial history (e.g. history of blood clots in the family), a thorough clinical evaluation and certain specialized tests. Clinical Testing and Workup
Doctors will run blood tests that will determine the activity of protein C in the blood. These tests are called assays and they measure the amount and activity of specific enzymes in the blood. Enzyme activity in infants with the severe form of protein C deficiency will range from 0% to 30%. In the mild form, the range is 30% to 70%. Molecular genetic testing can confirm a diagnosis of protein C deficiency, but usually is not necessary. Molecular genetic testing can detect alterations (mutations) in the PROC gene known to cause this disorder, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Protein C Deficiency. A diagnosis of protein C deficiency is based upon identification of characteristic symptoms (e.g. repeated blood clot formation), a detailed patient and familial history (e.g. history of blood clots in the family), a thorough clinical evaluation and certain specialized tests. Clinical Testing and Workup
Doctors will run blood tests that will determine the activity of protein C in the blood. These tests are called assays and they measure the amount and activity of specific enzymes in the blood. Enzyme activity in infants with the severe form of protein C deficiency will range from 0% to 30%. In the mild form, the range is 30% to 70%. Molecular genetic testing can confirm a diagnosis of protein C deficiency, but usually is not necessary. Molecular genetic testing can detect alterations (mutations) in the PROC gene known to cause this disorder, but is available only as a diagnostic service at specialized laboratories.
| 1,021 |
Protein C Deficiency
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nord_1021_6
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Therapies of Protein C Deficiency
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Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with protein C deficiency.Many individuals with mild forms of protein C deficiency will not need any treatment, except at times where there is an increased risk of blood clot formation such as during surgery, pregnancy, immobilization, or trauma. Some individuals with a strong family history to developing blood clots may receive preventive therapy (e.g. anticoagulant therapy). Anticoagulant therapy is the use of drugs like heparin and warfarin that thin the blood and make it harder for the blood to clot. Special care must be taken if warfarin is used because of the risk of warfarin-induced skin necrosis. The duration of anticoagulant therapy varies based upon an individual patient’s specific situation. In 2007, the US Food and Drug Administration approved the use of a protein C concentrate called Ceprotin for the treatment of individuals with severe protein C deficiency experiencing purpura fulminans or venous thrombosis. Infants with severe protein C deficiency who develop purpura fulminans require immediate treatment with Ceprotin. Fresh frozen plasma can be used if Ceprotin is unavailable. Some infants with severe protein C deficiency receive daily infusions of Ceprotin. One young child reported in the medical literature received continuous therapy through the use of an insulin pump. In Europe, there is another drug that is a plasma-derived concentrate of protein C. This drug is called Protexel. Warfarin-induced skin necrosis is a medical emergency. Warfarin should immediately be discontinued and affected individuals should be treated with vitamin K and therapeutic doses of heparin. In individuals with protein C deficiency, Ceprotin may be given to help normalize protein C activity. Fresh frozen plasma may be tried if Ceprotin is unavailable. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
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Therapies of Protein C Deficiency. Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with protein C deficiency.Many individuals with mild forms of protein C deficiency will not need any treatment, except at times where there is an increased risk of blood clot formation such as during surgery, pregnancy, immobilization, or trauma. Some individuals with a strong family history to developing blood clots may receive preventive therapy (e.g. anticoagulant therapy). Anticoagulant therapy is the use of drugs like heparin and warfarin that thin the blood and make it harder for the blood to clot. Special care must be taken if warfarin is used because of the risk of warfarin-induced skin necrosis. The duration of anticoagulant therapy varies based upon an individual patient’s specific situation. In 2007, the US Food and Drug Administration approved the use of a protein C concentrate called Ceprotin for the treatment of individuals with severe protein C deficiency experiencing purpura fulminans or venous thrombosis. Infants with severe protein C deficiency who develop purpura fulminans require immediate treatment with Ceprotin. Fresh frozen plasma can be used if Ceprotin is unavailable. Some infants with severe protein C deficiency receive daily infusions of Ceprotin. One young child reported in the medical literature received continuous therapy through the use of an insulin pump. In Europe, there is another drug that is a plasma-derived concentrate of protein C. This drug is called Protexel. Warfarin-induced skin necrosis is a medical emergency. Warfarin should immediately be discontinued and affected individuals should be treated with vitamin K and therapeutic doses of heparin. In individuals with protein C deficiency, Ceprotin may be given to help normalize protein C activity. Fresh frozen plasma may be tried if Ceprotin is unavailable. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
| 1,021 |
Protein C Deficiency
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nord_1022_0
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Overview of Protein S Deficiency
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Protein S deficiency is a rare genetic disorder of blood coagulation that is caused by a variation in the PROS1 gene. This variation is inherited in an autosomal dominant manner. Affected individuals are at an increased risk of developing blood clots in the legs (deep venous thrombosis), which can break off and travel to the lungs, which is termed pulmonary embolism. Affected individuals are deficient in protein S, which is a specialized blood protein. Specifically, protein S is involved in inhibiting coagulation. This means that it helps to prevent the blood from clotting too much. Affected individuals who inherit one abnormal protein S gene are at risk for developing blood clots. Although very rare, there is a severe form that is present at birth (congenital) due to the presence of 2 abnormal protein S genes that can potentially cause widespread small clots in the body and life-threatening complications in infancy. Occasionally protein S deficiency may be acquired as a result of acquired conditions such as kidney disease (i.e., nephrotic syndrome), pregnancy, or the use of oral contraceptives.
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Overview of Protein S Deficiency. Protein S deficiency is a rare genetic disorder of blood coagulation that is caused by a variation in the PROS1 gene. This variation is inherited in an autosomal dominant manner. Affected individuals are at an increased risk of developing blood clots in the legs (deep venous thrombosis), which can break off and travel to the lungs, which is termed pulmonary embolism. Affected individuals are deficient in protein S, which is a specialized blood protein. Specifically, protein S is involved in inhibiting coagulation. This means that it helps to prevent the blood from clotting too much. Affected individuals who inherit one abnormal protein S gene are at risk for developing blood clots. Although very rare, there is a severe form that is present at birth (congenital) due to the presence of 2 abnormal protein S genes that can potentially cause widespread small clots in the body and life-threatening complications in infancy. Occasionally protein S deficiency may be acquired as a result of acquired conditions such as kidney disease (i.e., nephrotic syndrome), pregnancy, or the use of oral contraceptives.
| 1,022 |
Protein S Deficiency
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nord_1022_1
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Symptoms of Protein S Deficiency
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Individuals with protein S deficiency are at risk for developing blood clots, specifically blood clots that begin in veins (venous thromboembolisms). Veins are the blood vessels in the body that carry blood to the heart. The exact risk of a blood clot, the age of onset of the disease, the severity of the disease, and the number and frequency and location of blood clots will vary greatly among affected individuals. This is due, in part, to the amount of residual protein S activity there is in the body. Some individuals with protein S deficiency due to inheritance of a single abnormal protein S gene (termed heterozygous) may never develop a blood clot and others may not develop one until adulthood. The two most common findings associated with protein S deficiency are deep vein thrombosis and pulmonary embolism. Deep vein thrombosis or DVT is a clot that forms in the legs. This can be painful and can cause the leg to swell, but the clots can form without pain or swelling too. A potential complication of this blood clot is that a piece of it can break off, travel through the bloodstream, and become lodged in the lungs. This can block the flow of blood to the lungs, a condition called pulmonary embolism. Blood clots can also form in the blood vessels that drain blood from the large and small intestines (mesenteric veins). Less often, blood clots may form in the cerebral veins or other areas. Infants with the severe forms of protein S deficiency (homozygous or compound heterozygous forms due to inheritance of abnormal protein S genes from both parents) can develop symptoms within hours to a few days after birth. They develop a potentially life-threatening condition called purpura fulminans. This condition is characterized by the formation of blood clots in blood vessels throughout the body. Blood clots affect the arms and legs most often, but can become widespread throughout the body (disseminated intravascular coagulation). Blood clots can block the normal flow of blood and lead to death (necrosis) of the surrounding tissue. Infants experience abnormal bleeding in affected areas and the formation of large, purple patches or spots on the skin and necrosis of the affected skin. Bruising and discoloration of the skin can be widespread over the body. Episodes of purpura fulminans may recur. Without treatment, purpura fulminans can be fatal.
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Symptoms of Protein S Deficiency. Individuals with protein S deficiency are at risk for developing blood clots, specifically blood clots that begin in veins (venous thromboembolisms). Veins are the blood vessels in the body that carry blood to the heart. The exact risk of a blood clot, the age of onset of the disease, the severity of the disease, and the number and frequency and location of blood clots will vary greatly among affected individuals. This is due, in part, to the amount of residual protein S activity there is in the body. Some individuals with protein S deficiency due to inheritance of a single abnormal protein S gene (termed heterozygous) may never develop a blood clot and others may not develop one until adulthood. The two most common findings associated with protein S deficiency are deep vein thrombosis and pulmonary embolism. Deep vein thrombosis or DVT is a clot that forms in the legs. This can be painful and can cause the leg to swell, but the clots can form without pain or swelling too. A potential complication of this blood clot is that a piece of it can break off, travel through the bloodstream, and become lodged in the lungs. This can block the flow of blood to the lungs, a condition called pulmonary embolism. Blood clots can also form in the blood vessels that drain blood from the large and small intestines (mesenteric veins). Less often, blood clots may form in the cerebral veins or other areas. Infants with the severe forms of protein S deficiency (homozygous or compound heterozygous forms due to inheritance of abnormal protein S genes from both parents) can develop symptoms within hours to a few days after birth. They develop a potentially life-threatening condition called purpura fulminans. This condition is characterized by the formation of blood clots in blood vessels throughout the body. Blood clots affect the arms and legs most often, but can become widespread throughout the body (disseminated intravascular coagulation). Blood clots can block the normal flow of blood and lead to death (necrosis) of the surrounding tissue. Infants experience abnormal bleeding in affected areas and the formation of large, purple patches or spots on the skin and necrosis of the affected skin. Bruising and discoloration of the skin can be widespread over the body. Episodes of purpura fulminans may recur. Without treatment, purpura fulminans can be fatal.
| 1,022 |
Protein S Deficiency
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nord_1022_2
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Causes of Protein S Deficiency
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Protein S deficiency is caused by a variation in the PROS1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.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. Some individuals inherit a variation in one PROS1 gene. These individuals usually have the mild form of protein S deficiency. Far less often, individuals inherit a variation in both of their PROS1 genes. These individuals usually have the severe form of protein S deficiency.Disorders inherited in a dominant pattern occur when only a single copy of a gene variation is necessary to cause a particular disease. The gene variation can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The risk to have a child to a parent who has one abnormal protein S gene is 50% with each pregnancy.Sometimes, episodes of blood clots are “triggered” or provoked by other risk factors such as surgery, pregnancy or immobilization, trauma, hormonal contraception or replacement therapy, or inactivity.
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Causes of Protein S Deficiency. Protein S deficiency is caused by a variation in the PROS1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.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. Some individuals inherit a variation in one PROS1 gene. These individuals usually have the mild form of protein S deficiency. Far less often, individuals inherit a variation in both of their PROS1 genes. These individuals usually have the severe form of protein S deficiency.Disorders inherited in a dominant pattern occur when only a single copy of a gene variation is necessary to cause a particular disease. The gene variation can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The risk to have a child to a parent who has one abnormal protein S gene is 50% with each pregnancy.Sometimes, episodes of blood clots are “triggered” or provoked by other risk factors such as surgery, pregnancy or immobilization, trauma, hormonal contraception or replacement therapy, or inactivity.
| 1,022 |
Protein S Deficiency
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nord_1022_3
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Affects of Protein S Deficiency
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Protein S deficiency is a rare disorder that affects both men and women. The exact prevalence the common form of protein S deficiency (the number of people who have the disorder in a given population) and incidence (new cases identified each year) of the disorder overall is unknown. Severe protein S deficiency is an extremely rare disorder and often goes undiagnosed or misdiagnosed making it difficult to determine its frequency in the general population.
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Affects of Protein S Deficiency. Protein S deficiency is a rare disorder that affects both men and women. The exact prevalence the common form of protein S deficiency (the number of people who have the disorder in a given population) and incidence (new cases identified each year) of the disorder overall is unknown. Severe protein S deficiency is an extremely rare disorder and often goes undiagnosed or misdiagnosed making it difficult to determine its frequency in the general population.
| 1,022 |
Protein S Deficiency
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nord_1022_4
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Related disorders of Protein S Deficiency
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Symptoms of the following disorders can be similar to those of protein S deficiency. Comparisons may be useful for a differential diagnosis.Protein S deficiency can also be acquired; this means that an affected individual does not have a variation in the PROS1 gene. Acquired protein S deficiency occurs as a result of another underlying condition such as liver disease, nephrotic syndrome, certain infections, the use of oral contraceptives, vitamin K deficiency, surgery, or people undergoing chemotherapy treatment. These varied conditions can alter the levels of protein S in the body. Antiphospholipid syndrome (APS) is a rare autoimmune disorder characterized by recurring blood clots (thromboses). Blood clots can form in any blood vessel of the body. The specific symptoms and severity of APS vary greatly from person to person depending upon the exact location of a blood clot and the organ system affected. APS may occur as an isolated disorder (primary antiphospholipid syndrome) or may occur along with another autoimmune disorder such as systemic lupus erythematosus (secondary antiphospholipid syndrome). APS is characterized by the presence of antiphospholipid antibodies in the body. Antibodies are specialized proteins produced by the body's immune system to fight infection. In individuals with APS, certain antibodies mistakenly attack healthy tissue. In APS, antibodies mistakenly attack certain proteins that bind to phospholipids, which are fat molecules that are involved in the proper function of cell membranes. Phospholipids are found throughout the body. The reason these antibodies attack these proteins and the process by which they cause blood clots to form is not known. (For more information on this disorder, choose “antiphospholipid syndrome” as your search term in the Rare Disease Database.)An inherited tendency to thrombosis is known as thrombophilia. In addition to protein S deficiency, the following disorders can predispose affected individuals to developing blood clots. Antithrombin deficiency is a blood disorder characterized by the tendency to form clots in the veins (thrombosis). Antithrombin is a substance in the blood that limits the blood's ability to clot and is the primary inhibitor of thrombin, which is required for the development of blood clots; it also is the primary inhibitor of two clotting factors, factor Xa and factor IXa, that are required for the generation of thrombin. In people with congenital antithrombin deficiency, there is a reduced amount of this substance in the blood due to a genetic abnormality. Antithrombin deficiency may also be acquired; in such cases, the disorder may be reversible with resolution/improvement in the disease process responsible for the deficiency. (For more information on this disorder, choose “antithrombin deficiency” as your search term in the Rare Disease Database.)Protein C deficiency is a genetic disorder characterized by a deficiency of protein C, which is a natural anticoagulant. This means it helps to prevent the blood from clotting too much. There is a form due to inheritance of a single abnormal protein C gene in which affected individuals are at risk for developing blood clots, particularly a type of blood clot called deep vein thrombosis. This is a clot that forms in the legs. Although very rare, there is a severe form that is present at birth (congenital) and can potentially cause widespread small clots in the body and life-threatening complications in infancy. Protein C deficiency is caused by alterations (mutations) in the PROC gene. The common form is caused by an alteration in one PROC gene. The severe form is caused by an alteration in both PROC genes. (For more information on this disorder, choose “protein C” as your search term in the Rare Disease Database.)
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Related disorders of Protein S Deficiency. Symptoms of the following disorders can be similar to those of protein S deficiency. Comparisons may be useful for a differential diagnosis.Protein S deficiency can also be acquired; this means that an affected individual does not have a variation in the PROS1 gene. Acquired protein S deficiency occurs as a result of another underlying condition such as liver disease, nephrotic syndrome, certain infections, the use of oral contraceptives, vitamin K deficiency, surgery, or people undergoing chemotherapy treatment. These varied conditions can alter the levels of protein S in the body. Antiphospholipid syndrome (APS) is a rare autoimmune disorder characterized by recurring blood clots (thromboses). Blood clots can form in any blood vessel of the body. The specific symptoms and severity of APS vary greatly from person to person depending upon the exact location of a blood clot and the organ system affected. APS may occur as an isolated disorder (primary antiphospholipid syndrome) or may occur along with another autoimmune disorder such as systemic lupus erythematosus (secondary antiphospholipid syndrome). APS is characterized by the presence of antiphospholipid antibodies in the body. Antibodies are specialized proteins produced by the body's immune system to fight infection. In individuals with APS, certain antibodies mistakenly attack healthy tissue. In APS, antibodies mistakenly attack certain proteins that bind to phospholipids, which are fat molecules that are involved in the proper function of cell membranes. Phospholipids are found throughout the body. The reason these antibodies attack these proteins and the process by which they cause blood clots to form is not known. (For more information on this disorder, choose “antiphospholipid syndrome” as your search term in the Rare Disease Database.)An inherited tendency to thrombosis is known as thrombophilia. In addition to protein S deficiency, the following disorders can predispose affected individuals to developing blood clots. Antithrombin deficiency is a blood disorder characterized by the tendency to form clots in the veins (thrombosis). Antithrombin is a substance in the blood that limits the blood's ability to clot and is the primary inhibitor of thrombin, which is required for the development of blood clots; it also is the primary inhibitor of two clotting factors, factor Xa and factor IXa, that are required for the generation of thrombin. In people with congenital antithrombin deficiency, there is a reduced amount of this substance in the blood due to a genetic abnormality. Antithrombin deficiency may also be acquired; in such cases, the disorder may be reversible with resolution/improvement in the disease process responsible for the deficiency. (For more information on this disorder, choose “antithrombin deficiency” as your search term in the Rare Disease Database.)Protein C deficiency is a genetic disorder characterized by a deficiency of protein C, which is a natural anticoagulant. This means it helps to prevent the blood from clotting too much. There is a form due to inheritance of a single abnormal protein C gene in which affected individuals are at risk for developing blood clots, particularly a type of blood clot called deep vein thrombosis. This is a clot that forms in the legs. Although very rare, there is a severe form that is present at birth (congenital) and can potentially cause widespread small clots in the body and life-threatening complications in infancy. Protein C deficiency is caused by alterations (mutations) in the PROC gene. The common form is caused by an alteration in one PROC gene. The severe form is caused by an alteration in both PROC genes. (For more information on this disorder, choose “protein C” as your search term in the Rare Disease Database.)
| 1,022 |
Protein S Deficiency
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nord_1022_5
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Diagnosis of Protein S Deficiency
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A diagnosis of protein S deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Some indications of a possible protein S deficiency include blood clots that develop before the age of 50 without an obvious cause, recurrent blood clots, blood clots in a person in a family with history of blood clot formation, and blood clots that occur in sites that are not normally affected by blood clots including veins in the small bowel (mesenteric veins), veins of the liver (portal veins), and veins in the brain (cerebral veins). A diagnosis of the genetic form of protein S deficiency can be challenging because there are many different conditions that can temporarily lower the levels of protein S in the blood (acquired protein S deficiency). Clinical Testing and Workup
Doctors will run blood tests that will determine the activity of protein S in the blood. These tests are called assays and they measure the amount and activity of specific enzymes in the blood. The amount of protein S can vary based on several factors including age. Molecular genetic testing can confirm a diagnosis of protein S deficiency in some people. Molecular genetic testing can detect a variation in the PROS1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Protein S Deficiency. A diagnosis of protein S deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Some indications of a possible protein S deficiency include blood clots that develop before the age of 50 without an obvious cause, recurrent blood clots, blood clots in a person in a family with history of blood clot formation, and blood clots that occur in sites that are not normally affected by blood clots including veins in the small bowel (mesenteric veins), veins of the liver (portal veins), and veins in the brain (cerebral veins). A diagnosis of the genetic form of protein S deficiency can be challenging because there are many different conditions that can temporarily lower the levels of protein S in the blood (acquired protein S deficiency). Clinical Testing and Workup
Doctors will run blood tests that will determine the activity of protein S in the blood. These tests are called assays and they measure the amount and activity of specific enzymes in the blood. The amount of protein S can vary based on several factors including age. Molecular genetic testing can confirm a diagnosis of protein S deficiency in some people. Molecular genetic testing can detect a variation in the PROS1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
| 1,022 |
Protein S Deficiency
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nord_1022_6
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Therapies of Protein S Deficiency
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There is not a specific therapy for patients with protein S deficiency. The use of anticoagulant therapy however is highly effective in the treatment and prevention of blood clots in patients with the common type of protein S deficiency (due to inheritance of one abnormal protein S gene). Such therapies are generally effective regardless of the underlying risk factor or genetic abnormality predisposing a patient to developing a blood clot.Anticoagulant therapy is the use of drugs like heparin and warfarin that thin the blood and make it harder for the blood to clot. The choice of drug, specific dosage, and duration of anticoagulant therapy will vary among affected individuals. Factors influencing treatment decisions include the severity and frequency of blood clots, potential drug and dietary interactions, an individual’s personal preference, and age or overall health. Some individuals with a severe form of protein S deficiency may remain on this therapy for life. Special care must be taken if warfarin is used because of the risk of warfarin-induced skin necrosis.Some individuals with protein S deficiency who have never had a blood clot will not need any treatment, except at times where there is an increased risk of blood clot formation such as during surgery, pregnancy, immobilization or trauma. Some individuals with a strong family history of developing blood clots may receive preventative therapy (e.g. anticoagulant therapy). Anticoagulant therapy is the use of drugs like heparin, warfarin or direct oral anticoagulants that thin the blood and make it harder for the blood to clot. The choice of drug, specific dosage, and duration of anticoagulant therapy will vary among affected individuals. Factors influencing treatment decisions include the severity and frequency of blood clots, potential drug and dietary interactions, an individual’s personal preference, and age or overall health. Some individuals with protein S deficiency may remain on this therapy for life.Genetic counseling may be of benefit for affected individuals and their families.
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Therapies of Protein S Deficiency. There is not a specific therapy for patients with protein S deficiency. The use of anticoagulant therapy however is highly effective in the treatment and prevention of blood clots in patients with the common type of protein S deficiency (due to inheritance of one abnormal protein S gene). Such therapies are generally effective regardless of the underlying risk factor or genetic abnormality predisposing a patient to developing a blood clot.Anticoagulant therapy is the use of drugs like heparin and warfarin that thin the blood and make it harder for the blood to clot. The choice of drug, specific dosage, and duration of anticoagulant therapy will vary among affected individuals. Factors influencing treatment decisions include the severity and frequency of blood clots, potential drug and dietary interactions, an individual’s personal preference, and age or overall health. Some individuals with a severe form of protein S deficiency may remain on this therapy for life. Special care must be taken if warfarin is used because of the risk of warfarin-induced skin necrosis.Some individuals with protein S deficiency who have never had a blood clot will not need any treatment, except at times where there is an increased risk of blood clot formation such as during surgery, pregnancy, immobilization or trauma. Some individuals with a strong family history of developing blood clots may receive preventative therapy (e.g. anticoagulant therapy). Anticoagulant therapy is the use of drugs like heparin, warfarin or direct oral anticoagulants that thin the blood and make it harder for the blood to clot. The choice of drug, specific dosage, and duration of anticoagulant therapy will vary among affected individuals. Factors influencing treatment decisions include the severity and frequency of blood clots, potential drug and dietary interactions, an individual’s personal preference, and age or overall health. Some individuals with protein S deficiency may remain on this therapy for life.Genetic counseling may be of benefit for affected individuals and their families.
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Overview of Proteus Syndrome
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Summary
Proteus syndrome is a rare disorder characterized by overgrowth of various tissues of the body. The cause of the disorder is a mosaic variant in a gene called AKT1. Disproportionate, asymmetric overgrowth occurs in a mosaic pattern (i.e., a random “patchy” pattern of affected and unaffected areas). Affected individuals may experience a wide variety of complications that may include progressive skeletal malformations, benign and malignant tumors, malformations of blood vessels (vascular malformations), cystic pulmonary disease and certain skin lesions. In some people, life-threatening conditions relating to abnormal blood clotting may develop including deep vein thrombosis and pulmonary embolism.Introduction
Proteus syndrome was first reported in the medical literature in 1979. Researchers now believe that Joseph Merrick, whose life was the subject of the play and movie The Elephant Man, had Proteus syndrome and not neurofibromatosis, as previously thought.
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Overview of Proteus Syndrome. Summary
Proteus syndrome is a rare disorder characterized by overgrowth of various tissues of the body. The cause of the disorder is a mosaic variant in a gene called AKT1. Disproportionate, asymmetric overgrowth occurs in a mosaic pattern (i.e., a random “patchy” pattern of affected and unaffected areas). Affected individuals may experience a wide variety of complications that may include progressive skeletal malformations, benign and malignant tumors, malformations of blood vessels (vascular malformations), cystic pulmonary disease and certain skin lesions. In some people, life-threatening conditions relating to abnormal blood clotting may develop including deep vein thrombosis and pulmonary embolism.Introduction
Proteus syndrome was first reported in the medical literature in 1979. Researchers now believe that Joseph Merrick, whose life was the subject of the play and movie The Elephant Man, had Proteus syndrome and not neurofibromatosis, as previously thought.
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Symptoms of Proteus Syndrome
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Proteus syndrome may affect bone and connective tissue, fatty tissues, skin, central nervous system and internal organs (viscera). Bone, connective tissue and fat are the most commonly affected tissues in the body. The specific symptoms and severity vary greatly from person to person. Some individuals may exhibit only a few, mild symptoms of Proteus syndrome, making diagnosis challenging.Most affected individuals are born without any noticeable symptoms. Some patients can have brain overgrowth at birth. Overgrowth usually begins between 6-18 months. Overgrowth associated with Proteus syndrome is irregular, disproportionate and may affect one side of the body such as only one foot and not the other (asymmetric). Overgrowth of bone may affect the skull, the long bones of the arms and legs, and the feet and hands. Overgrowth of long bones of the legs can often cause one leg to be longer than the other. The spine may be affected, resulting in an abnormally curved spine (scoliosis). Progressive, bony overgrowth can affect joints in the fingers or larger joints such as the knee limiting movement and range of motion. Ultimately, joints may become significantly overgrown and locked in place (immobilized).In childhood, affected individuals may develop abnormal skin conditions including localized areas of severe fatty overgrowth especially on the trunk or the arms and legs. In some, benign tumors consisting of fatty tissue (lipomas) may develop. In addition to fatty tissue overgrowth, some affected individuals may develop areas of fatty tissue loss (atrophy) especially in the chest.Affected children may also develop a raised, rough (verrucous) lesion (epidermal nevus) that is usually rough and dark brown or brownish black. An epidermal nevus may be present at birth. Another skin lesion known as cerebriform connective tissue nevus (CCTN) may occur. This slow-growing lesion is most often found on the feet and less commonly on the hands. It is not present at birth and is made up of thickened, abnormally firm subcutaneous tissue. The skin may develop deep grooves or furrows that look like the surface of a brain.Malformations of various blood vessels (vascular malformations) are common in Proteus syndrome. Capillaries, veins, and lymph vessels can be affected. The capillaries are tiny blood vessels that connect arteries and veins. Veins are blood vessels that take blood to the heart. Lymph vessels are part of the lymphatic system, the circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body.Individuals with Proteus syndrome may be at risk for developing blood clots in the legs, a condition known as deep vein thrombosis (DVT). The legs may become painful and swollen and blood vessels in the legs may be visibly enlarged. In some, a piece of a DVT may break off and travel up the bloodstream to the lungs. This blood clot in the lung, pulmonary embolism, can be life threatening. It can cause breathlessness, sudden pain in the chest, exhaustion or complications such as high blood pressure of the pulmonary artery.Additional findings can occur in Proteus syndrome including abnormal enlargement of certain internal organs such as the liver, spleen, kidney, and others. Eye abnormalities such as crossed eyes (strabismus) or benign tumors on the white part of the eye (epibulbar dermoid) may be present. Some individuals with Proteus syndrome may develop cystic lung disease that can lead to worsening breathing problems and require surgery.Affected individuals also have a predisposition of developing a wide variety of tumors, most of which are benign. The tumors most often associated with Proteus syndrome are ovarian and testicular cystadenoma, a rare salivary gland tumor known as monomorphic adenoma and meningioma.Less common findings in Proteus syndrome include malformations of the central nervous system such as overgrowth of half of the brain (hemimegalencephaly). In some patients, intellectual disability may be present, and seizures have been reported as well. Individuals with these abnormalities may also have distinct facial features including a long face, downward slanting eyelid folds (palpebral fissures), droopy eyelids (ptosis), low bridge of the nose, wide nostrils (nares) and a long narrow head (dolichocephaly). The reason for the association of neurological and facial abnormalities is unknown.
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Symptoms of Proteus Syndrome. Proteus syndrome may affect bone and connective tissue, fatty tissues, skin, central nervous system and internal organs (viscera). Bone, connective tissue and fat are the most commonly affected tissues in the body. The specific symptoms and severity vary greatly from person to person. Some individuals may exhibit only a few, mild symptoms of Proteus syndrome, making diagnosis challenging.Most affected individuals are born without any noticeable symptoms. Some patients can have brain overgrowth at birth. Overgrowth usually begins between 6-18 months. Overgrowth associated with Proteus syndrome is irregular, disproportionate and may affect one side of the body such as only one foot and not the other (asymmetric). Overgrowth of bone may affect the skull, the long bones of the arms and legs, and the feet and hands. Overgrowth of long bones of the legs can often cause one leg to be longer than the other. The spine may be affected, resulting in an abnormally curved spine (scoliosis). Progressive, bony overgrowth can affect joints in the fingers or larger joints such as the knee limiting movement and range of motion. Ultimately, joints may become significantly overgrown and locked in place (immobilized).In childhood, affected individuals may develop abnormal skin conditions including localized areas of severe fatty overgrowth especially on the trunk or the arms and legs. In some, benign tumors consisting of fatty tissue (lipomas) may develop. In addition to fatty tissue overgrowth, some affected individuals may develop areas of fatty tissue loss (atrophy) especially in the chest.Affected children may also develop a raised, rough (verrucous) lesion (epidermal nevus) that is usually rough and dark brown or brownish black. An epidermal nevus may be present at birth. Another skin lesion known as cerebriform connective tissue nevus (CCTN) may occur. This slow-growing lesion is most often found on the feet and less commonly on the hands. It is not present at birth and is made up of thickened, abnormally firm subcutaneous tissue. The skin may develop deep grooves or furrows that look like the surface of a brain.Malformations of various blood vessels (vascular malformations) are common in Proteus syndrome. Capillaries, veins, and lymph vessels can be affected. The capillaries are tiny blood vessels that connect arteries and veins. Veins are blood vessels that take blood to the heart. Lymph vessels are part of the lymphatic system, the circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body.Individuals with Proteus syndrome may be at risk for developing blood clots in the legs, a condition known as deep vein thrombosis (DVT). The legs may become painful and swollen and blood vessels in the legs may be visibly enlarged. In some, a piece of a DVT may break off and travel up the bloodstream to the lungs. This blood clot in the lung, pulmonary embolism, can be life threatening. It can cause breathlessness, sudden pain in the chest, exhaustion or complications such as high blood pressure of the pulmonary artery.Additional findings can occur in Proteus syndrome including abnormal enlargement of certain internal organs such as the liver, spleen, kidney, and others. Eye abnormalities such as crossed eyes (strabismus) or benign tumors on the white part of the eye (epibulbar dermoid) may be present. Some individuals with Proteus syndrome may develop cystic lung disease that can lead to worsening breathing problems and require surgery.Affected individuals also have a predisposition of developing a wide variety of tumors, most of which are benign. The tumors most often associated with Proteus syndrome are ovarian and testicular cystadenoma, a rare salivary gland tumor known as monomorphic adenoma and meningioma.Less common findings in Proteus syndrome include malformations of the central nervous system such as overgrowth of half of the brain (hemimegalencephaly). In some patients, intellectual disability may be present, and seizures have been reported as well. Individuals with these abnormalities may also have distinct facial features including a long face, downward slanting eyelid folds (palpebral fissures), droopy eyelids (ptosis), low bridge of the nose, wide nostrils (nares) and a long narrow head (dolichocephaly). The reason for the association of neurological and facial abnormalities is unknown.
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Causes of Proteus Syndrome
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Proteus syndrome is caused by a variant in a growth regulatory gene called AKT1 that occurs after fertilization (somatic mutation). Affected persons have some cells with a normal copy of this regulatory gene and some cells with the abnormal gene (mosaic). The variability of symptoms associated with Proteus syndrome is due in part to the ratio of cells with and without the gene variant. When all cells have the AKT1 gene variant, the condition is not compatible with life. Proteus syndrome is not inherited but is caused by a mutation that occurs during development. Researchers believe that this somatic mutation occurs randomly for no apparent reason (sporadically). Some researchers have attributed a subset of individuals with Proteus syndrome to variants in the PTEN gene located on chromosome 10. This has led to confusion for affected individuals. Other researchers believe that these patients, while similar to Proteus syndrome in some respects, do not fulfill the specific diagnostic criteria. This so-called Proteus syndrome or Proteus-like syndrome represents a different, distinct disorder. There have not been any patients confirmed to have Proteus syndrome who were found to have a PTEN gene variant.
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Causes of Proteus Syndrome. Proteus syndrome is caused by a variant in a growth regulatory gene called AKT1 that occurs after fertilization (somatic mutation). Affected persons have some cells with a normal copy of this regulatory gene and some cells with the abnormal gene (mosaic). The variability of symptoms associated with Proteus syndrome is due in part to the ratio of cells with and without the gene variant. When all cells have the AKT1 gene variant, the condition is not compatible with life. Proteus syndrome is not inherited but is caused by a mutation that occurs during development. Researchers believe that this somatic mutation occurs randomly for no apparent reason (sporadically). Some researchers have attributed a subset of individuals with Proteus syndrome to variants in the PTEN gene located on chromosome 10. This has led to confusion for affected individuals. Other researchers believe that these patients, while similar to Proteus syndrome in some respects, do not fulfill the specific diagnostic criteria. This so-called Proteus syndrome or Proteus-like syndrome represents a different, distinct disorder. There have not been any patients confirmed to have Proteus syndrome who were found to have a PTEN gene variant.
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Affects of Proteus Syndrome
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Proteus syndrome is an extremely rare disorder. It affects males slightly more than females. Approximately 200 patients have been reported in the medical literature and it seems to affect people of all ethnic and racial groups. However, researchers with extensive experience in Proteus syndrome reviewed these reports and determined that just fewer than 100 met the stringent diagnostic criteria for Proteus syndrome.Because the diagnosis of Proteus syndrome is so difficult some people may go undiagnosed, while others may be incorrectly diagnosed with Proteus syndrome when they instead have a different condition. Therefore, it is extremely difficult to determine the true frequency of this disorder in the general population.
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Affects of Proteus Syndrome. Proteus syndrome is an extremely rare disorder. It affects males slightly more than females. Approximately 200 patients have been reported in the medical literature and it seems to affect people of all ethnic and racial groups. However, researchers with extensive experience in Proteus syndrome reviewed these reports and determined that just fewer than 100 met the stringent diagnostic criteria for Proteus syndrome.Because the diagnosis of Proteus syndrome is so difficult some people may go undiagnosed, while others may be incorrectly diagnosed with Proteus syndrome when they instead have a different condition. Therefore, it is extremely difficult to determine the true frequency of this disorder in the general population.
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Related disorders of Proteus Syndrome
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Symptoms of the following disorders can be similar to those of Proteus syndrome. Comparisons may be useful for a differential diagnosis.PIK3CA-related overgrowth spectrum (PROS) disorders are a group of conditions that cause overgrowth due to the PIK3CA gene. This group includes many diagnoses with features similar to Proteus syndrome including Klippel-Trenaunay syndrome (KTS), hemihyperplasia multiple lipomatosis (HHML) and CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, skeletal/scoliosis and spinal abnormalities). (For more information on these disorders, choose “PIK3CA-related overgrowth spectrum” as your search term in the Rare Disease Database.)Encephalocraniocutaneous lipomatosis (ECCL) is an extremely rare disorder characterized by eye abnormalities, skin abnormalities including tumors consisting of fatty tissue (lipomas) affecting the scalp and central nervous system and skin lesions consisting of improperly developed connective tissue (connective tissue nevi). Specific symptoms vary greatly from person to person. Some individuals have normal intelligence while others have an intellectual disability. Seizures and cysts in the brain (porencephalic cysts) have been reported in some people. Additional symptoms may also be present. Although ECCL was previously thought to represent a form of Proteus syndrome limited to the head and neck, recently researchers have delineated more specific criteria for ECCL, and it appears to be a distinct disorder from Proteus syndrome. Several individuals with this disorder have mosaic variants in a gene called FGFR1.Maffucci syndrome is a rare genetic disorder characterized by benign overgrowths of cartilage (enchondromas), skeletal deformities, and dark red irregularly shaped patches of skin previously known as ‘cavernous hemangiomas’ but a more appropriately called venous malformations. Enchondromas are most often found in certain bones (phalanges) of the hands and feet. Skeletal malformations may include legs that are disproportionate in length and/or abnormal side-to-side curvature of the spine (scoliosis). In many people, bones may tend to fracture easily. (For more information on this disorder, choose “Maffucci” as your search term in the Rare Disease Database.)
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Related disorders of Proteus Syndrome. Symptoms of the following disorders can be similar to those of Proteus syndrome. Comparisons may be useful for a differential diagnosis.PIK3CA-related overgrowth spectrum (PROS) disorders are a group of conditions that cause overgrowth due to the PIK3CA gene. This group includes many diagnoses with features similar to Proteus syndrome including Klippel-Trenaunay syndrome (KTS), hemihyperplasia multiple lipomatosis (HHML) and CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, skeletal/scoliosis and spinal abnormalities). (For more information on these disorders, choose “PIK3CA-related overgrowth spectrum” as your search term in the Rare Disease Database.)Encephalocraniocutaneous lipomatosis (ECCL) is an extremely rare disorder characterized by eye abnormalities, skin abnormalities including tumors consisting of fatty tissue (lipomas) affecting the scalp and central nervous system and skin lesions consisting of improperly developed connective tissue (connective tissue nevi). Specific symptoms vary greatly from person to person. Some individuals have normal intelligence while others have an intellectual disability. Seizures and cysts in the brain (porencephalic cysts) have been reported in some people. Additional symptoms may also be present. Although ECCL was previously thought to represent a form of Proteus syndrome limited to the head and neck, recently researchers have delineated more specific criteria for ECCL, and it appears to be a distinct disorder from Proteus syndrome. Several individuals with this disorder have mosaic variants in a gene called FGFR1.Maffucci syndrome is a rare genetic disorder characterized by benign overgrowths of cartilage (enchondromas), skeletal deformities, and dark red irregularly shaped patches of skin previously known as ‘cavernous hemangiomas’ but a more appropriately called venous malformations. Enchondromas are most often found in certain bones (phalanges) of the hands and feet. Skeletal malformations may include legs that are disproportionate in length and/or abnormal side-to-side curvature of the spine (scoliosis). In many people, bones may tend to fracture easily. (For more information on this disorder, choose “Maffucci” as your search term in the Rare Disease Database.)
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Diagnosis of Proteus Syndrome
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Diagnosis of Proteus syndrome is made using published clinical diagnostic criteria and molecular testing. Confirming a diagnosis of Proteus syndrome can be difficult and the interpretation of the clinical diagnostic criteria is controversial. The identification of the causative gene variant in AKT1 can allow molecular diagnosis, although this too can be challenging. The gene change is not present in the blood and therefore DNA testing must be performed on biopsies of affected tissue, most often skin. Other diagnostic techniques that may be used in an evaluation include plain x-rays (radiography), computed tomography (CT) scans for skull lesions or lung cysts and magnetic resonance imaging (MRI) of the brain, abdomen, pelvis and limbs. Ultrasound is used to detect scrotal or ovarian masses and can be used to evaluate deep vein thromboses.
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Diagnosis of Proteus Syndrome. Diagnosis of Proteus syndrome is made using published clinical diagnostic criteria and molecular testing. Confirming a diagnosis of Proteus syndrome can be difficult and the interpretation of the clinical diagnostic criteria is controversial. The identification of the causative gene variant in AKT1 can allow molecular diagnosis, although this too can be challenging. The gene change is not present in the blood and therefore DNA testing must be performed on biopsies of affected tissue, most often skin. Other diagnostic techniques that may be used in an evaluation include plain x-rays (radiography), computed tomography (CT) scans for skull lesions or lung cysts and magnetic resonance imaging (MRI) of the brain, abdomen, pelvis and limbs. Ultrasound is used to detect scrotal or ovarian masses and can be used to evaluate deep vein thromboses.
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Therapies of Proteus Syndrome
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Treatment
The treatment of Proteus is directed toward the specific symptoms in each individual. Multiple orthopedic procedures are usually necessary to try and control the rapid overgrowth associated with Proteus syndrome. Surgery may be necessary when overgrowth interferes with joint function or causes scoliosis or angular deformities. Surgery to reduce overgrown tissues or body parts may be indicated. Epiphysiodesis (removal or ablation of growth plates in bones) may be especially useful to prevent or treat skeletal overgrowth in Proteus syndrome.Surgery can increase the risk of developing a blood clot. When undergoing surgery, close monitoring for blood clots and consideration of blood thinners to prevent blood clots (antithrombotic prophylaxis) is recommended.There is no approved medication treatment for Proteus syndrome. However, there are clinical trials to determine if AKT inhibitors can delay or slow overgrowth.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Proteus Syndrome. Treatment
The treatment of Proteus is directed toward the specific symptoms in each individual. Multiple orthopedic procedures are usually necessary to try and control the rapid overgrowth associated with Proteus syndrome. Surgery may be necessary when overgrowth interferes with joint function or causes scoliosis or angular deformities. Surgery to reduce overgrown tissues or body parts may be indicated. Epiphysiodesis (removal or ablation of growth plates in bones) may be especially useful to prevent or treat skeletal overgrowth in Proteus syndrome.Surgery can increase the risk of developing a blood clot. When undergoing surgery, close monitoring for blood clots and consideration of blood thinners to prevent blood clots (antithrombotic prophylaxis) is recommended.There is no approved medication treatment for Proteus syndrome. However, there are clinical trials to determine if AKT inhibitors can delay or slow overgrowth.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of PRRT2-Associated Paroxysmal Movement Disorders
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Summary
PRRT2-associated paroxysmal movement disorders are a group of rare movement and seizure disorders caused by changes (disease-causing variants or mutations) in the PRRT2 gene. They include a spectrum of specific disorders including paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and hemiplegic migraine (HM). It’s important to note that these disorders can also have different genetic causes. PRRT2-associated paroxysmal movement disorders are reported to have variable expressivity and reduced penetrance. Variable expressivity means that there is a range of symptoms that can occur in people affected with this genetic condition. Reduced penetrance is when not all people with a disease-causing genetic change will have symptoms. The average age of onset for PRRT2– paroxysmal kinesigenic dyskinesia is in childhood or adolescence. It is characterized by sudden attacks of involuntary movement that can be either unilateral (one side of the body) and bilateral (both sides of the body). The term kinesigenic means that the movement episodes are triggered by sudden movement or intention to move, while the term paroxysmal means that the abnormal movements come and go over time. Many PKD episodes last less than one minute but patients can have multiple in a day, some as high as 100. BFIE is defined by complex partial seizures or localization-related epilepsy with the onset being in the first year of life with resolution by 2 years old. Patients can experience multiple seizures per day occurring every 2-3 hours on average. PKD/IC is a combination of PKD and BFIE meaning that a patient would experience both seizures and PKD episodes of involuntary movement. Hemiplegic migraines are a specific type of migraine with aura, where the migraines are associated with temporary (transient) motor weakness or temporary paralysis of half of body (hemiparesis). Introduction
PRRT2-associated paroxysmal movement disorders include a wide and evolving spectrum of paroxysmal diseases. The PRRT2 gene encodes a protein that is involved in releasing neurotransmitters. Neurotransmitters are chemicals that carry messages (chemical signals) from one nerve cell to the target cell (which can be another nerve cell or muscle cell). Healthy neurotransmitters are constantly going between cells to carry messages and instructions. Improper functioning of neurotransmitters can cause dysregulation of the signals in a person’s central nervous system (brain and spinal cord). When nerve cells are not getting the proper signals, it can lead to the medical problems associated with PRRT2-associated paroxysmal movement disorders.
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Overview of PRRT2-Associated Paroxysmal Movement Disorders. Summary
PRRT2-associated paroxysmal movement disorders are a group of rare movement and seizure disorders caused by changes (disease-causing variants or mutations) in the PRRT2 gene. They include a spectrum of specific disorders including paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and hemiplegic migraine (HM). It’s important to note that these disorders can also have different genetic causes. PRRT2-associated paroxysmal movement disorders are reported to have variable expressivity and reduced penetrance. Variable expressivity means that there is a range of symptoms that can occur in people affected with this genetic condition. Reduced penetrance is when not all people with a disease-causing genetic change will have symptoms. The average age of onset for PRRT2– paroxysmal kinesigenic dyskinesia is in childhood or adolescence. It is characterized by sudden attacks of involuntary movement that can be either unilateral (one side of the body) and bilateral (both sides of the body). The term kinesigenic means that the movement episodes are triggered by sudden movement or intention to move, while the term paroxysmal means that the abnormal movements come and go over time. Many PKD episodes last less than one minute but patients can have multiple in a day, some as high as 100. BFIE is defined by complex partial seizures or localization-related epilepsy with the onset being in the first year of life with resolution by 2 years old. Patients can experience multiple seizures per day occurring every 2-3 hours on average. PKD/IC is a combination of PKD and BFIE meaning that a patient would experience both seizures and PKD episodes of involuntary movement. Hemiplegic migraines are a specific type of migraine with aura, where the migraines are associated with temporary (transient) motor weakness or temporary paralysis of half of body (hemiparesis). Introduction
PRRT2-associated paroxysmal movement disorders include a wide and evolving spectrum of paroxysmal diseases. The PRRT2 gene encodes a protein that is involved in releasing neurotransmitters. Neurotransmitters are chemicals that carry messages (chemical signals) from one nerve cell to the target cell (which can be another nerve cell or muscle cell). Healthy neurotransmitters are constantly going between cells to carry messages and instructions. Improper functioning of neurotransmitters can cause dysregulation of the signals in a person’s central nervous system (brain and spinal cord). When nerve cells are not getting the proper signals, it can lead to the medical problems associated with PRRT2-associated paroxysmal movement disorders.
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Symptoms of PRRT2-Associated Paroxysmal Movement Disorders
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paroxysmal kinesigenic dyskinesia (PKD)
The primary movement disorder associated with PRRT2 is paroxysmal kinesigenic dyskinesia (PKD). This is the most common type of paroxysmal dyskinesia. PKD attacks often occur in childhood and are thought to be induced by sudden movements, which can include being startled, going from walking to running, stress, or rapid, deep breathing (hyperventilation). Around 10% of people report having a warning sign of numbness or paresthesia in the limbs or face prior to the attack. It is often described as a crawling sensation in the affected areas. The attacks are characterized by abnormal muscle contraction (dystonia) and episodes of unwanted, uncontrollable movements, often of the muscles in the arms, legs, face and body (choreoathetosis). Additionally, patients can sometimes have irregular, frequently violent movements of the shoulder and arm while awake (ballism). Most attacks are brief, lasting only a few seconds to a minute, but some have been reported to last for as long as five minutes. There is significant variability in the frequency of attacks ranging from one per week to 100 per day. The average age of onset for PKD is 10 years old but can range from 1-20 years old, with attacks becoming less frequent with age. Common triggers for episodes are stress, sleep deprivation, fevers, and anxiety. Avoiding these in conjunction with specific medications can help reduce the number of episodes a patient experiences.hemiplegic migraine
Hemiplegic migraines are a rare type of migraine headache with sensory symptoms called aura that can include flashes of light, blind spots, or tingling. This can cause temporary paralysis on one side of the body. They are often accompanied by other neurological symptoms such as visual disturbances, confusion and difficulty speaking. Common triggers for hemiplegic migraines are stress, anxiety, heat or light. The age of onset for hemiplegic migraines can be as early as late childhood but are more commonly seen during puberty or early adulthood. It also has a range of frequency with some reporting as many as a few per week to only one per month. The duration of the migraine attacks also varies greatly from only fifteen minutes to three days. Individuals report that the frequency of migraines decreases over time with many claiming complete remission during adulthood. It has also been documented that there is improvement of hemiplegic migraines during pregnancy.benign infantile epilepsy
Benign familial infantile seizures (BFIS) are a rare form of epilepsy that typically begin during the first twelve months of life in otherwise healthy children. This condition is characterized by sudden jerking movements, eye deviation, or staring spells and are often triggered by excitement or fever. These seizures are characterized as self-limiting, meaning they stop on their own without intervention and are not known to cause any long-term neurological damage. Because of this, treatment is not typically required. Many times, the seizures diminish greatly or completely resolve by early childhood.Less Common Signs and Symptomsepisodic ataxia
Episodic ataxia is a neurological disorder characterized by recurrent episodes of unsteadiness and lack of coordination that vary in duration. Additional symptoms that can be seen are progressive, weakness between episodes (inter-attack weakness), dystonia and unbalanced walking (ataxia). Often these symptoms are due to differences in the cerebellum, the part of the brain that controls balance for walking and standing. Triggers that have been well documented for episodes of ataxia include stress, caffeine, hormonal changes and fatigue. The mechanism that causes the episodes is unknown. It has been noted that symptoms sometimes go away on their own or the severity lessens.paroxysmal torticollis
Paroxysmal torticollis is a rare condition in which there are recurrent episodes of head tilting associated with irritability, vomiting, hypotonia, malaise (discomfort) and/or pallor (pale appearance). Onset begins in infancy and typically resolves between two to five years of age with the frequency being two to three times a month, but lessens as the child ages. The episodes typically last around ten minutes, but they have been reported to last as long as two months. It has been proposed that an episode is a precursor for migraines in older children. There is currently no specific treatment for this condition. Many families have used over-the-counter pain and nausea medication to aid in treating with varying degrees of success.familial paroxysmal non-kinesigenic dyskinesia
Familial paroxysmal non-kinesigenic dyskinesia is a condition where there are unilateral or bilateral involuntary movements. Typically, episodes are triggered by alcohol, tea, coffee, excitement, stress, fatigue, or can be spontaneous. The onset of these episodes is typically in early childhood or early teens but can be as late as 50 years old. They can range from minutes to hours, but rarely occur more than once a day.
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Symptoms of PRRT2-Associated Paroxysmal Movement Disorders. paroxysmal kinesigenic dyskinesia (PKD)
The primary movement disorder associated with PRRT2 is paroxysmal kinesigenic dyskinesia (PKD). This is the most common type of paroxysmal dyskinesia. PKD attacks often occur in childhood and are thought to be induced by sudden movements, which can include being startled, going from walking to running, stress, or rapid, deep breathing (hyperventilation). Around 10% of people report having a warning sign of numbness or paresthesia in the limbs or face prior to the attack. It is often described as a crawling sensation in the affected areas. The attacks are characterized by abnormal muscle contraction (dystonia) and episodes of unwanted, uncontrollable movements, often of the muscles in the arms, legs, face and body (choreoathetosis). Additionally, patients can sometimes have irregular, frequently violent movements of the shoulder and arm while awake (ballism). Most attacks are brief, lasting only a few seconds to a minute, but some have been reported to last for as long as five minutes. There is significant variability in the frequency of attacks ranging from one per week to 100 per day. The average age of onset for PKD is 10 years old but can range from 1-20 years old, with attacks becoming less frequent with age. Common triggers for episodes are stress, sleep deprivation, fevers, and anxiety. Avoiding these in conjunction with specific medications can help reduce the number of episodes a patient experiences.hemiplegic migraine
Hemiplegic migraines are a rare type of migraine headache with sensory symptoms called aura that can include flashes of light, blind spots, or tingling. This can cause temporary paralysis on one side of the body. They are often accompanied by other neurological symptoms such as visual disturbances, confusion and difficulty speaking. Common triggers for hemiplegic migraines are stress, anxiety, heat or light. The age of onset for hemiplegic migraines can be as early as late childhood but are more commonly seen during puberty or early adulthood. It also has a range of frequency with some reporting as many as a few per week to only one per month. The duration of the migraine attacks also varies greatly from only fifteen minutes to three days. Individuals report that the frequency of migraines decreases over time with many claiming complete remission during adulthood. It has also been documented that there is improvement of hemiplegic migraines during pregnancy.benign infantile epilepsy
Benign familial infantile seizures (BFIS) are a rare form of epilepsy that typically begin during the first twelve months of life in otherwise healthy children. This condition is characterized by sudden jerking movements, eye deviation, or staring spells and are often triggered by excitement or fever. These seizures are characterized as self-limiting, meaning they stop on their own without intervention and are not known to cause any long-term neurological damage. Because of this, treatment is not typically required. Many times, the seizures diminish greatly or completely resolve by early childhood.Less Common Signs and Symptomsepisodic ataxia
Episodic ataxia is a neurological disorder characterized by recurrent episodes of unsteadiness and lack of coordination that vary in duration. Additional symptoms that can be seen are progressive, weakness between episodes (inter-attack weakness), dystonia and unbalanced walking (ataxia). Often these symptoms are due to differences in the cerebellum, the part of the brain that controls balance for walking and standing. Triggers that have been well documented for episodes of ataxia include stress, caffeine, hormonal changes and fatigue. The mechanism that causes the episodes is unknown. It has been noted that symptoms sometimes go away on their own or the severity lessens.paroxysmal torticollis
Paroxysmal torticollis is a rare condition in which there are recurrent episodes of head tilting associated with irritability, vomiting, hypotonia, malaise (discomfort) and/or pallor (pale appearance). Onset begins in infancy and typically resolves between two to five years of age with the frequency being two to three times a month, but lessens as the child ages. The episodes typically last around ten minutes, but they have been reported to last as long as two months. It has been proposed that an episode is a precursor for migraines in older children. There is currently no specific treatment for this condition. Many families have used over-the-counter pain and nausea medication to aid in treating with varying degrees of success.familial paroxysmal non-kinesigenic dyskinesia
Familial paroxysmal non-kinesigenic dyskinesia is a condition where there are unilateral or bilateral involuntary movements. Typically, episodes are triggered by alcohol, tea, coffee, excitement, stress, fatigue, or can be spontaneous. The onset of these episodes is typically in early childhood or early teens but can be as late as 50 years old. They can range from minutes to hours, but rarely occur more than once a day.
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Causes of PRRT2-Associated Paroxysmal Movement Disorders
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PRRT2-associated paroxysmal movement disorders are caused by changes (pathogenic variants or mutations) in the PRRT2 gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working in the body. Depending on the function of the protein, it can affect many parts of the body. The PRRT2 gene provides instructions for a protein involved in the release of neurotransmitters (chemical messengers) in the brain. The neurotransmitters are needed for proper communication from the brain to the rest of the body. Genetic changes in PRRT2 lead to abnormally short PRRT2 protein that causes an imbalance in neurotransmitter levels and causes the communication in the brain to not work properly leading to medical problems. The PRRT2 gene holds instructions for creating (encoding) the protein named proline-rich transmembrane protein 2. It is involved in synaptic transmission. Currently, there are more than 90 pathogenic variants reported with c.649dup (p.R217Pfs*8) being the pathogenic variant present in 80% of affected individuals. Most of the known pathogenic variants are nonsense or frameshift variants that lead to truncation of the protein (creating a shorter or smaller protein).
Additionally, there have been patients identified with a 16p11.2 microdeletion. This is a deletion on the 16th chromosome that includes PRRT2 in addition to other neighboring genes. This happens in less than 1% of affected individuals. Similarly, homozygous PRRT2 pathogenic variants (people with two genetic changes, one in each of their two copies of PRRT2) occurs less than 1% of time and typically causes more severely affected individuals. PRRT2-associated paroxysmal movement disorders follow an autosomal dominant pattern of inheritance. This means that an individual only needs a single pathogenic variant (referred to also as heterozygous) in the PRRT2 gene to cause medical problems. The non-working gene can be inherited from either parent or can be the result of a new genetic change in the individual (known as de novo). Approximately 90% of pathogenic variants are inherited from a parent. Males and females have the same level of risk, and the risk of passing a non-working gene to children is 50% for each pregnancy.
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Causes of PRRT2-Associated Paroxysmal Movement Disorders. PRRT2-associated paroxysmal movement disorders are caused by changes (pathogenic variants or mutations) in the PRRT2 gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working in the body. Depending on the function of the protein, it can affect many parts of the body. The PRRT2 gene provides instructions for a protein involved in the release of neurotransmitters (chemical messengers) in the brain. The neurotransmitters are needed for proper communication from the brain to the rest of the body. Genetic changes in PRRT2 lead to abnormally short PRRT2 protein that causes an imbalance in neurotransmitter levels and causes the communication in the brain to not work properly leading to medical problems. The PRRT2 gene holds instructions for creating (encoding) the protein named proline-rich transmembrane protein 2. It is involved in synaptic transmission. Currently, there are more than 90 pathogenic variants reported with c.649dup (p.R217Pfs*8) being the pathogenic variant present in 80% of affected individuals. Most of the known pathogenic variants are nonsense or frameshift variants that lead to truncation of the protein (creating a shorter or smaller protein).
Additionally, there have been patients identified with a 16p11.2 microdeletion. This is a deletion on the 16th chromosome that includes PRRT2 in addition to other neighboring genes. This happens in less than 1% of affected individuals. Similarly, homozygous PRRT2 pathogenic variants (people with two genetic changes, one in each of their two copies of PRRT2) occurs less than 1% of time and typically causes more severely affected individuals. PRRT2-associated paroxysmal movement disorders follow an autosomal dominant pattern of inheritance. This means that an individual only needs a single pathogenic variant (referred to also as heterozygous) in the PRRT2 gene to cause medical problems. The non-working gene can be inherited from either parent or can be the result of a new genetic change in the individual (known as de novo). Approximately 90% of pathogenic variants are inherited from a parent. Males and females have the same level of risk, and the risk of passing a non-working gene to children is 50% for each pregnancy.
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Affects of PRRT2-Associated Paroxysmal Movement Disorders
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In 2015, Ebrahimi-Fakhari, et al reported that there were about 600 individuals with PRRT2-BFIE, 560 with PRRT2-PKD and 210 with PRRT2-PKD/IC. These researchers also estimated that the prevalence of PRRT2-PKD is 1:150,000 individuals. PRRT2-PKD appears to be 1.5-times more common in males than females. However, rare disorders like PRRT2-associated paroxysmal movement disorders often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Affects of PRRT2-Associated Paroxysmal Movement Disorders. In 2015, Ebrahimi-Fakhari, et al reported that there were about 600 individuals with PRRT2-BFIE, 560 with PRRT2-PKD and 210 with PRRT2-PKD/IC. These researchers also estimated that the prevalence of PRRT2-PKD is 1:150,000 individuals. PRRT2-PKD appears to be 1.5-times more common in males than females. However, rare disorders like PRRT2-associated paroxysmal movement disorders often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Related disorders of PRRT2-Associated Paroxysmal Movement Disorders
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Some individuals with PRRT2-associated paroxysmal movement disorders will have paroxysmal dyskinesias similar to what is seen in paroxysmal non-kinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia (PED), GLUT1-deficiency syndrome, Wilson disease and ADCY5-related dyskinesia. Patients may experience paroxysmal ataxia similar to episodic ataxia type 1 and 2. Symptoms of hemiplegia may be indistinguishable from familial hemiplegic migraine, alternating hemiplegia of childhood. Lastly, benign familial neonatal infantile epilepsy or febrile epilepsy can be associated with pathogenic variants (mutations) in various other genes, including KCNQ2, KCNQ3, SCN2A, SCN1A and SCN1B.
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Related disorders of PRRT2-Associated Paroxysmal Movement Disorders. Some individuals with PRRT2-associated paroxysmal movement disorders will have paroxysmal dyskinesias similar to what is seen in paroxysmal non-kinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia (PED), GLUT1-deficiency syndrome, Wilson disease and ADCY5-related dyskinesia. Patients may experience paroxysmal ataxia similar to episodic ataxia type 1 and 2. Symptoms of hemiplegia may be indistinguishable from familial hemiplegic migraine, alternating hemiplegia of childhood. Lastly, benign familial neonatal infantile epilepsy or febrile epilepsy can be associated with pathogenic variants (mutations) in various other genes, including KCNQ2, KCNQ3, SCN2A, SCN1A and SCN1B.
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Diagnosis of PRRT2-Associated Paroxysmal Movement Disorders
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A diagnosis of PRRT2-associated paroxysmal movement disorders is based on molecular genetic testing results that show a disease-causing (pathogenic) variant in the PRRT2 gene. A clinical diagnosis cannot be used for this disorder.
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Diagnosis of PRRT2-Associated Paroxysmal Movement Disorders. A diagnosis of PRRT2-associated paroxysmal movement disorders is based on molecular genetic testing results that show a disease-causing (pathogenic) variant in the PRRT2 gene. A clinical diagnosis cannot be used for this disorder.
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Therapies of PRRT2-Associated Paroxysmal Movement Disorders
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There is currently no cure for PRRT2-associated paroxysmal movement disorders but there have been studies that support specific medication for patients affected with these disorders. Treatment for patients is based on what medical problems are present in a person. Many times, treatment and management can be carried out by a neurologist in addition to a patient’s primary care provider (PCP) or pediatrician. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
PKD and infantile seizures can be treated using antiepileptic drugs (AEDs), with carbamazepine being the most effective and phenytoin, valproate, oxcarbazepine, lamotrigine, levetiracetam, or topiramate being other effective options. If the seizures last longer than five minutes or are in clusters, then individuals often respond well to a class of drugs named benzodiazepines. To reduce the frequency of seizures, it is also important to treat fevers promptly with standard over the counter medication. For PKD, avoiding known triggers such as anxiety, stress, lack of sleep, and others has been shown to be successful in limiting the frequency of attacks. It is recommended that individuals with PKD be monitored by a neurologist every 1-2 years to evaluate medication and dosing.
There is no specific treatment for hemiplegic migraines but can be managed with medications for typical migraines with aura that do not contain agents that could increase the chance of low blood flow to the heart (ischemia). Episodes are mainly treated with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, aspirin and naproxen as well as antiemetics to prevent nausea. There have been some reports that show success with using intranasal ketamine at the onset of an attack.
As for paroxysmal torticollis, there is currently no treatment, but families have used over-the-counter pain and nausea medication to aid in treatment with varying degrees of success. Since it is suspected to be a sign of migraines NSAIDs and antiemetics are used to help treat.
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Therapies of PRRT2-Associated Paroxysmal Movement Disorders. There is currently no cure for PRRT2-associated paroxysmal movement disorders but there have been studies that support specific medication for patients affected with these disorders. Treatment for patients is based on what medical problems are present in a person. Many times, treatment and management can be carried out by a neurologist in addition to a patient’s primary care provider (PCP) or pediatrician. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
PKD and infantile seizures can be treated using antiepileptic drugs (AEDs), with carbamazepine being the most effective and phenytoin, valproate, oxcarbazepine, lamotrigine, levetiracetam, or topiramate being other effective options. If the seizures last longer than five minutes or are in clusters, then individuals often respond well to a class of drugs named benzodiazepines. To reduce the frequency of seizures, it is also important to treat fevers promptly with standard over the counter medication. For PKD, avoiding known triggers such as anxiety, stress, lack of sleep, and others has been shown to be successful in limiting the frequency of attacks. It is recommended that individuals with PKD be monitored by a neurologist every 1-2 years to evaluate medication and dosing.
There is no specific treatment for hemiplegic migraines but can be managed with medications for typical migraines with aura that do not contain agents that could increase the chance of low blood flow to the heart (ischemia). Episodes are mainly treated with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, aspirin and naproxen as well as antiemetics to prevent nausea. There have been some reports that show success with using intranasal ketamine at the onset of an attack.
As for paroxysmal torticollis, there is currently no treatment, but families have used over-the-counter pain and nausea medication to aid in treatment with varying degrees of success. Since it is suspected to be a sign of migraines NSAIDs and antiemetics are used to help treat.
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Overview of Prune Belly Syndrome
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Prune-Belly syndrome, also known as Eagle-Barrett syndrome, is a rare disorder characterized by partial or complete absence of the stomach (abdominal) muscles, failure of both testes to descend into the scrotum (bilateral cryptorchidism), and/or urinary tract malformations. The urinary malformations may include abnormal widening (dilation) of the tubes that bring urine to the bladder (ureters), accumulation of urine in the ureters (hydroureter) and the kidneys (hydronephrosis), and/or backflow of urine from the bladder into the ureters (vesicoureteral reflux). Complications associated with Prune-Belly syndrome may include underdevelopment of the lungs (pulmonary hypoplasia) and/or chronic renal failure. The exact cause of Prune-Belly syndrome is not known.
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Overview of Prune Belly Syndrome. Prune-Belly syndrome, also known as Eagle-Barrett syndrome, is a rare disorder characterized by partial or complete absence of the stomach (abdominal) muscles, failure of both testes to descend into the scrotum (bilateral cryptorchidism), and/or urinary tract malformations. The urinary malformations may include abnormal widening (dilation) of the tubes that bring urine to the bladder (ureters), accumulation of urine in the ureters (hydroureter) and the kidneys (hydronephrosis), and/or backflow of urine from the bladder into the ureters (vesicoureteral reflux). Complications associated with Prune-Belly syndrome may include underdevelopment of the lungs (pulmonary hypoplasia) and/or chronic renal failure. The exact cause of Prune-Belly syndrome is not known.
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Symptoms of Prune Belly Syndrome
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Prune Belly syndrome is characterized by partial absence of some or most abdominal muscles giving rise to a wrinkled or prune-like appearance. Often, the attachments of the muscles to the bones are present, but the muscles diminish in size and thickness over the bladder. The abdomen appears large and lax, the abdominal wall is thin and the intestinal loops can be seen through the thin abdominal wall. Skin folds may radiate from the navel or occur as transverse folds across the abdomen. A midline crease from the navel to pubic area may be present in some cases. The navel may appear as a vertical slit, or as a linear central scar, but it can also appear normal. Sometimes the navel is connected with the bladder through a canal (urachus) or a cyst. The chest is often deformed. Flaring of the rib margins or a horizontal depression under the chest (Harrison groove) can appear in many children born with Prune Belly Syndrome. Narrowing of the chest in the transverse direction (pigeon breast) may also occur.Enlargement of the bladder is present in almost all cases. Obstruction of the neck of the bladder is the primary problem, resulting in bladder distention and urine retention. The connection between the kidney and bladder (ureter) may be abnormal; the opening between ureter and bladder may be narrowed or closed. Obstruction may also occur at the junction of the ureter and kidney. Usually, the ureters are greatly widened. Occasionally this enlargement occurs only on one side or decreases as the ureter nears the bladder. Distention of the kidney with urine (hydronephrosis), on one or both sides, may also occur. In some cases, hydronephrosis occurs on one side while the kidney is underdeveloped on the other side. Kidney cysts may also be present. The canal that carries urine from the bladder to the outside of the body (urethra) usually is unobstructed. In males, absence of an opening (atresia) in the urethra, folds acting as valves below the entrance of the semen and prostate ducts (verumontanum), compression by a pouch and overdevelopment of the prostatic urethra also have been noted in some cases.Musculoskeletal abnormalities, especially club foot, are present in about 20% of cases, while cardiovascular abnormalities are seen in about 10% of cases.Blood and pus in the urine (hematuria and pyuria) often signal infection. Undescended testes (cryptorchidism) and testes that may be attached to a ureter, often occur in males with Prune Belly syndrome. Abnormal fixation of the gastrointestinal tract and failure to rotate during fetal development (malrotation) have also been described in the medical literature.
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Symptoms of Prune Belly Syndrome. Prune Belly syndrome is characterized by partial absence of some or most abdominal muscles giving rise to a wrinkled or prune-like appearance. Often, the attachments of the muscles to the bones are present, but the muscles diminish in size and thickness over the bladder. The abdomen appears large and lax, the abdominal wall is thin and the intestinal loops can be seen through the thin abdominal wall. Skin folds may radiate from the navel or occur as transverse folds across the abdomen. A midline crease from the navel to pubic area may be present in some cases. The navel may appear as a vertical slit, or as a linear central scar, but it can also appear normal. Sometimes the navel is connected with the bladder through a canal (urachus) or a cyst. The chest is often deformed. Flaring of the rib margins or a horizontal depression under the chest (Harrison groove) can appear in many children born with Prune Belly Syndrome. Narrowing of the chest in the transverse direction (pigeon breast) may also occur.Enlargement of the bladder is present in almost all cases. Obstruction of the neck of the bladder is the primary problem, resulting in bladder distention and urine retention. The connection between the kidney and bladder (ureter) may be abnormal; the opening between ureter and bladder may be narrowed or closed. Obstruction may also occur at the junction of the ureter and kidney. Usually, the ureters are greatly widened. Occasionally this enlargement occurs only on one side or decreases as the ureter nears the bladder. Distention of the kidney with urine (hydronephrosis), on one or both sides, may also occur. In some cases, hydronephrosis occurs on one side while the kidney is underdeveloped on the other side. Kidney cysts may also be present. The canal that carries urine from the bladder to the outside of the body (urethra) usually is unobstructed. In males, absence of an opening (atresia) in the urethra, folds acting as valves below the entrance of the semen and prostate ducts (verumontanum), compression by a pouch and overdevelopment of the prostatic urethra also have been noted in some cases.Musculoskeletal abnormalities, especially club foot, are present in about 20% of cases, while cardiovascular abnormalities are seen in about 10% of cases.Blood and pus in the urine (hematuria and pyuria) often signal infection. Undescended testes (cryptorchidism) and testes that may be attached to a ureter, often occur in males with Prune Belly syndrome. Abnormal fixation of the gastrointestinal tract and failure to rotate during fetal development (malrotation) have also been described in the medical literature.
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Causes of Prune Belly Syndrome
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The exact cause of Prune Belly syndrome is unknown. There are several theories.It may be caused by an abnormality in the bladder during fetal development. Accumulation of urine can distend the bladder, the ureters, and the kidney. As the bladder enlarges, it causes wasting (atrophy) of the abdominal muscles. Retention of the testes in the abdomen (cryptorchidism) may be attributed to obstruction by an unusually large bladder or to obliteration of the groin (inguinal) canals. By the time of birth, the obstruction at the bladder outlet or the urethral obstruction may have been resolved, so that no mechanical obstacle can be identified after birth.Other researchers consider the urinary abnormalities as secondary to the incomplete development of abdominal muscles. Incomplete emptying of the bladder leading to urinary retention and infection can occur as a result. Constipation and symptoms of indigestion are additional possible complications. Since the abdominal muscles are important for respiration, deformity of the chest could be explained by their absence.A third possibility is that the muscle deficiency and the urinary abnormalities have a common cause that has not yet been discovered. A nervous system defect that could be responsible for early malfunction of abdominal muscles may be the cause. Association with a congenital open spinal canal (spina bifida) has been identified in some children, and the presence of clubfeet is also fairly commonly associated with Prune Belly syndrome.
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Causes of Prune Belly Syndrome. The exact cause of Prune Belly syndrome is unknown. There are several theories.It may be caused by an abnormality in the bladder during fetal development. Accumulation of urine can distend the bladder, the ureters, and the kidney. As the bladder enlarges, it causes wasting (atrophy) of the abdominal muscles. Retention of the testes in the abdomen (cryptorchidism) may be attributed to obstruction by an unusually large bladder or to obliteration of the groin (inguinal) canals. By the time of birth, the obstruction at the bladder outlet or the urethral obstruction may have been resolved, so that no mechanical obstacle can be identified after birth.Other researchers consider the urinary abnormalities as secondary to the incomplete development of abdominal muscles. Incomplete emptying of the bladder leading to urinary retention and infection can occur as a result. Constipation and symptoms of indigestion are additional possible complications. Since the abdominal muscles are important for respiration, deformity of the chest could be explained by their absence.A third possibility is that the muscle deficiency and the urinary abnormalities have a common cause that has not yet been discovered. A nervous system defect that could be responsible for early malfunction of abdominal muscles may be the cause. Association with a congenital open spinal canal (spina bifida) has been identified in some children, and the presence of clubfeet is also fairly commonly associated with Prune Belly syndrome.
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Affects of Prune Belly Syndrome
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Prune Belly syndrome is a very rare disorder that is present at birth. The disorder affects mostly males but a few female cases have been described in the medical literature.
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Affects of Prune Belly Syndrome. Prune Belly syndrome is a very rare disorder that is present at birth. The disorder affects mostly males but a few female cases have been described in the medical literature.
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Related disorders of Prune Belly Syndrome
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Related disorders of Prune Belly Syndrome.
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Diagnosis of Prune Belly Syndrome
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The diagnosis is usually obvious from birth, but care and time are required to determine the location and number of abnormalities. A full understanding of the complications will involve imaging tests such as ultrasound, X-ray, and, in order to determine the extent of involvement of the genitourinary tract, intravenous pyelogram (IVP). An IVP makes use of a dye to map the degree of involvement of the kidneys and their ducts.
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Diagnosis of Prune Belly Syndrome. The diagnosis is usually obvious from birth, but care and time are required to determine the location and number of abnormalities. A full understanding of the complications will involve imaging tests such as ultrasound, X-ray, and, in order to determine the extent of involvement of the genitourinary tract, intravenous pyelogram (IVP). An IVP makes use of a dye to map the degree of involvement of the kidneys and their ducts.
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Therapies of Prune Belly Syndrome
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TreatmentTreatment will depend upon the severity of the symptoms. Some children will require rather modest surgical procedures such as the creation of a small opening in the bladder through the abdomen (vesicostomy) that will facilitate voiding of urine, or a procedure to help the testicles descend into the scrotum (orchiopexy). More extensive surgical procedures such a. bladder reconstruction (cystoplasty), surgical widening of the urethra, and augmentation of the muscles that contract the bladder (detrusor augmentation) using a paired graft of a hip muscle (rectus femoris) have been successfully undertaken on children with prune belly syndrome. In rare cases, kidney transplantation may be necessary.
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Therapies of Prune Belly Syndrome. TreatmentTreatment will depend upon the severity of the symptoms. Some children will require rather modest surgical procedures such as the creation of a small opening in the bladder through the abdomen (vesicostomy) that will facilitate voiding of urine, or a procedure to help the testicles descend into the scrotum (orchiopexy). More extensive surgical procedures such a. bladder reconstruction (cystoplasty), surgical widening of the urethra, and augmentation of the muscles that contract the bladder (detrusor augmentation) using a paired graft of a hip muscle (rectus femoris) have been successfully undertaken on children with prune belly syndrome. In rare cases, kidney transplantation may be necessary.
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Overview of Prurigo Nodularis
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SummaryPrurigo nodularis (PN) is a chronic inflammatory skin disease where an extremely itchy, symmetrically distributed rash appears most commonly on the arms, legs, the upper back and/or the abdomen. The itch associated with PN is so severe that it often interferes with sleep and psychological wellbeing. PN can appear on its own or be associated with other skin diseases or underlying medical conditions that affect multiple body systems, such as cancer, diabetes, chronic kidney disease or AIDS. The exact cause of PN is unknown, but altered function of the immune system and nerves in the skin is believed to be associated with heightened sensations of itchiness (pruritus) that leads to frequent scratching. Frequent scratching and picking of the skin is also thought to contribute to further lesion thickening and formation seen in the disease. PN can occur at any age but is more common in the elderly. When PN occurs in younger patients, it is more likely to be associated with inflammatory skin diseases, usually eczema (also called atopic dermatitis). Diagnosis is usually made by a dermatologist based on clinical symptoms and response to medications, but microscopic examination of a skin biopsy can aid in confirming the diagnosis. Although no FDA-approved treatments for PN currently exist, treatments used for other skin disorders ranging from topical creams to medications that alter the immune response are sometimes prescribed for patients with PN.
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Overview of Prurigo Nodularis. SummaryPrurigo nodularis (PN) is a chronic inflammatory skin disease where an extremely itchy, symmetrically distributed rash appears most commonly on the arms, legs, the upper back and/or the abdomen. The itch associated with PN is so severe that it often interferes with sleep and psychological wellbeing. PN can appear on its own or be associated with other skin diseases or underlying medical conditions that affect multiple body systems, such as cancer, diabetes, chronic kidney disease or AIDS. The exact cause of PN is unknown, but altered function of the immune system and nerves in the skin is believed to be associated with heightened sensations of itchiness (pruritus) that leads to frequent scratching. Frequent scratching and picking of the skin is also thought to contribute to further lesion thickening and formation seen in the disease. PN can occur at any age but is more common in the elderly. When PN occurs in younger patients, it is more likely to be associated with inflammatory skin diseases, usually eczema (also called atopic dermatitis). Diagnosis is usually made by a dermatologist based on clinical symptoms and response to medications, but microscopic examination of a skin biopsy can aid in confirming the diagnosis. Although no FDA-approved treatments for PN currently exist, treatments used for other skin disorders ranging from topical creams to medications that alter the immune response are sometimes prescribed for patients with PN.
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Symptoms of Prurigo Nodularis
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The rash associated with prurigo nodularis varies in appearance from patient to patient and is thought to occur from excessive, chronic scratching and picking due to sensations of intense itchiness (pruritus), burning and stinging. Pruritus associated with PN is usually severe; occurs in episodes but can be continuous; and is chronic, lasting longer than 6 weeks. It is typically worsened by sweat, heat, clothing, and stress.The rash can range in severity from just a few to several hundred lesions and lesions can range in size from a half centimeter to 2 centimeters wide. Lesions are usually symmetrical in distribution and can appear as firm, dome-shaped papules, nodules or plaques. Papules, nodules and plaques vary by width and depth in the skin layers. A papule is less than 1 cm in diameter and elevated above the skin surface; nodules are greater than 1 cm in diameter, extend into the dermis (skin layer beneath the top layer of the skin, the epidermis) and can be above, below, or level with the skin surface; plaques are elevated lesions greater than 1 cm in diameter and are broader than they are deep.Skin areas affected by PN become thickened (hyperkeratotic) as the protein keratin that makes up skin becomes overly abundant, similar to what happens with the formation of corns and calluses and dry and leathery (lichenified) as is seen in other skin conditions such as eczema where skin is repeatedly scratched. Lesions can be flesh-colored, pink, red, brown or black. Complications can occur if lesions become infected by bacteria. Healed lesions may leave scars and discolored marks.Lesions are most commonly found on the back of the scalp, trunk of the body (abdomen and upper and lower back) and on the arms and legs. The central back is usually lesion-free, presumably because this area cannot be easily scratched to contribute to lesion formation.Symptoms of PN require medical treatment and lesions rarely disappear spontaneously without treatment.
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Symptoms of Prurigo Nodularis. The rash associated with prurigo nodularis varies in appearance from patient to patient and is thought to occur from excessive, chronic scratching and picking due to sensations of intense itchiness (pruritus), burning and stinging. Pruritus associated with PN is usually severe; occurs in episodes but can be continuous; and is chronic, lasting longer than 6 weeks. It is typically worsened by sweat, heat, clothing, and stress.The rash can range in severity from just a few to several hundred lesions and lesions can range in size from a half centimeter to 2 centimeters wide. Lesions are usually symmetrical in distribution and can appear as firm, dome-shaped papules, nodules or plaques. Papules, nodules and plaques vary by width and depth in the skin layers. A papule is less than 1 cm in diameter and elevated above the skin surface; nodules are greater than 1 cm in diameter, extend into the dermis (skin layer beneath the top layer of the skin, the epidermis) and can be above, below, or level with the skin surface; plaques are elevated lesions greater than 1 cm in diameter and are broader than they are deep.Skin areas affected by PN become thickened (hyperkeratotic) as the protein keratin that makes up skin becomes overly abundant, similar to what happens with the formation of corns and calluses and dry and leathery (lichenified) as is seen in other skin conditions such as eczema where skin is repeatedly scratched. Lesions can be flesh-colored, pink, red, brown or black. Complications can occur if lesions become infected by bacteria. Healed lesions may leave scars and discolored marks.Lesions are most commonly found on the back of the scalp, trunk of the body (abdomen and upper and lower back) and on the arms and legs. The central back is usually lesion-free, presumably because this area cannot be easily scratched to contribute to lesion formation.Symptoms of PN require medical treatment and lesions rarely disappear spontaneously without treatment.
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Causes of Prurigo Nodularis
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Although the exact cause of prurigo nodularis is not known, symptoms are thought to stem from dysregulation of the nerves and immune system in the skin.Skin layers from top to bottom include the epidermis and dermis and both contain nerve fibers. Microscopic examination of skin biopsies in areas with and without lesions in PN patients has revealed a reduced number of nerve fibers in the epidermis but an increased number in the dermis. However, it is unknown if these changes in nerve fiber density are a cause or an effect of chronic scratching of the skin. With successful treatment of pruritus, skin nerve fiber density returns to normal. Another important finding in PN skin that distinguishes it from similar appearing skin diseases is an increase in structures important for skin sensation: Merkel cells, a special type of nerve cell, in the epidermis and papillary dermal nerves in the dermis.Compared to healthy patients, the skin of PN patients also has more immune cells that produce chemicals called cytokines that are involved in inflammatory responses that may contribute to increased itchiness. These cytokines include interleukin-4, -13 and -31 and are targeted by some medications currently used and being developed to treat PN. Increased release of substance P; vanilloid receptor subtype 1; and calcitonin-related gene peptide, proteins from skin nerves, is also believed to contribute to the pruritus of PN. Other alterations to the skin environment include an increased number of neutrophils and mast cells that release histamine and increased activity from eosinophils. The latter two types of immune cells are best known for their involvement in allergic reactions and eczema.Prurigo nodularis can occur on its own or can be associated with other skin diseases (dermatoses) or with infections, systemic diseases, neurological conditions or psychiatric conditions. The severity and outcome of PN are not predicted by the underlying cause.PN is most often found in patients with other skin diseases that are typically pruritic, including atopic dermatitis (eczema), cutaneous T-cell lymphoma, lichen planus, xerosis cutis, keratoacanthomas and bullous pemphigoid.Infections associated with PN include bacterial infections with tuberculosis, mucogenicum and H. pylori; viral infection with herpes zoster and hepatitis C; and parasitic infections with ascaris and strongyloidiasis.Systemic diseases that PN can be associated with include: HIV; kidney disease; liver disease; thyroid disease; hyperparathyroidism; hyperpituitarism; diabetes; gout; iron deficiency anemia; celiac disease; polycythemia vera; amyloidosis; and certain cancers, especially blood precancers (myelodysplasia, MGUS) and blood cancers (leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, primary cutaneous lymphoma), liver cancer, skin cancer, bladder cancer, lung cancer and cancers of the GI tract and female reproductive organs. Proper treatment of systemic and infectious causes may cure PN in some but not all cases.Neurological causes of PN are related to damage to the brain and spinal cord (less typically) or to the area of the nervous system throughout the rest of the body outside of the brain and spinal cord (more typically). Neurological conditions associated with PN include nerve damage from herpes or shingles infections, polyneuropathies, brachioradial pruritus, notalgia paresthetica, small fiber neuropathies, sensitive skin and post-burn itch.Psychiatric causes of PN include psychogenic pruritus. Psychogenic pruritus is an itching sensation associated with depression, anxiety, and dissociative disorders that lead to excessive scratching that can then lead to the skin changes associated with PN.Some medications may also cause PN. These include the chemotherapy agents pembrolizumab, paclitaxel, and carboplatin. PN in these cases is thought to be from prolonged activation of the immune system post-treatment.
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Causes of Prurigo Nodularis. Although the exact cause of prurigo nodularis is not known, symptoms are thought to stem from dysregulation of the nerves and immune system in the skin.Skin layers from top to bottom include the epidermis and dermis and both contain nerve fibers. Microscopic examination of skin biopsies in areas with and without lesions in PN patients has revealed a reduced number of nerve fibers in the epidermis but an increased number in the dermis. However, it is unknown if these changes in nerve fiber density are a cause or an effect of chronic scratching of the skin. With successful treatment of pruritus, skin nerve fiber density returns to normal. Another important finding in PN skin that distinguishes it from similar appearing skin diseases is an increase in structures important for skin sensation: Merkel cells, a special type of nerve cell, in the epidermis and papillary dermal nerves in the dermis.Compared to healthy patients, the skin of PN patients also has more immune cells that produce chemicals called cytokines that are involved in inflammatory responses that may contribute to increased itchiness. These cytokines include interleukin-4, -13 and -31 and are targeted by some medications currently used and being developed to treat PN. Increased release of substance P; vanilloid receptor subtype 1; and calcitonin-related gene peptide, proteins from skin nerves, is also believed to contribute to the pruritus of PN. Other alterations to the skin environment include an increased number of neutrophils and mast cells that release histamine and increased activity from eosinophils. The latter two types of immune cells are best known for their involvement in allergic reactions and eczema.Prurigo nodularis can occur on its own or can be associated with other skin diseases (dermatoses) or with infections, systemic diseases, neurological conditions or psychiatric conditions. The severity and outcome of PN are not predicted by the underlying cause.PN is most often found in patients with other skin diseases that are typically pruritic, including atopic dermatitis (eczema), cutaneous T-cell lymphoma, lichen planus, xerosis cutis, keratoacanthomas and bullous pemphigoid.Infections associated with PN include bacterial infections with tuberculosis, mucogenicum and H. pylori; viral infection with herpes zoster and hepatitis C; and parasitic infections with ascaris and strongyloidiasis.Systemic diseases that PN can be associated with include: HIV; kidney disease; liver disease; thyroid disease; hyperparathyroidism; hyperpituitarism; diabetes; gout; iron deficiency anemia; celiac disease; polycythemia vera; amyloidosis; and certain cancers, especially blood precancers (myelodysplasia, MGUS) and blood cancers (leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, primary cutaneous lymphoma), liver cancer, skin cancer, bladder cancer, lung cancer and cancers of the GI tract and female reproductive organs. Proper treatment of systemic and infectious causes may cure PN in some but not all cases.Neurological causes of PN are related to damage to the brain and spinal cord (less typically) or to the area of the nervous system throughout the rest of the body outside of the brain and spinal cord (more typically). Neurological conditions associated with PN include nerve damage from herpes or shingles infections, polyneuropathies, brachioradial pruritus, notalgia paresthetica, small fiber neuropathies, sensitive skin and post-burn itch.Psychiatric causes of PN include psychogenic pruritus. Psychogenic pruritus is an itching sensation associated with depression, anxiety, and dissociative disorders that lead to excessive scratching that can then lead to the skin changes associated with PN.Some medications may also cause PN. These include the chemotherapy agents pembrolizumab, paclitaxel, and carboplatin. PN in these cases is thought to be from prolonged activation of the immune system post-treatment.
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Affects of Prurigo Nodularis
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The number of new cases of PN per year (incidence) in the US is estimated to be 72 per 100,000 people, or 87,634 people a year in people aged 18 to 64 years old. PN is more common in the elderly, and in women (54.2%) compared to men (45.5%), with women experiencing more severe pruritus. While PN can occur at any age, it is more likely to occur between ages 40 to 69 years old. Younger patients with PN are more likely to have other skin disorders associated with allergic states, such as eczema. PN is 3.4 times more common in African Americans. It is more prevalent among patients with HIV infection.
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Affects of Prurigo Nodularis. The number of new cases of PN per year (incidence) in the US is estimated to be 72 per 100,000 people, or 87,634 people a year in people aged 18 to 64 years old. PN is more common in the elderly, and in women (54.2%) compared to men (45.5%), with women experiencing more severe pruritus. While PN can occur at any age, it is more likely to occur between ages 40 to 69 years old. Younger patients with PN are more likely to have other skin disorders associated with allergic states, such as eczema. PN is 3.4 times more common in African Americans. It is more prevalent among patients with HIV infection.
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Related disorders of Prurigo Nodularis
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PN is typically diagnosed based on clinical symptoms. Due to this and symptom overlap with other conditions that cause severe, chronic pruritus, PN can be mistaken for other skin diseases and can co-occur with some of them as well. These include:Pemphigoid nodularis – a rare type of autoimmune disease and variant of the disease bullous pemphigoid where fluid-filled blisters form on the skin of the arms and legs, usually in the elderly. Unlike PN, pemphigoid nodularis may go away on its own after several months to years.Actinic prurigo – a skin condition typically affecting girls where itchy papules and nodules appear after the skin has been exposed to the sun, usually on the upper extremities, face and neck. It typically begins in the spring and persists through the winter.Epidermolysis bullosa – a genetic skin disorder that normally appears in childhood that is characterized clinically by blister formation from mechanical trauma or friction against the skin.Lichen simplex chronicus (neurodermatitis) – a common type of eczema confined to one to two patches of skin that worsens with continued scratching.Lichen amyloidosis – a subtype of primary localized cutaneous amyloidosis where papules appear on the shins and forearms as a result of abnormal protein deposits in the skin due to altered protein metabolism.Hypertrophic lichen planus – a rare, chronic, inflammatory autoimmune skin and mucous membrane disease. Lichen planus (LP) most commonly presents as itchy, shiny, reddish-purple spots (lesions) on the skin (cutaneous LP) or as white-gray lesions in the mouth or on the lips (oral LP). Less commonly, LP may also involve the genitals (penile or vulvar LP), scalp (lichen planopilaris), ears (otic LP), nails, eyes and esophagus. Similar to lichen found growing on trees and rocks in forests, the skin lesions are often flat-topped and can be somewhat scaly, hence the name “lichen” planus. HLP in particular is the most common mimicker of PN.Dermatillomania –a mental condition related to obsessive compulsive disorder (OCD) where lesions form after chronic skin-picking, and picking may occur up to several hours a day.Nodular scabies – skin nodules that appear after infection with and treatment for the skin mite scabies. Nodular scabies is thought in some cases to be a persistent reaction to remaining mite parts in the skin. It consists of itchy nodules usually found in the groin and armpit and occurs in about 7% of scabies infections.Lupus erythematosus – an autoimmune condition that can affect multiple organs and body systems including the skin. Some cases of lupus are isolated to the skin, most commonly discoid lupus erythematosus (DLE), and some rashes associated with lupus can resemble PN. These PN-resembling lupus rashes are distinct from the cardinal butterfly lupus-associated rash occurring outside of the face and characterized by thick and scaly patches that can itch.Multiple keratoacanthomas – skin tumors from hair follicles that appear as nodules lined with blood vessels and a keratin plug. They may be associated with Muir-Torre syndrome, a rare inherited cancer syndrome where a rash of many of these skin growths occurs alongside an organ-specific cancer, usually colorectal cancer. Keratoacanthomas grow rapidly within days to weeks and cause scarring. They're usually found on sun-exposed skin.Atopic dermatitis – the most common type of eczema that's chronic and caused by an overactive immune system that damages the skin barrier to cause dryness, itching, rashes and increased susceptibility to skin infections. It typically begins in childhood and is associated with other allergic conditions like asthma and hay fever.Psoriasis vulgaris – an inflammatory, chronic skin condition and most common type of psoriasis characterized by red, raised skin plaques with white, shiny scales that can appear in multiple skin locations after localized skin trauma or irritation.
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Related disorders of Prurigo Nodularis. PN is typically diagnosed based on clinical symptoms. Due to this and symptom overlap with other conditions that cause severe, chronic pruritus, PN can be mistaken for other skin diseases and can co-occur with some of them as well. These include:Pemphigoid nodularis – a rare type of autoimmune disease and variant of the disease bullous pemphigoid where fluid-filled blisters form on the skin of the arms and legs, usually in the elderly. Unlike PN, pemphigoid nodularis may go away on its own after several months to years.Actinic prurigo – a skin condition typically affecting girls where itchy papules and nodules appear after the skin has been exposed to the sun, usually on the upper extremities, face and neck. It typically begins in the spring and persists through the winter.Epidermolysis bullosa – a genetic skin disorder that normally appears in childhood that is characterized clinically by blister formation from mechanical trauma or friction against the skin.Lichen simplex chronicus (neurodermatitis) – a common type of eczema confined to one to two patches of skin that worsens with continued scratching.Lichen amyloidosis – a subtype of primary localized cutaneous amyloidosis where papules appear on the shins and forearms as a result of abnormal protein deposits in the skin due to altered protein metabolism.Hypertrophic lichen planus – a rare, chronic, inflammatory autoimmune skin and mucous membrane disease. Lichen planus (LP) most commonly presents as itchy, shiny, reddish-purple spots (lesions) on the skin (cutaneous LP) or as white-gray lesions in the mouth or on the lips (oral LP). Less commonly, LP may also involve the genitals (penile or vulvar LP), scalp (lichen planopilaris), ears (otic LP), nails, eyes and esophagus. Similar to lichen found growing on trees and rocks in forests, the skin lesions are often flat-topped and can be somewhat scaly, hence the name “lichen” planus. HLP in particular is the most common mimicker of PN.Dermatillomania –a mental condition related to obsessive compulsive disorder (OCD) where lesions form after chronic skin-picking, and picking may occur up to several hours a day.Nodular scabies – skin nodules that appear after infection with and treatment for the skin mite scabies. Nodular scabies is thought in some cases to be a persistent reaction to remaining mite parts in the skin. It consists of itchy nodules usually found in the groin and armpit and occurs in about 7% of scabies infections.Lupus erythematosus – an autoimmune condition that can affect multiple organs and body systems including the skin. Some cases of lupus are isolated to the skin, most commonly discoid lupus erythematosus (DLE), and some rashes associated with lupus can resemble PN. These PN-resembling lupus rashes are distinct from the cardinal butterfly lupus-associated rash occurring outside of the face and characterized by thick and scaly patches that can itch.Multiple keratoacanthomas – skin tumors from hair follicles that appear as nodules lined with blood vessels and a keratin plug. They may be associated with Muir-Torre syndrome, a rare inherited cancer syndrome where a rash of many of these skin growths occurs alongside an organ-specific cancer, usually colorectal cancer. Keratoacanthomas grow rapidly within days to weeks and cause scarring. They're usually found on sun-exposed skin.Atopic dermatitis – the most common type of eczema that's chronic and caused by an overactive immune system that damages the skin barrier to cause dryness, itching, rashes and increased susceptibility to skin infections. It typically begins in childhood and is associated with other allergic conditions like asthma and hay fever.Psoriasis vulgaris – an inflammatory, chronic skin condition and most common type of psoriasis characterized by red, raised skin plaques with white, shiny scales that can appear in multiple skin locations after localized skin trauma or irritation.
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Diagnosis of Prurigo Nodularis
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For the best accuracy in diagnosis and to distinguish rashes of PN from similar skin disorders, clinical examination of signs and symptoms by a dermatologist combined with microscopic examination of lesions is recommended. Microscopic examinations include dermoscopy and biopsy, and these two methods combined together provide the best likelihood of an accurate diagnosis. With dermoscopy, dermatologists use a magnifying scope that shines light onto the skin to examine its structure through a portion of the dermis. It is a relatively new exam that was originally used to distinguish between different skin cancers but is now used to diagnose other skin disorders, including inflammatory and infectious ones. It is non-invasive and therefore not painful or likely to cause infection. Biopsy, on the other hand, is simple procedure where portions of the skin are removed with a blade to allow dermatologists to see the skin in greater detail under a microscope.Before microscopic examination, clinical clues alone that lead dermatologists to suspect PN include the distribution of the lesions on specific areas of the trunk and limbs; the physical characteristics of the rash, including darkened color, firmness, and itchiness; and the presence of other diseases that co-occur with PN in some cases.Biopsy of PN lesions reveals thickening of different areas of the outermost layer of the skin (the epidermis) with distinct changes to the skin protein keratin (e.g. hyperkeratosis). The layer below the epidermis, the dermis, shows an increase in several inflammatory white blood cell types, including lymphocytes, mast cells, neutrophils and macrophages. A decreased number of nerve fibers in the epidermis and an increased number in the dermis are also characteristic findings. Appropriate treatment often causes nerve fiber density in both layers to return to normal.Once PN diagnosis is confirmed from clinical and microscopy exams, blood tests including a complete blood cell count (CBC), a comprehensive metabolic panel (CMP) that included liver and kidney function tests, and thyroid hormone panel may be beneficial for diagnosing systemic diseases that may be contributing to the PN diagnosis, especially in patients who have PN without the more commonly associated skin conditions that can co-occur with it. Stool exams for the presence of parasites and HIV testing may also be beneficial when infectious causes of PN are suspected.
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Diagnosis of Prurigo Nodularis. For the best accuracy in diagnosis and to distinguish rashes of PN from similar skin disorders, clinical examination of signs and symptoms by a dermatologist combined with microscopic examination of lesions is recommended. Microscopic examinations include dermoscopy and biopsy, and these two methods combined together provide the best likelihood of an accurate diagnosis. With dermoscopy, dermatologists use a magnifying scope that shines light onto the skin to examine its structure through a portion of the dermis. It is a relatively new exam that was originally used to distinguish between different skin cancers but is now used to diagnose other skin disorders, including inflammatory and infectious ones. It is non-invasive and therefore not painful or likely to cause infection. Biopsy, on the other hand, is simple procedure where portions of the skin are removed with a blade to allow dermatologists to see the skin in greater detail under a microscope.Before microscopic examination, clinical clues alone that lead dermatologists to suspect PN include the distribution of the lesions on specific areas of the trunk and limbs; the physical characteristics of the rash, including darkened color, firmness, and itchiness; and the presence of other diseases that co-occur with PN in some cases.Biopsy of PN lesions reveals thickening of different areas of the outermost layer of the skin (the epidermis) with distinct changes to the skin protein keratin (e.g. hyperkeratosis). The layer below the epidermis, the dermis, shows an increase in several inflammatory white blood cell types, including lymphocytes, mast cells, neutrophils and macrophages. A decreased number of nerve fibers in the epidermis and an increased number in the dermis are also characteristic findings. Appropriate treatment often causes nerve fiber density in both layers to return to normal.Once PN diagnosis is confirmed from clinical and microscopy exams, blood tests including a complete blood cell count (CBC), a comprehensive metabolic panel (CMP) that included liver and kidney function tests, and thyroid hormone panel may be beneficial for diagnosing systemic diseases that may be contributing to the PN diagnosis, especially in patients who have PN without the more commonly associated skin conditions that can co-occur with it. Stool exams for the presence of parasites and HIV testing may also be beneficial when infectious causes of PN are suspected.
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Therapies of Prurigo Nodularis
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Standard treatments for PN are both behavioral and medical. No FDA-approved treatment currently exists for PN, but many medications used to treat other skin disorders or immune dysfunction are used to treat PN.Behavioral treatments for PN include ways to prevent scratching and dryness, such as keeping fingernails short, wearing long sleeves and gloves, bandaging lesions, cleaning skin with gentle cleansers, keeping skin moisturized with non-irritating lotions and avoiding warm environments to reduce sweating. Recommended anti-itch lotions include calamine, menthol and camphor lotions.Topical medications and medications injected directly into lesions (intralesional therapies) are also used for PN. Topical medications include corticosteroids, calcineurin inhibitors, capsaicin (the spicy ingredient in chili peppers) and vitamin D. Intralesional therapies include injected corticosteroids, such as injection with triamcinolone acetonide. The first types of treatment usually prescribed are antihistamines, topical corticosteroids and bandaging of lesions at night to prevent scratching.In 2022, dupilumab (Dupixent) was FDA approved to treat adults with prurigo nodularis. If first-line treatments are not successful, treatments including cryotherapy, phototherapy, and medications that suppress the immune system (immunosuppressants) are used to control symptoms. Cryotherapy is considered an alternative treatment. It involves applying freezing or near-freezing temperatures to the skin to improve the appearance of lesions and relieve itching. Phototherapy uses UVA and/or UVB light to heal lesions faster and reduce pruritus and is suspected to work by decreasing levels of calcitonin-gene related peptide, substance P and histamine released by inflammatory cells. Immunosuppressants are reserved for the most resistant cases of PN because they affect more body systems and can have more serious side effects. Specific immunosuppressants prescribed for PN are cyclosporine, methotrexate, azathioprine, cyclophosphamide and tacrolimus. Intravenous immunoglobulin, while not an immunosuppressant but a treatment for immune-mediated diseases, has also been used in PN. It involves using antibodies from donors to modulate abnormal immune responses. General adverse effects of immunosuppressants include interference with kidney function (nephrotoxicity), liver inflammation, high blood pressure, high potassium levels (hyperkalemia), high uric acid levels (hyperuricemia) and GI symptoms.Other treatments include antidepressants known as selective serotonin reuptake inhibitors (SSRIs); gabapentin, an antiseizure drug that also treats nerve pain; and sedatives, especially if sleeping difficulty from night-time itch occurs. These medications along with psychotherapy and relaxation therapy can help combat the psychological effects of PN as well.
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Therapies of Prurigo Nodularis. Standard treatments for PN are both behavioral and medical. No FDA-approved treatment currently exists for PN, but many medications used to treat other skin disorders or immune dysfunction are used to treat PN.Behavioral treatments for PN include ways to prevent scratching and dryness, such as keeping fingernails short, wearing long sleeves and gloves, bandaging lesions, cleaning skin with gentle cleansers, keeping skin moisturized with non-irritating lotions and avoiding warm environments to reduce sweating. Recommended anti-itch lotions include calamine, menthol and camphor lotions.Topical medications and medications injected directly into lesions (intralesional therapies) are also used for PN. Topical medications include corticosteroids, calcineurin inhibitors, capsaicin (the spicy ingredient in chili peppers) and vitamin D. Intralesional therapies include injected corticosteroids, such as injection with triamcinolone acetonide. The first types of treatment usually prescribed are antihistamines, topical corticosteroids and bandaging of lesions at night to prevent scratching.In 2022, dupilumab (Dupixent) was FDA approved to treat adults with prurigo nodularis. If first-line treatments are not successful, treatments including cryotherapy, phototherapy, and medications that suppress the immune system (immunosuppressants) are used to control symptoms. Cryotherapy is considered an alternative treatment. It involves applying freezing or near-freezing temperatures to the skin to improve the appearance of lesions and relieve itching. Phototherapy uses UVA and/or UVB light to heal lesions faster and reduce pruritus and is suspected to work by decreasing levels of calcitonin-gene related peptide, substance P and histamine released by inflammatory cells. Immunosuppressants are reserved for the most resistant cases of PN because they affect more body systems and can have more serious side effects. Specific immunosuppressants prescribed for PN are cyclosporine, methotrexate, azathioprine, cyclophosphamide and tacrolimus. Intravenous immunoglobulin, while not an immunosuppressant but a treatment for immune-mediated diseases, has also been used in PN. It involves using antibodies from donors to modulate abnormal immune responses. General adverse effects of immunosuppressants include interference with kidney function (nephrotoxicity), liver inflammation, high blood pressure, high potassium levels (hyperkalemia), high uric acid levels (hyperuricemia) and GI symptoms.Other treatments include antidepressants known as selective serotonin reuptake inhibitors (SSRIs); gabapentin, an antiseizure drug that also treats nerve pain; and sedatives, especially if sleeping difficulty from night-time itch occurs. These medications along with psychotherapy and relaxation therapy can help combat the psychological effects of PN as well.
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Overview of Pseudo Hurler Polydystrophy
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Pseudo-Hurler polydystrophy (mucolipidosis type III) is a rare genetic metabolic disorder characterized by a defective enzyme known as UPD-N-acetylglucosamine-1-phosphotransferase. This defective enzyme ultimately results in the accumulation of certain complex carbohydrates (mucopolysaccharides) and fatty substances (mucolipids) in various tissues of the body. The symptoms of this disorder are similar, but less severe than those of I-cell disease (mucolipidosis type II) and may include progressive joint stiffness, curvature of the spine (scoliosis), and/or skeletal deformities of the hands (e.g., claw-hands). Growth delays accompanied by deterioration of the hip joints typically develop in children with pseudo-Hurler polydystrophy. Additional symptoms may include clouding of the corneas of the eyes, mild to moderate coarseness of facial features, mild intellectual disability, easy fatigability, and/or heart disease. Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait.This disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Defective lysosomal enzymes associated with pseudo-Hurler polydystrophy leads to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.
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Overview of Pseudo Hurler Polydystrophy. Pseudo-Hurler polydystrophy (mucolipidosis type III) is a rare genetic metabolic disorder characterized by a defective enzyme known as UPD-N-acetylglucosamine-1-phosphotransferase. This defective enzyme ultimately results in the accumulation of certain complex carbohydrates (mucopolysaccharides) and fatty substances (mucolipids) in various tissues of the body. The symptoms of this disorder are similar, but less severe than those of I-cell disease (mucolipidosis type II) and may include progressive joint stiffness, curvature of the spine (scoliosis), and/or skeletal deformities of the hands (e.g., claw-hands). Growth delays accompanied by deterioration of the hip joints typically develop in children with pseudo-Hurler polydystrophy. Additional symptoms may include clouding of the corneas of the eyes, mild to moderate coarseness of facial features, mild intellectual disability, easy fatigability, and/or heart disease. Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait.This disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Defective lysosomal enzymes associated with pseudo-Hurler polydystrophy leads to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.
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Symptoms of Pseudo Hurler Polydystrophy
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In most cases, children with pseudo-Hurler polydystrophy do not exhibit symptoms until 2-4 years of age. Specific symptoms and rate of progression may vary from case to case although the disorder is often slowly progressive. Initial symptoms may include stiffness of the hands and shoulders. In some cases, claw-like deformities of the hands may occur. These symptoms may progress to cause difficulty with specific tasks (e.g., getting dressed). Eventually, carpal tunnel syndrome may develop. Carpal tunnel syndrome is a neurological disorder characterized by compression of the median nerve, which passes through the carpal tunnel inside the wrist (peripheral nerve entrapment). Symptoms of this disorder affect the hand and wrist and may include pain, numbness, loss of feeling in the fingertips, and/or unusual sensation such as burning or “pins and needles.”Additional symptoms associated with pseudo-Hurler polydystrophy may include side-to-side curvature of the spine (scoliosis), degeneration of the hip, joints that are permanently fixed in a bent or flexed position (contractures), and short stature. Progressive degeneration of the hip and joint contractures may cause difficulty walking or force affected individuals to walk with a characteristic waddling gait. Affected children may also develop coarse facial features, clouding (opacity) of the surface of the eye (cornea), abnormalities affecting the nerve-rich membrane (retina) lining the eyes (mild retinopathy), and irregular curvature of the cornea (hyperopic astigmatism). Although many children with pseudo-Hurler polydystrophy have normal intelligence, some may develop mild intellectual disability or learning disabilities. In some cases, affected children develop aortic insufficiency, a cardiovascular condition in which the aortic valve weakens preventing the valve from shutting and allowing backflow of blood from the major artery of the body (aorta) into one of the chambers of the heart (left ventricle). Symptoms of aortic insufficiency may include palpitations, fatigue, shortness of breath, and chest pain.
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Symptoms of Pseudo Hurler Polydystrophy. In most cases, children with pseudo-Hurler polydystrophy do not exhibit symptoms until 2-4 years of age. Specific symptoms and rate of progression may vary from case to case although the disorder is often slowly progressive. Initial symptoms may include stiffness of the hands and shoulders. In some cases, claw-like deformities of the hands may occur. These symptoms may progress to cause difficulty with specific tasks (e.g., getting dressed). Eventually, carpal tunnel syndrome may develop. Carpal tunnel syndrome is a neurological disorder characterized by compression of the median nerve, which passes through the carpal tunnel inside the wrist (peripheral nerve entrapment). Symptoms of this disorder affect the hand and wrist and may include pain, numbness, loss of feeling in the fingertips, and/or unusual sensation such as burning or “pins and needles.”Additional symptoms associated with pseudo-Hurler polydystrophy may include side-to-side curvature of the spine (scoliosis), degeneration of the hip, joints that are permanently fixed in a bent or flexed position (contractures), and short stature. Progressive degeneration of the hip and joint contractures may cause difficulty walking or force affected individuals to walk with a characteristic waddling gait. Affected children may also develop coarse facial features, clouding (opacity) of the surface of the eye (cornea), abnormalities affecting the nerve-rich membrane (retina) lining the eyes (mild retinopathy), and irregular curvature of the cornea (hyperopic astigmatism). Although many children with pseudo-Hurler polydystrophy have normal intelligence, some may develop mild intellectual disability or learning disabilities. In some cases, affected children develop aortic insufficiency, a cardiovascular condition in which the aortic valve weakens preventing the valve from shutting and allowing backflow of blood from the major artery of the body (aorta) into one of the chambers of the heart (left ventricle). Symptoms of aortic insufficiency may include palpitations, fatigue, shortness of breath, and chest pain.
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nord_1027_2
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Causes of Pseudo Hurler Polydystrophy
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Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. Investigators have determined that pseudo-Hurler polydystrophy is caused by disruption or changes (mutations) in the UDP-N-acetylglucosamine-1-phosphotransferase gene known as GNPTAB located on the long arm of chromosome 4 (4q21-q23). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 4q21-q23” refers to bands 21-23 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Investigators have determined that variant pseudo-Hurler polydystrophy (mucolipidosis IIIC) results from mutations in the GlcNAc-phosphotransferase -subunit gene located on chromosome 16.The symptoms of pseudo-Hurler polydystrophy result from a defective enzyme known as UPD-N-acetylglucosamine-1-phosphotransferase. Due to this defect, certain lysosomal enzymes fail to reach their proper destination (i.e., lysosomes). Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Lysosomal enzymes are mistakenly secreted outside cells resulting in elevated lysosomal enzymes in the serum and fluids of affected individuals. The failure of lysosomal enzymes to reach the lysosomes within cells results in the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells, which, in turn, results in the symptoms of the disorder.
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Causes of Pseudo Hurler Polydystrophy. Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. Investigators have determined that pseudo-Hurler polydystrophy is caused by disruption or changes (mutations) in the UDP-N-acetylglucosamine-1-phosphotransferase gene known as GNPTAB located on the long arm of chromosome 4 (4q21-q23). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 4q21-q23” refers to bands 21-23 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Investigators have determined that variant pseudo-Hurler polydystrophy (mucolipidosis IIIC) results from mutations in the GlcNAc-phosphotransferase -subunit gene located on chromosome 16.The symptoms of pseudo-Hurler polydystrophy result from a defective enzyme known as UPD-N-acetylglucosamine-1-phosphotransferase. Due to this defect, certain lysosomal enzymes fail to reach their proper destination (i.e., lysosomes). Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Lysosomal enzymes are mistakenly secreted outside cells resulting in elevated lysosomal enzymes in the serum and fluids of affected individuals. The failure of lysosomal enzymes to reach the lysosomes within cells results in the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells, which, in turn, results in the symptoms of the disorder.
| 1,027 |
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nord_1027_3
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Affects of Pseudo Hurler Polydystrophy
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Pseudo-Hurler polydystrophy affects males and females in equal numbers. The prevalence of the disorder is unknown. Pseudo-Hurler polydystrophy is often misdiagnosed making it difficult to determine its true frequency in the general population. One estimate places the frequency at 1 in 1 million births. As a group, lysosomal storage diseases are believed to have an estimated frequency of about one in every 5,000 live births. Although the individual diseases are rare, the group together affects many people around the world.
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Affects of Pseudo Hurler Polydystrophy. Pseudo-Hurler polydystrophy affects males and females in equal numbers. The prevalence of the disorder is unknown. Pseudo-Hurler polydystrophy is often misdiagnosed making it difficult to determine its true frequency in the general population. One estimate places the frequency at 1 in 1 million births. As a group, lysosomal storage diseases are believed to have an estimated frequency of about one in every 5,000 live births. Although the individual diseases are rare, the group together affects many people around the world.
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nord_1027_4
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Related disorders of Pseudo Hurler Polydystrophy
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Symptoms of the following disorders can be similar to those of pseudo-Hurler polydystrophy. Comparisons may be useful for a differential diagnosis: Hurler syndrome (mucopolysaccharidosis type 1-H; MPS 1-H) is the most severe form of mucopolysaccharidosis. It is characterized by a deficiency of the enzyme alpha-L-iduronidase, which results in an accumulation of dermatan and heparan sulfates. Symptoms of the disorder first become evident at six months to two years of age. Affected infants may experience developmental delays, recurrent urinary and upper respiratory tract infections, noisy breathing and persistent nasal discharge. Additional physical problems may include clouding of the cornea of the eye, an unusually large tongue, severe deformity of the spine, and joint stiffness. Mental development begins to regress at about the age of two. (For more information on this disorder, choose “Hurler” as your search term in the Rare Disease Database.)Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is characterized by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase. This form of MPS varies greatly among affected individuals. Some affected individuals only experience a few mild symptoms, other develop a more severe form of the disorder. Possible symptoms of Maroteaux-Lamy syndrome include coarse facial features, umbilical hernia, a prominent breastbone (pectus carinatum), joint contractures, clouding of the corneas, and abnormal enlargement of the liver and/or spleen (heptasplenomegaly). Skeletal malformations and heart disease may occur in individuals with this form of MPS. In most cases, intelligence is normal. (For more information on this disorder, choose “Maroteaux-Lamy” as your search term in the Rare Disease Database.) Hunter syndrome, also known as mucopolysaccharidosis II, is a rare inborn error of metabolism characterized by deficiency of an enzyme known as iduronate sulfatase. In individuals with Hunter syndrome, deficiency or improper functioning of this lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (glycosaminoglycans [mucopolysaccharides]) in cells within various bodily tissues, such as the skeleton, joints, brain, spinal cord, heart, spleen, or liver. Initial symptoms and findings associated with Hunter syndrome usually become apparent between ages two to four years. Such abnormalities may include progressive growth delays, resulting in short stature; joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue, and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly). Hunter syndrome is inherited as an X-linked recessive trait. (For more information on this disorder, choose “Hunter” as your search term in the Rare Disease Database.) Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. (For more information on this disorder, choose “lysosomal storage diseases” as your search term in the Rare Disease Database.)
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Related disorders of Pseudo Hurler Polydystrophy. Symptoms of the following disorders can be similar to those of pseudo-Hurler polydystrophy. Comparisons may be useful for a differential diagnosis: Hurler syndrome (mucopolysaccharidosis type 1-H; MPS 1-H) is the most severe form of mucopolysaccharidosis. It is characterized by a deficiency of the enzyme alpha-L-iduronidase, which results in an accumulation of dermatan and heparan sulfates. Symptoms of the disorder first become evident at six months to two years of age. Affected infants may experience developmental delays, recurrent urinary and upper respiratory tract infections, noisy breathing and persistent nasal discharge. Additional physical problems may include clouding of the cornea of the eye, an unusually large tongue, severe deformity of the spine, and joint stiffness. Mental development begins to regress at about the age of two. (For more information on this disorder, choose “Hurler” as your search term in the Rare Disease Database.)Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is characterized by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase. This form of MPS varies greatly among affected individuals. Some affected individuals only experience a few mild symptoms, other develop a more severe form of the disorder. Possible symptoms of Maroteaux-Lamy syndrome include coarse facial features, umbilical hernia, a prominent breastbone (pectus carinatum), joint contractures, clouding of the corneas, and abnormal enlargement of the liver and/or spleen (heptasplenomegaly). Skeletal malformations and heart disease may occur in individuals with this form of MPS. In most cases, intelligence is normal. (For more information on this disorder, choose “Maroteaux-Lamy” as your search term in the Rare Disease Database.) Hunter syndrome, also known as mucopolysaccharidosis II, is a rare inborn error of metabolism characterized by deficiency of an enzyme known as iduronate sulfatase. In individuals with Hunter syndrome, deficiency or improper functioning of this lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (glycosaminoglycans [mucopolysaccharides]) in cells within various bodily tissues, such as the skeleton, joints, brain, spinal cord, heart, spleen, or liver. Initial symptoms and findings associated with Hunter syndrome usually become apparent between ages two to four years. Such abnormalities may include progressive growth delays, resulting in short stature; joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue, and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly). Hunter syndrome is inherited as an X-linked recessive trait. (For more information on this disorder, choose “Hunter” as your search term in the Rare Disease Database.) Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. (For more information on this disorder, choose “lysosomal storage diseases” as your search term in the Rare Disease Database.)
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nord_1027_5
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Diagnosis of Pseudo Hurler Polydystrophy
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A diagnosis of pseudo-Hurler polydystrophy may be suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. A variety of specialized tests may confirm a diagnosis. These tests include detecting elevated lysosomal enzyme activity in serum or decreased enzyme levels in white blood cells or cultured connective tissue cells (fibroblasts).
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Diagnosis of Pseudo Hurler Polydystrophy. A diagnosis of pseudo-Hurler polydystrophy may be suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. A variety of specialized tests may confirm a diagnosis. These tests include detecting elevated lysosomal enzyme activity in serum or decreased enzyme levels in white blood cells or cultured connective tissue cells (fibroblasts).
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Pseudo Hurler Polydystrophy
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nord_1027_6
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Therapies of Pseudo Hurler Polydystrophy
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TreatmentThere is no definitive treatment for pseudo-Hurler polydystrophy. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, cardiologists, eye specialists, and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Surgery may be used to treat a variety of symptoms associated with pseudo-Hurler polydystrophy including carpal tunnel syndrome, skeletal malformations, and degeneration of the hip. Corneal transplantation has been performed with mixed results. Physical therapy and exercise may improve joint stiffness. Heart valve replacement may be necessary in some cases.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Pseudo Hurler Polydystrophy. TreatmentThere is no definitive treatment for pseudo-Hurler polydystrophy. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, cardiologists, eye specialists, and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Surgery may be used to treat a variety of symptoms associated with pseudo-Hurler polydystrophy including carpal tunnel syndrome, skeletal malformations, and degeneration of the hip. Corneal transplantation has been performed with mixed results. Physical therapy and exercise may improve joint stiffness. Heart valve replacement may be necessary in some cases.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Pseudo Hurler Polydystrophy
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nord_1028_0
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Overview of Pseudoachondroplasia
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SummaryPseudoachondroplasia (PSACH) is a short-limbed dwarfing condition characterized by disproportionate short stature, normal facial features and head size, and early onset osteoarthritis; intelligence is normal. There is marked laxity in the fingers, wrists, elbows and knees. Joint pain is common at all ages; osteoarthritis occurs in early adulthood and affects all the joints. Scoliosis or abnormal curvature of the spine and cervical spine instability are complications. Pseudoachondroplasia is caused by a change (mutation) in the cartilage oligomeric matrix protein (COMP) gene and is transmitted in an autosomal dominant pattern. Thirty percent of cases are familial with an affected parent transmitting the condition, while 70% occur as a random, new (de novo) mutation in COMP with no previous family history.IntroductionPseudoachondroplasia was first described in 1959 by Drs. Maroteaux and Lamy and was originally considered to be a type of spondyloepiphyseal dysplasia. It is now classified as a COMPopathy in the category of multiple epiphyseal dysplasia. While four different forms were previously reported based on severity and inheritance pattern in case reports, pseudoachondroplasia is now known to be a single, distinct disorder caused by mutations in the COMP gene.
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Overview of Pseudoachondroplasia. SummaryPseudoachondroplasia (PSACH) is a short-limbed dwarfing condition characterized by disproportionate short stature, normal facial features and head size, and early onset osteoarthritis; intelligence is normal. There is marked laxity in the fingers, wrists, elbows and knees. Joint pain is common at all ages; osteoarthritis occurs in early adulthood and affects all the joints. Scoliosis or abnormal curvature of the spine and cervical spine instability are complications. Pseudoachondroplasia is caused by a change (mutation) in the cartilage oligomeric matrix protein (COMP) gene and is transmitted in an autosomal dominant pattern. Thirty percent of cases are familial with an affected parent transmitting the condition, while 70% occur as a random, new (de novo) mutation in COMP with no previous family history.IntroductionPseudoachondroplasia was first described in 1959 by Drs. Maroteaux and Lamy and was originally considered to be a type of spondyloepiphyseal dysplasia. It is now classified as a COMPopathy in the category of multiple epiphyseal dysplasia. While four different forms were previously reported based on severity and inheritance pattern in case reports, pseudoachondroplasia is now known to be a single, distinct disorder caused by mutations in the COMP gene.
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Pseudoachondroplasia
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nord_1028_1
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Symptoms of Pseudoachondroplasia
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Pseudoachondroplasia shows variable expression with the severity varying within and between families. Infants with pseudoachondroplasia have normal birth parameters and cannot be distinguished from unaffected newborns. Generally, the first sign is diminished linear growth starting between 9 to 12 months first affecting length and eventually height, falling approximately two years behind the standard growth curve. Disproportionate short stature becomes more apparent with age. Affected children usually begin to walk between 12-18 months but gait is abnormal and described as ‘waddling’ reflecting underlying skeletal abnormalities involving the hips. The face has been described as angular. Disproportionate shortening of the arms and legs becomes apparent between 3-5 years of age. The hands and toes are very short, have redundant skin folds and marked joint laxity. Interestingly in contrast, the elbow may have limited extension. Joint laxity at the knees contributes to the lower extremity deformities that range from bowing (genu varum), knock knee (genu valgum) deformities or bowing in one leg and a knock knee deformity in the other called a windswept deformity. Surgical correction is generally required but should be delayed to get maximum sustainable correction.Spinal abnormalities are common and include: 1) scoliosis or S-shaped spinal curve 2) exaggerated lumbar lordosis, which is an abnormal inward curvature of the lower portion of the spine and 3) kyphosis, which is abnormal front-to-back (or outward) curvature of the spine so that the spine is abnormally rounded at the top. Underdevelopment (hypoplasia) of the small, tooth-like projection (odontoid) at the top of the spine can occur. Odontoid hypoplasia causes instability in the neck region (cervical instability), which increases the risk of spinal injury (cervical myelopathy). This complication requires surgical fusion of the upper spine.Pain, a common and universal complaint, starts in early childhood and is exacerbated by exercise. Activities that stress the joints should be avoided including all contact sports and the trampoline. Early joint pain may reflect an inflammatory process related to the underlying chondrocyte pathology. Osteoarthritis in early adulthood is a universal finding usually developing into chronic joint pain (arthralgia) specifically affecting the hips, ankles, shoulder, elbows and wrists. Degenerative joint disease is progressive and ultimately may require surgery starting with hip replacement followed by other joint replacements. Symptomatic treatment with anti-inflammatory medications is used for pain management with varying degrees of success.Final adult height on average is 3’8” (116 cm) for women and 3’9” for men (120 cm) but this can vary as some individuals may attain a height of 4’10”. Intelligence and life expectancy are unaffected and most individuals raise families and lead productive, active and full lives.
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Symptoms of Pseudoachondroplasia. Pseudoachondroplasia shows variable expression with the severity varying within and between families. Infants with pseudoachondroplasia have normal birth parameters and cannot be distinguished from unaffected newborns. Generally, the first sign is diminished linear growth starting between 9 to 12 months first affecting length and eventually height, falling approximately two years behind the standard growth curve. Disproportionate short stature becomes more apparent with age. Affected children usually begin to walk between 12-18 months but gait is abnormal and described as ‘waddling’ reflecting underlying skeletal abnormalities involving the hips. The face has been described as angular. Disproportionate shortening of the arms and legs becomes apparent between 3-5 years of age. The hands and toes are very short, have redundant skin folds and marked joint laxity. Interestingly in contrast, the elbow may have limited extension. Joint laxity at the knees contributes to the lower extremity deformities that range from bowing (genu varum), knock knee (genu valgum) deformities or bowing in one leg and a knock knee deformity in the other called a windswept deformity. Surgical correction is generally required but should be delayed to get maximum sustainable correction.Spinal abnormalities are common and include: 1) scoliosis or S-shaped spinal curve 2) exaggerated lumbar lordosis, which is an abnormal inward curvature of the lower portion of the spine and 3) kyphosis, which is abnormal front-to-back (or outward) curvature of the spine so that the spine is abnormally rounded at the top. Underdevelopment (hypoplasia) of the small, tooth-like projection (odontoid) at the top of the spine can occur. Odontoid hypoplasia causes instability in the neck region (cervical instability), which increases the risk of spinal injury (cervical myelopathy). This complication requires surgical fusion of the upper spine.Pain, a common and universal complaint, starts in early childhood and is exacerbated by exercise. Activities that stress the joints should be avoided including all contact sports and the trampoline. Early joint pain may reflect an inflammatory process related to the underlying chondrocyte pathology. Osteoarthritis in early adulthood is a universal finding usually developing into chronic joint pain (arthralgia) specifically affecting the hips, ankles, shoulder, elbows and wrists. Degenerative joint disease is progressive and ultimately may require surgery starting with hip replacement followed by other joint replacements. Symptomatic treatment with anti-inflammatory medications is used for pain management with varying degrees of success.Final adult height on average is 3’8” (116 cm) for women and 3’9” for men (120 cm) but this can vary as some individuals may attain a height of 4’10”. Intelligence and life expectancy are unaffected and most individuals raise families and lead productive, active and full lives.
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Pseudoachondroplasia
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nord_1028_2
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Causes of Pseudoachondroplasia
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Mutations in the COMP gene cause pseudoachondroplasia. Genes provide instructions for creating proteins that play critical roles in many functions of the body. When a gene mutation 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. COMP mutations specifically affect chondrocytes in the growth centers, which are the cells that specify for linear growth. The articular cartilage at the ends of all the long bones also contains chondrocytes and is easily eroded causing osteoarthritis and painful joints.Approximately 70% of cases occur as a new (sporadic or de novo) mutation, which means that in the majority of cases, the gene mutation occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. In this case, the disorder is usually not inherited from an affected parent. However, once the mutation has occurred, it is transmitted in a dominant pattern from the affected individual to their child. Dominant genetic disorders occur when only a single copy of an abnormal gene is present. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the child.Recurrence was reported in a few families in what appeared to be autosomal recessive inheritance. Mutational analysis revealed that these cases were the result of parental germline mosaicism for a COMP mutation. As a result, one or more of the parent’s children may inherit the germline COMP mutation, leading to pseudoachondroplasia, while the parent does not have this disorder because the mutation is not present in sufficient number of body cells. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation. There is no test for germline mutation prior to pregnancy. Testing during a pregnancy for familial cases with a known mutation is commercially available and should be discussed with a genetic specialist.
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Causes of Pseudoachondroplasia. Mutations in the COMP gene cause pseudoachondroplasia. Genes provide instructions for creating proteins that play critical roles in many functions of the body. When a gene mutation 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. COMP mutations specifically affect chondrocytes in the growth centers, which are the cells that specify for linear growth. The articular cartilage at the ends of all the long bones also contains chondrocytes and is easily eroded causing osteoarthritis and painful joints.Approximately 70% of cases occur as a new (sporadic or de novo) mutation, which means that in the majority of cases, the gene mutation occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. In this case, the disorder is usually not inherited from an affected parent. However, once the mutation has occurred, it is transmitted in a dominant pattern from the affected individual to their child. Dominant genetic disorders occur when only a single copy of an abnormal gene is present. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the child.Recurrence was reported in a few families in what appeared to be autosomal recessive inheritance. Mutational analysis revealed that these cases were the result of parental germline mosaicism for a COMP mutation. As a result, one or more of the parent’s children may inherit the germline COMP mutation, leading to pseudoachondroplasia, while the parent does not have this disorder because the mutation is not present in sufficient number of body cells. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation. There is no test for germline mutation prior to pregnancy. Testing during a pregnancy for familial cases with a known mutation is commercially available and should be discussed with a genetic specialist.
| 1,028 |
Pseudoachondroplasia
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nord_1028_3
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Affects of Pseudoachondroplasia
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The exact birth prevalence of pseudoachondroplasia is unknown, but estimated to be 1 in 50,000-100,000. Males and females are equally affected.
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Affects of Pseudoachondroplasia. The exact birth prevalence of pseudoachondroplasia is unknown, but estimated to be 1 in 50,000-100,000. Males and females are equally affected.
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Pseudoachondroplasia
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