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nord_57_1 | Symptoms of Alopecia Areata | Alopecia areata often begins suddenly with oval or round bald patches appearing most commonly on the scalp. Other areas of hairy skin may also be involved. Gradually, the affected skin becomes smooth. New patches may spread by joining existing bald patches. These larger bald areas can appear while hair is regrowing in older hairless patches. Loss of hair can be permanent in some cases. Hair follicles may deteriorate, but oil producing glands in the skin (sebaceous glands) usually change very little. The skin does not become hard or atrophied. In a very few cases, all body hair may be lost. Cases beginning during childhood tend to be more severe than cases with an onset during adulthood.The physical manifestations of this disorder may not be as difficult to handle for some individuals as the emotional ones. Most people with alopecia areata are generally healthy otherwise, and the disorder itself is not a sign of a serious or life-threatening disease. | Symptoms of Alopecia Areata. Alopecia areata often begins suddenly with oval or round bald patches appearing most commonly on the scalp. Other areas of hairy skin may also be involved. Gradually, the affected skin becomes smooth. New patches may spread by joining existing bald patches. These larger bald areas can appear while hair is regrowing in older hairless patches. Loss of hair can be permanent in some cases. Hair follicles may deteriorate, but oil producing glands in the skin (sebaceous glands) usually change very little. The skin does not become hard or atrophied. In a very few cases, all body hair may be lost. Cases beginning during childhood tend to be more severe than cases with an onset during adulthood.The physical manifestations of this disorder may not be as difficult to handle for some individuals as the emotional ones. Most people with alopecia areata are generally healthy otherwise, and the disorder itself is not a sign of a serious or life-threatening disease. | 57 | Alopecia Areata |
nord_57_2 | Causes of Alopecia Areata | The exact cause of alopecia areata is not known. An autoimmune mechanism is suspected in this disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. Some cases may be linked to abnormal reactions by blood cells (serum antibodies) to a thyroid protein (thyroglobulin), stomach (parietal) cells, or adrenal cells.In 20 percent of cases, a familial pattern has been proposed, suggesting that some individuals may have a genetic predisposition to alopecia areata. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease. It is not known whether this trigger comes from outside the body, such as a virus, or is internal. People who develop alopecia areata for the first time after age 30 are less likely to have other family members who also have the disorder. The gene responsible for alopecia universalis (total absence of hair on the body) is located on the short arm of chromosome 8 (8p12).Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females.Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. For example, chromosome 8p12 refers to band 12 on the short arm of chromosome 8. | Causes of Alopecia Areata. The exact cause of alopecia areata is not known. An autoimmune mechanism is suspected in this disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. Some cases may be linked to abnormal reactions by blood cells (serum antibodies) to a thyroid protein (thyroglobulin), stomach (parietal) cells, or adrenal cells.In 20 percent of cases, a familial pattern has been proposed, suggesting that some individuals may have a genetic predisposition to alopecia areata. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease. It is not known whether this trigger comes from outside the body, such as a virus, or is internal. People who develop alopecia areata for the first time after age 30 are less likely to have other family members who also have the disorder. The gene responsible for alopecia universalis (total absence of hair on the body) is located on the short arm of chromosome 8 (8p12).Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females.Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. For example, chromosome 8p12 refers to band 12 on the short arm of chromosome 8. | 57 | Alopecia Areata |
nord_57_3 | Affects of Alopecia Areata | Alopecia areata affects males and females in equal numbers. It may appear at any age, but most typically begins during childhood. There are approximately 2.5 million individuals in the United States affected by alopecia areata. | Affects of Alopecia Areata. Alopecia areata affects males and females in equal numbers. It may appear at any age, but most typically begins during childhood. There are approximately 2.5 million individuals in the United States affected by alopecia areata. | 57 | Alopecia Areata |
nord_57_4 | Related disorders of Alopecia Areata | Loss of hair (alopecia) can occur from a wide variety of causes. Symptoms of the following disorders can be similar to those of alopecia areata. Comparisons may be useful for a differential diagnosis:Trichotillomania, also known as hair pulling, is a neurotic habit that usually appears in children. It may remain undiagnosed for a long time. The hairs may be broken off or pulled out. Stubby regrowth may replace damaged hair or bald areas. This mental illness may be hard to distinguish from alopecia areata without careful observation of the affected child's habits. Hair can be similarly damaged by permanent wave solutions, softeners or hot combs. (For more information on this disorder, choose “trichotillomania” as your search term in the Rare Disease Database.)Hypotrichiasis (hypotrichosis, alopecia congenitalis, alopecia adnata, congenital alopecia, congenital baldness) is a condition characterized by the absence of hair at birth. This disorder is usually inherited as a dominant trait, but can also be due to a recessive gene. It often occurs in association with other surface skin layer (ectodermal) defects.Alopecia medicamentosa is characterized by widespread hair loss, most commonly of the scalp, caused by a reaction to various types of drugs in sensitive or allergic individuals. It may also be a result of chemotherapy used in treating various disorders (e.g., cancer).Alopecia mucinosa, also known as follicular mucinosis, occurs in children and young adults. Hard, reddish, well defined plaques underlie the areas of hair loss. A fine scaling may develop on the face, scalp, trunk, arms or legs. A loss of sensation may occur as the plaques develop. The exact cause of this form of hair loss in not known, although a skin inflammation is suspected. Symptoms often spontaneously resolve after a few months in many cases.Alopecia neurotica is characterized by hair loss caused by injury to the nerves in the area where balding occurs.Postpartum alopecia is characterized by temporary loss of hair at the termination of a pregnancy. The cause is not known.Premature alopecia is characterized by male pattern baldness occurring at an abnormally early age.Alopecia presenilis is characterized by ordinary or common baldness occurring in early or middle life without any apparent disease of the scalp. This condition is very common in males, but rare in females.Alopecia symptomatica is characterized by hair loss associated with other illnesses or conditions, most commonly following prolonged illnesses marked by high fever.Alopecia toxica, also known as toxic alopecia, is characterized by hair loss thought to be caused only by fever.Alopecia triangularis congenitalis is a congenital defect consisting of a triangular patch of baldness on the front of the scalp. | Related disorders of Alopecia Areata. Loss of hair (alopecia) can occur from a wide variety of causes. Symptoms of the following disorders can be similar to those of alopecia areata. Comparisons may be useful for a differential diagnosis:Trichotillomania, also known as hair pulling, is a neurotic habit that usually appears in children. It may remain undiagnosed for a long time. The hairs may be broken off or pulled out. Stubby regrowth may replace damaged hair or bald areas. This mental illness may be hard to distinguish from alopecia areata without careful observation of the affected child's habits. Hair can be similarly damaged by permanent wave solutions, softeners or hot combs. (For more information on this disorder, choose “trichotillomania” as your search term in the Rare Disease Database.)Hypotrichiasis (hypotrichosis, alopecia congenitalis, alopecia adnata, congenital alopecia, congenital baldness) is a condition characterized by the absence of hair at birth. This disorder is usually inherited as a dominant trait, but can also be due to a recessive gene. It often occurs in association with other surface skin layer (ectodermal) defects.Alopecia medicamentosa is characterized by widespread hair loss, most commonly of the scalp, caused by a reaction to various types of drugs in sensitive or allergic individuals. It may also be a result of chemotherapy used in treating various disorders (e.g., cancer).Alopecia mucinosa, also known as follicular mucinosis, occurs in children and young adults. Hard, reddish, well defined plaques underlie the areas of hair loss. A fine scaling may develop on the face, scalp, trunk, arms or legs. A loss of sensation may occur as the plaques develop. The exact cause of this form of hair loss in not known, although a skin inflammation is suspected. Symptoms often spontaneously resolve after a few months in many cases.Alopecia neurotica is characterized by hair loss caused by injury to the nerves in the area where balding occurs.Postpartum alopecia is characterized by temporary loss of hair at the termination of a pregnancy. The cause is not known.Premature alopecia is characterized by male pattern baldness occurring at an abnormally early age.Alopecia presenilis is characterized by ordinary or common baldness occurring in early or middle life without any apparent disease of the scalp. This condition is very common in males, but rare in females.Alopecia symptomatica is characterized by hair loss associated with other illnesses or conditions, most commonly following prolonged illnesses marked by high fever.Alopecia toxica, also known as toxic alopecia, is characterized by hair loss thought to be caused only by fever.Alopecia triangularis congenitalis is a congenital defect consisting of a triangular patch of baldness on the front of the scalp. | 57 | Alopecia Areata |
nord_57_5 | Diagnosis of Alopecia Areata | Diagnosis of Alopecia Areata. | 57 | Alopecia Areata |
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nord_57_6 | Therapies of Alopecia Areata | Treatment of alopecia areata is directed at producing regrowth of hair. Although there is no cure for alopecia areata at the present time, the hair may sometimes return by itself. In some cases, it may also fall out again after returning. The course of this disorder varies among individuals, and is difficult to predict.For mild, patchy alopecia areata, in which less than 50% of the scalp hair is gone, cortisone may be injected locally into areas of bare skin. These injections are done with tiny needles, and repeated once a month. Topical solutions, creams and ointments may also help.For more extensive alopecia areata, cortisone pills are sometimes given. However, these pills may have undesirable side effects that should be discussed with a physician beforehand.In 2022, the U.S. Food and Drug Administration (FDA) approved baricitinib (Olumiant) oral tablets as a treatment option for adult patients with severe alopecia areata, being the first FDA approval of a systemic treatment for the disorder.Treatment tends to be less effective for more extensive alopecia areata than in cases of mild, patchy alopecia areata.For cosmetic reasons, wigs and hairpieces may be necessary, especially for affected women and children. | Therapies of Alopecia Areata. Treatment of alopecia areata is directed at producing regrowth of hair. Although there is no cure for alopecia areata at the present time, the hair may sometimes return by itself. In some cases, it may also fall out again after returning. The course of this disorder varies among individuals, and is difficult to predict.For mild, patchy alopecia areata, in which less than 50% of the scalp hair is gone, cortisone may be injected locally into areas of bare skin. These injections are done with tiny needles, and repeated once a month. Topical solutions, creams and ointments may also help.For more extensive alopecia areata, cortisone pills are sometimes given. However, these pills may have undesirable side effects that should be discussed with a physician beforehand.In 2022, the U.S. Food and Drug Administration (FDA) approved baricitinib (Olumiant) oral tablets as a treatment option for adult patients with severe alopecia areata, being the first FDA approval of a systemic treatment for the disorder.Treatment tends to be less effective for more extensive alopecia areata than in cases of mild, patchy alopecia areata.For cosmetic reasons, wigs and hairpieces may be necessary, especially for affected women and children. | 57 | Alopecia Areata |
nord_58_0 | Overview of Alpers Disease | Alpers disease is a progressive neurologic disorder that begins during childhood and is complicated in many instances by serious liver disease. Symptoms include increased muscle tone with exaggerated reflexes (spasticity), seizures, and loss of cognitive ability (dementia). | Overview of Alpers Disease. Alpers disease is a progressive neurologic disorder that begins during childhood and is complicated in many instances by serious liver disease. Symptoms include increased muscle tone with exaggerated reflexes (spasticity), seizures, and loss of cognitive ability (dementia). | 58 | Alpers Disease |
nord_58_1 | Symptoms of Alpers Disease | Alpers disease usually begins during early childhood, usually indicated by seizures at any age between 3 months and 5 years. It is characterized by lack of coordination of motor movement, partial paralysis, seizures, and muscle twitching. The child is unable to achieve normal muscle tone (hypotonia), yet the limbs appear to be stiff. On MRI examination an increased density of the grey matter in the brain is noted. Usually, but not always, Alpers disease is associated with liver damage. Mental retardation may be severe and is progressive. The loss of intellectual functions such as thinking, remembering, and reasoning may also interfere with a person's daily functioning (dementia). In later stages, patients may lose control of the movement of their arms and legs (spastic quadriplegia). The liver may become cirrhotic and fail completely, or may not progress beyond signs of jaundice. Affected individuals may also become blind as a result of optic atrophy as the optic nerve degenerates. | Symptoms of Alpers Disease. Alpers disease usually begins during early childhood, usually indicated by seizures at any age between 3 months and 5 years. It is characterized by lack of coordination of motor movement, partial paralysis, seizures, and muscle twitching. The child is unable to achieve normal muscle tone (hypotonia), yet the limbs appear to be stiff. On MRI examination an increased density of the grey matter in the brain is noted. Usually, but not always, Alpers disease is associated with liver damage. Mental retardation may be severe and is progressive. The loss of intellectual functions such as thinking, remembering, and reasoning may also interfere with a person's daily functioning (dementia). In later stages, patients may lose control of the movement of their arms and legs (spastic quadriplegia). The liver may become cirrhotic and fail completely, or may not progress beyond signs of jaundice. Affected individuals may also become blind as a result of optic atrophy as the optic nerve degenerates. | 58 | Alpers Disease |
nord_58_2 | Causes of Alpers Disease | Many researchers believe that Alpers Syndrome, rather than being a distinct disorder, is a clinical entity (i.e., cerebral gray matter degeneration in association with liver disease) that may be due to a number of different causes. In some cases, it is believed that the syndrome may be inherited as an autosomal recessive genetic trait. In other cases, clinicians attribute the disorder to a prion or prion-like molecule. Some researchers believe that certain individuals may inherit a genetic predisposition for the disorder; in such cases, certain environmental factors in combination with such a genetic predisposition may ultimately result in expression of the disorder. Research has also indicated that certain metabolic defects or mitochondrial abnormalities may play some role in causing the disorder.Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. | Causes of Alpers Disease. Many researchers believe that Alpers Syndrome, rather than being a distinct disorder, is a clinical entity (i.e., cerebral gray matter degeneration in association with liver disease) that may be due to a number of different causes. In some cases, it is believed that the syndrome may be inherited as an autosomal recessive genetic trait. In other cases, clinicians attribute the disorder to a prion or prion-like molecule. Some researchers believe that certain individuals may inherit a genetic predisposition for the disorder; in such cases, certain environmental factors in combination with such a genetic predisposition may ultimately result in expression of the disorder. Research has also indicated that certain metabolic defects or mitochondrial abnormalities may play some role in causing the disorder.Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. | 58 | Alpers Disease |
nord_58_3 | Affects of Alpers Disease | It is thought that Alpers disease affects males and females in equal numbers usually during early childhood. However, some clinicians are convinced that the difficulty of diagnosis makes estimating the frequency of this disorder less accurate. It is probable that Alpers disease affects fewer, than one (1) person per 200,000 of population. | Affects of Alpers Disease. It is thought that Alpers disease affects males and females in equal numbers usually during early childhood. However, some clinicians are convinced that the difficulty of diagnosis makes estimating the frequency of this disorder less accurate. It is probable that Alpers disease affects fewer, than one (1) person per 200,000 of population. | 58 | Alpers Disease |
nord_58_4 | Related disorders of Alpers Disease | Symptoms of the following disorders can be similar to those of Alpers disease. Comparisons may be useful for a differential diagnosis:Myoclonic epilepsy is a hereditary neurologic disorder inherited through recessive genes. It is characterized by sudden brief contractions of groups of muscles. Onset is usually between the ages of six and sixteen. During the initial period of seizures there is loss of consciousness. After years of attacks of increasing frequency and severity, spasms involving the muscles of the face, trunk, arms, and legs intensify. Untreated, this type of epilepsy can lead to progressive dementia. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)Leigh's disease is a genetic metabolic disorder characterized by lesions of the brain, spinal cord, optic nerve and in some cases, an enlarged heart. The disorder is usually first diagnosed during infancy but may begin later. Symptoms during infancy may include low body weight, slow growth, tremors, skin changes and interrupted breathing patterns. Progressive neurological disturbances, mental retardation, slurred speech and loss of motor coordination (ataxia) may occur. Abnormalities of eye movement and other vision problems may develop in cases with later onset. (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)Wernicke encephalopathy is a degenerative brain disorder characterized by a deficiency of thiamine. It is marked by loss of coordination (ataxia) and apathy, confusion, disorientation or delirium. Various vision dysfunctions may also develop. This disorder often occurs in conjunction with Korsakoff syndrome which involves a Vitamin B1 (thiamine) deficiency usually caused by alcoholism. Wernicke encephalopathy can be severely disabling and life threatening if it is not recognized and treated early. (For more information on this disorder, choose “Korsakoff” as your search term in the Rare Disease Database.)Batten disease is a hereditary lipid storage disorder transmitted as a recessive trait. It is characterized by rapidly progressive vision failure (optic atrophy), deterioration of intellect, seizures, loss of muscular coordination (ataxia) and a backward lateral curvature of the spinal column (kyphoscoliosis). Occurring mostly in white families of Northern European Scandinavian ancestry, Batten Disease usually begins between five and seven years of age. (For more information on this disorder, choose “Batten” as your search term in the Rare Disease Database.)Tay-Sachs disease is a genetic disorder in children that causes the progressive destruction of the central nervous system. It is generally found among children of eastern European Jewish heritage. Infants with Tay-Sachs disease appear normal at birth and seem to develop normally until the age of about six months. The first signs of the disease vary and become evident at different ages. These signs may include slowed development, loss of peripheral vision, abnormal startle response, progression of feeding difficulties, weakness, restlessness and cherry red spots on the retina. At the age of one year, recurrent convulsions, loss of previously learned skills and muscle coordination, blindness, mental retardation, flaccidity and/or paralysis may occur. This disorder is inherited as a recessive trait. (For more information on this disorder, choose “Tay-Sachs” as your search term in the Rare Disease Database.) | Related disorders of Alpers Disease. Symptoms of the following disorders can be similar to those of Alpers disease. Comparisons may be useful for a differential diagnosis:Myoclonic epilepsy is a hereditary neurologic disorder inherited through recessive genes. It is characterized by sudden brief contractions of groups of muscles. Onset is usually between the ages of six and sixteen. During the initial period of seizures there is loss of consciousness. After years of attacks of increasing frequency and severity, spasms involving the muscles of the face, trunk, arms, and legs intensify. Untreated, this type of epilepsy can lead to progressive dementia. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)Leigh's disease is a genetic metabolic disorder characterized by lesions of the brain, spinal cord, optic nerve and in some cases, an enlarged heart. The disorder is usually first diagnosed during infancy but may begin later. Symptoms during infancy may include low body weight, slow growth, tremors, skin changes and interrupted breathing patterns. Progressive neurological disturbances, mental retardation, slurred speech and loss of motor coordination (ataxia) may occur. Abnormalities of eye movement and other vision problems may develop in cases with later onset. (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)Wernicke encephalopathy is a degenerative brain disorder characterized by a deficiency of thiamine. It is marked by loss of coordination (ataxia) and apathy, confusion, disorientation or delirium. Various vision dysfunctions may also develop. This disorder often occurs in conjunction with Korsakoff syndrome which involves a Vitamin B1 (thiamine) deficiency usually caused by alcoholism. Wernicke encephalopathy can be severely disabling and life threatening if it is not recognized and treated early. (For more information on this disorder, choose “Korsakoff” as your search term in the Rare Disease Database.)Batten disease is a hereditary lipid storage disorder transmitted as a recessive trait. It is characterized by rapidly progressive vision failure (optic atrophy), deterioration of intellect, seizures, loss of muscular coordination (ataxia) and a backward lateral curvature of the spinal column (kyphoscoliosis). Occurring mostly in white families of Northern European Scandinavian ancestry, Batten Disease usually begins between five and seven years of age. (For more information on this disorder, choose “Batten” as your search term in the Rare Disease Database.)Tay-Sachs disease is a genetic disorder in children that causes the progressive destruction of the central nervous system. It is generally found among children of eastern European Jewish heritage. Infants with Tay-Sachs disease appear normal at birth and seem to develop normally until the age of about six months. The first signs of the disease vary and become evident at different ages. These signs may include slowed development, loss of peripheral vision, abnormal startle response, progression of feeding difficulties, weakness, restlessness and cherry red spots on the retina. At the age of one year, recurrent convulsions, loss of previously learned skills and muscle coordination, blindness, mental retardation, flaccidity and/or paralysis may occur. This disorder is inherited as a recessive trait. (For more information on this disorder, choose “Tay-Sachs” as your search term in the Rare Disease Database.) | 58 | Alpers Disease |
nord_58_5 | Diagnosis of Alpers Disease | Alpers Syndrome is usually diagnosed during infancy based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Such tests may include specialized imaging studies of the brain, which may reveal degeneration of the outer portion (cerebral cortex) and, in some cases, other areas of the brain.Electroencephalography (EEG), which records the brain's electrical impulses, may reveal an overall slowing of the brain's electrical activity and/or other electrical discharge abnormalities characteristic of seizure activity. Only post mortem confirmation is possible by means of a brain biopsy. | Diagnosis of Alpers Disease. Alpers Syndrome is usually diagnosed during infancy based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Such tests may include specialized imaging studies of the brain, which may reveal degeneration of the outer portion (cerebral cortex) and, in some cases, other areas of the brain.Electroencephalography (EEG), which records the brain's electrical impulses, may reveal an overall slowing of the brain's electrical activity and/or other electrical discharge abnormalities characteristic of seizure activity. Only post mortem confirmation is possible by means of a brain biopsy. | 58 | Alpers Disease |
nord_58_6 | Therapies of Alpers Disease | TreatmentThere is no treatments available that will stop the progress of the disease. However, some of the symptoms can be treated in order to make the patient as comfortable as possible under the circumstances. There are drugs available to treat the frequency of the seizures, to cope with muscle spasms and joint pain, and to treat infection.Physical therapists may be able to help parents to find more comfortable positions for the child while sitting or standing. Massage often reduces the stress involved. All treatment for Alpers Syndrome is symptomatic and supportive. | Therapies of Alpers Disease. TreatmentThere is no treatments available that will stop the progress of the disease. However, some of the symptoms can be treated in order to make the patient as comfortable as possible under the circumstances. There are drugs available to treat the frequency of the seizures, to cope with muscle spasms and joint pain, and to treat infection.Physical therapists may be able to help parents to find more comfortable positions for the child while sitting or standing. Massage often reduces the stress involved. All treatment for Alpers Syndrome is symptomatic and supportive. | 58 | Alpers Disease |
nord_59_0 | Overview of Alpha Thalassemia | SummaryAlpha thalassemia is a general term for a group of inherited blood disorders characterized by reduced or absent production of alpha-globin subunits, resulting in low levels of hemoglobin that is otherwise fully functional. Hemoglobin is found in red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood. A main function of red blood cells is to deliver oxygen throughout the body. There are two main forms of alpha thalassemia that are associated with significant health problems – hemoglobin (Hb) Bart’s hydrops fetalis and hemoglobin H (HbH) disease. Hb Bart’s hydrops fetalis is a severe syndrome that is usually fatal to the developing embryo during gestation or shortly after birth; however, recent advances have led to improved treatments for this condition. HbH disease is highly variable, and the specific symptoms and severity can vary greatly from one person to another. Some individuals will have only minor symptoms, while others will develop potentially serious complications. The characteristic finding of all forms of alpha thalassemia is anemia, with red blood cells that are small (microcytic), contain low levels of functional hemoglobin (hypochromic), and may break down in prematurely in both the bone marrow (ineffective erythropoiesis) and in the peripheral circulation (hemolysis). Consequently, severely affected individuals may not circulate sufficient oxygen-rich blood throughout the body. These individuals may experience fatigue, weakness, shortness of breath, dizziness or headaches. Severe anemia can cause serious, even life-threatening, complications if left untreated. Individuals with severe forms of HbH disease are usually treated with regular blood transfusions, which can result in the accumulation of excess iron in the body (iron overload). Although iron overload can damage numerous organs in the body, it can be effectively treated using several highly effective medications. Alpha thalassemia is caused by mutations in two different genes, the HBA1 and the HBA2 genes. Most individuals inherit two copies of each gene (for a total of four genes); one of each from a person’s father, and one of each gene from a person’s mother. A mutation in any one of the four alpha genes results in a condition that has no symptoms (alpha thalassemia silent carrier), but individuals can pass the mutant gene on to their children. A mutation (or mutations) that affects two of the four alpha genes results in a condition that is asymptomatic or only very mild symptoms (alpha thalassemia minor). A mutation (or mutations) that affect three genes results in HbH disease, while defects that affect all four genes result in Hb Bart’s hydrops fetalis.IntroductionThalassemia is a general term for a group of congenital, genetic disorders characterized by low levels of hemoglobin, decreased red blood cell production, and anemia. There are two main forms – alpha thalassemia and beta thalassemia – each with various subtypes. Alpha thalassemia is caused by reduced or absent production of alpha-globin subunits, while beta thalassemia is caused by reduced or absent production of beta-globin subunits. Alpha thalassemia minor and beta thalassemia minor, also known as alpha thalassemia trait or beta thalassemia trait, are common conditions in many demographics. Beta thalassemia major was first described in the medical literature in 1925 by an American physician named Thomas Cooley. Beta thalassemia major is also known as Cooley’s anemia. These disorders are related, but distinct entities. The similar terminology and symptomology can cause confusion for affected individuals, their families, and physicians who are unfamiliar with these disorders or are not specialists in diagnosing and treating disorders of the blood and blood-forming organs (hematologists). NORD has a separate report on beta thalassemia. | Overview of Alpha Thalassemia. SummaryAlpha thalassemia is a general term for a group of inherited blood disorders characterized by reduced or absent production of alpha-globin subunits, resulting in low levels of hemoglobin that is otherwise fully functional. Hemoglobin is found in red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood. A main function of red blood cells is to deliver oxygen throughout the body. There are two main forms of alpha thalassemia that are associated with significant health problems – hemoglobin (Hb) Bart’s hydrops fetalis and hemoglobin H (HbH) disease. Hb Bart’s hydrops fetalis is a severe syndrome that is usually fatal to the developing embryo during gestation or shortly after birth; however, recent advances have led to improved treatments for this condition. HbH disease is highly variable, and the specific symptoms and severity can vary greatly from one person to another. Some individuals will have only minor symptoms, while others will develop potentially serious complications. The characteristic finding of all forms of alpha thalassemia is anemia, with red blood cells that are small (microcytic), contain low levels of functional hemoglobin (hypochromic), and may break down in prematurely in both the bone marrow (ineffective erythropoiesis) and in the peripheral circulation (hemolysis). Consequently, severely affected individuals may not circulate sufficient oxygen-rich blood throughout the body. These individuals may experience fatigue, weakness, shortness of breath, dizziness or headaches. Severe anemia can cause serious, even life-threatening, complications if left untreated. Individuals with severe forms of HbH disease are usually treated with regular blood transfusions, which can result in the accumulation of excess iron in the body (iron overload). Although iron overload can damage numerous organs in the body, it can be effectively treated using several highly effective medications. Alpha thalassemia is caused by mutations in two different genes, the HBA1 and the HBA2 genes. Most individuals inherit two copies of each gene (for a total of four genes); one of each from a person’s father, and one of each gene from a person’s mother. A mutation in any one of the four alpha genes results in a condition that has no symptoms (alpha thalassemia silent carrier), but individuals can pass the mutant gene on to their children. A mutation (or mutations) that affects two of the four alpha genes results in a condition that is asymptomatic or only very mild symptoms (alpha thalassemia minor). A mutation (or mutations) that affect three genes results in HbH disease, while defects that affect all four genes result in Hb Bart’s hydrops fetalis.IntroductionThalassemia is a general term for a group of congenital, genetic disorders characterized by low levels of hemoglobin, decreased red blood cell production, and anemia. There are two main forms – alpha thalassemia and beta thalassemia – each with various subtypes. Alpha thalassemia is caused by reduced or absent production of alpha-globin subunits, while beta thalassemia is caused by reduced or absent production of beta-globin subunits. Alpha thalassemia minor and beta thalassemia minor, also known as alpha thalassemia trait or beta thalassemia trait, are common conditions in many demographics. Beta thalassemia major was first described in the medical literature in 1925 by an American physician named Thomas Cooley. Beta thalassemia major is also known as Cooley’s anemia. These disorders are related, but distinct entities. The similar terminology and symptomology can cause confusion for affected individuals, their families, and physicians who are unfamiliar with these disorders or are not specialists in diagnosing and treating disorders of the blood and blood-forming organs (hematologists). NORD has a separate report on beta thalassemia. | 59 | Alpha Thalassemia |
nord_59_1 | Symptoms of Alpha Thalassemia | The specific symptoms and severities of the alpha thalassemia conditions vary greatly from one person to another. Individuals with alpha thalassemia silent carrier do not develop symptoms, while individuals with alpha thalassemia minor do not develop any symptoms or are only mildly anemic. Many individuals with either form of alpha thalassemia go through life never knowing they carry an altered gene(s) for the disorder. In some cases, a diagnosis is made incidentally while they are being evaluated for another condition. Two forms of alpha thalassemia are associated with significant symptoms, hemoglobin H disease and Hb Bart’s hydrops fetalis. HEMOGLOBIN H (HbH) DISEASE
The specific symptoms and severity of HbH disease can vary greatly from one person to another. Some individuals do not develop symptoms and only become aware of the disorder upon routine blood testing. In some cases, affected individuals do not develop symptoms until adulthood. Most individuals exhibit symptoms associated with minor to moderate anemia. However, some individuals will develop severe symptoms that can develop during childhood or even the first year of life. It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals or parents of affected children should talk to their physicians and medical teams about their specific case, associated symptoms and overall prognosis.Disease severity is influenced, in part, by the specific type of mutations present. HbH disease may be caused by deletional or nondeletional mutations, either alone or in combination. Deletional HbH disease occurs when a combination of deletion mutations remove three of the four genes that express the alpha-globin protein. This is the most common form of HbH disease. Nondeletional HbH disease occurs when a deletion mutation removes two alpha genes, and a nondeletional point mutation inactivates the third gene without physically removing it. Nondeletional mutations are generally associated with more severe anemia, are more likely to cause an enlargement of spleen and liver, and are more likely to require therapeutic blood transfusions. HbH disease usually presents with anemia, which can be of varying degrees and severity. Anemia can be associated with fatigue, weakness, shortness of breath, lightheadedness, headaches, and yellowing of the skin, mucous membranes and whites of the eyes (jaundice). Severely affected infants often fail to grow and gain weight as expected based upon age and gender (failure to thrive). Some infants become progressively pale (pallor). Feeding problems, irritability or fussiness, abnormal enlargement of the liver (hepatomegaly), and the abnormal enlargement of the spleen (splenomegaly) may also occur. Growth deficiency can occur in some cases. Splenomegaly may cause enlargement or swelling of the abdomen. Splenomegaly may be associated with an overactive spleen (hypersplenism), a condition that can develops because too many blood cells build up and are destroyed within the spleen. Hypersplenism can contribute to anemia in individuals with alpha thalassemia and cause low levels of white blood cells, increasing the risk of infection, and low levels of platelets, which can predispose to bleeding. Additional symptoms that may occur include masses that form because of blood cell production outside of the bone marrow (extramedullary hematopoiesis). These masses primarily form in the spleen, liver, chest, and spine. These masses can potentially cause compression of nearby structures and a variety of symptoms. Affected individuals may also exhibit leg ulcers, gallstones (cholelithiasis), and folic acid deficiency. Additionally, HbH disease tends to worsen when individuals take oxidant drugs, are exposed to certain chemicals, or have an infection because of the increased pace of destruction of red blood cells (hemolysis). Some older adults with HbH disease, as well as individuals treated by regular blood transfusions, may develop iron overload, a condition characterized by the buildup of iron in various tissues of the body. Iron overload can cause tissue damage and impaired function of affected organs such as the heart, liver and endocrine glands. Iron overload can damage the heart and cause abnormal heart rhythms, inflammation of the membrane (pericardium) that lines the heart (pericarditis), and enlargement of the heart and disease of the heart muscle (dilated cardiomyopathy). Heart involvement can eventually progress to life-threatening complications such as heart failure. Involvement of the liver can cause scarring and inflammation of the liver (cirrhosis) and high blood pressure of the main vein of the liver (portal hypertension). Involvement of the endocrine glands can cause insufficiency of certain glands such as the thyroid (hypothyroidism) and pancreas (diabetes mellitus). Iron overload is a complication of repeated blood transfusions that may be used to treat some individuals with HbH disease. However, many adults who have never received a blood transfusion have developed iron overload, most likely due to increased absorption of iron from the gastrointestinal tract. Hemoglobin H-Constant Spring is a variant of HbH disease and the most common nondeletional form of the disorder. Individuals with hemoglobin H-Constant Spring tend to have more severe anemia because red blood cell production is even less efficient than in nondeletional forms of HbH disease (ineffective erythropoiesis). Moderately severe splenomegaly is common in these individuals. Additional common symptoms include leg ulcers, gallstones, jaundice, and an increased risk for infection. Growth delays are more significant in affected children than in children with HbH disease. Affected individuals may be at particular risk of sudden, severe anemia that develops following an acute febrile illness, which is a nonspecific term for any illness, although it is usually one of rapid onset, accompanied by a fever. HEMOGLOBIN (Hb) BART’S HYDROPS FETALIS
Hb Bart’s hydrops fetalis, also known as alpha thalassemia major, is the most severe form of alpha thalassemia. The term hydrops fetalis describes the accumulation of large amounts of fluid (edema) in the tissues and organs of a developing fetus. Edema is widespread (diffuse). A developing fetus may also exhibit profound anemia, an abnormally enlarged liver (hepatomegaly), an abnormally enlarged spleen (splenomegaly), impaired brain development, and signs of heart failure. Abnormal accumulation of cerebrospinal fluid within the skull (hydrocephaly) may also occur. Hydrocephaly causes increased pressure on, and swelling of, the brain. A newborn infant may be pale and exhibit abnormalities of the skeleton and urinary (urogenital) tract. Hb Bart’s hydrops fetalis is usually fatal before birth (stillbirth) or shortly after birth (neonatal period). | Symptoms of Alpha Thalassemia. The specific symptoms and severities of the alpha thalassemia conditions vary greatly from one person to another. Individuals with alpha thalassemia silent carrier do not develop symptoms, while individuals with alpha thalassemia minor do not develop any symptoms or are only mildly anemic. Many individuals with either form of alpha thalassemia go through life never knowing they carry an altered gene(s) for the disorder. In some cases, a diagnosis is made incidentally while they are being evaluated for another condition. Two forms of alpha thalassemia are associated with significant symptoms, hemoglobin H disease and Hb Bart’s hydrops fetalis. HEMOGLOBIN H (HbH) DISEASE
The specific symptoms and severity of HbH disease can vary greatly from one person to another. Some individuals do not develop symptoms and only become aware of the disorder upon routine blood testing. In some cases, affected individuals do not develop symptoms until adulthood. Most individuals exhibit symptoms associated with minor to moderate anemia. However, some individuals will develop severe symptoms that can develop during childhood or even the first year of life. It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals or parents of affected children should talk to their physicians and medical teams about their specific case, associated symptoms and overall prognosis.Disease severity is influenced, in part, by the specific type of mutations present. HbH disease may be caused by deletional or nondeletional mutations, either alone or in combination. Deletional HbH disease occurs when a combination of deletion mutations remove three of the four genes that express the alpha-globin protein. This is the most common form of HbH disease. Nondeletional HbH disease occurs when a deletion mutation removes two alpha genes, and a nondeletional point mutation inactivates the third gene without physically removing it. Nondeletional mutations are generally associated with more severe anemia, are more likely to cause an enlargement of spleen and liver, and are more likely to require therapeutic blood transfusions. HbH disease usually presents with anemia, which can be of varying degrees and severity. Anemia can be associated with fatigue, weakness, shortness of breath, lightheadedness, headaches, and yellowing of the skin, mucous membranes and whites of the eyes (jaundice). Severely affected infants often fail to grow and gain weight as expected based upon age and gender (failure to thrive). Some infants become progressively pale (pallor). Feeding problems, irritability or fussiness, abnormal enlargement of the liver (hepatomegaly), and the abnormal enlargement of the spleen (splenomegaly) may also occur. Growth deficiency can occur in some cases. Splenomegaly may cause enlargement or swelling of the abdomen. Splenomegaly may be associated with an overactive spleen (hypersplenism), a condition that can develops because too many blood cells build up and are destroyed within the spleen. Hypersplenism can contribute to anemia in individuals with alpha thalassemia and cause low levels of white blood cells, increasing the risk of infection, and low levels of platelets, which can predispose to bleeding. Additional symptoms that may occur include masses that form because of blood cell production outside of the bone marrow (extramedullary hematopoiesis). These masses primarily form in the spleen, liver, chest, and spine. These masses can potentially cause compression of nearby structures and a variety of symptoms. Affected individuals may also exhibit leg ulcers, gallstones (cholelithiasis), and folic acid deficiency. Additionally, HbH disease tends to worsen when individuals take oxidant drugs, are exposed to certain chemicals, or have an infection because of the increased pace of destruction of red blood cells (hemolysis). Some older adults with HbH disease, as well as individuals treated by regular blood transfusions, may develop iron overload, a condition characterized by the buildup of iron in various tissues of the body. Iron overload can cause tissue damage and impaired function of affected organs such as the heart, liver and endocrine glands. Iron overload can damage the heart and cause abnormal heart rhythms, inflammation of the membrane (pericardium) that lines the heart (pericarditis), and enlargement of the heart and disease of the heart muscle (dilated cardiomyopathy). Heart involvement can eventually progress to life-threatening complications such as heart failure. Involvement of the liver can cause scarring and inflammation of the liver (cirrhosis) and high blood pressure of the main vein of the liver (portal hypertension). Involvement of the endocrine glands can cause insufficiency of certain glands such as the thyroid (hypothyroidism) and pancreas (diabetes mellitus). Iron overload is a complication of repeated blood transfusions that may be used to treat some individuals with HbH disease. However, many adults who have never received a blood transfusion have developed iron overload, most likely due to increased absorption of iron from the gastrointestinal tract. Hemoglobin H-Constant Spring is a variant of HbH disease and the most common nondeletional form of the disorder. Individuals with hemoglobin H-Constant Spring tend to have more severe anemia because red blood cell production is even less efficient than in nondeletional forms of HbH disease (ineffective erythropoiesis). Moderately severe splenomegaly is common in these individuals. Additional common symptoms include leg ulcers, gallstones, jaundice, and an increased risk for infection. Growth delays are more significant in affected children than in children with HbH disease. Affected individuals may be at particular risk of sudden, severe anemia that develops following an acute febrile illness, which is a nonspecific term for any illness, although it is usually one of rapid onset, accompanied by a fever. HEMOGLOBIN (Hb) BART’S HYDROPS FETALIS
Hb Bart’s hydrops fetalis, also known as alpha thalassemia major, is the most severe form of alpha thalassemia. The term hydrops fetalis describes the accumulation of large amounts of fluid (edema) in the tissues and organs of a developing fetus. Edema is widespread (diffuse). A developing fetus may also exhibit profound anemia, an abnormally enlarged liver (hepatomegaly), an abnormally enlarged spleen (splenomegaly), impaired brain development, and signs of heart failure. Abnormal accumulation of cerebrospinal fluid within the skull (hydrocephaly) may also occur. Hydrocephaly causes increased pressure on, and swelling of, the brain. A newborn infant may be pale and exhibit abnormalities of the skeleton and urinary (urogenital) tract. Hb Bart’s hydrops fetalis is usually fatal before birth (stillbirth) or shortly after birth (neonatal period). | 59 | Alpha Thalassemia |
nord_59_2 | Causes of Alpha Thalassemia | Alpha thalassemia is caused by alterations (mutations) in two adjacent genes, the HBA1 and the HBA2 genes. Every person has two copies of the HBA1 gene (one from each parent) and two copies of the HBA2 gene (also one from each parent). Affected individuals may have a mutation or combination of mutations in one gene, two genes, three genes, or all four copies of these genes. 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 either function normally but be reduced in quantity, or function abnormally and be produced at normal levels. Depending upon the functions of the 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. Investigators have determined that the HBA1 and the HBA2 genes are located on the short arm (p) of chromosome 16 (16p13.3). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. The HBA1 and HBA2 genes specify the production of (encode) alpha globin protein chains. There are three main types of hemoglobins: embryonic, fetal and adult. Embryonic hemoglobins are made during the first few months after conception. Fetal hemoglobins begin to express at eight weeks of gestation and rapidly replace embryonic hemoglobins. Starting at birth, fetal hemoglobins are replaced by adult hemoglobins in a process that is largely completed by ages 6-12 months. Normal hemoglobins are made up of specialized proteins called globins; fetal and adult hemoglobins comprise two alpha chains and two other protein chains, either gamma chains (in fetal hemoglobins) or beta chains (in adult hemoglobins). A mutation in one alpha gene results in slightly lower production of functional alpha chains and does not cause any symptoms (silent alpha thalassemia carrier). A mutation in two genes causes decreased production of functional alpha chains, but not enough to cause significant symptoms, although some individuals may have mild anemia (alpha thalassemia minor). When the two mutated genes are on the same chromosome 16, it is called a ‘cis’ deletion; when one mutated gene is from one chromosome 16 and the other mutated gene from the other chromosome 16, it is called a ‘trans’ deletion. A mutation in three genes results in greatly reduced alpha chain production (hemoglobin H disease). The reduction or lack of alpha protein chains leads to an imbalance with the beta protein chains that are expressed in normal quantity. When the beta chains are present in vast excess (as occurs in Hb H disease), the excess chains bind together to create an abnormal type of hemoglobin called hemoglobin H. Hemoglobin H is unstable and causes red blood cells to break down faster than normal in the bone marrow (ineffective erythropoiesis) and in the peripheral circulation (hemolysis). Hemoglobin H-Constant Spring is an unusual form of HbH disease that is characterized by a significantly worse clinical course, and differs from the more common forms of Hb H disease insofar as one (of the three) affected alpha genes carries a non-deletional mutation.A mutation in all four genes results in severely reduced or absent production of alpha chains (Hb Bart’s hydrops fetalis). Mutations in the alpha genes are inherited in an autosomal recessive manner. Recessive genetic disorders become manifest when an individual inherits a mutation of the corresponding gene 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 that two carrier parents both pass a defective gene to an offspring and producing an affected child, therefore, is 25% for each pregnancy. The risk of bearing a child who is also a carrier (like each parent) is 50% for each pregnancy. The chance that a child will receive a normal gene from both parents and be genetically normal for that particular trait is 25% for each pregnancy. For genes carries on chromosomes 1-22, risk is the same for males and females. The inheritance of alpha thalassemia is somewhat more complicated insofar as each parent contributes two alpha genes to an offspring, rather than only one. The HBA1 and HBA2 genes are inherited in pairs, meaning that both genes from one chromosome are passed on from a parent to a child. Consultation with a genetic counselor is recommended for families or parents who are known or suspected of carrying an alpha thalassemia mutation, even if it does not cause symptoms. Additionally, the organizations listed in the Resources section of this report have more detailed information on the genetics of alpha thalassemia. Researchers have determined that the progression and severity of alpha thalassemia tend to vary based upon the specific type of mutation present in a gene(s) as well as the specific location of the mutation on the gene(s). This is known as genotype-phenotype correlation and allows physicians to predict individuals who are at risk of developing more severe symptoms (e.g. individuals with HbH-Constant Spring). However, because of the number of genes involved, the expression of genotype and phenotypes in alpha thalassemia is diverse and varied, and the specific genotype-phenotype correlations are not completely understood. More research is necessary to fully clarify genotype-phenotype correlations in alpha thalassemia.Researchers also believe that additional factors influence the severity of HbH disease and Hb Bart’s hydrops fetalis, including modifier genes and environmental factors. Modifier genes, unlike the gene that causes alpha thalassemia, can affect the clinical severity of the disorder. More research is necessary to discover the various genetic and environmental factors associated with alpha thalassemia and their exact role in the development of the disorder. | Causes of Alpha Thalassemia. Alpha thalassemia is caused by alterations (mutations) in two adjacent genes, the HBA1 and the HBA2 genes. Every person has two copies of the HBA1 gene (one from each parent) and two copies of the HBA2 gene (also one from each parent). Affected individuals may have a mutation or combination of mutations in one gene, two genes, three genes, or all four copies of these genes. 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 either function normally but be reduced in quantity, or function abnormally and be produced at normal levels. Depending upon the functions of the 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. Investigators have determined that the HBA1 and the HBA2 genes are located on the short arm (p) of chromosome 16 (16p13.3). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. The HBA1 and HBA2 genes specify the production of (encode) alpha globin protein chains. There are three main types of hemoglobins: embryonic, fetal and adult. Embryonic hemoglobins are made during the first few months after conception. Fetal hemoglobins begin to express at eight weeks of gestation and rapidly replace embryonic hemoglobins. Starting at birth, fetal hemoglobins are replaced by adult hemoglobins in a process that is largely completed by ages 6-12 months. Normal hemoglobins are made up of specialized proteins called globins; fetal and adult hemoglobins comprise two alpha chains and two other protein chains, either gamma chains (in fetal hemoglobins) or beta chains (in adult hemoglobins). A mutation in one alpha gene results in slightly lower production of functional alpha chains and does not cause any symptoms (silent alpha thalassemia carrier). A mutation in two genes causes decreased production of functional alpha chains, but not enough to cause significant symptoms, although some individuals may have mild anemia (alpha thalassemia minor). When the two mutated genes are on the same chromosome 16, it is called a ‘cis’ deletion; when one mutated gene is from one chromosome 16 and the other mutated gene from the other chromosome 16, it is called a ‘trans’ deletion. A mutation in three genes results in greatly reduced alpha chain production (hemoglobin H disease). The reduction or lack of alpha protein chains leads to an imbalance with the beta protein chains that are expressed in normal quantity. When the beta chains are present in vast excess (as occurs in Hb H disease), the excess chains bind together to create an abnormal type of hemoglobin called hemoglobin H. Hemoglobin H is unstable and causes red blood cells to break down faster than normal in the bone marrow (ineffective erythropoiesis) and in the peripheral circulation (hemolysis). Hemoglobin H-Constant Spring is an unusual form of HbH disease that is characterized by a significantly worse clinical course, and differs from the more common forms of Hb H disease insofar as one (of the three) affected alpha genes carries a non-deletional mutation.A mutation in all four genes results in severely reduced or absent production of alpha chains (Hb Bart’s hydrops fetalis). Mutations in the alpha genes are inherited in an autosomal recessive manner. Recessive genetic disorders become manifest when an individual inherits a mutation of the corresponding gene 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 that two carrier parents both pass a defective gene to an offspring and producing an affected child, therefore, is 25% for each pregnancy. The risk of bearing a child who is also a carrier (like each parent) is 50% for each pregnancy. The chance that a child will receive a normal gene from both parents and be genetically normal for that particular trait is 25% for each pregnancy. For genes carries on chromosomes 1-22, risk is the same for males and females. The inheritance of alpha thalassemia is somewhat more complicated insofar as each parent contributes two alpha genes to an offspring, rather than only one. The HBA1 and HBA2 genes are inherited in pairs, meaning that both genes from one chromosome are passed on from a parent to a child. Consultation with a genetic counselor is recommended for families or parents who are known or suspected of carrying an alpha thalassemia mutation, even if it does not cause symptoms. Additionally, the organizations listed in the Resources section of this report have more detailed information on the genetics of alpha thalassemia. Researchers have determined that the progression and severity of alpha thalassemia tend to vary based upon the specific type of mutation present in a gene(s) as well as the specific location of the mutation on the gene(s). This is known as genotype-phenotype correlation and allows physicians to predict individuals who are at risk of developing more severe symptoms (e.g. individuals with HbH-Constant Spring). However, because of the number of genes involved, the expression of genotype and phenotypes in alpha thalassemia is diverse and varied, and the specific genotype-phenotype correlations are not completely understood. More research is necessary to fully clarify genotype-phenotype correlations in alpha thalassemia.Researchers also believe that additional factors influence the severity of HbH disease and Hb Bart’s hydrops fetalis, including modifier genes and environmental factors. Modifier genes, unlike the gene that causes alpha thalassemia, can affect the clinical severity of the disorder. More research is necessary to discover the various genetic and environmental factors associated with alpha thalassemia and their exact role in the development of the disorder. | 59 | Alpha Thalassemia |
nord_59_3 | Affects of Alpha Thalassemia | Alpha thalassemia is one of the most common autosomal recessive disorders in the world. Increased immigration of people from areas with a higher incidence of alpha thalassemia has led to an increased incidence of the alpha-globin disorders in the US and other Western nations. Although the incidence and prevalence is increasing in United States and Northern Europe, the exact incidence or prevalence remains unknown. Severe forms of alpha thalassemia (HbH disease and Hb Bart’s hydrops fetalis) have been estimated to occur in approximately 1 in 1,000,000 individuals in the general population in Northern Europe and North America. However, some studies have shown that alpha thalassemia may be under-recognized and underdiagnosed in these countries, making it difficult to determine their true frequency. Alpha thalassemia is found in most populations worldwide, but is most common in the Middle East, Southeast Asia, and certain Mediterranean countries. Hb Bart’s hydrops fetalis and HbH disease are primarily recognized in Southeast Asia. The estimated incidence of Hb Bart’s hydrops fetalis in Southeast Asia is 1 in 200-2,000 births; its incidence in other parts of the world is unknown. The incidence of HbH disease in these countries is approximately 4-20 individuals per every 1,000 births. Some studies have estimated that as much as 5% of the world’s population carries an alpha-thalassemia variant (i.e., a mutation in one of the two pairs of genes associated with alpha thalassemia). | Affects of Alpha Thalassemia. Alpha thalassemia is one of the most common autosomal recessive disorders in the world. Increased immigration of people from areas with a higher incidence of alpha thalassemia has led to an increased incidence of the alpha-globin disorders in the US and other Western nations. Although the incidence and prevalence is increasing in United States and Northern Europe, the exact incidence or prevalence remains unknown. Severe forms of alpha thalassemia (HbH disease and Hb Bart’s hydrops fetalis) have been estimated to occur in approximately 1 in 1,000,000 individuals in the general population in Northern Europe and North America. However, some studies have shown that alpha thalassemia may be under-recognized and underdiagnosed in these countries, making it difficult to determine their true frequency. Alpha thalassemia is found in most populations worldwide, but is most common in the Middle East, Southeast Asia, and certain Mediterranean countries. Hb Bart’s hydrops fetalis and HbH disease are primarily recognized in Southeast Asia. The estimated incidence of Hb Bart’s hydrops fetalis in Southeast Asia is 1 in 200-2,000 births; its incidence in other parts of the world is unknown. The incidence of HbH disease in these countries is approximately 4-20 individuals per every 1,000 births. Some studies have estimated that as much as 5% of the world’s population carries an alpha-thalassemia variant (i.e., a mutation in one of the two pairs of genes associated with alpha thalassemia). | 59 | Alpha Thalassemia |
nord_59_4 | Related disorders of Alpha Thalassemia | Symptoms of the following disorders can be similar to those of alpha thalassemia. Comparisons may be useful for a differential diagnosis.Hydrops fetalis can occur in association with other conditions including various chromosomal disorders, numerous genetic disorders, fetal cardiac abnormalities, fetal infections, and maternal and placental disorders. The combination of hydrops fetalis and the presence of a high proportion of Hb Bart's (an assembly excess fetal gamma chains) is unique to alpha thalassemia conditions. Hemolytic anemia, which occurs in HbH disease, can be associated with numerous other disorders. ATR-16 syndrome is an extremely rare genetic disorder in which affected individuals lose a large amount of genetic material (monosomy) on chromosome 16 that includes both the alpha globin genes as well as several important adjacent genes. The condition typically results in either alpha thalassemia trait or a mild form of hemoglobin H disease. A variety of additional symptoms may occur including intellectual disability, microcephaly, clubfoot, and distinctive facial features that include widely spaced eyes (hypertelorism), a broad, prominent bridge of the nose, small ears, and a short neck. In males, certain genital abnormalities may be present such as failure of the testes to descend (cryptorchidism) and the abnormal placement of the urinary opening on the underside of the penis (hypospadias). ATR-16 syndrome occurs as a spontaneous (de novo) event with no previous family history or in parents with a balanced chromosomal translocation that is inherited in an unbalanced manner. ATR-16 syndrome is a contiguous gene syndrome, in which the loss of genetic material on a chromosome causes the loss of function of several adjacent genes. In ATR-16 syndrome both the HBA1 and the HBA2 genes are affected. Alpha thalassemia X-linked intellectual disability (ATR-X) syndrome is a rare genetic disorder that affects multiple organ systems of the body. ATR-X syndrome is characterized by intellectual disability, characteristic facial features, abnormalities of the genitourinary tract, and alpha thalassemia. Alpha thalassemia is not seen in every case. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition. Some researchers have suggested the name XLID-hypotonic face syndrome be used to designate several disorders formerly considered separate entities including ATR-X syndrome, Carpenter-Waziri syndrome, Chudley-Lowry syndrome, Holmes-Gang syndrome and X-linked intellectual disability-arch fingerprints-hypotonia syndrome. These syndromes occur due to mutations of the same gene on the X chromosome. Some researchers prefer use of the name ATR-X syndrome because it is the most widely-recognized term for this disorder. (For more information on this disorder, choose “ATR-X syndrome” as your search term in the Rare Disease Database.)An acquired form of alpha thalassemia, sometimes known as alpha thalassemia-myelodysplastic syndrome or ATMDS, has been identified that occurs in certain individuals with myelodysplasia. Myelodysplastic syndromes is a general term for a group of blood disorders that occur as a result of disordered development of blood cells within the bone marrow. ATMDS involves acquired mutations in the same gene that causes ATR-X syndrome, but most likely involves additional genetic and environmental factors. | Related disorders of Alpha Thalassemia. Symptoms of the following disorders can be similar to those of alpha thalassemia. Comparisons may be useful for a differential diagnosis.Hydrops fetalis can occur in association with other conditions including various chromosomal disorders, numerous genetic disorders, fetal cardiac abnormalities, fetal infections, and maternal and placental disorders. The combination of hydrops fetalis and the presence of a high proportion of Hb Bart's (an assembly excess fetal gamma chains) is unique to alpha thalassemia conditions. Hemolytic anemia, which occurs in HbH disease, can be associated with numerous other disorders. ATR-16 syndrome is an extremely rare genetic disorder in which affected individuals lose a large amount of genetic material (monosomy) on chromosome 16 that includes both the alpha globin genes as well as several important adjacent genes. The condition typically results in either alpha thalassemia trait or a mild form of hemoglobin H disease. A variety of additional symptoms may occur including intellectual disability, microcephaly, clubfoot, and distinctive facial features that include widely spaced eyes (hypertelorism), a broad, prominent bridge of the nose, small ears, and a short neck. In males, certain genital abnormalities may be present such as failure of the testes to descend (cryptorchidism) and the abnormal placement of the urinary opening on the underside of the penis (hypospadias). ATR-16 syndrome occurs as a spontaneous (de novo) event with no previous family history or in parents with a balanced chromosomal translocation that is inherited in an unbalanced manner. ATR-16 syndrome is a contiguous gene syndrome, in which the loss of genetic material on a chromosome causes the loss of function of several adjacent genes. In ATR-16 syndrome both the HBA1 and the HBA2 genes are affected. Alpha thalassemia X-linked intellectual disability (ATR-X) syndrome is a rare genetic disorder that affects multiple organ systems of the body. ATR-X syndrome is characterized by intellectual disability, characteristic facial features, abnormalities of the genitourinary tract, and alpha thalassemia. Alpha thalassemia is not seen in every case. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition. Some researchers have suggested the name XLID-hypotonic face syndrome be used to designate several disorders formerly considered separate entities including ATR-X syndrome, Carpenter-Waziri syndrome, Chudley-Lowry syndrome, Holmes-Gang syndrome and X-linked intellectual disability-arch fingerprints-hypotonia syndrome. These syndromes occur due to mutations of the same gene on the X chromosome. Some researchers prefer use of the name ATR-X syndrome because it is the most widely-recognized term for this disorder. (For more information on this disorder, choose “ATR-X syndrome” as your search term in the Rare Disease Database.)An acquired form of alpha thalassemia, sometimes known as alpha thalassemia-myelodysplastic syndrome or ATMDS, has been identified that occurs in certain individuals with myelodysplasia. Myelodysplastic syndromes is a general term for a group of blood disorders that occur as a result of disordered development of blood cells within the bone marrow. ATMDS involves acquired mutations in the same gene that causes ATR-X syndrome, but most likely involves additional genetic and environmental factors. | 59 | Alpha Thalassemia |
nord_59_5 | Diagnosis of Alpha Thalassemia | A diagnosis of alpha thalassemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Hb Bart’s hydrops fetalis can be diagnosed before birth in most cases. In the United States, infants may be diagnosed with alpha thalassemia through newborn screening. Newborn screening is a public health program that mandates the evaluation of newborn infants for a variety of disorders that are treatable, but not readily apparent at birth. Each state’s newborn screening program (and the specific disorders tested) is different. Further testing is required to determine the exact type of alpha thalassemia present. Clinical Testing and Workup
Physicians will take a blood sample from individuals suspected of having one of the alpha thalassemia conditions. Several different tests can be performed on a single blood sample. Individuals suspected of having alpha thalassemia will undergo blood tests such as a complete blood count (CBC). A CBC measures several components and aspects of blood including the number, concentration, size, shape, and maturity of blood cells. A specialized blood test known as hemoglobin electrophoresis measures the different types of hemoglobin found in blood. With alpha thalassemia, a CBC is required to measure the amount of hemoglobin and the number and the size and shape of red blood cells, which are fewer in number and smaller in size (microcytic) than in individuals without alpha thalassemia. Red blood cells may also be pale in color (hypochromic) and of varying shapes. A blood sample can also be tested to measure the amount of iron in the blood, which can be elevated in certain individuals with alpha thalassemia. Molecular genetic testing can confirm a diagnosis of alpha thalassemia. Molecular genetic testing can detect mutations in the HBA1 and HBA2 genes known to cause the disorder, but is available only as a diagnostic service through specialized laboratories.Prenatal diagnosis in pregnancies with an increased risk of Hb Bart’s hydrops fetalis is possible by Doppler ultrasonography, a non-invasive procedure in which reflected sound waves are used to create an image of the developing fetus that allows physicians to see how blood flows through blood vessels. Specifically, this test is used to measure the rate of blood flow through the cerebral arteries of the fetus, which correlates strongly with anemia in the fetus. In at-risk pregnancies, Hb Bart’s hydrops fetalis can be diagnosed as early as the 13th to 14th week of gestation Testing of immediate family members such as other children or an affected parent’s siblings is recommended because, even in the absence of symptoms, these individuals may be carriers for alpha thalassemia silent carrier or alpha thalassemia minor. | Diagnosis of Alpha Thalassemia. A diagnosis of alpha thalassemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Hb Bart’s hydrops fetalis can be diagnosed before birth in most cases. In the United States, infants may be diagnosed with alpha thalassemia through newborn screening. Newborn screening is a public health program that mandates the evaluation of newborn infants for a variety of disorders that are treatable, but not readily apparent at birth. Each state’s newborn screening program (and the specific disorders tested) is different. Further testing is required to determine the exact type of alpha thalassemia present. Clinical Testing and Workup
Physicians will take a blood sample from individuals suspected of having one of the alpha thalassemia conditions. Several different tests can be performed on a single blood sample. Individuals suspected of having alpha thalassemia will undergo blood tests such as a complete blood count (CBC). A CBC measures several components and aspects of blood including the number, concentration, size, shape, and maturity of blood cells. A specialized blood test known as hemoglobin electrophoresis measures the different types of hemoglobin found in blood. With alpha thalassemia, a CBC is required to measure the amount of hemoglobin and the number and the size and shape of red blood cells, which are fewer in number and smaller in size (microcytic) than in individuals without alpha thalassemia. Red blood cells may also be pale in color (hypochromic) and of varying shapes. A blood sample can also be tested to measure the amount of iron in the blood, which can be elevated in certain individuals with alpha thalassemia. Molecular genetic testing can confirm a diagnosis of alpha thalassemia. Molecular genetic testing can detect mutations in the HBA1 and HBA2 genes known to cause the disorder, but is available only as a diagnostic service through specialized laboratories.Prenatal diagnosis in pregnancies with an increased risk of Hb Bart’s hydrops fetalis is possible by Doppler ultrasonography, a non-invasive procedure in which reflected sound waves are used to create an image of the developing fetus that allows physicians to see how blood flows through blood vessels. Specifically, this test is used to measure the rate of blood flow through the cerebral arteries of the fetus, which correlates strongly with anemia in the fetus. In at-risk pregnancies, Hb Bart’s hydrops fetalis can be diagnosed as early as the 13th to 14th week of gestation Testing of immediate family members such as other children or an affected parent’s siblings is recommended because, even in the absence of symptoms, these individuals may be carriers for alpha thalassemia silent carrier or alpha thalassemia minor. | 59 | Alpha Thalassemia |
nord_59_6 | Therapies of Alpha Thalassemia | Treatment
Alpha-thalassemia pregnancies are rising in North America and require prenatal counseling, overall community education, and well-developed intrauterine management plans. Individuals with alpha thalassemia, particular the intermediate or severe forms, will benefit from referral to a thalassemia treatment center. These specialized centers can provide comprehensive care for individuals with alpha thalassemia including the development of specific treatment plans, monitoring and follow up of affected individuals, and state-of-the-art medical care. Treatment at such a center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapists, social workers and genetic counselors) experienced in the treatment of individuals with alpha thalassemia. Genetic counseling will be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the specific type of alpha thalassemia; the progression of the disease; the presence or absence of certain symptoms; severity of the disease upon diagnosis; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Individuals with alpha thalassemia silent carrier and alpha thalassemia minor usually do not develop symptoms and do not require treatment. It is important that individuals with alpha thalassemia minor be correctly diagnosed, however, in order to avoid unnecessary treatments for similarly appearing conditions such as iron deficiency anemia.Many individuals with HbH disease do not require treatment. Physicians may recommend folic acid and vitamin (minus iron) supplementation in some cases. Supplementation with folic acid, a B vitamin, may facilitate the production of red blood cells in certain individuals. Folic acid may be given at the same time as blood transfusions, and does not interfere with the effectiveness of medications that are given to lower iron levels. Vitamin supplementation is given because of the risk for vitamin D or calcium deficiency. Individuals with HbH disease should avoid oxidative medications, fava beans, and mothballs, all of which can contribute to the rapid, premature destruction of red blood cells (hemolytic crisis) and potentially an episode of acute, severe anemia. Affected individuals should also receive prompt treatment for infection, which can also trigger hemolytic crisis. Some individuals with HbH disease may require blood transfusions. A blood transfusion is a common procedure in which affected individuals receive donated blood in order to restore the levels of healthy, functioning hemoglobin to their blood. During this procedure, donated blood is delivered to the body through a small, plastic tube inserted into a blood vessel (intravenously). The procedure may take anywhere from 1-4 hours. Individuals with HbH disease occasionally require blood transfusions such as when suffering from an illness or infection or when planning to undergo surgery. Repeated transfusions may be required, particularly during early infancy or later adulthood. Less often, specific individuals with HbH disease require blood transfusions on a regular basis. Such individuals include those with severe anemia affecting the function of the heart or those with expansion of the bone marrow. The decision to undergo regular blood transfusions in HbH disease is difficult and is best made after close consultation with an experienced treatment team. Regular blood transfusions may contribute to the accumulation of excess iron in the body (iron overload). Iron overload can result in excess amounts of iron accumulating in various tissues of the body and can potentially cause a variety of symptoms depending on the specific organ systems involved. Iron overload is treated by medications that remove excess iron from the body (chelation) such as deferoxamine. Deferoxamine is an iron chelator, a drug that binds to iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Other oral iron chelators, such as deferiprone and deferasirox, are also been used to lower excess levels of iron. The surgical removal of the spleen (splenectomy) may be recommended in certain cases of nondeletional HbH or HbH-Constant Spring, specifically in children with massive splenic enlargement (splenomegaly) or overactivity of the spleen (hypersplenism). An abnormally enlarged spleen can cause severe pain and contribute to anemia. Removal the spleen may be considered if other forms of therapy fail or cannot be tolerated. Splenectomy has led to improvement in certain cases. However, this surgical procedure carries risks such as blood clot formation within a vein (venous thrombosis), which are weighed against the benefits in each individual case. Because of advances in treatment in the past several years, splenectomy is performed less often for individuals with HbH disease. Treatment of additional complications sometimes associated with alpha thalassemia or iron overload is symptomatic and supportive and often follows standard guidelines. For example, the repeated occurrence of gallstones may necessitate the surgical removal of the gall bladder (cholecystectomy). Special attention is recommended for the early diagnosis and prompt treatment of heart (cardiac) disease potentially associated with iron overload. PREGNANCY
Women with HbH disease who are pregnant are at risk of complications such as preeclampsia, excessive bleeding just before childbirth (antepartum hemorrhage), congestive heart failure, miscarriage, and premature delivery. Preeclampsia is a condition characterized by high blood pressure and the presence of protein in the urine; it can be associated with swelling, vision changes, headaches, and sudden weight gain. Women with HbH disease require high-risk perinatal care. Women who are carrying a fetus with Hb Bart’s hydrops fetalis are at risk for potentially serious complications during the pregnancy including abnormally low amniotic fluid levels (oligohydramnios), preeclampsia, excessive bleeding (hemorrhage), anemia, kidney failure, congestive heart failure, infections, tearing away of the placenta from the inner wall of the uterus (placental abruption), and premature labor. Women who are carrying a fetus with Hb Bart’s hydrops fetalis require high-risk perinatal care. Early therapeutic termination of such at-risk pregnancies may be discussed as an option because of the potentially serious complications to the mother and because of the severity of the syndrome. | Therapies of Alpha Thalassemia. Treatment
Alpha-thalassemia pregnancies are rising in North America and require prenatal counseling, overall community education, and well-developed intrauterine management plans. Individuals with alpha thalassemia, particular the intermediate or severe forms, will benefit from referral to a thalassemia treatment center. These specialized centers can provide comprehensive care for individuals with alpha thalassemia including the development of specific treatment plans, monitoring and follow up of affected individuals, and state-of-the-art medical care. Treatment at such a center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapists, social workers and genetic counselors) experienced in the treatment of individuals with alpha thalassemia. Genetic counseling will be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the specific type of alpha thalassemia; the progression of the disease; the presence or absence of certain symptoms; severity of the disease upon diagnosis; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Individuals with alpha thalassemia silent carrier and alpha thalassemia minor usually do not develop symptoms and do not require treatment. It is important that individuals with alpha thalassemia minor be correctly diagnosed, however, in order to avoid unnecessary treatments for similarly appearing conditions such as iron deficiency anemia.Many individuals with HbH disease do not require treatment. Physicians may recommend folic acid and vitamin (minus iron) supplementation in some cases. Supplementation with folic acid, a B vitamin, may facilitate the production of red blood cells in certain individuals. Folic acid may be given at the same time as blood transfusions, and does not interfere with the effectiveness of medications that are given to lower iron levels. Vitamin supplementation is given because of the risk for vitamin D or calcium deficiency. Individuals with HbH disease should avoid oxidative medications, fava beans, and mothballs, all of which can contribute to the rapid, premature destruction of red blood cells (hemolytic crisis) and potentially an episode of acute, severe anemia. Affected individuals should also receive prompt treatment for infection, which can also trigger hemolytic crisis. Some individuals with HbH disease may require blood transfusions. A blood transfusion is a common procedure in which affected individuals receive donated blood in order to restore the levels of healthy, functioning hemoglobin to their blood. During this procedure, donated blood is delivered to the body through a small, plastic tube inserted into a blood vessel (intravenously). The procedure may take anywhere from 1-4 hours. Individuals with HbH disease occasionally require blood transfusions such as when suffering from an illness or infection or when planning to undergo surgery. Repeated transfusions may be required, particularly during early infancy or later adulthood. Less often, specific individuals with HbH disease require blood transfusions on a regular basis. Such individuals include those with severe anemia affecting the function of the heart or those with expansion of the bone marrow. The decision to undergo regular blood transfusions in HbH disease is difficult and is best made after close consultation with an experienced treatment team. Regular blood transfusions may contribute to the accumulation of excess iron in the body (iron overload). Iron overload can result in excess amounts of iron accumulating in various tissues of the body and can potentially cause a variety of symptoms depending on the specific organ systems involved. Iron overload is treated by medications that remove excess iron from the body (chelation) such as deferoxamine. Deferoxamine is an iron chelator, a drug that binds to iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Other oral iron chelators, such as deferiprone and deferasirox, are also been used to lower excess levels of iron. The surgical removal of the spleen (splenectomy) may be recommended in certain cases of nondeletional HbH or HbH-Constant Spring, specifically in children with massive splenic enlargement (splenomegaly) or overactivity of the spleen (hypersplenism). An abnormally enlarged spleen can cause severe pain and contribute to anemia. Removal the spleen may be considered if other forms of therapy fail or cannot be tolerated. Splenectomy has led to improvement in certain cases. However, this surgical procedure carries risks such as blood clot formation within a vein (venous thrombosis), which are weighed against the benefits in each individual case. Because of advances in treatment in the past several years, splenectomy is performed less often for individuals with HbH disease. Treatment of additional complications sometimes associated with alpha thalassemia or iron overload is symptomatic and supportive and often follows standard guidelines. For example, the repeated occurrence of gallstones may necessitate the surgical removal of the gall bladder (cholecystectomy). Special attention is recommended for the early diagnosis and prompt treatment of heart (cardiac) disease potentially associated with iron overload. PREGNANCY
Women with HbH disease who are pregnant are at risk of complications such as preeclampsia, excessive bleeding just before childbirth (antepartum hemorrhage), congestive heart failure, miscarriage, and premature delivery. Preeclampsia is a condition characterized by high blood pressure and the presence of protein in the urine; it can be associated with swelling, vision changes, headaches, and sudden weight gain. Women with HbH disease require high-risk perinatal care. Women who are carrying a fetus with Hb Bart’s hydrops fetalis are at risk for potentially serious complications during the pregnancy including abnormally low amniotic fluid levels (oligohydramnios), preeclampsia, excessive bleeding (hemorrhage), anemia, kidney failure, congestive heart failure, infections, tearing away of the placenta from the inner wall of the uterus (placental abruption), and premature labor. Women who are carrying a fetus with Hb Bart’s hydrops fetalis require high-risk perinatal care. Early therapeutic termination of such at-risk pregnancies may be discussed as an option because of the potentially serious complications to the mother and because of the severity of the syndrome. | 59 | Alpha Thalassemia |
nord_60_0 | Overview of Alpha Thalassemia X-linked Intellectual Disability Syndrome | Summary
Alpha thalassemia X-linked intellectual disability (ATR-X) syndrome is a rare genetic disorder affecting multiple organ systems of the body. ATR-X syndrome is characterized by intellectual disability, characteristic facial features, abnormalities of the genitourinary tract and alpha thalassemia. Alpha thalassemia, a condition where there is a defect in the production of the oxygen-carrying pigments of red blood cells (hemoglobin), is not seen in every patient. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition.Introduction
Some researchers have suggested the name XLID-hypotonic face syndrome be used to designate several disorders formerly considered separate entities including ATR-X syndrome, Carpenter-Waziri syndrome, Chudley-Lowry syndrome, Holmes-Gang syndrome and X-linked intellectual disability-arch fingerprints-hypotonia syndrome. All of these syndromes occur due to changes (pathogenic variants or mutations) of the same gene on the X chromosome. The name ATR-X syndrome is the most widely recognized term for this disorder. | Overview of Alpha Thalassemia X-linked Intellectual Disability Syndrome. Summary
Alpha thalassemia X-linked intellectual disability (ATR-X) syndrome is a rare genetic disorder affecting multiple organ systems of the body. ATR-X syndrome is characterized by intellectual disability, characteristic facial features, abnormalities of the genitourinary tract and alpha thalassemia. Alpha thalassemia, a condition where there is a defect in the production of the oxygen-carrying pigments of red blood cells (hemoglobin), is not seen in every patient. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition.Introduction
Some researchers have suggested the name XLID-hypotonic face syndrome be used to designate several disorders formerly considered separate entities including ATR-X syndrome, Carpenter-Waziri syndrome, Chudley-Lowry syndrome, Holmes-Gang syndrome and X-linked intellectual disability-arch fingerprints-hypotonia syndrome. All of these syndromes occur due to changes (pathogenic variants or mutations) of the same gene on the X chromosome. The name ATR-X syndrome is the most widely recognized term for this disorder. | 60 | Alpha Thalassemia X-linked Intellectual Disability Syndrome |
nord_60_1 | Symptoms of Alpha Thalassemia X-linked Intellectual Disability Syndrome | The specific signs and symptoms present and their severity vary greatly from person to person. Many of the signs associated with ATR-X syndrome are apparent during infancy. Affected infants may exhibit diminished muscle tone (hypotonia), feeding difficulties and significant delays in reaching developmental milestones especially speaking or walking. Some affected individuals do not walk independently or fail to develop the ability to speak outside of a limited vocabulary. Intellectual disability is the most important of the clinical findings, but genital abnormalities, seizures and stiff movements of the legs also occur. Growth deficiency occurs after birth (postnatally) but may not become apparent until adolescence. Ultimately, growth deficiency may result in short stature.Individuals with ATR-X syndrome have characteristic facial features including an abnormally large space between the eyes (hypertelorism), vertical skin folds (epicanthal folds) that may cover the eyes’ inner corners, underdevelopment of the middle portion of the face (mid-face hypoplasia), an abnormally flat bridge of the nose and a small triangular nose. Most infants also have microcephaly, a finding that indicates that the head circumference is smaller than would be expected for an infant’s age and sex. Additional features include an abnormally large, protruding tongue, improper positioning of the teeth of the upper jaw in relation to those of the lower jaw (malocclusion), spacing of the teeth and abnormal configuration of the outer, visible portions of the ears (pinnae). Some affected males do not have the typical facial features, or the typical features become less apparent with age.Many affected individuals have abnormalities of the genitourinary tract including failure of the testes to descend into the scrotum (cryptorchidism), unusual placement of the urinary opening (meatus) on the underside of the penis (hypospadias) and underdevelopment of the scrotum. Rarely, the development of the external genitals will be intermediate between male and female (ambiguous genitalia).In some patients, anomalies of the skeletal system may be present including shortening of the fingers and toes (brachydactyly), permanent fixation of certain fingers in a bent position (clinodactyly), joint contractures and abnormal side-to-side and front-to-back curvature of the spine (kyphoscoliosis).Some affected individuals may have alpha thalassemia, a condition where there is a defect in the production of the oxygen-carrying pigments of red blood cells (hemoglobin). The form of alpha-thalassemia associated with ATR-X syndrome is called hemoglobin H (HbH) disease, which may result in low levels of circulating red blood cells (anemia). This is usually not symptomatic or clinically significant. | Symptoms of Alpha Thalassemia X-linked Intellectual Disability Syndrome. The specific signs and symptoms present and their severity vary greatly from person to person. Many of the signs associated with ATR-X syndrome are apparent during infancy. Affected infants may exhibit diminished muscle tone (hypotonia), feeding difficulties and significant delays in reaching developmental milestones especially speaking or walking. Some affected individuals do not walk independently or fail to develop the ability to speak outside of a limited vocabulary. Intellectual disability is the most important of the clinical findings, but genital abnormalities, seizures and stiff movements of the legs also occur. Growth deficiency occurs after birth (postnatally) but may not become apparent until adolescence. Ultimately, growth deficiency may result in short stature.Individuals with ATR-X syndrome have characteristic facial features including an abnormally large space between the eyes (hypertelorism), vertical skin folds (epicanthal folds) that may cover the eyes’ inner corners, underdevelopment of the middle portion of the face (mid-face hypoplasia), an abnormally flat bridge of the nose and a small triangular nose. Most infants also have microcephaly, a finding that indicates that the head circumference is smaller than would be expected for an infant’s age and sex. Additional features include an abnormally large, protruding tongue, improper positioning of the teeth of the upper jaw in relation to those of the lower jaw (malocclusion), spacing of the teeth and abnormal configuration of the outer, visible portions of the ears (pinnae). Some affected males do not have the typical facial features, or the typical features become less apparent with age.Many affected individuals have abnormalities of the genitourinary tract including failure of the testes to descend into the scrotum (cryptorchidism), unusual placement of the urinary opening (meatus) on the underside of the penis (hypospadias) and underdevelopment of the scrotum. Rarely, the development of the external genitals will be intermediate between male and female (ambiguous genitalia).In some patients, anomalies of the skeletal system may be present including shortening of the fingers and toes (brachydactyly), permanent fixation of certain fingers in a bent position (clinodactyly), joint contractures and abnormal side-to-side and front-to-back curvature of the spine (kyphoscoliosis).Some affected individuals may have alpha thalassemia, a condition where there is a defect in the production of the oxygen-carrying pigments of red blood cells (hemoglobin). The form of alpha-thalassemia associated with ATR-X syndrome is called hemoglobin H (HbH) disease, which may result in low levels of circulating red blood cells (anemia). This is usually not symptomatic or clinically significant. | 60 | Alpha Thalassemia X-linked Intellectual Disability Syndrome |
nord_60_2 | Causes of Alpha Thalassemia X-linked Intellectual Disability Syndrome | ATR-X syndrome is inherited as an X-linked recessive genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with X-linked disorders is able to reproduce, he will pass the abnormal gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. No male with ATR-X is known to have reproduced.ATR-X syndrome occurs due to disruption or changes (pathogenic variants or mutations) in the ATRX gene located on the X chromosome. 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.Females who carry the mutated ATRX gene are intellectually normal and do not have clinical symptoms because of a process known as marked skewing of X chromosome inactivation. In this process, early during fetal development, one of a female’s two X chromosomes is inactivated. With rare exceptions, the X chromosome carrying the mutated ATRX gene is inactivated (preferential inactivation). | Causes of Alpha Thalassemia X-linked Intellectual Disability Syndrome. ATR-X syndrome is inherited as an X-linked recessive genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with X-linked disorders is able to reproduce, he will pass the abnormal gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. No male with ATR-X is known to have reproduced.ATR-X syndrome occurs due to disruption or changes (pathogenic variants or mutations) in the ATRX gene located on the X chromosome. 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.Females who carry the mutated ATRX gene are intellectually normal and do not have clinical symptoms because of a process known as marked skewing of X chromosome inactivation. In this process, early during fetal development, one of a female’s two X chromosomes is inactivated. With rare exceptions, the X chromosome carrying the mutated ATRX gene is inactivated (preferential inactivation). | 60 | Alpha Thalassemia X-linked Intellectual Disability Syndrome |
nord_60_3 | Affects of Alpha Thalassemia X-linked Intellectual Disability Syndrome | ATR-X syndrome affects males. More than 200 families have been reported by laboratories conducting molecular genetic testing. However, because this disorder is underdiagnosed it is difficult to determine its true frequency in the general population. Female carriers of the mutated gene do not usually develop any manifestations. | Affects of Alpha Thalassemia X-linked Intellectual Disability Syndrome. ATR-X syndrome affects males. More than 200 families have been reported by laboratories conducting molecular genetic testing. However, because this disorder is underdiagnosed it is difficult to determine its true frequency in the general population. Female carriers of the mutated gene do not usually develop any manifestations. | 60 | Alpha Thalassemia X-linked Intellectual Disability Syndrome |
nord_60_4 | Related disorders of Alpha Thalassemia X-linked Intellectual Disability Syndrome | Symptoms of the following disorders can be similar to those of ATR-X syndrome. Comparisons may be useful for a differential diagnosis.Coffin-Lowry syndrome is a rare genetic disorder characterized by intellectual disability; abnormalities of the head and facial (craniofacial) area, large, soft hands with short, tapered fingers, short stature and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, down-slanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (pectus carinatum). Coffin-Lowry syndrome is caused by mutations in the RPS6KA3 gene and is inherited as an X-linked dominant genetic condition. Males are more severely affected than females. (For more information on this disorder, choose “Coffin-Lowry syndrome” as your search term in the Rare Disease Database.)Smith-Fineman-Myers syndrome is a rare genetic disorder characterized by intellectual disability, diminished muscle tone (hypotonia), characteristic facial features, short stature and additional abnormalities. Common findings include an abnormally small jaw (micrognathia), failure of the testes to descend into the scrotum (cryptorchidism) and delays in reaching developmental milestones. Smith-Fineman-Myers syndrome is inherited as an X-linked recessive genetic condition. One family diagnosed with Smith-Fineman-Myers syndrome had a mutation in ATRX, but the original family has not been studied at a molecular level.Duplication of the ATRX gene may cause intellectual disability, growth impairment, minor changes, genital anomalies and hypotonia but lacks the typical craniofacial manifestations of ATR-X syndrome.Alpha thalassemia/intellectual disability chromosome 16 (ATR-16) syndrome is an extremely rare disorder characterized by intellectual disability, which is milder than in ATR-X syndrome, and alpha thalassemia, which is more severe than in ATR-X syndrome. ATR-16 syndrome occurs due to deletion of genes at the end of chromosome 16. | Related disorders of Alpha Thalassemia X-linked Intellectual Disability Syndrome. Symptoms of the following disorders can be similar to those of ATR-X syndrome. Comparisons may be useful for a differential diagnosis.Coffin-Lowry syndrome is a rare genetic disorder characterized by intellectual disability; abnormalities of the head and facial (craniofacial) area, large, soft hands with short, tapered fingers, short stature and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, down-slanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (pectus carinatum). Coffin-Lowry syndrome is caused by mutations in the RPS6KA3 gene and is inherited as an X-linked dominant genetic condition. Males are more severely affected than females. (For more information on this disorder, choose “Coffin-Lowry syndrome” as your search term in the Rare Disease Database.)Smith-Fineman-Myers syndrome is a rare genetic disorder characterized by intellectual disability, diminished muscle tone (hypotonia), characteristic facial features, short stature and additional abnormalities. Common findings include an abnormally small jaw (micrognathia), failure of the testes to descend into the scrotum (cryptorchidism) and delays in reaching developmental milestones. Smith-Fineman-Myers syndrome is inherited as an X-linked recessive genetic condition. One family diagnosed with Smith-Fineman-Myers syndrome had a mutation in ATRX, but the original family has not been studied at a molecular level.Duplication of the ATRX gene may cause intellectual disability, growth impairment, minor changes, genital anomalies and hypotonia but lacks the typical craniofacial manifestations of ATR-X syndrome.Alpha thalassemia/intellectual disability chromosome 16 (ATR-16) syndrome is an extremely rare disorder characterized by intellectual disability, which is milder than in ATR-X syndrome, and alpha thalassemia, which is more severe than in ATR-X syndrome. ATR-16 syndrome occurs due to deletion of genes at the end of chromosome 16. | 60 | Alpha Thalassemia X-linked Intellectual Disability Syndrome |
nord_60_5 | Diagnosis of Alpha Thalassemia X-linked Intellectual Disability Syndrome | ATR-X syndrome may be suspected at birth or during infancy based upon a thorough clinical evaluation and identification of characteristic findings (e.g., intellectual disability, distinctive facial features, genitourinary abnormalities). Blood tests (e.g., brilliant cresyl blue stain) that demonstrate the presence of hemoglobin H inclusion bodies in red blood cells may assist in diagnosis. However, HbH is a variable finding in ATR-X syndrome and failure to detect HbH inclusion bodies does not rule out ATR-X syndrome. A diagnosis of ATR-X syndrome may be confirmed by molecular genetic testing that identifies a mutation of the ATRX gene. A specific DNA methylation profile is available to help clarify the pathogenicity of alterations of uncertain significance in the ATRX gene. | Diagnosis of Alpha Thalassemia X-linked Intellectual Disability Syndrome. ATR-X syndrome may be suspected at birth or during infancy based upon a thorough clinical evaluation and identification of characteristic findings (e.g., intellectual disability, distinctive facial features, genitourinary abnormalities). Blood tests (e.g., brilliant cresyl blue stain) that demonstrate the presence of hemoglobin H inclusion bodies in red blood cells may assist in diagnosis. However, HbH is a variable finding in ATR-X syndrome and failure to detect HbH inclusion bodies does not rule out ATR-X syndrome. A diagnosis of ATR-X syndrome may be confirmed by molecular genetic testing that identifies a mutation of the ATRX gene. A specific DNA methylation profile is available to help clarify the pathogenicity of alterations of uncertain significance in the ATRX gene. | 60 | Alpha Thalassemia X-linked Intellectual Disability Syndrome |
nord_60_6 | Therapies of Alpha Thalassemia X-linked Intellectual Disability Syndrome | The treatment of ATR-X syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, speech pathologists, eye specialists, specialists in treating skeletal disorders (orthopedists) and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Early developmental intervention is important in ensuring that affected children with ATR-X syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social and/or vocational services.Genetic counseling is recommended for families of affected individuals. | Therapies of Alpha Thalassemia X-linked Intellectual Disability Syndrome. The treatment of ATR-X syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, speech pathologists, eye specialists, specialists in treating skeletal disorders (orthopedists) and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Early developmental intervention is important in ensuring that affected children with ATR-X syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social and/or vocational services.Genetic counseling is recommended for families of affected individuals. | 60 | Alpha Thalassemia X-linked Intellectual Disability Syndrome |
nord_61_0 | Overview of Alpha-1 Antitrypsin Deficiency | Alpha-1 antitrypsin deficiency (A1AD) is a hereditary disorder characterized by low levels of a protein called alpha-1 antitrypsin (A1AT) which is found in the blood. This deficiency may predispose an individual to several illnesses and most commonly manifests as chronic obstructive pulmonary disease (including bronchiectasis) and liver disease (especially cirrhosis and hepatoma), or more rarely, as a skin condition called panniculitis. A1AD is also more frequent among individuals with Wegener's granulomatosis, now called polyangiitis with granulomatosis. A deficiency of A1AT allows substances that break down proteins (so-called proteolytic enzymes) to attack various tissues of the body. The attack results in destructive changes in the lungs (emphysema) and may also affect the liver and skin. Alpha-1 antitrypsin is ordinarily released by specialized, granules within a type of white blood cells (called neutrophils or polymorphonuclear leukocytes) in response to infection or inflammation. Deficiency of alpha-1 antitrypsin results in unbalanced (i.e., relatively unopposed) rapid breakdown of proteins (protease activity), especially in the supporting elastic structures of the lungs. Over years, this destruction can lead to progressive emphysema and is accelerated by smoking, some occupational exposures, and likely by other genetic modifiers of this risk which remain incompletely understood. | Overview of Alpha-1 Antitrypsin Deficiency. Alpha-1 antitrypsin deficiency (A1AD) is a hereditary disorder characterized by low levels of a protein called alpha-1 antitrypsin (A1AT) which is found in the blood. This deficiency may predispose an individual to several illnesses and most commonly manifests as chronic obstructive pulmonary disease (including bronchiectasis) and liver disease (especially cirrhosis and hepatoma), or more rarely, as a skin condition called panniculitis. A1AD is also more frequent among individuals with Wegener's granulomatosis, now called polyangiitis with granulomatosis. A deficiency of A1AT allows substances that break down proteins (so-called proteolytic enzymes) to attack various tissues of the body. The attack results in destructive changes in the lungs (emphysema) and may also affect the liver and skin. Alpha-1 antitrypsin is ordinarily released by specialized, granules within a type of white blood cells (called neutrophils or polymorphonuclear leukocytes) in response to infection or inflammation. Deficiency of alpha-1 antitrypsin results in unbalanced (i.e., relatively unopposed) rapid breakdown of proteins (protease activity), especially in the supporting elastic structures of the lungs. Over years, this destruction can lead to progressive emphysema and is accelerated by smoking, some occupational exposures, and likely by other genetic modifiers of this risk which remain incompletely understood. | 61 | Alpha-1 Antitrypsin Deficiency |
nord_61_1 | Symptoms of Alpha-1 Antitrypsin Deficiency | LUNG DISEASE
Alpha-1 antitrypsin deficiency-associated lung disease is characterized by progressive degenerative and destructive changes in the lungs (emphysema, commonly of the panacinar type). Emphysema is a chronic, usually slowly progressive illness, which most commonly causes shortness of breath. Other symptoms may include chronic cough, phlegm production, and wheezing. Frequent respiratory infections may also occur. Serious changes that occur in the lungs and other organs of the body may develop by the time the person reaches the age of 40 – 50 years (but may also occur only later in life). Some individuals with severe deficiency of A1AT never develop emphysema and have a normal life, especially if they never smoke. Individuals affected by A1AD often experience long diagnostic delays and visits to many different health care providers before the diagnosis is made for the first time.Pulmonary function tests may reveal reduction in expiratory air flow, hyperinflation, low diffusing capacity, and a CT scan of the chest may show loss of lung tissue that may not be apparent on breathing test results. An abnormal level of oxygen in the arterial blood (arterial hypoxemia), with or without the retention of carbon dioxide, may also occur, especially if the lung disease is advanced.Most commonly, changes are evident in the lower lung zones of plain chest X-rays or CT scans (about 2/3 of cases), though more classic changes of emphysema that affect predominantly the upper lung zones also occur in a minority of individuals.LIVER DISEASE
Liver disease caused by A1AD may occur during infancy, childhood, adolescence, or only newly during adulthood. Symptoms in infancy include prolonged yellow appearance of the skin (jaundice), mildly elevated liver enzymes, and symptoms of cholestasis (e.g., jaundice, dark urine, pale stools and itching). Other symptoms may include enlarged liver, bleeding, an abnormal accumulation of fluids within the abdominal cavity (ascites), feeding difficulties, and poor growth or failure to thrive. Children and adolescents with this disorder may have symptoms of mildly elevated liver enzymes, severe liver dysfunction, portal hypertension and/or severe liver dysfunction. They may also become easily fatigued, or experience decreased appetite, swelling of the legs or abdomen, and/or enlargement of the liver (hepatomegaly). A1AD-associated liver disease findings in adults are any or all of the following: chronic active hepatitis, cirrhosis, portal hypertension, and hepatocellular carcinoma.Other complications that may occur are an increase of the pressure within blood vessels in the liver (portal hypertension) that may cause bleeding from the esophagus or stomach, easy bruising, fluid accumulation in the chest, abnormally enlarged vessels within the stomach or esophagus, and/or a generally increased bleeding risk. Laboratory tests of liver function may have abnormal results and the assessment of patients for and with liver disease increasingly depend on imaging studies (i.e., liver ultrasound, etc.).Later in the course of the cirrhosis, drowsiness may occur because the liver is unable to properly dispose of the waste products of protein metabolism (urea). A late symptom of this disorder may include an increased susceptibility to infection.Chronic degenerative changes in the liver (scarring or cirrhosis) eventually develop in up to 30-40% of individuals with severe deficiency of A1AT, especially in individuals who escape the associated emphysema. Because the mechanism of the liver disease (i.e., accumulation of unsecreted protein within the liver cells) differs from that of the emphysema (i.e., proteolytic damage to the lung support tissues), liver disease may occur separately from the emphysema (though both may co-occur in some individuals).PANNICULITIS
The dermatologic manifestation of A1AD is a rare form of skin disease called panniculitis. Panniculitis appears to affect males and females equally, occurs at any age, and may occur in individuals with various A1AT genotypes, not confined to those associated with severe deficiency of A1AT.Panniculitis seems to develop in only a few patients with A1AD (approximately 1 per thousand individuals with the most common form of severe deficiency, so-called PI*ZZ). The pathogenesis of panniculitis and why it occurs so rarely is unknown, though the observed favorable effects of augmenting serum levels of A1AD with infused, purified A1AD protein suggests that panniculitis may be on the basis of unopposed proteolytic activity in the skin.The skin lesions of panniculitis associated with A1AD begin as nodules that are tender, red and inflamed (erythematous), hardened (indurated), and occur beneath the skin (subcutaneous), often with an irregular border. The panniculitis often widely affects the torso or extremities, and is characterized by ulceration in addition to serosanguineous (serum and blood) drainage and accompanying systemic symptoms, including fever.In some patients, direct trauma often precedes the development of the lesions. | Symptoms of Alpha-1 Antitrypsin Deficiency. LUNG DISEASE
Alpha-1 antitrypsin deficiency-associated lung disease is characterized by progressive degenerative and destructive changes in the lungs (emphysema, commonly of the panacinar type). Emphysema is a chronic, usually slowly progressive illness, which most commonly causes shortness of breath. Other symptoms may include chronic cough, phlegm production, and wheezing. Frequent respiratory infections may also occur. Serious changes that occur in the lungs and other organs of the body may develop by the time the person reaches the age of 40 – 50 years (but may also occur only later in life). Some individuals with severe deficiency of A1AT never develop emphysema and have a normal life, especially if they never smoke. Individuals affected by A1AD often experience long diagnostic delays and visits to many different health care providers before the diagnosis is made for the first time.Pulmonary function tests may reveal reduction in expiratory air flow, hyperinflation, low diffusing capacity, and a CT scan of the chest may show loss of lung tissue that may not be apparent on breathing test results. An abnormal level of oxygen in the arterial blood (arterial hypoxemia), with or without the retention of carbon dioxide, may also occur, especially if the lung disease is advanced.Most commonly, changes are evident in the lower lung zones of plain chest X-rays or CT scans (about 2/3 of cases), though more classic changes of emphysema that affect predominantly the upper lung zones also occur in a minority of individuals.LIVER DISEASE
Liver disease caused by A1AD may occur during infancy, childhood, adolescence, or only newly during adulthood. Symptoms in infancy include prolonged yellow appearance of the skin (jaundice), mildly elevated liver enzymes, and symptoms of cholestasis (e.g., jaundice, dark urine, pale stools and itching). Other symptoms may include enlarged liver, bleeding, an abnormal accumulation of fluids within the abdominal cavity (ascites), feeding difficulties, and poor growth or failure to thrive. Children and adolescents with this disorder may have symptoms of mildly elevated liver enzymes, severe liver dysfunction, portal hypertension and/or severe liver dysfunction. They may also become easily fatigued, or experience decreased appetite, swelling of the legs or abdomen, and/or enlargement of the liver (hepatomegaly). A1AD-associated liver disease findings in adults are any or all of the following: chronic active hepatitis, cirrhosis, portal hypertension, and hepatocellular carcinoma.Other complications that may occur are an increase of the pressure within blood vessels in the liver (portal hypertension) that may cause bleeding from the esophagus or stomach, easy bruising, fluid accumulation in the chest, abnormally enlarged vessels within the stomach or esophagus, and/or a generally increased bleeding risk. Laboratory tests of liver function may have abnormal results and the assessment of patients for and with liver disease increasingly depend on imaging studies (i.e., liver ultrasound, etc.).Later in the course of the cirrhosis, drowsiness may occur because the liver is unable to properly dispose of the waste products of protein metabolism (urea). A late symptom of this disorder may include an increased susceptibility to infection.Chronic degenerative changes in the liver (scarring or cirrhosis) eventually develop in up to 30-40% of individuals with severe deficiency of A1AT, especially in individuals who escape the associated emphysema. Because the mechanism of the liver disease (i.e., accumulation of unsecreted protein within the liver cells) differs from that of the emphysema (i.e., proteolytic damage to the lung support tissues), liver disease may occur separately from the emphysema (though both may co-occur in some individuals).PANNICULITIS
The dermatologic manifestation of A1AD is a rare form of skin disease called panniculitis. Panniculitis appears to affect males and females equally, occurs at any age, and may occur in individuals with various A1AT genotypes, not confined to those associated with severe deficiency of A1AT.Panniculitis seems to develop in only a few patients with A1AD (approximately 1 per thousand individuals with the most common form of severe deficiency, so-called PI*ZZ). The pathogenesis of panniculitis and why it occurs so rarely is unknown, though the observed favorable effects of augmenting serum levels of A1AD with infused, purified A1AD protein suggests that panniculitis may be on the basis of unopposed proteolytic activity in the skin.The skin lesions of panniculitis associated with A1AD begin as nodules that are tender, red and inflamed (erythematous), hardened (indurated), and occur beneath the skin (subcutaneous), often with an irregular border. The panniculitis often widely affects the torso or extremities, and is characterized by ulceration in addition to serosanguineous (serum and blood) drainage and accompanying systemic symptoms, including fever.In some patients, direct trauma often precedes the development of the lesions. | 61 | Alpha-1 Antitrypsin Deficiency |
nord_61_2 | Causes of Alpha-1 Antitrypsin Deficiency | A1AT is caused by mutations in the SERPINA1 gene that is responsible for production of the alpha-1 antitrypsin protein. Normally, this protein is produced in the liver and released in the blood and functions to protect the body from the neutrophil elastase enzyme. A1AT also appears to have anti-inflammatory effects independent of its anti-neutrophil elastase activity. Mutations in the SERPINA1 gene result in production of an abnormal protein that gets trapped in the liver, resulting in low serum levels of A1AT that can predispose to lung breakdown by neutrophil elastase and other proteolytic enzymes (enzymes that break down proteins). In addition, abnormal A1AT protein can accumulate in the liver and cause scarring damage. Over 150 different mutations in the SERPINA1 gene have been identified to date, with the most common termed S and Z, whereas the normal version (allele) of the gene is termed M. The S allele causes serum levels of A1AT to be moderately low and the Z allele is associated with very low A1AT levels in the serum (~10-15% of normal). Other rare variants, called null, are associated with the complete absence of A1AT in the bloodstream, because no protein is produced.A1AT is inherited as an autosomal co-dominant genetic condition. Co-dominant genetic disorders occur when each inherited allele expresses some effect (like a lowered serum level of A1AT). In general, in a co-dominant condition, when the individual inherits two copies of an abnormal gene for the same trait, one from each parent, the risk of disease is higher than when only one abnormal allele is inherited. People who have two copies of the Z allele (ZZ) have severe deficiency of A1AT and are at high risk of developing emphysema. The risk for two carrier parents to both pass the altered gene and to have an affected (ZZ) child is 25% with each pregnancy, and in this circumstance, the risk to have a child who is a carrier like the parents is 50% with each pregnancy. Finally, the chance for a child to receive normal genes from both parents is 25%. In autosomal conditions, the inheritance risk is the same for males and females because the abnormal gene does not reside on the sex chromosomes (X or Y). In A1AT, the SERPIN1A gene resides on the long arm of the 14th chromosome.If an individual receives one normal allele and one Z allele (MZ), the clinical risk of developing lung disease is considered to be small, though there may be a subset of these so-called heterozygous patients who are at higher risk, especially if they smoke. If an individual receives one S allele and one Z allele (SZ), they are also considered to be at increased risk to develop chronic obstructive pulmonary disease if they smoke. | Causes of Alpha-1 Antitrypsin Deficiency. A1AT is caused by mutations in the SERPINA1 gene that is responsible for production of the alpha-1 antitrypsin protein. Normally, this protein is produced in the liver and released in the blood and functions to protect the body from the neutrophil elastase enzyme. A1AT also appears to have anti-inflammatory effects independent of its anti-neutrophil elastase activity. Mutations in the SERPINA1 gene result in production of an abnormal protein that gets trapped in the liver, resulting in low serum levels of A1AT that can predispose to lung breakdown by neutrophil elastase and other proteolytic enzymes (enzymes that break down proteins). In addition, abnormal A1AT protein can accumulate in the liver and cause scarring damage. Over 150 different mutations in the SERPINA1 gene have been identified to date, with the most common termed S and Z, whereas the normal version (allele) of the gene is termed M. The S allele causes serum levels of A1AT to be moderately low and the Z allele is associated with very low A1AT levels in the serum (~10-15% of normal). Other rare variants, called null, are associated with the complete absence of A1AT in the bloodstream, because no protein is produced.A1AT is inherited as an autosomal co-dominant genetic condition. Co-dominant genetic disorders occur when each inherited allele expresses some effect (like a lowered serum level of A1AT). In general, in a co-dominant condition, when the individual inherits two copies of an abnormal gene for the same trait, one from each parent, the risk of disease is higher than when only one abnormal allele is inherited. People who have two copies of the Z allele (ZZ) have severe deficiency of A1AT and are at high risk of developing emphysema. The risk for two carrier parents to both pass the altered gene and to have an affected (ZZ) child is 25% with each pregnancy, and in this circumstance, the risk to have a child who is a carrier like the parents is 50% with each pregnancy. Finally, the chance for a child to receive normal genes from both parents is 25%. In autosomal conditions, the inheritance risk is the same for males and females because the abnormal gene does not reside on the sex chromosomes (X or Y). In A1AT, the SERPIN1A gene resides on the long arm of the 14th chromosome.If an individual receives one normal allele and one Z allele (MZ), the clinical risk of developing lung disease is considered to be small, though there may be a subset of these so-called heterozygous patients who are at higher risk, especially if they smoke. If an individual receives one S allele and one Z allele (SZ), they are also considered to be at increased risk to develop chronic obstructive pulmonary disease if they smoke. | 61 | Alpha-1 Antitrypsin Deficiency |
nord_61_3 | Affects of Alpha-1 Antitrypsin Deficiency | Alpha-1 antitrypsin deficiency (A1AD) is a disorder that occurs most frequently in Americans of Northern or Central European descent, affecting approximately 100,000 Americans. However, because most cases of A1AD go unrecognized, the disorder is very much under-diagnosed. Estimates suggest that only 10% or fewer of these estimated 100,000 individuals with severe deficiency of A1AT have been diagnosed, with the others either having chronic obstructive pulmonary disease (COPD) that has not been recognized to be on the basis of A1AD or being unaffected. Several lines of evidence show that A1AD is under-recognized: 1. Many A1AD individuals experience long delays (i.e., mean of 5 – 8 years) between initial symptoms (often shortness of breath) and initial diagnosis of A1AD, and 2. Affected individuals often see many physicians with A1AD-related symptoms before initial diagnosis is made. That under-recognition persists is suggested by the fact that the diagnostic delay intervals remain long even in more recently diagnosed individuals. | Affects of Alpha-1 Antitrypsin Deficiency. Alpha-1 antitrypsin deficiency (A1AD) is a disorder that occurs most frequently in Americans of Northern or Central European descent, affecting approximately 100,000 Americans. However, because most cases of A1AD go unrecognized, the disorder is very much under-diagnosed. Estimates suggest that only 10% or fewer of these estimated 100,000 individuals with severe deficiency of A1AT have been diagnosed, with the others either having chronic obstructive pulmonary disease (COPD) that has not been recognized to be on the basis of A1AD or being unaffected. Several lines of evidence show that A1AD is under-recognized: 1. Many A1AD individuals experience long delays (i.e., mean of 5 – 8 years) between initial symptoms (often shortness of breath) and initial diagnosis of A1AD, and 2. Affected individuals often see many physicians with A1AD-related symptoms before initial diagnosis is made. That under-recognition persists is suggested by the fact that the diagnostic delay intervals remain long even in more recently diagnosed individuals. | 61 | Alpha-1 Antitrypsin Deficiency |
nord_61_4 | Related disorders of Alpha-1 Antitrypsin Deficiency | Symptoms of the following disorders can be similar to those of alpha-1 antitrypsin deficiency:Pulmonary emphysema is a common, chronic obstructive pulmonary disease (COPD) characterized by the enlargement of the air spaces in the lungs and destructive changes to the walls of the air sacs of the lungs (called alveoli). The lungs lose their elasticity and there is a progressive decrease in the ability of the lungs to exchange oxygen that must be carried to the tissues of the body by the blood. Symptoms of emphysema typically include progressive shortness of breath, and may also include chronic cough that frequently produces sputum, wheezing, weakness, and/or frequent respiratory infections. Conditions that are commonly associated with COPD commonly include cardiovascular disease, muscle weakness, osteoporosis, and depression. The exact cause of pulmonary emphysema is unknown, although it is often associated with cigarette smoking or other exposure to noxious inflammatory inhaled substances (e.g., smoke from indoor cooking with biomass fuels, severe pollution, etc.). Alpha-1 antitrypsin deficiency is an hereditary form of emphysema, which accounts for 2-3% of all instances of emphysema and which is worsened by other risk factors for COPD (like cigarette smoking). | Related disorders of Alpha-1 Antitrypsin Deficiency. Symptoms of the following disorders can be similar to those of alpha-1 antitrypsin deficiency:Pulmonary emphysema is a common, chronic obstructive pulmonary disease (COPD) characterized by the enlargement of the air spaces in the lungs and destructive changes to the walls of the air sacs of the lungs (called alveoli). The lungs lose their elasticity and there is a progressive decrease in the ability of the lungs to exchange oxygen that must be carried to the tissues of the body by the blood. Symptoms of emphysema typically include progressive shortness of breath, and may also include chronic cough that frequently produces sputum, wheezing, weakness, and/or frequent respiratory infections. Conditions that are commonly associated with COPD commonly include cardiovascular disease, muscle weakness, osteoporosis, and depression. The exact cause of pulmonary emphysema is unknown, although it is often associated with cigarette smoking or other exposure to noxious inflammatory inhaled substances (e.g., smoke from indoor cooking with biomass fuels, severe pollution, etc.). Alpha-1 antitrypsin deficiency is an hereditary form of emphysema, which accounts for 2-3% of all instances of emphysema and which is worsened by other risk factors for COPD (like cigarette smoking). | 61 | Alpha-1 Antitrypsin Deficiency |
nord_61_5 | Diagnosis of Alpha-1 Antitrypsin Deficiency | The diagnosis of A1AD is based on a low concentration of A1AT blood plasma in combination with a high-risk phenotype (demonstrated by isoelectric focusing) or genotype (by specific allele analysis [usually for the Z and S alleles and sometimes for additional alleles like the F and I alleles and some others on commercial tests]). In some instances, further testing to sequence the A1AT gene is needed to establish a firm diagnosis (i.e., mapping all the chemical elements [called nucleotides] that make up the A1AT gene).Because A1AD often goes unrecognized, official guideline documents recommend that all individuals with fixed airflow obstruction on spirometry testing should be tested for the disorder. Also, all first-degree relatives of individuals found to have severe A1AD (i.e., siblings, children, and parents), individuals with panniculitis, and individuals with unexplained liver disease or bronchiectasis should be tested.This disorder may be suspected when emphysema occurs in a young person, a nonsmoker, or someone with a family history of emphysema. A1AD should also be suspected in individuals with jaundice, hepatitis, portal hypertension, hepatocellular carcinoma, or someone with a family history of liver disease. As noted above, however, under-recognition may result from testing only a minority of at-risk individuals; thus, as noted above, recommendations for testing suggest that all adults with symptomatic COPD, along with other groups cited above, should be tested for A1AD.Once clinical suspicion of panniculitis is aroused by a suggestive history and physical examination, the diagnosis of panniculitis is made by biopsy specimens of the skin lesions and blood tests to determine the level of circulating A1AT and the genotype. | Diagnosis of Alpha-1 Antitrypsin Deficiency. The diagnosis of A1AD is based on a low concentration of A1AT blood plasma in combination with a high-risk phenotype (demonstrated by isoelectric focusing) or genotype (by specific allele analysis [usually for the Z and S alleles and sometimes for additional alleles like the F and I alleles and some others on commercial tests]). In some instances, further testing to sequence the A1AT gene is needed to establish a firm diagnosis (i.e., mapping all the chemical elements [called nucleotides] that make up the A1AT gene).Because A1AD often goes unrecognized, official guideline documents recommend that all individuals with fixed airflow obstruction on spirometry testing should be tested for the disorder. Also, all first-degree relatives of individuals found to have severe A1AD (i.e., siblings, children, and parents), individuals with panniculitis, and individuals with unexplained liver disease or bronchiectasis should be tested.This disorder may be suspected when emphysema occurs in a young person, a nonsmoker, or someone with a family history of emphysema. A1AD should also be suspected in individuals with jaundice, hepatitis, portal hypertension, hepatocellular carcinoma, or someone with a family history of liver disease. As noted above, however, under-recognition may result from testing only a minority of at-risk individuals; thus, as noted above, recommendations for testing suggest that all adults with symptomatic COPD, along with other groups cited above, should be tested for A1AD.Once clinical suspicion of panniculitis is aroused by a suggestive history and physical examination, the diagnosis of panniculitis is made by biopsy specimens of the skin lesions and blood tests to determine the level of circulating A1AT and the genotype. | 61 | Alpha-1 Antitrypsin Deficiency |
nord_61_6 | Therapies of Alpha-1 Antitrypsin Deficiency | Treatment
Treatments for emphysema associated with A1AD include standard medications used in managing patients with emphysema of all causes (such as inhaled bronchodilators, inhaled steroids, anticholinergics, oxygen therapy, and the administration of antibiotics or phosphodiesterase 5 inhibitors for the frequent respiratory infections) as well as (in specific subgroups) specific A1AT treatment called augmentation therapy. Exercise programs (pulmonary rehabilitation) and good nutrition may help increase overall quality of daily living. It is very important that people with emphysema avoid smoking, employment that exposes the patient to lung irritants, and the use of non-medical aerosol sprays. Preventing infection as possible with yearly influenza and periodic pneumococcal vaccinations is also recommended.Specific treatment of A1AD (for individuals with established emphysema) may also involve the use of augmentation therapy, which is the regular (usually once weekly), long-term infusion into the veins of deficient individuals of purified, pooled human plasma-derived A1AT. Currently, six drugs for augmentation therapy have received approval by the U.S. Food and Drug Administration: Prolastin, Aralast, Aralast NP, Zemaira, Prolastin-C, and Glassia, of which the latter four are currently available. The best available evidence suggests that augmentation therapy may help slow the progression of lung damage due to A1AD. Augmentation therapy does not treat A1AD-related liver disease.Lung volume reduction surgery (LVRS) or the surgical removal of large confluent areas of emphysema (bullae) may be appropriate in highly selected patients, though LVRS may confer less benefit to individuals with emphysema due to A1AD than to individuals with emphysema not due to recognized genetic causes. As such, LVRS is rarely recommended for patients with A1AD.Lung transplantation, single and double, has been performed successfully on many A1AD patients. This treatment option is performed only on patients with end-stage severe lung disease who otherwise qualify as candidates for such surgery.No specific therapy is available for the liver disease associated with A1AD, though animal studies have shown promise for several drugs that can increase the liver’s ability to break down unsecreted A1AT (e.g., rapamycin and carbamazepine) and have prompted research studies in A1AD individuals. Similarly, other approaches currently under investigation regard agents that will decrease the production of the abnormal Z protein by liver cells, which could conceivably lessen the liver risk, though of course much more study is needed before any conclusion can be offered regarding these currently research-based approaches. Currently, management of A1AD-associated liver disease is directed at controlling symptoms. Special procedures may become necessary for some people with liver disease associated with A1AD. For example, shunts may be inserted to lower the pressure within the blood vessels in the liver and dilated veins in the food tube (esophagus) may be clipped or banded to lower the risk of bleeding. Liver transplantation may be recommended for individuals with end-stage liver disease. Transplantation of a normal liver into an individual with A1AD should correct the liver abnormalities and restore the blood levels of A1AT to normal. At the same time, transplantation carries some risk related to the procedure itself and to the suppressed immunity from drugs taken to prevent rejection of the transplanted organ.Genetic counseling is recommended for patients and their families. | Therapies of Alpha-1 Antitrypsin Deficiency. Treatment
Treatments for emphysema associated with A1AD include standard medications used in managing patients with emphysema of all causes (such as inhaled bronchodilators, inhaled steroids, anticholinergics, oxygen therapy, and the administration of antibiotics or phosphodiesterase 5 inhibitors for the frequent respiratory infections) as well as (in specific subgroups) specific A1AT treatment called augmentation therapy. Exercise programs (pulmonary rehabilitation) and good nutrition may help increase overall quality of daily living. It is very important that people with emphysema avoid smoking, employment that exposes the patient to lung irritants, and the use of non-medical aerosol sprays. Preventing infection as possible with yearly influenza and periodic pneumococcal vaccinations is also recommended.Specific treatment of A1AD (for individuals with established emphysema) may also involve the use of augmentation therapy, which is the regular (usually once weekly), long-term infusion into the veins of deficient individuals of purified, pooled human plasma-derived A1AT. Currently, six drugs for augmentation therapy have received approval by the U.S. Food and Drug Administration: Prolastin, Aralast, Aralast NP, Zemaira, Prolastin-C, and Glassia, of which the latter four are currently available. The best available evidence suggests that augmentation therapy may help slow the progression of lung damage due to A1AD. Augmentation therapy does not treat A1AD-related liver disease.Lung volume reduction surgery (LVRS) or the surgical removal of large confluent areas of emphysema (bullae) may be appropriate in highly selected patients, though LVRS may confer less benefit to individuals with emphysema due to A1AD than to individuals with emphysema not due to recognized genetic causes. As such, LVRS is rarely recommended for patients with A1AD.Lung transplantation, single and double, has been performed successfully on many A1AD patients. This treatment option is performed only on patients with end-stage severe lung disease who otherwise qualify as candidates for such surgery.No specific therapy is available for the liver disease associated with A1AD, though animal studies have shown promise for several drugs that can increase the liver’s ability to break down unsecreted A1AT (e.g., rapamycin and carbamazepine) and have prompted research studies in A1AD individuals. Similarly, other approaches currently under investigation regard agents that will decrease the production of the abnormal Z protein by liver cells, which could conceivably lessen the liver risk, though of course much more study is needed before any conclusion can be offered regarding these currently research-based approaches. Currently, management of A1AD-associated liver disease is directed at controlling symptoms. Special procedures may become necessary for some people with liver disease associated with A1AD. For example, shunts may be inserted to lower the pressure within the blood vessels in the liver and dilated veins in the food tube (esophagus) may be clipped or banded to lower the risk of bleeding. Liver transplantation may be recommended for individuals with end-stage liver disease. Transplantation of a normal liver into an individual with A1AD should correct the liver abnormalities and restore the blood levels of A1AT to normal. At the same time, transplantation carries some risk related to the procedure itself and to the suppressed immunity from drugs taken to prevent rejection of the transplanted organ.Genetic counseling is recommended for patients and their families. | 61 | Alpha-1 Antitrypsin Deficiency |
nord_62_0 | Overview of Alpha-Mannosidosis | SummaryAlpha-mannosidosis is a rare genetic disorder characterized by a deficiency of the enzyme alpha-D-mannosidase. Alpha-mannosidosis is best thought of as a continuum of disease that is generally broken down into three forms: a mild, slowly progressive form (type 1); a moderate form (type 2); and a severe, often rapidly progressive and potentially life-threatening form (type 3). The symptoms and severity of the disorder are highly variable. Symptoms may include distinctive facial features, skeletal abnormalities, hearing loss, intellectual disability, and dysfunction of the immune system. Alpha-mannosidosis is caused by mutations of the MAN2B1 gene. This genetic mutation is inherited as an autosomal recessive trait.IntroductionAlpha-mannosidosis belongs to a group of diseases known as the lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units. Enzymes within the lysosomes break down or digest particular nutrients, such as complex molecules composed of a sugar attached to a protein (glycoproteins). Low levels or inactivity of the alpha-mannosidase enzyme leads to the abnormal accumulation of compounds upstream in the metabolic pathway in the cells of affected individuals with unwanted consequences. | Overview of Alpha-Mannosidosis. SummaryAlpha-mannosidosis is a rare genetic disorder characterized by a deficiency of the enzyme alpha-D-mannosidase. Alpha-mannosidosis is best thought of as a continuum of disease that is generally broken down into three forms: a mild, slowly progressive form (type 1); a moderate form (type 2); and a severe, often rapidly progressive and potentially life-threatening form (type 3). The symptoms and severity of the disorder are highly variable. Symptoms may include distinctive facial features, skeletal abnormalities, hearing loss, intellectual disability, and dysfunction of the immune system. Alpha-mannosidosis is caused by mutations of the MAN2B1 gene. This genetic mutation is inherited as an autosomal recessive trait.IntroductionAlpha-mannosidosis belongs to a group of diseases known as the lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units. Enzymes within the lysosomes break down or digest particular nutrients, such as complex molecules composed of a sugar attached to a protein (glycoproteins). Low levels or inactivity of the alpha-mannosidase enzyme leads to the abnormal accumulation of compounds upstream in the metabolic pathway in the cells of affected individuals with unwanted consequences. | 62 | Alpha-Mannosidosis |
nord_62_1 | Symptoms of Alpha-Mannosidosis | The symptoms, progression and severity of alpha-mannosidosis vary widely from one person to another, including between siblings who share the same mutation. Alpha-mannosidosis represents a spectrum or continuum of disease and is highly individualized. Some individuals develop symptoms shortly after birth and may develop potentially life-threatening complications in infancy or early childhood. Other individuals develop more moderate symptoms usually with onset before the age of 10. In some cases, individuals may not be diagnosed until adulthood.The disorder is generally broken down into three separate subtypes: mild (type 1), moderate (type 2) and severe (type 3). Most affected individuals fall into the moderate subtype. It is important to note, because of the highly variable nature of the disorder, that affected individuals will not have all of the symptoms discussed below.The mild form (type 1) may not be evident until the teen years and progresses slowly. Symptoms typically include muscle weakness. Skeletal abnormalities are usually not present. The person with type 1 may have normal cognitive and physical development. However, even this later-onset form may be accompanied by mild to moderate intellectual disability. In some cases, the clinical progression of the disease appears to slow down or stop as the affected individual grows beyond school age.In the moderate form of the disorder (type 2), signs of skeletal abnormalities and muscle weakness may appear before ten years of age and progress slowly. Ataxia (an impaired ability to coordinate voluntary movements) may develop by the age of 20-30.The severe form (type 3) begins within the first year of life. In most cases, infants appear normal at birth, but the condition grows progressively worse. Type 3 alpha-mannosidosis is characterized by rapid progression of intellectual disability, hydrocephalus, progressive impairment of the ability to coordinate voluntary movements (ataxia), enlargement of the liver and spleen (hepatosplenomegaly), skeletal abnormalities, and coarse facial features.Intellectual disabilities associated with alpha-mannosidosis can range from mild cognitive impairment to profound mental deficiency. The severity can vary dramatically even among siblings. Children often experience delays achieving the ability to speak, and their speech stays blured.Motor skills may also be affected in alpha-mannosidosis. Affected children may experience delays in learning to walk and may appear clumsy. Diminished muscle tone (hypotonia) is often present.Many individuals with alpha-mannosidosis develop moderate to severe hearing loss. Hearing loss is caused by a defect of the inner ear or the auditory nerve that prevents sound vibrations from being transmitted to the brain (With normal hearing, a portion of the inner ear serves to convert sound vibrations to nerve impulses, which are then transmitted via the auditory nerve to the brain.). Hearing can worsen even further with otitis with accumulation of fluid in the middle ear.The skeletal abnormalities associated with type 2 and type 3 may include facial abnormalities such as a prominent forehead and jaw, and a flattened nose. Affected children may be especially prone to dental problems such as cavities. In addition, some infants are born with an abnormally twisted ankle (ankle equinus) or hydrocephalus, a condition in which the accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain.Types 2 and 3 also may be characterized by distinctive facial features including widely spaced or unevenly developed teeth, a thickened, enlarged tongue (macroglossia), prominent forehead, flattened nasal bridge, and a protruding lower jaw (prognathism). Abnormalities affecting the eyes may include an inability to align the eyes (strabismus or crossed eyes), clouding (opacity) of the transparent outer covering of the eye (cornea), and farsightedness (hyperopia) and, less commonly, nearsightedness (myopia).Growth rates can fluctuate with accelerated early growth but subsequent impaired growth, causing short stature. Thin arms and/or legs with stiff joints may develop. Spinal abnormalities may lead to extreme curvature in some cases. Over time, affected individuals may eventually develop degenerative disease affecting multiple joints (destructive polyarthropathy).In type 3 disease, a diminished or abnormal immune system response can make affected individuals more susceptible to bacterial infections, particularly of the respiratory system. Infections affecting the middle ear and gastrointestinal tract are also common. Recurrent infections are more common during the first decade of life.Some individuals with alpha-mannosidosis develop psychiatric abnormalities such as confusion, anxiety, depression or hallucinations. These symptoms may persist for days or weeks, followed by a need for excessive amounts of sleep (hypersomnia). Psychiatric symptoms or behavioral problems occur in almost half of those affected and usually develop during adolescence or early adulthood. | Symptoms of Alpha-Mannosidosis. The symptoms, progression and severity of alpha-mannosidosis vary widely from one person to another, including between siblings who share the same mutation. Alpha-mannosidosis represents a spectrum or continuum of disease and is highly individualized. Some individuals develop symptoms shortly after birth and may develop potentially life-threatening complications in infancy or early childhood. Other individuals develop more moderate symptoms usually with onset before the age of 10. In some cases, individuals may not be diagnosed until adulthood.The disorder is generally broken down into three separate subtypes: mild (type 1), moderate (type 2) and severe (type 3). Most affected individuals fall into the moderate subtype. It is important to note, because of the highly variable nature of the disorder, that affected individuals will not have all of the symptoms discussed below.The mild form (type 1) may not be evident until the teen years and progresses slowly. Symptoms typically include muscle weakness. Skeletal abnormalities are usually not present. The person with type 1 may have normal cognitive and physical development. However, even this later-onset form may be accompanied by mild to moderate intellectual disability. In some cases, the clinical progression of the disease appears to slow down or stop as the affected individual grows beyond school age.In the moderate form of the disorder (type 2), signs of skeletal abnormalities and muscle weakness may appear before ten years of age and progress slowly. Ataxia (an impaired ability to coordinate voluntary movements) may develop by the age of 20-30.The severe form (type 3) begins within the first year of life. In most cases, infants appear normal at birth, but the condition grows progressively worse. Type 3 alpha-mannosidosis is characterized by rapid progression of intellectual disability, hydrocephalus, progressive impairment of the ability to coordinate voluntary movements (ataxia), enlargement of the liver and spleen (hepatosplenomegaly), skeletal abnormalities, and coarse facial features.Intellectual disabilities associated with alpha-mannosidosis can range from mild cognitive impairment to profound mental deficiency. The severity can vary dramatically even among siblings. Children often experience delays achieving the ability to speak, and their speech stays blured.Motor skills may also be affected in alpha-mannosidosis. Affected children may experience delays in learning to walk and may appear clumsy. Diminished muscle tone (hypotonia) is often present.Many individuals with alpha-mannosidosis develop moderate to severe hearing loss. Hearing loss is caused by a defect of the inner ear or the auditory nerve that prevents sound vibrations from being transmitted to the brain (With normal hearing, a portion of the inner ear serves to convert sound vibrations to nerve impulses, which are then transmitted via the auditory nerve to the brain.). Hearing can worsen even further with otitis with accumulation of fluid in the middle ear.The skeletal abnormalities associated with type 2 and type 3 may include facial abnormalities such as a prominent forehead and jaw, and a flattened nose. Affected children may be especially prone to dental problems such as cavities. In addition, some infants are born with an abnormally twisted ankle (ankle equinus) or hydrocephalus, a condition in which the accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain.Types 2 and 3 also may be characterized by distinctive facial features including widely spaced or unevenly developed teeth, a thickened, enlarged tongue (macroglossia), prominent forehead, flattened nasal bridge, and a protruding lower jaw (prognathism). Abnormalities affecting the eyes may include an inability to align the eyes (strabismus or crossed eyes), clouding (opacity) of the transparent outer covering of the eye (cornea), and farsightedness (hyperopia) and, less commonly, nearsightedness (myopia).Growth rates can fluctuate with accelerated early growth but subsequent impaired growth, causing short stature. Thin arms and/or legs with stiff joints may develop. Spinal abnormalities may lead to extreme curvature in some cases. Over time, affected individuals may eventually develop degenerative disease affecting multiple joints (destructive polyarthropathy).In type 3 disease, a diminished or abnormal immune system response can make affected individuals more susceptible to bacterial infections, particularly of the respiratory system. Infections affecting the middle ear and gastrointestinal tract are also common. Recurrent infections are more common during the first decade of life.Some individuals with alpha-mannosidosis develop psychiatric abnormalities such as confusion, anxiety, depression or hallucinations. These symptoms may persist for days or weeks, followed by a need for excessive amounts of sleep (hypersomnia). Psychiatric symptoms or behavioral problems occur in almost half of those affected and usually develop during adolescence or early adulthood. | 62 | Alpha-Mannosidosis |
nord_62_2 | Causes of Alpha-Mannosidosis | Alpha-mannosidosis is caused by changes (mutations) in the MAN2B1 gene. The MAN2B1 gene contains instructions for producing the enzyme lysosomal alpha-mannosidase (LAMAN). This enzyme is essential for breaking down (metabolizing) certain glycoproteins. Without proper levels of functional version of this enzyme, these glycoproteins abnormally accumulate in and damage various tissues and organs of the body. Mutations of the MAN2B1 gene result in the lack of production of the alpha-D-mannosidase enzyme or the production of a defective, inactive form of the enzyme.Alpha-mannosidosis 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. | Causes of Alpha-Mannosidosis. Alpha-mannosidosis is caused by changes (mutations) in the MAN2B1 gene. The MAN2B1 gene contains instructions for producing the enzyme lysosomal alpha-mannosidase (LAMAN). This enzyme is essential for breaking down (metabolizing) certain glycoproteins. Without proper levels of functional version of this enzyme, these glycoproteins abnormally accumulate in and damage various tissues and organs of the body. Mutations of the MAN2B1 gene result in the lack of production of the alpha-D-mannosidase enzyme or the production of a defective, inactive form of the enzyme.Alpha-mannosidosis 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. | 62 | Alpha-Mannosidosis |
nord_62_3 | Affects of Alpha-Mannosidosis | The prevalence of alpha-mannosidosis is estimated to be 1 in every 500,000 people in the general population. Alpha-mannosidosis affects men and women in equal numbers and can potentially affect individuals of any ethnic group worldwide. | Affects of Alpha-Mannosidosis. The prevalence of alpha-mannosidosis is estimated to be 1 in every 500,000 people in the general population. Alpha-mannosidosis affects men and women in equal numbers and can potentially affect individuals of any ethnic group worldwide. | 62 | Alpha-Mannosidosis |
nord_62_4 | Related disorders of Alpha-Mannosidosis | Symptoms of the following disorders can be similar to alpha-mannosidosis. Comparisons may be useful for a differential diagnosis: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 choose lysosomal storage disease as your search term in the Rare Disease Database.)Mannosidosis, beta A lysosomal is a very rare lysosomal disorder only a few cases of which (one to two dozen) have been reported. Like alpha-mannosidosis, this disorder is characterized by the accumulation of polysaccharides (larger molecules composed of several linked sugar molecules) in the cell. Some clinicians believe that the symptoms of this disorder are less severe than those of alpha-mannosidosis. The symptoms resemble those of alpha-mannosidosis in being multi-systemic.The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis. These disorders, with one exception, are inherited as autosomal recessive traits. (For more information on MPS Disorders, choose “MPS” as your search term in the Rare Disease Database.)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 mental retardation, easy fatigability, and/or heart disease. Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait. (For more information on Pseudo-Hurler polydystrophy, use “I-Cell” as your search term in the Rare Disease Database.)Pseudo-Hurler polydystrophy (mucolipidosis III) is a genetic disorder beginning during childhood. This disorder is characterized by symptoms such as painless joint stiffness, decreased mobility, short stature, some coarseness of the facial features, mild mental retardation, multiple defective bone formations, and aortic valve heart disease. Mobility may gradually diminish until puberty after which no further changes occur. Pseudo-Hurler polydystrophy is a milder form of I-cell disease (mucolipidosis II). (For more information on Pseudo-Hurler polydystrophy, use “I-Cell” as your search term in the Rare Disease Database.) | Related disorders of Alpha-Mannosidosis. Symptoms of the following disorders can be similar to alpha-mannosidosis. Comparisons may be useful for a differential diagnosis: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 choose lysosomal storage disease as your search term in the Rare Disease Database.)Mannosidosis, beta A lysosomal is a very rare lysosomal disorder only a few cases of which (one to two dozen) have been reported. Like alpha-mannosidosis, this disorder is characterized by the accumulation of polysaccharides (larger molecules composed of several linked sugar molecules) in the cell. Some clinicians believe that the symptoms of this disorder are less severe than those of alpha-mannosidosis. The symptoms resemble those of alpha-mannosidosis in being multi-systemic.The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis. These disorders, with one exception, are inherited as autosomal recessive traits. (For more information on MPS Disorders, choose “MPS” as your search term in the Rare Disease Database.)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 mental retardation, easy fatigability, and/or heart disease. Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait. (For more information on Pseudo-Hurler polydystrophy, use “I-Cell” as your search term in the Rare Disease Database.)Pseudo-Hurler polydystrophy (mucolipidosis III) is a genetic disorder beginning during childhood. This disorder is characterized by symptoms such as painless joint stiffness, decreased mobility, short stature, some coarseness of the facial features, mild mental retardation, multiple defective bone formations, and aortic valve heart disease. Mobility may gradually diminish until puberty after which no further changes occur. Pseudo-Hurler polydystrophy is a milder form of I-cell disease (mucolipidosis II). (For more information on Pseudo-Hurler polydystrophy, use “I-Cell” as your search term in the Rare Disease Database.) | 62 | Alpha-Mannosidosis |
nord_62_5 | Diagnosis of Alpha-Mannosidosis | A diagnosis of alpha-mannosidosis is suspected based upon identification of characteristic findings, a thorough clinical evaluation, a detailed a patient history, and specialized tests that can detect deficient levels or activity of the enzyme alpha-mannosidase in white blood cells (leukocytes) or cultured tissue cells (fibroblasts).A diagnosis of alpha-mannosidosis can be confirmed through molecular genetic testing, which can reveal the characteristic mutation of the MAN2B1 gene that causes the disorder. Molecular genetic testing is available on a clinical basis.Elevated levels of certain mannose-rich oligosaccharides (a complex carbohydrate) may be found through urinary analysis. Although this finding is considered suggestive of alpha-mannosidosis, it is not diagnostic. | Diagnosis of Alpha-Mannosidosis. A diagnosis of alpha-mannosidosis is suspected based upon identification of characteristic findings, a thorough clinical evaluation, a detailed a patient history, and specialized tests that can detect deficient levels or activity of the enzyme alpha-mannosidase in white blood cells (leukocytes) or cultured tissue cells (fibroblasts).A diagnosis of alpha-mannosidosis can be confirmed through molecular genetic testing, which can reveal the characteristic mutation of the MAN2B1 gene that causes the disorder. Molecular genetic testing is available on a clinical basis.Elevated levels of certain mannose-rich oligosaccharides (a complex carbohydrate) may be found through urinary analysis. Although this finding is considered suggestive of alpha-mannosidosis, it is not diagnostic. | 62 | Alpha-Mannosidosis |
nord_62_6 | Therapies of Alpha-Mannosidosis | Treatment
Treatment of alpha-mannosidosis is symptomatic and supportive. Therapy is directed at preventing and treating the complications of the disorder. Thus, it is important to be pro-active. Antibiotics are used to suppress bacterial infections. Hearing aids and pressure equalizing tubes are used to improve hearing. Physiotherapy for muscle weakness is often prescribed.Orthopedic interventions including surgery or the use of assistive devices (e.g., special shoes or orthosis) may be necessary to treat associated skeletal abnormalities. Some individuals may require the use of a wheelchair.Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed.Early intervention is important in ensuring that children with alpha-mannosidosis reach their highest potential. Services that may be beneficial may include special education, speech therapy, special services for children with hearing loss, and other medical, social, and/or vocational services. Genetic counseling may be of benefit for patients and their families. | Therapies of Alpha-Mannosidosis. Treatment
Treatment of alpha-mannosidosis is symptomatic and supportive. Therapy is directed at preventing and treating the complications of the disorder. Thus, it is important to be pro-active. Antibiotics are used to suppress bacterial infections. Hearing aids and pressure equalizing tubes are used to improve hearing. Physiotherapy for muscle weakness is often prescribed.Orthopedic interventions including surgery or the use of assistive devices (e.g., special shoes or orthosis) may be necessary to treat associated skeletal abnormalities. Some individuals may require the use of a wheelchair.Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed.Early intervention is important in ensuring that children with alpha-mannosidosis reach their highest potential. Services that may be beneficial may include special education, speech therapy, special services for children with hearing loss, and other medical, social, and/or vocational services. Genetic counseling may be of benefit for patients and their families. | 62 | Alpha-Mannosidosis |
nord_63_0 | Overview of Alport Syndrome | SummaryAlport syndrome is a rare genetic disorder characterized by progressive kidney disease and abnormalities of the inner ear and the eye. There are three genetic types. X-linked Alport syndrome (XLAS) is the most common; in these families affected males typically have more severe disease than affected females. In autosomal recessive Alport syndrome (ARAS) the severity of disease in affected males and females is similar. There is also an autosomal dominant form (ADAS) that affects males and females with equal severity. The hallmark of the disease is the presence of blood in the urine (hematuria) early in life, with progressive decline in kidney function (kidney insufficiency) that ultimately results in kidney failure, especially in affected males. About 50% of untreated males with XLAS develop kidney failure by age 25, increasing to 90% by age 40 and nearly 100% by age 60. Females with XLAS usually do not develop kidney insufficiency until later in life. They may not develop kidney insufficiency or failure at all, but the risk increases as they grow older. Both males and females with ARAS develop kidney failure, often in the teen-age years or early adulthood. ADAS tends to be a slowly progressive disorder in which renal insufficiency does not develop until well into adulthood. Individuals with Alport syndrome can also develop progressive hearing loss of varying severity and abnormalities of the eyes that usually do not result in impaired vision. XLAS is caused by variants in the COL4A5 gene. ARAS is caused by variants in both copies of either the COL4A3 or the COL4A4 gene. ADAS is caused by variants in one copy of the COL4A3 or COL4A4 gene. Alport syndrome is treated symptomatically and certain medications can potentially delay the progression of kidney disease and the onset of kidney failure. Ultimately, in many patients, a kidney transplant is required.IntroductionThe disease we now know as Alport syndrome was first described in the British medical literature in the early years of the 20th century. In 1927 Dr. Cecil Alport published a paper describing the association of kidney disease and deafness in affected individuals. Many additional cases were described in the literature and the disorder was named after Dr. Alport in 1961. Alport syndrome is often discussed with a related disorder known as thin basement membrane nephropathy (TBMN), in which the predominant pathologic abnormality is thinning of glomerular basement membranes. Many people diagnosed with TBMN have variants in the same genes that cause Alport syndrome. People diagnosed with TBMN have persistent microscopic blood in the urine (hematuria) in a similar pattern as seen in individuals with Alport syndrome. Patients given a diagnosis of TBMN are less likely to have symptoms outside of the kidney (extrarenal abnormalities) than patients with Alport syndrome, and additional kidney findings such as protein in the urine (proteinuria), high blood pressure (hypertension), kidney insufficiency, and kidney failure are less common than in Alport syndrome. Patients who have hematuria and variants in the COL4A3, COL4A4 or COL4A5 genes should be given a diagnosis of Alport syndrome, while those with thin glomerular basement membranes but no variants in these genes should be diagnosed with hematuria with thin glomerular basement membranes. Differentiating Alport syndrome and TBMN can be challenging, especially in young patients and in women. For more information on this topic see the Related Disorders section of this report. | Overview of Alport Syndrome. SummaryAlport syndrome is a rare genetic disorder characterized by progressive kidney disease and abnormalities of the inner ear and the eye. There are three genetic types. X-linked Alport syndrome (XLAS) is the most common; in these families affected males typically have more severe disease than affected females. In autosomal recessive Alport syndrome (ARAS) the severity of disease in affected males and females is similar. There is also an autosomal dominant form (ADAS) that affects males and females with equal severity. The hallmark of the disease is the presence of blood in the urine (hematuria) early in life, with progressive decline in kidney function (kidney insufficiency) that ultimately results in kidney failure, especially in affected males. About 50% of untreated males with XLAS develop kidney failure by age 25, increasing to 90% by age 40 and nearly 100% by age 60. Females with XLAS usually do not develop kidney insufficiency until later in life. They may not develop kidney insufficiency or failure at all, but the risk increases as they grow older. Both males and females with ARAS develop kidney failure, often in the teen-age years or early adulthood. ADAS tends to be a slowly progressive disorder in which renal insufficiency does not develop until well into adulthood. Individuals with Alport syndrome can also develop progressive hearing loss of varying severity and abnormalities of the eyes that usually do not result in impaired vision. XLAS is caused by variants in the COL4A5 gene. ARAS is caused by variants in both copies of either the COL4A3 or the COL4A4 gene. ADAS is caused by variants in one copy of the COL4A3 or COL4A4 gene. Alport syndrome is treated symptomatically and certain medications can potentially delay the progression of kidney disease and the onset of kidney failure. Ultimately, in many patients, a kidney transplant is required.IntroductionThe disease we now know as Alport syndrome was first described in the British medical literature in the early years of the 20th century. In 1927 Dr. Cecil Alport published a paper describing the association of kidney disease and deafness in affected individuals. Many additional cases were described in the literature and the disorder was named after Dr. Alport in 1961. Alport syndrome is often discussed with a related disorder known as thin basement membrane nephropathy (TBMN), in which the predominant pathologic abnormality is thinning of glomerular basement membranes. Many people diagnosed with TBMN have variants in the same genes that cause Alport syndrome. People diagnosed with TBMN have persistent microscopic blood in the urine (hematuria) in a similar pattern as seen in individuals with Alport syndrome. Patients given a diagnosis of TBMN are less likely to have symptoms outside of the kidney (extrarenal abnormalities) than patients with Alport syndrome, and additional kidney findings such as protein in the urine (proteinuria), high blood pressure (hypertension), kidney insufficiency, and kidney failure are less common than in Alport syndrome. Patients who have hematuria and variants in the COL4A3, COL4A4 or COL4A5 genes should be given a diagnosis of Alport syndrome, while those with thin glomerular basement membranes but no variants in these genes should be diagnosed with hematuria with thin glomerular basement membranes. Differentiating Alport syndrome and TBMN can be challenging, especially in young patients and in women. For more information on this topic see the Related Disorders section of this report. | 63 | Alport Syndrome |
nord_63_1 | Symptoms of Alport Syndrome | The onset, symptoms, progression, and severity of Alport syndrome can vary greatly from one person to another due, in part, to the specific subtype and gene variant present. Some individuals may have a mild, slowly progressive form of the disorder, while others have earlier onset of severe complications.The first sign of kidney disease is blood in the urine (hematuria). Hematuria is usually not visible to the naked eye, but can be seen when the urine is examined under a microscope. This is referred to as microscopic hematuria. Sometimes, blood may be visible in the urine (i.e. the urine may be brown, pink, or red) for a few days, usually when an affected individual has a cold or the flu. This is referred to as an episode of gross hematuria. Males with XLAS usually exhibit persistent microscopic hematuria early in life. About 95% of females with XLAS syndrome have microscopic hematuria, but it may come and go (intermittent). Both males and females with ARAS develop hematuria during childhood. Males and females with ADAS also have hematuria.With time many affected individuals exhibit elevated levels of albumin and other proteins in the urine (albuminuria and proteinuria), which are indications that kidney disease is progressing. The next stage in progression is gradual loss of kidney function, frequently associated with high blood pressure (hypertension), until, ultimately, the kidneys fail to work (end stage renal disease or ESRD). The kidneys have several functions including filtering and excreting wastes products from the blood and body, creating certain hormones, and helping maintain the balance of certain minerals in the body such as potassium, sodium, chloride, and other electrolytes. A variety of symptoms can be associated with ERSD including weakness and fatigue, changes in appetite, puffiness or swelling (edema), poor digestion, excessive thirst and frequent urination.As noted above, the rate of progression of kidney disease varies greatly. Many males with XLAS develop ERSD by their teen-age years or early adulthood, although some will not develop kidney failure until their 40s or 50s. Most females with XLAS do not develop kidney insufficiency until later in life. Kidney failure is less common than in males with XLAS but still a significant risk – about 15% by age 45 and 20-30% by age 60.Progressive hearing loss (sensorineural deafness) occurs frequently in people with Alport syndrome. Sensorineural deafness results from impaired transmission of sound input from the inner ears (cochleae) to the brain via the auditory nerves. The hearing loss is bilateral, meaning it affects both ears. Diminished hearing is usually evident by late childhood in males with XLAS although it may be mild or subtle. In males with XLAS the frequency of hearing loss is approximately 50% by age 15, 75% by age 20 and 90% by age 40. Hearing loss is progressive and may require hearing aids as early as the teen-age years. Hearing aids are typically very helpful in people with deafness caused by Alport syndrome.The onset, progression and severity of hearing loss in Alport syndrome varies greatly due to, in part, the specific genetic variant present in each individual. Hearing loss in females with XLAS occurs less frequently than in males and usually occurs later in life, although a smaller percentage of females will develop hearing loss in their teen-age years. Both males and females with ARAS develop hearing loss, usually during late childhood or early adolescence. Individuals with ADAS may develop hearing loss, although this occurs much later during life, usually as older adults.Individuals with Alport syndrome may also develop abnormalities in several parts of the eyes including the lens, retina and cornea. Eye abnormalities in XLAS and ARAS are very similar in presentation. Eye abnormalities are uncommon in ADAS.Anterior lenticonus is a condition in which the lenses of the eyes are shaped abnormally, specifically the lens bulges forward into the space (anterior chamber) behind the cornea. Anterior lenticonus can result in the need for glasses and sometimes leads to cataract formation. Anterior lenticonus occurs in about 20% of males with XLAS and often becomes apparent by late adolescence or early adulthood.The retina, which is the nerve-rich, light-sensitive membrane that lines the back of the eyes, may also be affected, usually by pigmentary changes caused by the development of yellow or white flecks superficially located on the retina. These changes do not appear to affect vision. Rare patients develop progressive thinning of the retina that can result in holes (macular holes) that can impair vision.The cornea, which is the clear (transparent) outer layer of the eyes, may also be affected, although the specific abnormalities can vary. The effects on the cornea may be slowly progressive. Recurrent corneal erosions in which the outermost layer of the cornea (epithelium) does not stick (adhere) to the eye properly may occur. Recurrent corneal erosions can cause discomfort or severe eye pain, an abnormal sensitivity to light (photophobia), blurred vision, and the sensation of a foreign body (such as dirt or an eyelash) in the eye. Posterior polymorphous corneal dystrophy may also occur. Effects on the cornea may be slowly progressive. Both eyes may be affected; one eye can be more severely affected than the other. In severe cases, posterior polymorphous corneal dystrophy can cause swelling (edema) of a specific layer of the cornea, photophobia, the sensation of a foreign body (such as dirt or an eyelash) in the eye, and decreased vision.Additional symptoms can occur in certain individuals with Alport syndrome. In a small number of males, aneurysms of the chest or abdominal portions of the aorta, the main artery that carries blood away from the heart, have occurred. Aneurysms occur when the walls of blood vessels balloon or bulge outward, potentially rupturing causing bleeding within the body. | Symptoms of Alport Syndrome. The onset, symptoms, progression, and severity of Alport syndrome can vary greatly from one person to another due, in part, to the specific subtype and gene variant present. Some individuals may have a mild, slowly progressive form of the disorder, while others have earlier onset of severe complications.The first sign of kidney disease is blood in the urine (hematuria). Hematuria is usually not visible to the naked eye, but can be seen when the urine is examined under a microscope. This is referred to as microscopic hematuria. Sometimes, blood may be visible in the urine (i.e. the urine may be brown, pink, or red) for a few days, usually when an affected individual has a cold or the flu. This is referred to as an episode of gross hematuria. Males with XLAS usually exhibit persistent microscopic hematuria early in life. About 95% of females with XLAS syndrome have microscopic hematuria, but it may come and go (intermittent). Both males and females with ARAS develop hematuria during childhood. Males and females with ADAS also have hematuria.With time many affected individuals exhibit elevated levels of albumin and other proteins in the urine (albuminuria and proteinuria), which are indications that kidney disease is progressing. The next stage in progression is gradual loss of kidney function, frequently associated with high blood pressure (hypertension), until, ultimately, the kidneys fail to work (end stage renal disease or ESRD). The kidneys have several functions including filtering and excreting wastes products from the blood and body, creating certain hormones, and helping maintain the balance of certain minerals in the body such as potassium, sodium, chloride, and other electrolytes. A variety of symptoms can be associated with ERSD including weakness and fatigue, changes in appetite, puffiness or swelling (edema), poor digestion, excessive thirst and frequent urination.As noted above, the rate of progression of kidney disease varies greatly. Many males with XLAS develop ERSD by their teen-age years or early adulthood, although some will not develop kidney failure until their 40s or 50s. Most females with XLAS do not develop kidney insufficiency until later in life. Kidney failure is less common than in males with XLAS but still a significant risk – about 15% by age 45 and 20-30% by age 60.Progressive hearing loss (sensorineural deafness) occurs frequently in people with Alport syndrome. Sensorineural deafness results from impaired transmission of sound input from the inner ears (cochleae) to the brain via the auditory nerves. The hearing loss is bilateral, meaning it affects both ears. Diminished hearing is usually evident by late childhood in males with XLAS although it may be mild or subtle. In males with XLAS the frequency of hearing loss is approximately 50% by age 15, 75% by age 20 and 90% by age 40. Hearing loss is progressive and may require hearing aids as early as the teen-age years. Hearing aids are typically very helpful in people with deafness caused by Alport syndrome.The onset, progression and severity of hearing loss in Alport syndrome varies greatly due to, in part, the specific genetic variant present in each individual. Hearing loss in females with XLAS occurs less frequently than in males and usually occurs later in life, although a smaller percentage of females will develop hearing loss in their teen-age years. Both males and females with ARAS develop hearing loss, usually during late childhood or early adolescence. Individuals with ADAS may develop hearing loss, although this occurs much later during life, usually as older adults.Individuals with Alport syndrome may also develop abnormalities in several parts of the eyes including the lens, retina and cornea. Eye abnormalities in XLAS and ARAS are very similar in presentation. Eye abnormalities are uncommon in ADAS.Anterior lenticonus is a condition in which the lenses of the eyes are shaped abnormally, specifically the lens bulges forward into the space (anterior chamber) behind the cornea. Anterior lenticonus can result in the need for glasses and sometimes leads to cataract formation. Anterior lenticonus occurs in about 20% of males with XLAS and often becomes apparent by late adolescence or early adulthood.The retina, which is the nerve-rich, light-sensitive membrane that lines the back of the eyes, may also be affected, usually by pigmentary changes caused by the development of yellow or white flecks superficially located on the retina. These changes do not appear to affect vision. Rare patients develop progressive thinning of the retina that can result in holes (macular holes) that can impair vision.The cornea, which is the clear (transparent) outer layer of the eyes, may also be affected, although the specific abnormalities can vary. The effects on the cornea may be slowly progressive. Recurrent corneal erosions in which the outermost layer of the cornea (epithelium) does not stick (adhere) to the eye properly may occur. Recurrent corneal erosions can cause discomfort or severe eye pain, an abnormal sensitivity to light (photophobia), blurred vision, and the sensation of a foreign body (such as dirt or an eyelash) in the eye. Posterior polymorphous corneal dystrophy may also occur. Effects on the cornea may be slowly progressive. Both eyes may be affected; one eye can be more severely affected than the other. In severe cases, posterior polymorphous corneal dystrophy can cause swelling (edema) of a specific layer of the cornea, photophobia, the sensation of a foreign body (such as dirt or an eyelash) in the eye, and decreased vision.Additional symptoms can occur in certain individuals with Alport syndrome. In a small number of males, aneurysms of the chest or abdominal portions of the aorta, the main artery that carries blood away from the heart, have occurred. Aneurysms occur when the walls of blood vessels balloon or bulge outward, potentially rupturing causing bleeding within the body. | 63 | Alport Syndrome |
nord_63_2 | Causes of Alport Syndrome | Alport syndrome is caused by disease-causing variants in the DNA sequences of specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a disease-causing variant in the DNA sequence of genes 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 COL4A5 gene is located on the X chromosome. The COL4A3 and the COL4A4 genes are located on chromosome 2. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.X-linked Alport syndrome is caused by disease-causing variants in the COL4A5 gene, which resides on the X chromosome. X-linked disorders cause more severe symptoms in affected males than in affected females. Females have two X chromosomes in their cells, but one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization,” and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are heterozygous for that disorder, meaning they have one abnormal copy of the gene and one normal copy. As the result of the lyonization process, most heterozygous females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then heterozygous females can be and remain completely asymptomatic. If the mutant copy prevails, then heterozygous females can be affected as severely as males.Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be heterozygous because they inherit a normal copy of the gene from their mothers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female who is heterozygous for an X-linked disorder has a 50% chance with each pregnancy of having a heterozygous daughter, a 50% chance of having a daughter with two normal copies of the gene, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son. Approximately 10-15% of males with XLAS have a variant that occurs randomly (spontaneously) for no known reason. In these cases, the mutation was not inherited from the mother.Autosomal recessive Alport syndrome is caused by disease-causing variants in both copies of either the COL4A3 or the COL4A4 genes. Autosomes are the non-sex chromosomes that carry most of our genes. There are 22 autosomes and cells have two copies of each autosome, one inherited from the mother and the other inherited from the father. Each cell has two copies (alleles) of every autosomal gene. Autosomal recessive genetic disorders occur when an individual inherits an abnormal copy of a gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be heterozygous for the disease, and may or may not show symptoms. The risk for two heterozygous parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is heterozygous 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.Autosomal dominant Alport syndrome is caused by disease-causing variants in one copy of either the COL4A3 gene or the COL4A4 gene. 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 variant (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Researchers have determined that the progression and severity of Alport syndrome tend to vary based upon the specific variant present in a gene as well as the specific location of the variant in the gene. This is known as genotype-phenotype correlation and allows physicians to predict individuals who are at risk of early-onset kidney failure or more likely to develop extra-renal abnormalities. More than 1000 different disease-causing variants have been identified in XLAS.Some individuals with Alport syndrome have loss of genetic material (microdeletion) and loss of function of several adjacent genes (contiguous gene syndrome) on the long arm of the X chromosome, which affects both the COL4A5 and COL4A6 genes. In addition to the classic symptoms of Alport syndrome, affected individuals can develop leiomyomatosis (tumors of smooth muscle that are not malignant). This is known as Alport syndrome with diffuse leiomyomatosis. Another disorder involving a contiguous gene syndrome associated with X-linked Alport syndrome is the AMME complex. For more information on these disorders, see the Related Disorders section below.The COL4A3, COL4A4, and COL4A5 genes create (encode) proteins known as alpha chains of collagen IV, a protein family that serves as the major structural component of basement membranes, specifically those of the kidneys, ears and eyes. Basement membranes are delicate protein matrices that separate the thin outer layer of tissue (epithelium) of a structure from the underlying tissue. The basement membrane anchors the epithelium to the loose connective tissue beneath it and also serves as a barrier. The COL4A3 gene encodes the collagen IV alpha-3 chain. The COL4A4 gene encodes the collagen IV alpha-4 chain. The COL4A5 gene encodes the collagen IV alpha-5 chain. Disease-causing variants in these genes impair the production of functional copies of the corresponding proteins, leading in turn to the improper health and maintenance of collagen IV. The negative effects of collagen IV abnormalities result in the progressive damage to the basement membranes and ultimately the signs and symptoms of Alport syndrome.For example, in the kidneys the glomerular basement membrane (GBM) is a vital component of the walls of the small blood vessels (capillaries) that make up glomeruli. The glomeruli are the filtering units of the kidney. Blood flows through very small capillaries in each glomerulus where it is filtered through the GBM to form urine. Collagen IV acts to strengthen and hold the GBM together. In individuals with Alport syndrome the GBM is initially thin and can develop microscopic ruptures that allow blood cells to leak into the urine, causing hematuria. The cells of the glomeruli respond to the abnormal collagen IV by laying down other proteins that lead to thickening of the GBM while impairing the GBM’s ability to keep protein out of the urine. This results in proteinuria. Further damage such as the formation of scar tissue (fibrosis) in the kidneys may also occur. Damage to the GBM and the kidneys is progressive, causing worsening kidney function and, in many cases, eventually kidney failure. | Causes of Alport Syndrome. Alport syndrome is caused by disease-causing variants in the DNA sequences of specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a disease-causing variant in the DNA sequence of genes 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 COL4A5 gene is located on the X chromosome. The COL4A3 and the COL4A4 genes are located on chromosome 2. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.X-linked Alport syndrome is caused by disease-causing variants in the COL4A5 gene, which resides on the X chromosome. X-linked disorders cause more severe symptoms in affected males than in affected females. Females have two X chromosomes in their cells, but one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization,” and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are heterozygous for that disorder, meaning they have one abnormal copy of the gene and one normal copy. As the result of the lyonization process, most heterozygous females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then heterozygous females can be and remain completely asymptomatic. If the mutant copy prevails, then heterozygous females can be affected as severely as males.Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be heterozygous because they inherit a normal copy of the gene from their mothers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female who is heterozygous for an X-linked disorder has a 50% chance with each pregnancy of having a heterozygous daughter, a 50% chance of having a daughter with two normal copies of the gene, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son. Approximately 10-15% of males with XLAS have a variant that occurs randomly (spontaneously) for no known reason. In these cases, the mutation was not inherited from the mother.Autosomal recessive Alport syndrome is caused by disease-causing variants in both copies of either the COL4A3 or the COL4A4 genes. Autosomes are the non-sex chromosomes that carry most of our genes. There are 22 autosomes and cells have two copies of each autosome, one inherited from the mother and the other inherited from the father. Each cell has two copies (alleles) of every autosomal gene. Autosomal recessive genetic disorders occur when an individual inherits an abnormal copy of a gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be heterozygous for the disease, and may or may not show symptoms. The risk for two heterozygous parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is heterozygous 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.Autosomal dominant Alport syndrome is caused by disease-causing variants in one copy of either the COL4A3 gene or the COL4A4 gene. 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 variant (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Researchers have determined that the progression and severity of Alport syndrome tend to vary based upon the specific variant present in a gene as well as the specific location of the variant in the gene. This is known as genotype-phenotype correlation and allows physicians to predict individuals who are at risk of early-onset kidney failure or more likely to develop extra-renal abnormalities. More than 1000 different disease-causing variants have been identified in XLAS.Some individuals with Alport syndrome have loss of genetic material (microdeletion) and loss of function of several adjacent genes (contiguous gene syndrome) on the long arm of the X chromosome, which affects both the COL4A5 and COL4A6 genes. In addition to the classic symptoms of Alport syndrome, affected individuals can develop leiomyomatosis (tumors of smooth muscle that are not malignant). This is known as Alport syndrome with diffuse leiomyomatosis. Another disorder involving a contiguous gene syndrome associated with X-linked Alport syndrome is the AMME complex. For more information on these disorders, see the Related Disorders section below.The COL4A3, COL4A4, and COL4A5 genes create (encode) proteins known as alpha chains of collagen IV, a protein family that serves as the major structural component of basement membranes, specifically those of the kidneys, ears and eyes. Basement membranes are delicate protein matrices that separate the thin outer layer of tissue (epithelium) of a structure from the underlying tissue. The basement membrane anchors the epithelium to the loose connective tissue beneath it and also serves as a barrier. The COL4A3 gene encodes the collagen IV alpha-3 chain. The COL4A4 gene encodes the collagen IV alpha-4 chain. The COL4A5 gene encodes the collagen IV alpha-5 chain. Disease-causing variants in these genes impair the production of functional copies of the corresponding proteins, leading in turn to the improper health and maintenance of collagen IV. The negative effects of collagen IV abnormalities result in the progressive damage to the basement membranes and ultimately the signs and symptoms of Alport syndrome.For example, in the kidneys the glomerular basement membrane (GBM) is a vital component of the walls of the small blood vessels (capillaries) that make up glomeruli. The glomeruli are the filtering units of the kidney. Blood flows through very small capillaries in each glomerulus where it is filtered through the GBM to form urine. Collagen IV acts to strengthen and hold the GBM together. In individuals with Alport syndrome the GBM is initially thin and can develop microscopic ruptures that allow blood cells to leak into the urine, causing hematuria. The cells of the glomeruli respond to the abnormal collagen IV by laying down other proteins that lead to thickening of the GBM while impairing the GBM’s ability to keep protein out of the urine. This results in proteinuria. Further damage such as the formation of scar tissue (fibrosis) in the kidneys may also occur. Damage to the GBM and the kidneys is progressive, causing worsening kidney function and, in many cases, eventually kidney failure. | 63 | Alport Syndrome |
nord_63_3 | Affects of Alport Syndrome | Alport syndrome is estimated to affect approximately 1 in 5,000-10,000 people in the general population in the United States, which means that approximately 30,000-60,000 people in the United States have the disorder. Alport syndrome is estimated to account for 3% of children with chronic kidney disease and 0.2% of adults with end-stage renal disease in the United States. In XLAS, males are affected more severely than females. In the autosomal forms of Alport syndrome, males and females are affected with equal severity. | Affects of Alport Syndrome. Alport syndrome is estimated to affect approximately 1 in 5,000-10,000 people in the general population in the United States, which means that approximately 30,000-60,000 people in the United States have the disorder. Alport syndrome is estimated to account for 3% of children with chronic kidney disease and 0.2% of adults with end-stage renal disease in the United States. In XLAS, males are affected more severely than females. In the autosomal forms of Alport syndrome, males and females are affected with equal severity. | 63 | Alport Syndrome |
nord_63_4 | Related disorders of Alport Syndrome | Symptoms of the following disorders can be similar to those of Alport syndrome. Comparisons may be useful for a differential diagnosis.Rare individuals with X-linked Alport syndrome have a specific genetic defect known as a contiguous gene syndrome (see Causes section above) and can develop leiomyomatosis, a condition characterized by the uncontrolled growth (proliferation) of smooth muscle cells. There are essentially two types of muscles in the body – voluntary and involuntary. Smooth muscles are involuntary muscles – the brain has no conscious control over them. Smooth muscles react involuntarily in response to various stimuli. For example, smooth muscle that lines the walls of the digestive tract causes wave-like contractions (peristalsis) that aid in the digestion and transport of food. Leiomyomatosis can affect the esophagus and specific airways of the respiratory system (tracheobronchial tree) where it causes difficulty swallowing (dysphagia), shortness of breath (dyspnea), stridor, cough, recurrent bronchitis, vomiting, pain in the upper central portion of the abdomen (epigastric pain), and complications during anesthesia. Affected females often develop thickening of the skin of the vulva and clitoris (vulvar and clitoral hypertrophy). Individuals with have this disorder also develop the symptoms of Alport syndrome including progressive kidney disease and hearing loss.AMME complex is an extremely rare disorder that has only been described in a handful of individuals in a few families (kindreds). AMME stands for Alport syndrome, intellectual disability, midface hypoplasia and elliptocytosis. Affected individuals exhibit the symptoms of X-linked Alport syndrome along with intellectual disability, underdevelopment (hypoplasia) of the middle portion of the face, and abnormally shaped red blood cell (elliptocytosis), which can lead to low levels of circulating red blood cells (anemia). AMME complex is caused by deletion of genetic material on the long arm of the X chromosome which includes the COL4A5 gene and some adjacent genes.Thin basement membrane nephropathy (TBMN) is a term frequently used to describe people who have hematuria without other signs of kidney disease, thin glomerular basement membranes (GBM) on kidney biopsy and negative family history for kidney failure. There is a large degree of overlap between Alport syndrome and so-called TBMN because many people with a diagnosis of TBMN have disease-causing variants in one of the collagen IV genes, and thin GBM is a common pathological finding in people with Alport syndrome. Patients who have hematuria and variants in the COL4A3, COL4A4 or COL4A5 genes should be given a diagnosis of Alport syndrome. Disease-causing variants in collagen IV genes are not always detectable in individuals with hematuria and thin glomerular basement membranes; these individuals should be given a diagnosis of hematuria with thin glomerular basement membranes. There are many disorders in which persistent hematuria is a prominent symptom. Such disorders include IgA nephropathy, dense deposit disease, sickle cell anemia, polycystic kidney disease, atypical hemolytic uremic syndrome and C3 nephropathy. Other familial forms of progressive kidney disease include polycystic kidney disease, nephronophthisis, and Fabry disease. There are a number of rare genetic disorders in which kidney disease is associated with hearing loss, including branchio-oto-renal syndrome, MYH9-related disorders, Townes-Brock syndrome, Bardet-Biedl syndrome, some forms of distal renal tubular acidosis, Bartter syndrome, MELAS syndrome, Fabry disease, branchio-oto-renal syndrome, Townes-Brock syndrome, CHARGE syndrome, Kallmann syndrome, Alstrom syndrome and Muckle-Wells syndrome. NORD has individual reports on many of these disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Alport Syndrome. Symptoms of the following disorders can be similar to those of Alport syndrome. Comparisons may be useful for a differential diagnosis.Rare individuals with X-linked Alport syndrome have a specific genetic defect known as a contiguous gene syndrome (see Causes section above) and can develop leiomyomatosis, a condition characterized by the uncontrolled growth (proliferation) of smooth muscle cells. There are essentially two types of muscles in the body – voluntary and involuntary. Smooth muscles are involuntary muscles – the brain has no conscious control over them. Smooth muscles react involuntarily in response to various stimuli. For example, smooth muscle that lines the walls of the digestive tract causes wave-like contractions (peristalsis) that aid in the digestion and transport of food. Leiomyomatosis can affect the esophagus and specific airways of the respiratory system (tracheobronchial tree) where it causes difficulty swallowing (dysphagia), shortness of breath (dyspnea), stridor, cough, recurrent bronchitis, vomiting, pain in the upper central portion of the abdomen (epigastric pain), and complications during anesthesia. Affected females often develop thickening of the skin of the vulva and clitoris (vulvar and clitoral hypertrophy). Individuals with have this disorder also develop the symptoms of Alport syndrome including progressive kidney disease and hearing loss.AMME complex is an extremely rare disorder that has only been described in a handful of individuals in a few families (kindreds). AMME stands for Alport syndrome, intellectual disability, midface hypoplasia and elliptocytosis. Affected individuals exhibit the symptoms of X-linked Alport syndrome along with intellectual disability, underdevelopment (hypoplasia) of the middle portion of the face, and abnormally shaped red blood cell (elliptocytosis), which can lead to low levels of circulating red blood cells (anemia). AMME complex is caused by deletion of genetic material on the long arm of the X chromosome which includes the COL4A5 gene and some adjacent genes.Thin basement membrane nephropathy (TBMN) is a term frequently used to describe people who have hematuria without other signs of kidney disease, thin glomerular basement membranes (GBM) on kidney biopsy and negative family history for kidney failure. There is a large degree of overlap between Alport syndrome and so-called TBMN because many people with a diagnosis of TBMN have disease-causing variants in one of the collagen IV genes, and thin GBM is a common pathological finding in people with Alport syndrome. Patients who have hematuria and variants in the COL4A3, COL4A4 or COL4A5 genes should be given a diagnosis of Alport syndrome. Disease-causing variants in collagen IV genes are not always detectable in individuals with hematuria and thin glomerular basement membranes; these individuals should be given a diagnosis of hematuria with thin glomerular basement membranes. There are many disorders in which persistent hematuria is a prominent symptom. Such disorders include IgA nephropathy, dense deposit disease, sickle cell anemia, polycystic kidney disease, atypical hemolytic uremic syndrome and C3 nephropathy. Other familial forms of progressive kidney disease include polycystic kidney disease, nephronophthisis, and Fabry disease. There are a number of rare genetic disorders in which kidney disease is associated with hearing loss, including branchio-oto-renal syndrome, MYH9-related disorders, Townes-Brock syndrome, Bardet-Biedl syndrome, some forms of distal renal tubular acidosis, Bartter syndrome, MELAS syndrome, Fabry disease, branchio-oto-renal syndrome, Townes-Brock syndrome, CHARGE syndrome, Kallmann syndrome, Alstrom syndrome and Muckle-Wells syndrome. NORD has individual reports on many of these disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 63 | Alport Syndrome |
nord_63_5 | Diagnosis of Alport Syndrome | A diagnosis of Alport syndrome is suspected based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. The likelihood of diagnosis increases in individuals with a family history of Alport syndrome, kidney failure without known cause, early hearing loss or hematuria. A variety of specialized tests can help to confirm a suspected diagnosis.Clinical Testing and Workup
The diagnostic approach to confirming a suspected diagnosis of Alport syndrome has been evolving over the past decade. While tissue studies (kidney or skin biopsy) are very useful tools in the evaluation of patients with hematuria, early genetic testing is becoming increasingly important. When clinical information and family history strongly suggest a diagnosis of Alport syndrome, genetic testing, using the techniques of next generation or whole exome sequencing, can confirm the diagnosis, establish the inheritance pattern and provide useful prognostic information. Genetic testing for Alport syndrome is offered by several commercial laboratories as well as some hospital laboratories, but there is wide variation in insurance coverage.When genetic testing is unavailable or inaccessible, studies of tissue specimens (biopsies) are performed. A suspected diagnosis of XLAS may be confirmed by skin biopsy. A specific test known as immunostaining is performed on the sample. With immunostaining, an antibody that reacts against collagen type IV alpha-5 chain proteins is added to the skin sample. This allows physicians to determine whether a specific protein is present and in what quantity. Normally, alpha-5 chains are found in skin samples, but in males with XLAS they are nearly completely absent. Alpha-3 and alpha-4 chains are not present in the skin and, therefore, skin biopsies cannot be used to diagnose ARAS or ADAS.A kidney biopsy may be also performed. A kidney biopsy can reveal characteristic changes to kidney tissue including abnormalities of the glomerular basement membrane (GBM) that can be detected by an electron microscope. Immunostaining can also be performed on a kidney biopsy sample. In addition to detecting alpha-5 chains, kidney samples can be assessed to determine whether type IV collagen alpha-3 or alpha-4 chains are present and in what quantity.Examination of urine samples (urinalysis) can reveal microscopic or gross amounts of blood (hematuria) in the urine. Hematuria may come and go (intermittent) in some cases, especially females with XLAS or individuals with ADAS. If kidney disease has progressed, elevated levels of protein can also be detected in urine samples.Individuals diagnosed with Alport syndrome should undergo hearing tests that determine a person’s audible range for tones and speech (audiometry) and a complete eye (ophthalmological) exam.In cases where a parent has a known genetic abnormality (i.e. heterozygous mothers) prenatal diagnosis or pre-implantation genetic diagnosis (PGD) may be options. Prenatal diagnosis is possible through chorionic villi sampling (CVS) or amniocentesis. During CVS, fetal tissue samples are removed and enzyme tests (assays) are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes). During amniocentesis, a sample of the fluid that surrounds the developing fetus is removed and studied.PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional. | Diagnosis of Alport Syndrome. A diagnosis of Alport syndrome is suspected based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. The likelihood of diagnosis increases in individuals with a family history of Alport syndrome, kidney failure without known cause, early hearing loss or hematuria. A variety of specialized tests can help to confirm a suspected diagnosis.Clinical Testing and Workup
The diagnostic approach to confirming a suspected diagnosis of Alport syndrome has been evolving over the past decade. While tissue studies (kidney or skin biopsy) are very useful tools in the evaluation of patients with hematuria, early genetic testing is becoming increasingly important. When clinical information and family history strongly suggest a diagnosis of Alport syndrome, genetic testing, using the techniques of next generation or whole exome sequencing, can confirm the diagnosis, establish the inheritance pattern and provide useful prognostic information. Genetic testing for Alport syndrome is offered by several commercial laboratories as well as some hospital laboratories, but there is wide variation in insurance coverage.When genetic testing is unavailable or inaccessible, studies of tissue specimens (biopsies) are performed. A suspected diagnosis of XLAS may be confirmed by skin biopsy. A specific test known as immunostaining is performed on the sample. With immunostaining, an antibody that reacts against collagen type IV alpha-5 chain proteins is added to the skin sample. This allows physicians to determine whether a specific protein is present and in what quantity. Normally, alpha-5 chains are found in skin samples, but in males with XLAS they are nearly completely absent. Alpha-3 and alpha-4 chains are not present in the skin and, therefore, skin biopsies cannot be used to diagnose ARAS or ADAS.A kidney biopsy may be also performed. A kidney biopsy can reveal characteristic changes to kidney tissue including abnormalities of the glomerular basement membrane (GBM) that can be detected by an electron microscope. Immunostaining can also be performed on a kidney biopsy sample. In addition to detecting alpha-5 chains, kidney samples can be assessed to determine whether type IV collagen alpha-3 or alpha-4 chains are present and in what quantity.Examination of urine samples (urinalysis) can reveal microscopic or gross amounts of blood (hematuria) in the urine. Hematuria may come and go (intermittent) in some cases, especially females with XLAS or individuals with ADAS. If kidney disease has progressed, elevated levels of protein can also be detected in urine samples.Individuals diagnosed with Alport syndrome should undergo hearing tests that determine a person’s audible range for tones and speech (audiometry) and a complete eye (ophthalmological) exam.In cases where a parent has a known genetic abnormality (i.e. heterozygous mothers) prenatal diagnosis or pre-implantation genetic diagnosis (PGD) may be options. Prenatal diagnosis is possible through chorionic villi sampling (CVS) or amniocentesis. During CVS, fetal tissue samples are removed and enzyme tests (assays) are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes). During amniocentesis, a sample of the fluid that surrounds the developing fetus is removed and studied.PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional. | 63 | Alport Syndrome |
nord_63_6 | Therapies of Alport Syndrome | TreatmentThe treatment of Alport syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, nephrologists, audiologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Due to the rarity of Alport syndrome, treatment trials that have been tested on a large group of patients are lacking until recently. Clinical practice recommendations based on empiric findings have been published (Kashtan C., et al. 2013 and Savige J., et al. 2013) and discuss the treatment of Alport syndrome, including information on identifying and treating children with a high risk of developing early-onset renal failure.Medications known as angiotensin-converting enzyme (ACE) inhibitors have been used to treat individuals with Alport syndrome. Historical (retrospective) data strongly suggests that early treatment with ACE inhibitors can delays progression to end-stage renal disease in males and females with Alport syndrome. This off-label use may not be appropriate for all affected individuals and several factors must be considered before starting the therapy such as baseline kidney function, family history, and specific symptoms present. ACE inhibitor therapy should be considered in all patients with Alport syndrome who have elevated levels of protein in the urine (overt proteinuria). These drugs are blood pressure medications that prevent (inhibit) an enzyme in the body from producing angiotensin II. Angiotensin II is a chemical that acts to narrow blood vessels and can raise blood pressure. ACE inhibitors in individuals with Alport syndrome have been shown to reduce proteinuria and slow the progression of kidney disease, delaying the onset of renal failure.Some individuals do not respond to or cannot tolerate ACE inhibitors. These individuals may be treated with drugs known as angiotensin receptor blockers (ARBs). ARBs prevent angiotensin II from binding to the corresponding receptors on blood vessels.In the medical literature, ACE inhibitor therapy or ARB therapy is recommended in individuals with Alport syndrome who show overt proteinuria. These therapies may also be considered in affected individuals who have small amounts of albumin in the urine (microalbuminuria), but have not yet developed overt proteinuria. Albumin is a marker for kidney disease because the kidney may leak small amounts of albumin when damaged.Although treatment may slow the progression of kidney disease in Alport syndrome, there is no cure for the disorder and no treatment has thus far been shown to completely stop kidney decline. The rate of progression of kidney decline in individuals with Alport syndrome is highly variable. In many affected individuals kidney function eventually deteriorates to the point where dialysis or a kidney transplant is required.Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney — filtering waste products from the bloodstream, helping to control blood pressure, and helping to maintain proper levels of essential chemicals such as potassium. End-stage renal disease is not reversible so individuals will require lifelong dialysis treatment or a kidney transplant.A kidney transplant is preferred for individuals with Alport syndrome over dialysis and has generally been associated with excellent outcomes in treating affected individuals. Some individuals with Alport syndrome will require a kidney transplant in adolescence or the teen-age years, while others may not require a transplant until they are in their 40s or 50s. Most females with XLAS and some individuals will ADAS syndrome never require a transplant. If a kidney transplant is indicated, great care must be taken in selecting living related kidney donors to ensure that affected individuals are not chosen. Alport syndrome does not recur in kidney transplants. However about 3% or less of transplanted Alport patients make antibodies to the normal collagen IV proteins in the transplanted kidney, causing severe inflammation of the transplant (anti-GBM nephritis).Specific symptoms associated with Alport syndrome are treated by routine, accepted guidelines. For example, hearing aids are used to treat hearing loss when appropriate. Hearing aids are usually effective in people with Alport syndrome because they do not lose the ability to distinguish the various sounds of speech from each other another, as long as the sounds are amplified. Surgery to remove cataracts is performed when necessary. | Therapies of Alport Syndrome. TreatmentThe treatment of Alport syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, nephrologists, audiologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Due to the rarity of Alport syndrome, treatment trials that have been tested on a large group of patients are lacking until recently. Clinical practice recommendations based on empiric findings have been published (Kashtan C., et al. 2013 and Savige J., et al. 2013) and discuss the treatment of Alport syndrome, including information on identifying and treating children with a high risk of developing early-onset renal failure.Medications known as angiotensin-converting enzyme (ACE) inhibitors have been used to treat individuals with Alport syndrome. Historical (retrospective) data strongly suggests that early treatment with ACE inhibitors can delays progression to end-stage renal disease in males and females with Alport syndrome. This off-label use may not be appropriate for all affected individuals and several factors must be considered before starting the therapy such as baseline kidney function, family history, and specific symptoms present. ACE inhibitor therapy should be considered in all patients with Alport syndrome who have elevated levels of protein in the urine (overt proteinuria). These drugs are blood pressure medications that prevent (inhibit) an enzyme in the body from producing angiotensin II. Angiotensin II is a chemical that acts to narrow blood vessels and can raise blood pressure. ACE inhibitors in individuals with Alport syndrome have been shown to reduce proteinuria and slow the progression of kidney disease, delaying the onset of renal failure.Some individuals do not respond to or cannot tolerate ACE inhibitors. These individuals may be treated with drugs known as angiotensin receptor blockers (ARBs). ARBs prevent angiotensin II from binding to the corresponding receptors on blood vessels.In the medical literature, ACE inhibitor therapy or ARB therapy is recommended in individuals with Alport syndrome who show overt proteinuria. These therapies may also be considered in affected individuals who have small amounts of albumin in the urine (microalbuminuria), but have not yet developed overt proteinuria. Albumin is a marker for kidney disease because the kidney may leak small amounts of albumin when damaged.Although treatment may slow the progression of kidney disease in Alport syndrome, there is no cure for the disorder and no treatment has thus far been shown to completely stop kidney decline. The rate of progression of kidney decline in individuals with Alport syndrome is highly variable. In many affected individuals kidney function eventually deteriorates to the point where dialysis or a kidney transplant is required.Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney — filtering waste products from the bloodstream, helping to control blood pressure, and helping to maintain proper levels of essential chemicals such as potassium. End-stage renal disease is not reversible so individuals will require lifelong dialysis treatment or a kidney transplant.A kidney transplant is preferred for individuals with Alport syndrome over dialysis and has generally been associated with excellent outcomes in treating affected individuals. Some individuals with Alport syndrome will require a kidney transplant in adolescence or the teen-age years, while others may not require a transplant until they are in their 40s or 50s. Most females with XLAS and some individuals will ADAS syndrome never require a transplant. If a kidney transplant is indicated, great care must be taken in selecting living related kidney donors to ensure that affected individuals are not chosen. Alport syndrome does not recur in kidney transplants. However about 3% or less of transplanted Alport patients make antibodies to the normal collagen IV proteins in the transplanted kidney, causing severe inflammation of the transplant (anti-GBM nephritis).Specific symptoms associated with Alport syndrome are treated by routine, accepted guidelines. For example, hearing aids are used to treat hearing loss when appropriate. Hearing aids are usually effective in people with Alport syndrome because they do not lose the ability to distinguish the various sounds of speech from each other another, as long as the sounds are amplified. Surgery to remove cataracts is performed when necessary. | 63 | Alport Syndrome |
nord_64_0 | Overview of Alström Syndrome | SummaryAlström syndrome is a rare complex genetic disorder that is associated with a wide variety of symptoms affecting multiple organ systems of the body. The disorder is generally characterized by vision and hearing abnormalities, and obesity in childhood, insulin resistance, diabetes mellitus, heart disease (dilated cardiomyopathy) and slowly progressive kidney (renal) dysfunction, potentially leading to renal failure. Additional symptoms including lung (pulmonary), liver (hepatic), kidney (renal), and endocrine dysfunction can also occur. Although some children may experience delays in attaining developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by disruptions or defects (mutations) in the ALMS1 gene. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. Alström syndrome is inherited as an autosomal recessive trait.IntroductionThe disorder is named after Carl-Henry Alström, a Swedish psychiatrist who, in 1959, first described the condition in the medical literature. | Overview of Alström Syndrome. SummaryAlström syndrome is a rare complex genetic disorder that is associated with a wide variety of symptoms affecting multiple organ systems of the body. The disorder is generally characterized by vision and hearing abnormalities, and obesity in childhood, insulin resistance, diabetes mellitus, heart disease (dilated cardiomyopathy) and slowly progressive kidney (renal) dysfunction, potentially leading to renal failure. Additional symptoms including lung (pulmonary), liver (hepatic), kidney (renal), and endocrine dysfunction can also occur. Although some children may experience delays in attaining developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by disruptions or defects (mutations) in the ALMS1 gene. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. Alström syndrome is inherited as an autosomal recessive trait.IntroductionThe disorder is named after Carl-Henry Alström, a Swedish psychiatrist who, in 1959, first described the condition in the medical literature. | 64 | Alström Syndrome |
nord_64_1 | Symptoms of Alström Syndrome | Alström syndrome may potentially affect several different organ systems of the body. The specific symptoms associated with Alström syndrome, their severity and their rate of progression vary greatly from one person to another, even among members of the same family. It is important to note that affected individuals will not have all of the symptoms discussed below and individual cases may be dramatically different. Some symptoms may present in the first weeks of life, others symptoms may not develop until adolescence or early adulthood.Individuals with Alström syndrome often develop vision abnormalities, specifically cone-rod dystrophy, between birth and 15 months of age. Cone-rod dystrophy is a form of retinal dysfunction. The retina is the light-sensitive membrane upon which images are focused at the back of the eye. In affected individuals, the cells in the retina (cones and rods [photoreceptors]) that convert light into nerve impulses gradually deteriorate (cone-rod dystrophy), causing vision loss. In addition to visual impairment, affected individuals may develop severe sensitivity of the eyes to light (photophobia) and rapid, involuntary eye movements (nystagmus). The progression and degree of visual impairment varies among affected individuals. Some individuals may also develop clouding of the lenses of the eyes (cataracts). In most cases, vision becomes progressively worse through the first and second decade and may result in blindness by the mid-teens. Some individual are able to read large print into their third decade.Hearing may also be affected in Alström syndrome. Hearing is usually normal at birth, but sometime during the first decade of life, progressive sensorineural hearing loss may affect both ears (bilateral) in approximately 70% of patients. Sensorineural hearing loss is caused by an impaired ability of the auditory nerves to transmit sensory input to the brain. Hearing loss may be mild to moderate in degree or may progress to severe or moderately severe by the end of the first or second decade of life. Chronic infection or inflammation of the middle ear (otitis media) may also occur. Some individuals may develop the accumulation of thick, sticky fluid behind the eardrum (glue ear). Long-standing glue ear can cause conductive hearing loss in some cases. Conductive hearing loss is cause by the blockage of sound waves.While vision and hearing are affected in individuals with Alström syndrome, intelligence is usually unaffected. Some infants and children may experience delays in reaching developmental milestones such as crawling or walking. Some children may have delays in developing certain language skills or develop learning disabilities.Birth weight is normal in infants with Alström syndrome, but excessive eating beyond the normal need to satisfy hunger (hyperphagia) and rapid weight gain may occur during the first year of life. Some affected children develop childhood truncal obesity, a condition in which fat is disproportionately distributed on the abdomen and chest rather than the arms and legs. As affected individuals age, some may see their body weight fall, often regaining normal or slightly above-average weight for their size.In childhood, height is typically normal or above normal. As the child grows into adolescence and adulthood, growth slows and final adult height is below the 50th percentile.More than 60 percent of children with Alström syndrome develop a condition known as dilated cardiomyopathy, in which weakening of the myocardium–the heart muscle forming the walls of the heart chambers–leads to enlargement (dilatation) of the heart’s lower chambers (ventricles). Dilated cardiomyopathy may not be associated with any symptoms initially, but eventually leads to weakening of the heart’s pumping action, which impairs the circulation of blood through the lungs and the rest of the body resulting in fluid buildup in the heart, lung and various body tissues (congestive heart failure).Associated symptoms and findings may depend upon the degree of heart failure, the affected child’s age, and other factors. For example, in some infants, signs of heart failure may include feeding difficulties and poor weight gain, irritability, excessive sweating; labored, rapid breathing (tachypnea); bluish discoloration of the skin and mucous membranes due to abnormally low levels of circulating oxygen (cyanosis), among other findings. Children with heart failure may develop fatigue; shortness of breath (dyspnea), coughing, lack of appetite (anorexia); or abdominal pain.The onset, severity and progression of dilated cardiomyopathy vary greatly even among members of the same family. Dilated cardiomyopathy can develop during infancy or in early adulthood. In some cases, it has preceded the development of the characteristic eye abnormalities of Alström syndrome. In older children and adults, restrictive cardiomyopathy can develop.Affected children often experience insulin resistance, a condition in which the body fails to react to insulin. Insulin is a hormone secreted by the pancreas that regulates blood glucose levels by promoting the movement of glucose into cells for energy production or into the liver and fat cells for storage. Glucose is a simple sugar that is the body’s primary source of energy for cell metabolism. In response to insulin resistance, the pancreas secretes more insulin, resulting in abnormally high levels of insulin in the blood (hyperinsulinemia).Individuals with Alström syndrome eventually develop type 2 diabetes mellitus, although the age of onset varies. Children as young as five have developed type 2 diabetes mellitus. In this form of diabetes, the pancreas produces insulin but the body becomes resistant to its effects, leading to insufficient absorption of glucose and abnormally increased glucose levels in the blood (hyperglycemia) and urine. As a result, there may be a gradual onset of certain symptoms, including excessive urination (polyuria) and increased thirst (polydipsia), and the development of particular complications without appropriate treatment.Individuals with Alström syndrome often develop a condition known as acanthosis nigricans, a skin disorder characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Acanthosis nigricans may be a skin manifestation of insulin resistance.Affected individuals may also have elevated levels of certain fats (lipids) in the blood (hyperlipidemia). Hyperlipidemia is usually characterized by elevated triglycerides in the blood (hypertryglyceridemia). Some affected individuals are at risk of a rapid increase in triglycerides, which can cause inflammation of the pancreas (pancreatitis). Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.Some males with Alström syndrome may experience diminished hormone production by the testes (hypogonadotrophic hypogonadism). The onset of puberty may be delayed. Some affected males may develop abnormally enlarged breasts (gynecomastia).Hypogonadism also occurs in affected females, but may not be apparent until puberty. Affected females may develop polycystic ovarian syndrome (PCOS). PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin. PCOS may occur as a symptom of insulin resistance. In some cases, females enter puberty early (before the age of 8), a condition called precocious puberty.Some individuals with Alström syndrome develop various urological abnormalities. As with other symptoms, the severity of urological abnormalities can vary greatly. Affected individuals may be unable to coordinate the muscles of the bladder and the tube that carries urine from the bladder out of the body (urethral dysynergia). Additional abnormalities include difficulty beginning urination, reduced flow, increased time between urinating, inability to control bladder movements (incontinence), and urinary retention. Urinary abnormalities may alternate between underactivity and over activity of the bladder. Many individuals with Alström syndrome also have recurrent urinary tract infections.Affected individuals often experience slowly progressive dysfunction of the kidneys. Onset of kidney dysfunction may be during adolescence or adulthood. In many individuals, early kidney dysfunction may not cause symptoms (asymptomatic). Two common signs of kidney disease are excessive urination (polyuria) and excessive thirst (polydipsia). Eventually, symptoms including swelling of the ankles or a general feeling of ill health (malaise) may develop. Kidney dysfunction may progressively worsen eventually causing end stage renal failure, which can occur as early as the mid or late teen-aged years.Some individuals may develop breathing (respiratory) or lung (pulmonary) problems such as chronic respiratory infections beginning early during childhood. These chronic infections can contribute to the development of asthma, chronic inflammation of the sinuses (sinusitis), a dry cough, and repeated episodes of inflammation of the bronchial tubes (bronchitis) or pneumonia. More serious pulmonary complications can occur including high blood pressure of the main artery of the lungs (pulmonary hypertension), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, and emphysema.The liver may be involved in some cases resulting in abnormal enlargement of the liver (hepatomegaly). The severity of liver involvement can range from elevated liver enzymes, which are common in childhood to fatty liver disease (steatohepatitis). Steatohepatitis is characterized by the accumulation of fatty material in the liver and is often associated with diabetes or obesity. Liver (hepatic) dysfunction may occur and can progress to cause scarring (cirrhosis) within the liver, high blood pressure of the main vein of the liver (portal hypertension), abnormal enlargement of the spleen (splenomegaly), the abnormal accumulation of fluid in the abdominal cavity (ascites) and, eventually, liver failure by the second or third decade.Additional serious complications associated with liver disease including esophageal varices and hepatic encephalopathy can develop. Esophageal varices are damaged, swollen blood vessels in the throat that are prone to bleeding and can rupture potentially causing life-threatening bleeding complications. Hepatic encephalopathy is a brain disorder that occurs in some individuals with chronic liver disease. It is a complex disorder that encompasses a spectrum of disease ranging from a subtle condition with no outward signs to a severe form that can cause life-threatening neurological complications.Additional symptoms may be associated with Alström syndrome including low levels of growth hormone, which may result in short stature in adulthood; high blood pressure (hypertension), abnormally decreased activity of the thyroid gland and underproduction of thyroid hormones (hypothyroidism), advanced bone age; patchy areas of hair loss (alopecia); gastroesophageal reflux; pain in the middle of the abdomen just below the sternum (epigastric pain); and abnormal side-to-side (scoliosis) or front-to-back (kyphosis) curvature of the spine.A variety of neurobehavioral findings have been reported including seizures, decreased reflexes (hyporeflexia), exaggerated response when startled, unexplained joint or muscle pain and dystonia, a group of neurological conditions generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful movements and positions. | Symptoms of Alström Syndrome. Alström syndrome may potentially affect several different organ systems of the body. The specific symptoms associated with Alström syndrome, their severity and their rate of progression vary greatly from one person to another, even among members of the same family. It is important to note that affected individuals will not have all of the symptoms discussed below and individual cases may be dramatically different. Some symptoms may present in the first weeks of life, others symptoms may not develop until adolescence or early adulthood.Individuals with Alström syndrome often develop vision abnormalities, specifically cone-rod dystrophy, between birth and 15 months of age. Cone-rod dystrophy is a form of retinal dysfunction. The retina is the light-sensitive membrane upon which images are focused at the back of the eye. In affected individuals, the cells in the retina (cones and rods [photoreceptors]) that convert light into nerve impulses gradually deteriorate (cone-rod dystrophy), causing vision loss. In addition to visual impairment, affected individuals may develop severe sensitivity of the eyes to light (photophobia) and rapid, involuntary eye movements (nystagmus). The progression and degree of visual impairment varies among affected individuals. Some individuals may also develop clouding of the lenses of the eyes (cataracts). In most cases, vision becomes progressively worse through the first and second decade and may result in blindness by the mid-teens. Some individual are able to read large print into their third decade.Hearing may also be affected in Alström syndrome. Hearing is usually normal at birth, but sometime during the first decade of life, progressive sensorineural hearing loss may affect both ears (bilateral) in approximately 70% of patients. Sensorineural hearing loss is caused by an impaired ability of the auditory nerves to transmit sensory input to the brain. Hearing loss may be mild to moderate in degree or may progress to severe or moderately severe by the end of the first or second decade of life. Chronic infection or inflammation of the middle ear (otitis media) may also occur. Some individuals may develop the accumulation of thick, sticky fluid behind the eardrum (glue ear). Long-standing glue ear can cause conductive hearing loss in some cases. Conductive hearing loss is cause by the blockage of sound waves.While vision and hearing are affected in individuals with Alström syndrome, intelligence is usually unaffected. Some infants and children may experience delays in reaching developmental milestones such as crawling or walking. Some children may have delays in developing certain language skills or develop learning disabilities.Birth weight is normal in infants with Alström syndrome, but excessive eating beyond the normal need to satisfy hunger (hyperphagia) and rapid weight gain may occur during the first year of life. Some affected children develop childhood truncal obesity, a condition in which fat is disproportionately distributed on the abdomen and chest rather than the arms and legs. As affected individuals age, some may see their body weight fall, often regaining normal or slightly above-average weight for their size.In childhood, height is typically normal or above normal. As the child grows into adolescence and adulthood, growth slows and final adult height is below the 50th percentile.More than 60 percent of children with Alström syndrome develop a condition known as dilated cardiomyopathy, in which weakening of the myocardium–the heart muscle forming the walls of the heart chambers–leads to enlargement (dilatation) of the heart’s lower chambers (ventricles). Dilated cardiomyopathy may not be associated with any symptoms initially, but eventually leads to weakening of the heart’s pumping action, which impairs the circulation of blood through the lungs and the rest of the body resulting in fluid buildup in the heart, lung and various body tissues (congestive heart failure).Associated symptoms and findings may depend upon the degree of heart failure, the affected child’s age, and other factors. For example, in some infants, signs of heart failure may include feeding difficulties and poor weight gain, irritability, excessive sweating; labored, rapid breathing (tachypnea); bluish discoloration of the skin and mucous membranes due to abnormally low levels of circulating oxygen (cyanosis), among other findings. Children with heart failure may develop fatigue; shortness of breath (dyspnea), coughing, lack of appetite (anorexia); or abdominal pain.The onset, severity and progression of dilated cardiomyopathy vary greatly even among members of the same family. Dilated cardiomyopathy can develop during infancy or in early adulthood. In some cases, it has preceded the development of the characteristic eye abnormalities of Alström syndrome. In older children and adults, restrictive cardiomyopathy can develop.Affected children often experience insulin resistance, a condition in which the body fails to react to insulin. Insulin is a hormone secreted by the pancreas that regulates blood glucose levels by promoting the movement of glucose into cells for energy production or into the liver and fat cells for storage. Glucose is a simple sugar that is the body’s primary source of energy for cell metabolism. In response to insulin resistance, the pancreas secretes more insulin, resulting in abnormally high levels of insulin in the blood (hyperinsulinemia).Individuals with Alström syndrome eventually develop type 2 diabetes mellitus, although the age of onset varies. Children as young as five have developed type 2 diabetes mellitus. In this form of diabetes, the pancreas produces insulin but the body becomes resistant to its effects, leading to insufficient absorption of glucose and abnormally increased glucose levels in the blood (hyperglycemia) and urine. As a result, there may be a gradual onset of certain symptoms, including excessive urination (polyuria) and increased thirst (polydipsia), and the development of particular complications without appropriate treatment.Individuals with Alström syndrome often develop a condition known as acanthosis nigricans, a skin disorder characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Acanthosis nigricans may be a skin manifestation of insulin resistance.Affected individuals may also have elevated levels of certain fats (lipids) in the blood (hyperlipidemia). Hyperlipidemia is usually characterized by elevated triglycerides in the blood (hypertryglyceridemia). Some affected individuals are at risk of a rapid increase in triglycerides, which can cause inflammation of the pancreas (pancreatitis). Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.Some males with Alström syndrome may experience diminished hormone production by the testes (hypogonadotrophic hypogonadism). The onset of puberty may be delayed. Some affected males may develop abnormally enlarged breasts (gynecomastia).Hypogonadism also occurs in affected females, but may not be apparent until puberty. Affected females may develop polycystic ovarian syndrome (PCOS). PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin. PCOS may occur as a symptom of insulin resistance. In some cases, females enter puberty early (before the age of 8), a condition called precocious puberty.Some individuals with Alström syndrome develop various urological abnormalities. As with other symptoms, the severity of urological abnormalities can vary greatly. Affected individuals may be unable to coordinate the muscles of the bladder and the tube that carries urine from the bladder out of the body (urethral dysynergia). Additional abnormalities include difficulty beginning urination, reduced flow, increased time between urinating, inability to control bladder movements (incontinence), and urinary retention. Urinary abnormalities may alternate between underactivity and over activity of the bladder. Many individuals with Alström syndrome also have recurrent urinary tract infections.Affected individuals often experience slowly progressive dysfunction of the kidneys. Onset of kidney dysfunction may be during adolescence or adulthood. In many individuals, early kidney dysfunction may not cause symptoms (asymptomatic). Two common signs of kidney disease are excessive urination (polyuria) and excessive thirst (polydipsia). Eventually, symptoms including swelling of the ankles or a general feeling of ill health (malaise) may develop. Kidney dysfunction may progressively worsen eventually causing end stage renal failure, which can occur as early as the mid or late teen-aged years.Some individuals may develop breathing (respiratory) or lung (pulmonary) problems such as chronic respiratory infections beginning early during childhood. These chronic infections can contribute to the development of asthma, chronic inflammation of the sinuses (sinusitis), a dry cough, and repeated episodes of inflammation of the bronchial tubes (bronchitis) or pneumonia. More serious pulmonary complications can occur including high blood pressure of the main artery of the lungs (pulmonary hypertension), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, and emphysema.The liver may be involved in some cases resulting in abnormal enlargement of the liver (hepatomegaly). The severity of liver involvement can range from elevated liver enzymes, which are common in childhood to fatty liver disease (steatohepatitis). Steatohepatitis is characterized by the accumulation of fatty material in the liver and is often associated with diabetes or obesity. Liver (hepatic) dysfunction may occur and can progress to cause scarring (cirrhosis) within the liver, high blood pressure of the main vein of the liver (portal hypertension), abnormal enlargement of the spleen (splenomegaly), the abnormal accumulation of fluid in the abdominal cavity (ascites) and, eventually, liver failure by the second or third decade.Additional serious complications associated with liver disease including esophageal varices and hepatic encephalopathy can develop. Esophageal varices are damaged, swollen blood vessels in the throat that are prone to bleeding and can rupture potentially causing life-threatening bleeding complications. Hepatic encephalopathy is a brain disorder that occurs in some individuals with chronic liver disease. It is a complex disorder that encompasses a spectrum of disease ranging from a subtle condition with no outward signs to a severe form that can cause life-threatening neurological complications.Additional symptoms may be associated with Alström syndrome including low levels of growth hormone, which may result in short stature in adulthood; high blood pressure (hypertension), abnormally decreased activity of the thyroid gland and underproduction of thyroid hormones (hypothyroidism), advanced bone age; patchy areas of hair loss (alopecia); gastroesophageal reflux; pain in the middle of the abdomen just below the sternum (epigastric pain); and abnormal side-to-side (scoliosis) or front-to-back (kyphosis) curvature of the spine.A variety of neurobehavioral findings have been reported including seizures, decreased reflexes (hyporeflexia), exaggerated response when startled, unexplained joint or muscle pain and dystonia, a group of neurological conditions generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful movements and positions. | 64 | Alström Syndrome |
nord_64_2 | Causes of Alström Syndrome | Alström syndrome is caused by mutations in the ALMS1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.In Alström syndrome, the gene mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk 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. 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. Investigators have determined that the ALMS1 gene is located on the short arm (p) of chromosome 2 (2p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. 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 2q13” refers to band 13 on the long arm of chromosome 2. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The ALMS1 gene contains instructions for creating (encoding) a specific protein known as ALMS1. The role and function of this protein in the body is not fully understood, but believed to be involved in ciliary function, cell cycle control and intracellular transport. The ALMS1 protein is expressed in all organ tissues of the body (ubiquitously expressed). Research is underway to determine this protein’s exact functions, which should greatly increase the understanding of Alström syndrome. Because symptoms of Alström syndrome vary greatly among family members, researchers suspect that additional genetic or environmental factors may play a role in the development and progression of Alström syndrome.As mentioned above, some research has indicated that the protein encoded by the ALMS1 gene has a role in the proper function, formation, and/or maintenance of cilia, the hair-like structures that can be found in almost all types of cells in the body, and possibly some related structures such as the basal body (which “anchors” the cilia to a cell). A related disorder known as Bardet-Biedl syndrome has also been linked to ciliary dysfunction. Several disorders, referred to as ciliopathies, have been linked to ciliary dysfunction. More research is necessary to determine what role, if any, that cilia and related structures play in the development of Alström syndrome. | Causes of Alström Syndrome. Alström syndrome is caused by mutations in the ALMS1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.In Alström syndrome, the gene mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk 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. 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. Investigators have determined that the ALMS1 gene is located on the short arm (p) of chromosome 2 (2p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. 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 2q13” refers to band 13 on the long arm of chromosome 2. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The ALMS1 gene contains instructions for creating (encoding) a specific protein known as ALMS1. The role and function of this protein in the body is not fully understood, but believed to be involved in ciliary function, cell cycle control and intracellular transport. The ALMS1 protein is expressed in all organ tissues of the body (ubiquitously expressed). Research is underway to determine this protein’s exact functions, which should greatly increase the understanding of Alström syndrome. Because symptoms of Alström syndrome vary greatly among family members, researchers suspect that additional genetic or environmental factors may play a role in the development and progression of Alström syndrome.As mentioned above, some research has indicated that the protein encoded by the ALMS1 gene has a role in the proper function, formation, and/or maintenance of cilia, the hair-like structures that can be found in almost all types of cells in the body, and possibly some related structures such as the basal body (which “anchors” the cilia to a cell). A related disorder known as Bardet-Biedl syndrome has also been linked to ciliary dysfunction. Several disorders, referred to as ciliopathies, have been linked to ciliary dysfunction. More research is necessary to determine what role, if any, that cilia and related structures play in the development of Alström syndrome. | 64 | Alström Syndrome |
nord_64_3 | Affects of Alström Syndrome | Alström syndrome affects males and females in equal numbers. The exact incidence is unknown. Estimates have ranged from 1 in 10,000 to less than 1 in 1,000,000 individuals in the general population. Approximately 1200 affected individuals have been identified worldwide. Because some cases of Alström syndrome may go unrecognized or misdiagnosed, the disorder may be under-diagnosed, making it difficult to determine its true frequency in the general population.Alström syndrome occurs with greater frequency in ethnically isolated communities. | Affects of Alström Syndrome. Alström syndrome affects males and females in equal numbers. The exact incidence is unknown. Estimates have ranged from 1 in 10,000 to less than 1 in 1,000,000 individuals in the general population. Approximately 1200 affected individuals have been identified worldwide. Because some cases of Alström syndrome may go unrecognized or misdiagnosed, the disorder may be under-diagnosed, making it difficult to determine its true frequency in the general population.Alström syndrome occurs with greater frequency in ethnically isolated communities. | 64 | Alström Syndrome |
nord_64_4 | Related disorders of Alström Syndrome | Symptoms of the following disorders can be similar to those of Alström syndrome. Comparisons may be useful for a differential diagnosis.Bardet-Biedl syndrome is a rare, genetic multisystem disorder characterized primarily by deterioration of the cells that receive light stimuli (rod and cone cells) in the retina of the eyes (progressive rod-cone dystrophy), an extra finger near the pinky or an extra toe near the fifth toe (postaxial polydactyly), a condition in which fat is disproportionately distributed on the abdomen and chest rather than the arms and legs (truncal obesity), diminished size and decreased function of the gonads (testes) in males (hypogonadism), kidney (renal) abnormalities, and learning difficulties. Visual abnormalities usually become progressively worse and may ultimately result in blindness. Kidney (renal) abnormalities may progress to cause life-threatening complications. Learning difficulties are a common finding due, in part, to vision loss. Only a minority of affected individuals have severe intellectual disability. Bardet-Biedl syndrome is usually inherited as an autosomal recessive trait. Bardet-Biedl syndrome shows significant overlap with a disorder called Laurence-Moon syndrome. In fact, in the past, these disorders were considered the same and referred to as Laurence-Bardet-Biedl syndrome. Eventually, researchers decided that the two disorders despite numerous similarities were distinct entities. However, recent research has demonstrated that some individuals with the clinical findings of Laurence-Moon syndrome have had mutations in genes linked to Bardet-Biedl syndrome. This discovery has led some researchers to suggest that little evidence exists to continue to classify these two disorders as distinct entities. (For more information on these disorders, choose “Bardet-Biedl” or “Laurence-Moon” as your search term in the Rare Disease Database.)Leber congenital amaurosis (LCA) is a rare genetic eye disorder. Affected infants are often blind at birth or loss their sight within the first few of years of life. Other symptoms may include crossed eyes (strabismus); rapid, involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lenses of the eyes (cataracts); and/or abnormal protrusion of the front (anterior), clear portion of the eye through which light passes (cornea) (keratoconus). In addition, some infants may exhibit hearing loss, intellectual disability, and/or a delay in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor disability). Leber congenital amaurosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Leber Congenital Amaurosis” as your search term in the Rare Disease Database.)Usher syndrome is a rare genetic disorder primarily characterized by deafness due to an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss) accompanied by retinitis pigmentosa, a disorder that causes progressive loss of vision. Researchers have identified three types of Usher’s syndrome and debated the existence of a fourth type. The age at which the disorder appears along with the severity of symptoms distinguishes the different types of Usher syndrome. Usher syndrome may be associated with failure of muscle coordination (ataxia) and night blindness. Usher syndrome is inherited as an autosomal recessive trait. The possible fourth type of Usher syndrome may be inherited as an X-linked trait. (For more information on this disorder, choose “Usher” as your search term in the Rare Disease Database.)Mitochondrial disorders are a group of inherited disorders characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial diseases often hamper the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body and can be associated with similar symptoms to Alström syndrome including cardiomyopathy, sensorineural hearing loss, vision abnormalities and diabetes mellitus. Mitochondrial disorders that share similar characteristics to Alström syndrome include Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia (CPEO). (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Alström Syndrome. Symptoms of the following disorders can be similar to those of Alström syndrome. Comparisons may be useful for a differential diagnosis.Bardet-Biedl syndrome is a rare, genetic multisystem disorder characterized primarily by deterioration of the cells that receive light stimuli (rod and cone cells) in the retina of the eyes (progressive rod-cone dystrophy), an extra finger near the pinky or an extra toe near the fifth toe (postaxial polydactyly), a condition in which fat is disproportionately distributed on the abdomen and chest rather than the arms and legs (truncal obesity), diminished size and decreased function of the gonads (testes) in males (hypogonadism), kidney (renal) abnormalities, and learning difficulties. Visual abnormalities usually become progressively worse and may ultimately result in blindness. Kidney (renal) abnormalities may progress to cause life-threatening complications. Learning difficulties are a common finding due, in part, to vision loss. Only a minority of affected individuals have severe intellectual disability. Bardet-Biedl syndrome is usually inherited as an autosomal recessive trait. Bardet-Biedl syndrome shows significant overlap with a disorder called Laurence-Moon syndrome. In fact, in the past, these disorders were considered the same and referred to as Laurence-Bardet-Biedl syndrome. Eventually, researchers decided that the two disorders despite numerous similarities were distinct entities. However, recent research has demonstrated that some individuals with the clinical findings of Laurence-Moon syndrome have had mutations in genes linked to Bardet-Biedl syndrome. This discovery has led some researchers to suggest that little evidence exists to continue to classify these two disorders as distinct entities. (For more information on these disorders, choose “Bardet-Biedl” or “Laurence-Moon” as your search term in the Rare Disease Database.)Leber congenital amaurosis (LCA) is a rare genetic eye disorder. Affected infants are often blind at birth or loss their sight within the first few of years of life. Other symptoms may include crossed eyes (strabismus); rapid, involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lenses of the eyes (cataracts); and/or abnormal protrusion of the front (anterior), clear portion of the eye through which light passes (cornea) (keratoconus). In addition, some infants may exhibit hearing loss, intellectual disability, and/or a delay in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor disability). Leber congenital amaurosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Leber Congenital Amaurosis” as your search term in the Rare Disease Database.)Usher syndrome is a rare genetic disorder primarily characterized by deafness due to an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss) accompanied by retinitis pigmentosa, a disorder that causes progressive loss of vision. Researchers have identified three types of Usher’s syndrome and debated the existence of a fourth type. The age at which the disorder appears along with the severity of symptoms distinguishes the different types of Usher syndrome. Usher syndrome may be associated with failure of muscle coordination (ataxia) and night blindness. Usher syndrome is inherited as an autosomal recessive trait. The possible fourth type of Usher syndrome may be inherited as an X-linked trait. (For more information on this disorder, choose “Usher” as your search term in the Rare Disease Database.)Mitochondrial disorders are a group of inherited disorders characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial diseases often hamper the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body and can be associated with similar symptoms to Alström syndrome including cardiomyopathy, sensorineural hearing loss, vision abnormalities and diabetes mellitus. Mitochondrial disorders that share similar characteristics to Alström syndrome include Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia (CPEO). (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | 64 | Alström Syndrome |
nord_64_5 | Diagnosis of Alström Syndrome | A diagnosis of Alström syndrome is made upon a thorough clinical evaluation, identification of characteristic findings (e.g., cone-rod dystrophy, sensorineural hearing impairment, cardiomyopathy, obesity, kidney dysfunction, diabetes), and a variety of specialized tests. A diagnosis of Alström syndrome may be difficult because of delayed onset of certain key characteristics including diabetes, cardiomyopathy, and kidney disease. The absence of certain findings (e.g., polydactyly, intellectual disability) distinguishes Alström syndrome from similar syndromes such as Bardet-Biedl syndrome or Laurence-Moon syndrome.Clinical Testing and Work-UpAn eye specialist (ophthalmologist) using specialized tests can make diagnosis of disorders affecting the retina of the eye such as Alström syndrome. An electroretinogram (ERG) may be used to detect abnormalities in the retina, and an electro-oculogram (EOG) may be used to measure retinal function. Sensorineural deafness may be confirmed through a variety of specialized hearing (auditory) tests.Individuals with a suspected diagnosis of Alström syndrome should receive a thorough physical examination to detect the potential presence of additional heart, endocrinological, and kidney abnormalities often associated with Alström syndrome.Molecular genetic testing can confirm a diagnosis of Alström syndrome. Molecular genetic testing can detect mutations in the ALMS1 gene known to cause the disorder. Molecular genetic testing detects ALMS1 mutations in approximately 70%-80% of individuals of Northern European descent and in approximately 40% of individuals worldwide. | Diagnosis of Alström Syndrome. A diagnosis of Alström syndrome is made upon a thorough clinical evaluation, identification of characteristic findings (e.g., cone-rod dystrophy, sensorineural hearing impairment, cardiomyopathy, obesity, kidney dysfunction, diabetes), and a variety of specialized tests. A diagnosis of Alström syndrome may be difficult because of delayed onset of certain key characteristics including diabetes, cardiomyopathy, and kidney disease. The absence of certain findings (e.g., polydactyly, intellectual disability) distinguishes Alström syndrome from similar syndromes such as Bardet-Biedl syndrome or Laurence-Moon syndrome.Clinical Testing and Work-UpAn eye specialist (ophthalmologist) using specialized tests can make diagnosis of disorders affecting the retina of the eye such as Alström syndrome. An electroretinogram (ERG) may be used to detect abnormalities in the retina, and an electro-oculogram (EOG) may be used to measure retinal function. Sensorineural deafness may be confirmed through a variety of specialized hearing (auditory) tests.Individuals with a suspected diagnosis of Alström syndrome should receive a thorough physical examination to detect the potential presence of additional heart, endocrinological, and kidney abnormalities often associated with Alström syndrome.Molecular genetic testing can confirm a diagnosis of Alström syndrome. Molecular genetic testing can detect mutations in the ALMS1 gene known to cause the disorder. Molecular genetic testing detects ALMS1 mutations in approximately 70%-80% of individuals of Northern European descent and in approximately 40% of individuals worldwide. | 64 | Alström Syndrome |
nord_64_6 | Therapies of Alström Syndrome | Treatment
There is no specific treatment for individuals with Alström syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment will require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, specialists who asses and treat hearing problems (audiologists), specialists who asses and treat vision problems (ophthalmologists), specialists who deal with the system of glands that secrete hormones into the bloodstream (endocrinologists), specialists who assess and treat skeletal problems (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Photophobia may be treated with specially-tinted, prescription glasses. In cases where cataracts significantly interfere with vision, they may be removed surgically. Whether or not surgery helps to improve vision often depends on how far the retinal changes have advanced.Various vision aids may help people with Alström syndrome to make the maximum use of their remaining vision. These include optical aids such as Corning and NOIR glasses, the Fresnel Prising telescope, microscopes, and night vision devices. Non-optical aids that may also be useful include the Apollo Laser, Visualtek closed circuit television, the Wide Angle Mobility Light, paper guides, large-print typewriters, and adjustable stands. There are also reading machines and talking computers that can enhance the quality of life for individuals whose vision is severely impaired by Alström syndrome.Children with Alström syndrome should receive instruction while they retain sight. Physicians have recommended that, in anticipation of total blindness, children learn mobility training, adaptive living skills, computing skills such as voice recognition and transcription software, and the use of Braille before sight is lost.There is no specific treatment for sensorineural hearing loss. Hearing aids may help to maximize remaining hearing, and speech therapy may enhance the ability of a child to communicate orally. In the case of deafness associated with Alström syndrome, teaching a child sign language may not be an option as vision loss may also occur. Therefore, educational methods and options should be chosen carefully. A surgical procedure called a myringotomy, in which a thin incision is made in the eardrum to release fluid, may be performed for individuals with glue ear. Cochlear implants, which improve hearing by stimulating nerve fibers within the inner ear, have been beneficial in some cases. Tactile sign language could be of help for some deaf-blind individuals.Strict dietary measures and exercise programs may help to control obesity, as well as aid in the management of diabetes mellitus and/or glucose intolerance associated with Alström syndrome. In most of the diagnosed patients of Alström syndrome, diabetes is controlled by diet and exercise alone. However, it is necessary in some cases to treat the diabetes with oral anti-diabetic agents or insulin. Patients may control diabetes for many years with insulin-sensitizing agents such as metformin. In several individuals, the group of incretins agents such as the Glucagon-like peptide 1 (GLP-1) analogues and the dipeptidyl peptidase-4 (DPP-4) inhibitors have been used with success.If insulin therapy should become necessary for diabetes associated with Alström syndrome, a daily routine of insulin-injection, a controlled diet, exercise to burn off glucose, and testing for blood sugar level is vital in achieving and maintaining good blood sugar control. Self-monitoring of blood glucose levels uses a single drop of blood which is obtained with a finger stick, and placed on a chemically treated pad on a plastic strip; the color change of the chemically treated pad is compared to a color chart or “read” by a battery-operated portable meter. For blind individuals, talking glucose meters are available so that testing can be done independently.In many individuals with Alstrom Syndrome, insulin is ineffective. Insulin must be given by injection, usually two or more times each day. Portable “insulin pumps” have been developed that permit continuous administration of insulin, as well as additional amounts of insulin when needed to control the changes in blood sugar level that occur after meals.If excess levels of protein are detected in the urine (proteinuria), drugs known as angiotensinogen-converting enzyme (ACE) inhibitors may be recommended. In the event of kidney failure a procedure to remove toxins from the blood (dialysis) may be necessary. Kidney transplantation has been successfully performed in a growing number of individuals with Alström syndrome. However, the procedure can be contraindicated by other potential complications of the disorder such as morbid obesity, uncontrolled diabetes or cardiomyopathy.Hypertriglyceridemia may be treated with a low-fat diet or lipid lowering medications.Cardiac abnormalities may be treated with a variety of drugs including ACE inhibitors, which relax blood vessels, thereby lowering the blood pressure and minimizing the effort needed by the heart to pump blood throughout the body; drugs that reduce abnormal fluid retention by promoting the production and excretion of water and sodium from the body through the urine (diuretics); drugs such as digoxin that increase the efficiency of heart muscle contractions and produce a more regular heartbeat; and, in some cases, drugs that reduce the workload of the heart by blocking certain substances from binding to structures within the heart (beta blockers).Rarely, a heart (cardiac) transplant has been successfully performed on individuals with Alström syndrome.As children attain puberty, an evaluation should be performed to see whether hormonal adjustment therapy is necessary. For example, male hypogonadism should be treated with testosterone to preserve sexuality, muscle strength and bone health. Individuals who have hypothyroidism may be treated with L-thyroxine, a type of thyroid hormone. Pediatric patients may be treated with recombinant growth hormone to promote their linear growth. Although controversial for Alstrom patients growth hormone therapy may benefit body composition (the balance between the fat mass and fat free mass) and bone health. Some female disorders such as irregular menses, PCOS and hyperandrogenism may be treated with estrogen and progestin. Female individuals with PCOS and who are overweight and have diabetes may benefit from treatment with diet, exercise and insulin-sensitizing agents such as metformin.A variety of techniques may be used to treat the complications of liver involvement. Portal hypertension may be treated with beta-blocker drugs. Sclerotherapy may be used to treat esophageal varices. Sclerotherapy is a procedure in which a solution, called a sclerosant or sclerosing agent, is injected directly into the affected veins of the throat and the areas adjacent to the affected veins. The solution injected into the veins causes blood clots to form in the veins stopping bleeding. The solution injected into the surrounding areas causes stops bleeding by thickening and swelling the vein to compress the blood vessel.Banding (the application of rubber bands at the bleeding site) may be done to prevent bleeding in the upper gastrointestinal tract. Individuals who fail to respond to other methods may be candidates for transjugular intrahepatic portosystemic shunt (TIPS). During this procedure, a small metal device called a stent is placed into the liver creating an artificial passage from the portal vein to the hepatic vein, thereby improving blood flow. It can decrease the risk of variceal bleeding associated with portal hypertension. Some individuals with severe liver complications may be evaluated for a liver transplantation.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Alström Syndrome. Treatment
There is no specific treatment for individuals with Alström syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment will require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, specialists who asses and treat hearing problems (audiologists), specialists who asses and treat vision problems (ophthalmologists), specialists who deal with the system of glands that secrete hormones into the bloodstream (endocrinologists), specialists who assess and treat skeletal problems (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Photophobia may be treated with specially-tinted, prescription glasses. In cases where cataracts significantly interfere with vision, they may be removed surgically. Whether or not surgery helps to improve vision often depends on how far the retinal changes have advanced.Various vision aids may help people with Alström syndrome to make the maximum use of their remaining vision. These include optical aids such as Corning and NOIR glasses, the Fresnel Prising telescope, microscopes, and night vision devices. Non-optical aids that may also be useful include the Apollo Laser, Visualtek closed circuit television, the Wide Angle Mobility Light, paper guides, large-print typewriters, and adjustable stands. There are also reading machines and talking computers that can enhance the quality of life for individuals whose vision is severely impaired by Alström syndrome.Children with Alström syndrome should receive instruction while they retain sight. Physicians have recommended that, in anticipation of total blindness, children learn mobility training, adaptive living skills, computing skills such as voice recognition and transcription software, and the use of Braille before sight is lost.There is no specific treatment for sensorineural hearing loss. Hearing aids may help to maximize remaining hearing, and speech therapy may enhance the ability of a child to communicate orally. In the case of deafness associated with Alström syndrome, teaching a child sign language may not be an option as vision loss may also occur. Therefore, educational methods and options should be chosen carefully. A surgical procedure called a myringotomy, in which a thin incision is made in the eardrum to release fluid, may be performed for individuals with glue ear. Cochlear implants, which improve hearing by stimulating nerve fibers within the inner ear, have been beneficial in some cases. Tactile sign language could be of help for some deaf-blind individuals.Strict dietary measures and exercise programs may help to control obesity, as well as aid in the management of diabetes mellitus and/or glucose intolerance associated with Alström syndrome. In most of the diagnosed patients of Alström syndrome, diabetes is controlled by diet and exercise alone. However, it is necessary in some cases to treat the diabetes with oral anti-diabetic agents or insulin. Patients may control diabetes for many years with insulin-sensitizing agents such as metformin. In several individuals, the group of incretins agents such as the Glucagon-like peptide 1 (GLP-1) analogues and the dipeptidyl peptidase-4 (DPP-4) inhibitors have been used with success.If insulin therapy should become necessary for diabetes associated with Alström syndrome, a daily routine of insulin-injection, a controlled diet, exercise to burn off glucose, and testing for blood sugar level is vital in achieving and maintaining good blood sugar control. Self-monitoring of blood glucose levels uses a single drop of blood which is obtained with a finger stick, and placed on a chemically treated pad on a plastic strip; the color change of the chemically treated pad is compared to a color chart or “read” by a battery-operated portable meter. For blind individuals, talking glucose meters are available so that testing can be done independently.In many individuals with Alstrom Syndrome, insulin is ineffective. Insulin must be given by injection, usually two or more times each day. Portable “insulin pumps” have been developed that permit continuous administration of insulin, as well as additional amounts of insulin when needed to control the changes in blood sugar level that occur after meals.If excess levels of protein are detected in the urine (proteinuria), drugs known as angiotensinogen-converting enzyme (ACE) inhibitors may be recommended. In the event of kidney failure a procedure to remove toxins from the blood (dialysis) may be necessary. Kidney transplantation has been successfully performed in a growing number of individuals with Alström syndrome. However, the procedure can be contraindicated by other potential complications of the disorder such as morbid obesity, uncontrolled diabetes or cardiomyopathy.Hypertriglyceridemia may be treated with a low-fat diet or lipid lowering medications.Cardiac abnormalities may be treated with a variety of drugs including ACE inhibitors, which relax blood vessels, thereby lowering the blood pressure and minimizing the effort needed by the heart to pump blood throughout the body; drugs that reduce abnormal fluid retention by promoting the production and excretion of water and sodium from the body through the urine (diuretics); drugs such as digoxin that increase the efficiency of heart muscle contractions and produce a more regular heartbeat; and, in some cases, drugs that reduce the workload of the heart by blocking certain substances from binding to structures within the heart (beta blockers).Rarely, a heart (cardiac) transplant has been successfully performed on individuals with Alström syndrome.As children attain puberty, an evaluation should be performed to see whether hormonal adjustment therapy is necessary. For example, male hypogonadism should be treated with testosterone to preserve sexuality, muscle strength and bone health. Individuals who have hypothyroidism may be treated with L-thyroxine, a type of thyroid hormone. Pediatric patients may be treated with recombinant growth hormone to promote their linear growth. Although controversial for Alstrom patients growth hormone therapy may benefit body composition (the balance between the fat mass and fat free mass) and bone health. Some female disorders such as irregular menses, PCOS and hyperandrogenism may be treated with estrogen and progestin. Female individuals with PCOS and who are overweight and have diabetes may benefit from treatment with diet, exercise and insulin-sensitizing agents such as metformin.A variety of techniques may be used to treat the complications of liver involvement. Portal hypertension may be treated with beta-blocker drugs. Sclerotherapy may be used to treat esophageal varices. Sclerotherapy is a procedure in which a solution, called a sclerosant or sclerosing agent, is injected directly into the affected veins of the throat and the areas adjacent to the affected veins. The solution injected into the veins causes blood clots to form in the veins stopping bleeding. The solution injected into the surrounding areas causes stops bleeding by thickening and swelling the vein to compress the blood vessel.Banding (the application of rubber bands at the bleeding site) may be done to prevent bleeding in the upper gastrointestinal tract. Individuals who fail to respond to other methods may be candidates for transjugular intrahepatic portosystemic shunt (TIPS). During this procedure, a small metal device called a stent is placed into the liver creating an artificial passage from the portal vein to the hepatic vein, thereby improving blood flow. It can decrease the risk of variceal bleeding associated with portal hypertension. Some individuals with severe liver complications may be evaluated for a liver transplantation.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 64 | Alström Syndrome |
nord_65_0 | Overview of Alternating Hemiplegia of Childhood | Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by repeated episodes of weakness or paralysis that may affect one side of the body or the other (hemiplegia) or both sides of the body at once (quadriplegia). Additional episodic symptoms usually include intermittent abnormal eye movements, episodes of muscle stiffness or posturing (dystonia), and in a substantial percentage of cases, seizures. Delays in attaining developmental milestones (developmental delays), cognitive impairment, and persistent issues with balance and the presence of continuous dance-like movements of limbs or facial muscles (chorea) may occur independently of episodes of paralysis, weakness or stiffness and persist between episodes. The severity of AHC and the specific types of episodes that occur can vary dramatically from one individual to another. First symptoms usually begin before the age of 18 months. AHC is caused by mutations in the ATP1A3 gene in the majority of those affected. AHC is a rare disorder that was first reported in the medical literature in 1971 by doctors Simon Verret and John C. Steele. They described an unusual disorder in eight children who demonstrated intermittent episodes of weakness, affecting first one side of the body, then the other, with onset in early childhood, including one child who manifested symptoms as early as 3 months of age. However, the disorder remained poorly understood for many years, in part, because of its rarity and complex and highly variable symptoms. More research is necessary to improve early diagnosis, understand the full range of symptoms, and develop more effective treatments. The identification of a causative gene for AHC should lead to a better understanding of the disorder and open new avenues for treatment. The spectrum of related disorders with overlapping symptoms continues to expand, and has led to the increasingly common use of the term “ATP1A3-related neurologic disorders”. This umbrella includes patients with rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. However, an increasing number of patients with overlapping symptoms that further expand the phenotypes even beyond these well-described disorders, initially thought to be completely distinct, continues to expand. | Overview of Alternating Hemiplegia of Childhood. Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by repeated episodes of weakness or paralysis that may affect one side of the body or the other (hemiplegia) or both sides of the body at once (quadriplegia). Additional episodic symptoms usually include intermittent abnormal eye movements, episodes of muscle stiffness or posturing (dystonia), and in a substantial percentage of cases, seizures. Delays in attaining developmental milestones (developmental delays), cognitive impairment, and persistent issues with balance and the presence of continuous dance-like movements of limbs or facial muscles (chorea) may occur independently of episodes of paralysis, weakness or stiffness and persist between episodes. The severity of AHC and the specific types of episodes that occur can vary dramatically from one individual to another. First symptoms usually begin before the age of 18 months. AHC is caused by mutations in the ATP1A3 gene in the majority of those affected. AHC is a rare disorder that was first reported in the medical literature in 1971 by doctors Simon Verret and John C. Steele. They described an unusual disorder in eight children who demonstrated intermittent episodes of weakness, affecting first one side of the body, then the other, with onset in early childhood, including one child who manifested symptoms as early as 3 months of age. However, the disorder remained poorly understood for many years, in part, because of its rarity and complex and highly variable symptoms. More research is necessary to improve early diagnosis, understand the full range of symptoms, and develop more effective treatments. The identification of a causative gene for AHC should lead to a better understanding of the disorder and open new avenues for treatment. The spectrum of related disorders with overlapping symptoms continues to expand, and has led to the increasingly common use of the term “ATP1A3-related neurologic disorders”. This umbrella includes patients with rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. However, an increasing number of patients with overlapping symptoms that further expand the phenotypes even beyond these well-described disorders, initially thought to be completely distinct, continues to expand. | 65 | Alternating Hemiplegia of Childhood |
nord_65_1 | Symptoms of Alternating Hemiplegia of Childhood | AHC is a highly variable and unpredictable disorder and the specific symptoms and severity of the disorder can vary greatly from one person to another. Some individuals may have mild forms of the disorder with a good prognosis, and develop almost normally. However, others may have a severe form with the potential for serious and disabling complications that can disrupt various aspects of life and manifest as persistent neurologic disability.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Symptoms usually develop before 18 months of age.The most prominent symptom is repeated episodes of weakness or paralysis affecting one side of the body at a time in an alternating fashion (alternating hemiplegia or hemiparesis). Weakness or paralysis may also sometimes affect both sides of the body (quadriplegia) or rapidly transition from one side to the other. These episodes typically last for minutes to hours, but in some children under certain circumstances can persist for several days or even weeks in some cases. They may occur daily, weekly or once every few months. In some individuals one side of the body is affected more than the other. In episodes when both sides are involved, one side may recover more quickly than the other. The face may be spared during an episode, but weakness of facial muscles (facial paresis) can occur with mouth deviation, slurred speech, and difficulty swallowing. The intensity of individual episodes varies as well and can range from numbness to a complete loss of feeling and movement. Episodes often begin to appear in early infancy, and sometimes even in the first few days of life.During an episode, affected individuals usually remain alert and may be able to communicate verbally. A unique aspect of these episodes is that they cease when sleeping and may not resume for approximately 15-20 minutes upon waking. In severe, prolonged cases, this window of time may allow affected individuals to eat and drink. Episodes can become worse over time and, in severe cases, can make walking unassisted difficult. Some affected individuals may feel tired or unwell shortly before a hemiplegic episode occurs.Some individuals with AHC may also have additional neurologic symptoms that may occur isolated from or during hemiplegic episodes. These symptoms include sudden, dance-like, involuntary movements of the limbs and facial muscles (choreoathetosis), difficulty breathing (dyspnea), difficulty coordinating muscles (ataxia) causing walking and balance problems, and dystonia. Dystonia is a general term for a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Dystonic attacks can involve the tongue potentially causing breathing and swallowing difficulties.During these episodes, some affected individuals may experience dysfunction of the autonomic nervous system, which regulates certain involuntary body functions such as heart rate, blood pressure, sweating, and bowel and bladder control. Symptoms associated with autonomic dysfunction can vary greatly, but may include excessive or lack of sweating, changes in body temperature, skin discoloration, altered pain perception and gastrointestinal problems. Cardiorespiratory problems such as a slow heartbeat (bradycardia), a high-pitched wheezing (stridor), sudden constriction of the walls of the tiny airway branches called bronchioles (bronchospasm), and difficulty breathing or gasping for breath may also develop.The characteristic episodes that define AHC are not epileptic in nature, although are frequently mistaken for epileptic seizures early in life. However, 50% or more of affected individuals develop epilepsy as they get older. Epileptic seizures typically occur much less frequently than hemiplegic episodes, but when they do, may result in status epilepticus, or persistent seizure activity requiring medical intervention. Epilepsy in children with AHC is often treated with standard antiepileptic medications, but may sometimes prove resistant to traditional epilepsy treatments (intractable epilepsy).Some infants and children with AHC exhibit developmental delays. In addition, some children who experience prolonged, recurrent episodes may develop slowly progressive neurological problems including loss of previously acquired skills (psychomotor regression) and cognitive impairment. Behavioral or psychiatric issues such as impulsivity, short-temperedness, poor communication and poor concentration may also occur. Some affected children may have learning disabilities and issues with skills that require movement and coordination (dyspraxia).A common, frequent type of spell in infants with AHC results in irregular eye movements including rapid, involuntary, “jerking” eye movements that may be side to side, up and down or rotary (episodic nystagmus). Nystagmus often affects only one eye (monocular). In some patients, these irregular eye movements are the first noticeable symptom of AHC, but they often go unrecognized, or are considered most likely to represent seizure activity. Some affected individuals may intermittently appear crossed-eyed, where the eyes are misaligned either outward (exotropia) or inward (esotropia). With exotropia, one eye drifts outward toward the ear, while the other eye faces straight ahead. With esotropia, one eye drifts inward toward the nose, while the other eye faces straight ahead. | Symptoms of Alternating Hemiplegia of Childhood. AHC is a highly variable and unpredictable disorder and the specific symptoms and severity of the disorder can vary greatly from one person to another. Some individuals may have mild forms of the disorder with a good prognosis, and develop almost normally. However, others may have a severe form with the potential for serious and disabling complications that can disrupt various aspects of life and manifest as persistent neurologic disability.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Symptoms usually develop before 18 months of age.The most prominent symptom is repeated episodes of weakness or paralysis affecting one side of the body at a time in an alternating fashion (alternating hemiplegia or hemiparesis). Weakness or paralysis may also sometimes affect both sides of the body (quadriplegia) or rapidly transition from one side to the other. These episodes typically last for minutes to hours, but in some children under certain circumstances can persist for several days or even weeks in some cases. They may occur daily, weekly or once every few months. In some individuals one side of the body is affected more than the other. In episodes when both sides are involved, one side may recover more quickly than the other. The face may be spared during an episode, but weakness of facial muscles (facial paresis) can occur with mouth deviation, slurred speech, and difficulty swallowing. The intensity of individual episodes varies as well and can range from numbness to a complete loss of feeling and movement. Episodes often begin to appear in early infancy, and sometimes even in the first few days of life.During an episode, affected individuals usually remain alert and may be able to communicate verbally. A unique aspect of these episodes is that they cease when sleeping and may not resume for approximately 15-20 minutes upon waking. In severe, prolonged cases, this window of time may allow affected individuals to eat and drink. Episodes can become worse over time and, in severe cases, can make walking unassisted difficult. Some affected individuals may feel tired or unwell shortly before a hemiplegic episode occurs.Some individuals with AHC may also have additional neurologic symptoms that may occur isolated from or during hemiplegic episodes. These symptoms include sudden, dance-like, involuntary movements of the limbs and facial muscles (choreoathetosis), difficulty breathing (dyspnea), difficulty coordinating muscles (ataxia) causing walking and balance problems, and dystonia. Dystonia is a general term for a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Dystonic attacks can involve the tongue potentially causing breathing and swallowing difficulties.During these episodes, some affected individuals may experience dysfunction of the autonomic nervous system, which regulates certain involuntary body functions such as heart rate, blood pressure, sweating, and bowel and bladder control. Symptoms associated with autonomic dysfunction can vary greatly, but may include excessive or lack of sweating, changes in body temperature, skin discoloration, altered pain perception and gastrointestinal problems. Cardiorespiratory problems such as a slow heartbeat (bradycardia), a high-pitched wheezing (stridor), sudden constriction of the walls of the tiny airway branches called bronchioles (bronchospasm), and difficulty breathing or gasping for breath may also develop.The characteristic episodes that define AHC are not epileptic in nature, although are frequently mistaken for epileptic seizures early in life. However, 50% or more of affected individuals develop epilepsy as they get older. Epileptic seizures typically occur much less frequently than hemiplegic episodes, but when they do, may result in status epilepticus, or persistent seizure activity requiring medical intervention. Epilepsy in children with AHC is often treated with standard antiepileptic medications, but may sometimes prove resistant to traditional epilepsy treatments (intractable epilepsy).Some infants and children with AHC exhibit developmental delays. In addition, some children who experience prolonged, recurrent episodes may develop slowly progressive neurological problems including loss of previously acquired skills (psychomotor regression) and cognitive impairment. Behavioral or psychiatric issues such as impulsivity, short-temperedness, poor communication and poor concentration may also occur. Some affected children may have learning disabilities and issues with skills that require movement and coordination (dyspraxia).A common, frequent type of spell in infants with AHC results in irregular eye movements including rapid, involuntary, “jerking” eye movements that may be side to side, up and down or rotary (episodic nystagmus). Nystagmus often affects only one eye (monocular). In some patients, these irregular eye movements are the first noticeable symptom of AHC, but they often go unrecognized, or are considered most likely to represent seizure activity. Some affected individuals may intermittently appear crossed-eyed, where the eyes are misaligned either outward (exotropia) or inward (esotropia). With exotropia, one eye drifts outward toward the ear, while the other eye faces straight ahead. With esotropia, one eye drifts inward toward the nose, while the other eye faces straight ahead. | 65 | Alternating Hemiplegia of Childhood |
nord_65_2 | Causes of Alternating Hemiplegia of Childhood | In at least 2/3 of individuals, AHC is caused by a mutation in the ATP1A3 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.In cases where a mutation in ATP1a3 is disease causing, AHC almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent, and in AHC, de novo mutations are more common than inherited mutations. However, dominant inheritance (where a trait is transmitted from either an affected mother or father to their child) has been documented in at least one affected family with classic AHC, and in a number of patients with rapid onset dystonia parkinsonism, also due to mutations in ATP1A3.The ATP1A3 gene is responsible for the production of the protein, ATPase, Na+K+ transporting, alpha 3 polypeptide, that is required for the normal function of nerve cells in the brain. This protein plays a role in the transport of sodium and potassium ions across a channel that connects nerve cells (neurons), helping to regulate brain activity. Consequently, AHC may be classified as a channelopathy, a group of disorders characterized by abnormalities in the flow of electrically charged particles known as ions (commonly calcium, sodium, and potassium) through pores in cell membranes (ion channels). These channels are involved in various functions of the body and, therefore, channelopathies can potentially cause a wide variety of symptoms.Because some individuals with AHC do not have an identifiable mutation of the ATP1A3 gene, it is possible that mutations in other, yet to be discovered, genes may also be associated with AHC. Other genes which cause AHC or a disorder with similar symptoms include the CACNA1A, SLC1A3, and ATP1A2 in less than 1% of patients.In rare cases where AHC runs in families, it is thought that the disorder is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. The spectrum of ATP1A3-related neurologic disorders includes rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome.Families have noted that individuals may have “triggers” that precede a hemiplegic episode. Identified triggers for AHC include certain environmental situations such as extreme temperatures, crowds, irregular sleep habits, or specific odors; certain physical activities such as exercise: water exposure including bathing, swimming or showering; bright sunlight or fluorescent bulbs; certain foods such as chocolate or food dyes; certain medications; childhood illnesses and infections: and certain emotional situations such as stress, anxiety or fright. Although many different triggers have been reported, many episodes occur with no identifiable trigger. | Causes of Alternating Hemiplegia of Childhood. In at least 2/3 of individuals, AHC is caused by a mutation in the ATP1A3 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.In cases where a mutation in ATP1a3 is disease causing, AHC almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent, and in AHC, de novo mutations are more common than inherited mutations. However, dominant inheritance (where a trait is transmitted from either an affected mother or father to their child) has been documented in at least one affected family with classic AHC, and in a number of patients with rapid onset dystonia parkinsonism, also due to mutations in ATP1A3.The ATP1A3 gene is responsible for the production of the protein, ATPase, Na+K+ transporting, alpha 3 polypeptide, that is required for the normal function of nerve cells in the brain. This protein plays a role in the transport of sodium and potassium ions across a channel that connects nerve cells (neurons), helping to regulate brain activity. Consequently, AHC may be classified as a channelopathy, a group of disorders characterized by abnormalities in the flow of electrically charged particles known as ions (commonly calcium, sodium, and potassium) through pores in cell membranes (ion channels). These channels are involved in various functions of the body and, therefore, channelopathies can potentially cause a wide variety of symptoms.Because some individuals with AHC do not have an identifiable mutation of the ATP1A3 gene, it is possible that mutations in other, yet to be discovered, genes may also be associated with AHC. Other genes which cause AHC or a disorder with similar symptoms include the CACNA1A, SLC1A3, and ATP1A2 in less than 1% of patients.In rare cases where AHC runs in families, it is thought that the disorder is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. The spectrum of ATP1A3-related neurologic disorders includes rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome.Families have noted that individuals may have “triggers” that precede a hemiplegic episode. Identified triggers for AHC include certain environmental situations such as extreme temperatures, crowds, irregular sleep habits, or specific odors; certain physical activities such as exercise: water exposure including bathing, swimming or showering; bright sunlight or fluorescent bulbs; certain foods such as chocolate or food dyes; certain medications; childhood illnesses and infections: and certain emotional situations such as stress, anxiety or fright. Although many different triggers have been reported, many episodes occur with no identifiable trigger. | 65 | Alternating Hemiplegia of Childhood |
nord_65_3 | Affects of Alternating Hemiplegia of Childhood | AHC affects males and females in equal numbers. It is estimated to occur in approximately 1 in 1,000,000 births. However, since cases may go unrecognized or misdiagnosed, it is difficult to determine the true frequency of AHC in the general population. Symptoms usually become apparent within the first 18 months. | Affects of Alternating Hemiplegia of Childhood. AHC affects males and females in equal numbers. It is estimated to occur in approximately 1 in 1,000,000 births. However, since cases may go unrecognized or misdiagnosed, it is difficult to determine the true frequency of AHC in the general population. Symptoms usually become apparent within the first 18 months. | 65 | Alternating Hemiplegia of Childhood |
nord_65_4 | Related disorders of Alternating Hemiplegia of Childhood | Symptoms of the following disorders can be similar to those of AHC. Comparisons may be useful for a differential diagnosis.Familial hemiplegic migraine (FHM) is a rare genetic form of migraine headache. The disorder is characterized be recurrent episodes of migraine and additional symptoms. Onset is usually within the first or second decade of life. The frequency of these episodes can range from one per day to fewer than several in a lifetime. Long-term episode free intervals have been reported. The duration of an episode also varies as well, ranging from a few hours to a few days. Triggers that normally induce a migraine such as certain odors and food, minor head trauma, and emotional situations causing stress or anxiety can also induce an episode of FHM. Additional symptoms can vary from one person to another. Affected individuals may also develop vision abnormalities, sensory issues such as numbness or a sensation of tingling or burning of the extremities or face, and motor problems such as temporary weakness or paralysis of one side of the body (hemiplegia). Confusion and drowsiness and difficulties with speech (dysphasia) have also been reported. Approximately 40-50 percent of affected individuals may develop such as irregular, involuntary eye movements (nystagmus) or an inability to coordinate voluntary movements (ataxia). FHM is inherited as an autosomal dominant trait. To date, several different genes including CACNA1A, ATP1A2, and SCN1A have been identified as causes of FHM.Cerebral palsy is a relatively rare (approximately 3 per 1000 live births) non-progressive neuromuscular disorder that results in impaired movement. Infants with cerebral palsy may display developmental delays before the third year of life and may have abnormally low (hypotonia) or high (hypertonia) muscle tone. Affected infants and children often have some combination of impaired movements including tremors, an inability to coordinate voluntary movements (ataxia), unsteadiness when walking or inability to walk, exaggerated reflexes (hyperreflexia), involuntary muscle spasms (spasticity) that result in slow, stiff rigid movements. Additional characteristics may include difficulty chewing and swallowing, difficulty in gaining bladder or bowel control, convulsions, and/or poor vision and hearing. Since cerebral palsy primarily involves movement and motor function, intelligence may be average to above average, or there may be mild to severe mental impairment. Cerebral palsy may be caused by brain injury during the early stages of fetal development, at birth, or after birth (postnatal). Injury may result from maternal/fetal infection, lack of oxygen (hypoxia), or bleeding into the brain. (For more information on this disorder, choose “Cerebral Palsy” as your search term in the Rare Disease Database.)Epilepsy is a general term for a group of neurological disorders characterized by recurrent seizures and associated with abnormal electrical discharges in the brain. The appearance of an epileptic seizure may be highly variable, but can include loss of consciousness, convulsions, spasms, sensory symptoms, and disturbances in the autonomic nervous system. Attacks may be preceded by an “aura”, a feeling of unease or sensory discomfort; the aura marks the beginning of the seizure in the brain. This is typically seen in partial-onset seizures. There are many different causes of epilepsy, including head injuries, brain malformations, and metabolic syndromes in which the body is unable to use certain energy sources correctly, making it easier for seizures to happen; however in many cases of epilepsy the exact cause is unknown (idiopathic). Epilepsy can also occur as part of larger syndromes. Types of epilepsy or disorders associated with epilepsy include Lennox-Gestaut syndrome, Rett syndrome, Angelman syndrome, Landau-Kleffner syndrome, Dravet syndrome, and the neuronal ceroid lipofuscinoses. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) A wide variety of additional disorders may have signs or symptoms that are similar to those seen in some individuals with AHC including vascular disorders such as Moyamoya disease and arteriovenous malformations; certain metabolic disorders such as glucose transporter type 1 deficiency syndrome, aromatic l-amino acid decarboxylase (AADC) deficiency, homocystinuria, congenital disorders of glycosylation and mitochondrial disorders such as MELAS or pyruvate dehydrogenase deficiency; and neurotransmitter deficiency disorders such as aromatic L-amino acid decarboxylase deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Alternating Hemiplegia of Childhood. Symptoms of the following disorders can be similar to those of AHC. Comparisons may be useful for a differential diagnosis.Familial hemiplegic migraine (FHM) is a rare genetic form of migraine headache. The disorder is characterized be recurrent episodes of migraine and additional symptoms. Onset is usually within the first or second decade of life. The frequency of these episodes can range from one per day to fewer than several in a lifetime. Long-term episode free intervals have been reported. The duration of an episode also varies as well, ranging from a few hours to a few days. Triggers that normally induce a migraine such as certain odors and food, minor head trauma, and emotional situations causing stress or anxiety can also induce an episode of FHM. Additional symptoms can vary from one person to another. Affected individuals may also develop vision abnormalities, sensory issues such as numbness or a sensation of tingling or burning of the extremities or face, and motor problems such as temporary weakness or paralysis of one side of the body (hemiplegia). Confusion and drowsiness and difficulties with speech (dysphasia) have also been reported. Approximately 40-50 percent of affected individuals may develop such as irregular, involuntary eye movements (nystagmus) or an inability to coordinate voluntary movements (ataxia). FHM is inherited as an autosomal dominant trait. To date, several different genes including CACNA1A, ATP1A2, and SCN1A have been identified as causes of FHM.Cerebral palsy is a relatively rare (approximately 3 per 1000 live births) non-progressive neuromuscular disorder that results in impaired movement. Infants with cerebral palsy may display developmental delays before the third year of life and may have abnormally low (hypotonia) or high (hypertonia) muscle tone. Affected infants and children often have some combination of impaired movements including tremors, an inability to coordinate voluntary movements (ataxia), unsteadiness when walking or inability to walk, exaggerated reflexes (hyperreflexia), involuntary muscle spasms (spasticity) that result in slow, stiff rigid movements. Additional characteristics may include difficulty chewing and swallowing, difficulty in gaining bladder or bowel control, convulsions, and/or poor vision and hearing. Since cerebral palsy primarily involves movement and motor function, intelligence may be average to above average, or there may be mild to severe mental impairment. Cerebral palsy may be caused by brain injury during the early stages of fetal development, at birth, or after birth (postnatal). Injury may result from maternal/fetal infection, lack of oxygen (hypoxia), or bleeding into the brain. (For more information on this disorder, choose “Cerebral Palsy” as your search term in the Rare Disease Database.)Epilepsy is a general term for a group of neurological disorders characterized by recurrent seizures and associated with abnormal electrical discharges in the brain. The appearance of an epileptic seizure may be highly variable, but can include loss of consciousness, convulsions, spasms, sensory symptoms, and disturbances in the autonomic nervous system. Attacks may be preceded by an “aura”, a feeling of unease or sensory discomfort; the aura marks the beginning of the seizure in the brain. This is typically seen in partial-onset seizures. There are many different causes of epilepsy, including head injuries, brain malformations, and metabolic syndromes in which the body is unable to use certain energy sources correctly, making it easier for seizures to happen; however in many cases of epilepsy the exact cause is unknown (idiopathic). Epilepsy can also occur as part of larger syndromes. Types of epilepsy or disorders associated with epilepsy include Lennox-Gestaut syndrome, Rett syndrome, Angelman syndrome, Landau-Kleffner syndrome, Dravet syndrome, and the neuronal ceroid lipofuscinoses. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) A wide variety of additional disorders may have signs or symptoms that are similar to those seen in some individuals with AHC including vascular disorders such as Moyamoya disease and arteriovenous malformations; certain metabolic disorders such as glucose transporter type 1 deficiency syndrome, aromatic l-amino acid decarboxylase (AADC) deficiency, homocystinuria, congenital disorders of glycosylation and mitochondrial disorders such as MELAS or pyruvate dehydrogenase deficiency; and neurotransmitter deficiency disorders such as aromatic L-amino acid decarboxylase deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 65 | Alternating Hemiplegia of Childhood |
nord_65_5 | Diagnosis of Alternating Hemiplegia of Childhood | A diagnosis of AHC is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Specific diagnostic criteria have been proposed for AHC. The seven criteria are: (1) onset of symptoms before 18 months; (2) repeated episodes of hemiplegia that sometimes involve both sides of the body; (3) quadriplegia that occurs as an isolated incident or as part of a hemiplegic attack; (4) relief from symptoms upon sleeping; (5) additional paroxysmal attacks such as dystonia, tonic episodes, abnormal eye movements or autonomic dysfunction; (6) evidence of developmental delay or neurological abnormalities such as choreoathetosis, ataxia or cognitive disability; (7) cannot be attributed to another cause.Clinical Testing and Work-upA diagnosis of AHC is primarily one of exclusion. A wide variety of specialized tests may be used to rule out other conditions. Such tests include magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance spectroscopy (MRS). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as brain tissue. An MRA, images are produced to evaluate the blood vessels. An MRS is used to detect metabolic changes in the brain and other organs.Additional tests may include electroencephalogram (EEG), which measures electrical responses in the brain, and is typically used to identify epilepsy; metabolic screening to detect urine organic acids, which is indicative of certain metabolic disorders; studies of cerebrospinal fluid (CSF), which can exclude neurotransmitter deficiency disorders with similar episodic oculomotor abnormalities; erythrocyte sedimentation rates, which measures how long it takes red blood cells to settle in a test tube over a given period to detect inflammatory disorders; and hypercoagulable studies to detect disorders with a predisposition to forming blood clots.Molecular genetic testing for mutations in the ATP1A3 gene is available on a clinical basis via individual targeted gene sequencing or as part of larger gene panels. Increasingly, ATP1A3 mutations are identified in the context of clinical exome sequencing. | Diagnosis of Alternating Hemiplegia of Childhood. A diagnosis of AHC is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Specific diagnostic criteria have been proposed for AHC. The seven criteria are: (1) onset of symptoms before 18 months; (2) repeated episodes of hemiplegia that sometimes involve both sides of the body; (3) quadriplegia that occurs as an isolated incident or as part of a hemiplegic attack; (4) relief from symptoms upon sleeping; (5) additional paroxysmal attacks such as dystonia, tonic episodes, abnormal eye movements or autonomic dysfunction; (6) evidence of developmental delay or neurological abnormalities such as choreoathetosis, ataxia or cognitive disability; (7) cannot be attributed to another cause.Clinical Testing and Work-upA diagnosis of AHC is primarily one of exclusion. A wide variety of specialized tests may be used to rule out other conditions. Such tests include magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance spectroscopy (MRS). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as brain tissue. An MRA, images are produced to evaluate the blood vessels. An MRS is used to detect metabolic changes in the brain and other organs.Additional tests may include electroencephalogram (EEG), which measures electrical responses in the brain, and is typically used to identify epilepsy; metabolic screening to detect urine organic acids, which is indicative of certain metabolic disorders; studies of cerebrospinal fluid (CSF), which can exclude neurotransmitter deficiency disorders with similar episodic oculomotor abnormalities; erythrocyte sedimentation rates, which measures how long it takes red blood cells to settle in a test tube over a given period to detect inflammatory disorders; and hypercoagulable studies to detect disorders with a predisposition to forming blood clots.Molecular genetic testing for mutations in the ATP1A3 gene is available on a clinical basis via individual targeted gene sequencing or as part of larger gene panels. Increasingly, ATP1A3 mutations are identified in the context of clinical exome sequencing. | 65 | Alternating Hemiplegia of Childhood |
nord_65_6 | Therapies of Alternating Hemiplegia of Childhood | TreatmentNo specific therapy exists for individuals with AHC. Treatment is directed toward the specific symptoms apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, neurologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Because AHC is highly variable, an individualized treatment program needs to be devised for each child. The effectiveness of current therapies for AHC will vary greatly among affected individuals. What is effective for one person may not be effective for another.Treatment is generally focused on trying to reduce the frequency and severity of the characteristic episodes and the management of episodes when they occur. Triggers include psychological stress/excitement; environmental stressors (e.g., bright light, excessive heat or cold, excessive sound, crowds); water exposure (e.g., bathing, swimming); certain foods or odors (e.g., chocolate, food dyes, missed meals); excessive or atypically strenuous exercise; illness; irregular sleep (missing a nap, delayed bedtime. Avoiding triggers to the extent possible is recommended for individuals with AHC. In addition, long-term drug therapy may be recommended to help lessen the frequency of episodes.A medication which has proved effective in reducing the frequency or severity of episodes in some individuals is a drug called flunarizine, a drug with calcium channel blocking properties. Flunarizine is given as a preventive (prophylactic) agent and has lessened the frequency, duration and severity of non-epileptic episodes in some individuals with AHC. Flunarizine is not readily available in the US. However, flunarizine is available in other countries for the treatment of migraine and other neurological symptoms.Anti-seizure medications (anti-convulsants) are also used either alone or in combination to treat individuals with AHC who also have epilepsy and to prevent non-epileptic symptoms such as hemiplegia and dystonia. The effectiveness of these medications is highly variable and they are often minimally effective or ineffective. Benzodiazepines such as diazepam have been used to reduce the duration of dystonic episodes.Because some hemiplegic episodes have an early phase where individuals feel unwell, some researchers have recommended using certain medications to prematurely induce sleep. This can lessen the duration and severity of an episode. Such medications include buccal midazolam, chloral hydrate, melatonin, niaprazine or rectal diazepam.Severe episodes of AHC can require hospitalization. In some cases, epileptic seizures can necessitate urgent medical intervention including intravenous to halt seizures or induce sleep in the setting of severe prolonged dystonia.The various symptoms of AHC can affect a child’s growth and development. Episodes can disrupt daily life and impact a child’s ability to learn and participate in various activities. Proactive management of potential complications is required. A supportive team approach for children with AHC is of benefit and may include special education, physical therapy, and additional social, medical or vocational services. Genetic counseling may be of benefit for affected individuals and their families. | Therapies of Alternating Hemiplegia of Childhood. TreatmentNo specific therapy exists for individuals with AHC. Treatment is directed toward the specific symptoms apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, neurologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Because AHC is highly variable, an individualized treatment program needs to be devised for each child. The effectiveness of current therapies for AHC will vary greatly among affected individuals. What is effective for one person may not be effective for another.Treatment is generally focused on trying to reduce the frequency and severity of the characteristic episodes and the management of episodes when they occur. Triggers include psychological stress/excitement; environmental stressors (e.g., bright light, excessive heat or cold, excessive sound, crowds); water exposure (e.g., bathing, swimming); certain foods or odors (e.g., chocolate, food dyes, missed meals); excessive or atypically strenuous exercise; illness; irregular sleep (missing a nap, delayed bedtime. Avoiding triggers to the extent possible is recommended for individuals with AHC. In addition, long-term drug therapy may be recommended to help lessen the frequency of episodes.A medication which has proved effective in reducing the frequency or severity of episodes in some individuals is a drug called flunarizine, a drug with calcium channel blocking properties. Flunarizine is given as a preventive (prophylactic) agent and has lessened the frequency, duration and severity of non-epileptic episodes in some individuals with AHC. Flunarizine is not readily available in the US. However, flunarizine is available in other countries for the treatment of migraine and other neurological symptoms.Anti-seizure medications (anti-convulsants) are also used either alone or in combination to treat individuals with AHC who also have epilepsy and to prevent non-epileptic symptoms such as hemiplegia and dystonia. The effectiveness of these medications is highly variable and they are often minimally effective or ineffective. Benzodiazepines such as diazepam have been used to reduce the duration of dystonic episodes.Because some hemiplegic episodes have an early phase where individuals feel unwell, some researchers have recommended using certain medications to prematurely induce sleep. This can lessen the duration and severity of an episode. Such medications include buccal midazolam, chloral hydrate, melatonin, niaprazine or rectal diazepam.Severe episodes of AHC can require hospitalization. In some cases, epileptic seizures can necessitate urgent medical intervention including intravenous to halt seizures or induce sleep in the setting of severe prolonged dystonia.The various symptoms of AHC can affect a child’s growth and development. Episodes can disrupt daily life and impact a child’s ability to learn and participate in various activities. Proactive management of potential complications is required. A supportive team approach for children with AHC is of benefit and may include special education, physical therapy, and additional social, medical or vocational services. Genetic counseling may be of benefit for affected individuals and their families. | 65 | Alternating Hemiplegia of Childhood |
nord_66_0 | Overview of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins | Summary
Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a rarely diagnosed lethal lung developmental disorder in newborns (neonates) that is present at birth (congenital). Infants experience severe, life-threatening breathing problems (respiratory distress) and high blood pressure in the arterial blood vessels of the lungs (pulmonary hypertension). These problems may occur within a few hours or a couple of days after birth. Almost all infants with this condition die within the first month of life. Very rarely, the disorder presents later (late-onset form). Infants often have additional symptoms involving the gastrointestinal tract, cardiovascular system or genitourinary system. In most affected children, AVDMPV is caused by point mutations (single nucleotide variants in DNA) involving the FOXF1 gene or by a loss of genetic material (copy-number variant (CNV) deletions (or genomic deletion) that include the FOXF1 gene or its distant regulatory genomic region (lung-specific enhancer). The disorder is usually not inherited but there are very rare instances where ACDMPV has been reported to run in families and can be inherited. | Overview of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. Summary
Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a rarely diagnosed lethal lung developmental disorder in newborns (neonates) that is present at birth (congenital). Infants experience severe, life-threatening breathing problems (respiratory distress) and high blood pressure in the arterial blood vessels of the lungs (pulmonary hypertension). These problems may occur within a few hours or a couple of days after birth. Almost all infants with this condition die within the first month of life. Very rarely, the disorder presents later (late-onset form). Infants often have additional symptoms involving the gastrointestinal tract, cardiovascular system or genitourinary system. In most affected children, AVDMPV is caused by point mutations (single nucleotide variants in DNA) involving the FOXF1 gene or by a loss of genetic material (copy-number variant (CNV) deletions (or genomic deletion) that include the FOXF1 gene or its distant regulatory genomic region (lung-specific enhancer). The disorder is usually not inherited but there are very rare instances where ACDMPV has been reported to run in families and can be inherited. | 66 | Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins |
nord_66_1 | Symptoms of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins | Within the first few days after birth, infants with ACDMPV develop severe breathing problems and lack of oxygen in the blood (hypoxemia). They experience shortness of breath and cyanosis, a condition marked by abnormal bluish discoloration of the skin that occurs because of low levels of oxygen in the blood. High blood pressure in the arterial blood vessels of the lungs (pulmonary hypertension) also occurs. Breathing issues become progressively worse and most infants experience respiratory failure. Very rarely, infants may not show signs of the disorder until weeks or even months after birth, usually when pulmonary hypertension of variable severity is noted.Affected infants often have additional symptoms, including gastrointestinal symptoms such as twisting of the large intestines, genitourinary symptoms such as swelling of the kidneys because of urine backing up (hydronephrosis) or cardiovascular symptoms such as underdevelopment of the left side of the heart. | Symptoms of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. Within the first few days after birth, infants with ACDMPV develop severe breathing problems and lack of oxygen in the blood (hypoxemia). They experience shortness of breath and cyanosis, a condition marked by abnormal bluish discoloration of the skin that occurs because of low levels of oxygen in the blood. High blood pressure in the arterial blood vessels of the lungs (pulmonary hypertension) also occurs. Breathing issues become progressively worse and most infants experience respiratory failure. Very rarely, infants may not show signs of the disorder until weeks or even months after birth, usually when pulmonary hypertension of variable severity is noted.Affected infants often have additional symptoms, including gastrointestinal symptoms such as twisting of the large intestines, genitourinary symptoms such as swelling of the kidneys because of urine backing up (hydronephrosis) or cardiovascular symptoms such as underdevelopment of the left side of the heart. | 66 | Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins |
nord_66_2 | Causes of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins | In most affected children, ACDMPV is caused by a point mutation in the FOXF1 gene, or by a loss of genetic material on chromosome 16q24.1 that includes the FOXF1 gene or non-coding elements (promoter and lung-specific enhancer) that regulate the expression of FOXF1. 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 or inefficient. Depending upon the functions of the protein, this can affect many organ systems of the body. For a minority of infants (~10-20%) with ACDMPV, the molecular cause remains unknown. In most instances, the disorder is sporadic, which means that the genetic changes occur at the time of fertilization and are not inherited from the parents. However, there are very rare instances where ACDMPV has been reported to run in families and can be inherited.The FOXF1 gene creates a protein that is a type of transcription factor. Transcription factors are proteins that help to control which genes are turned on and which genes are turned off. They do this by binding with DNA, other protein factors and RNA polymerase. When the FOXF1 gene is altered it does not produce enough of the transcription factor that it is supposed to (or it creates a damaged or inefficient version of it). The lack of this protein causes many problems, particularly affecting the small blood vessels within the lungs.In infants with ACDMPV, the alveolar capillaries fail to develop properly. Alveolar refers to the alveoli, the millions of tiny air sacs that are scattered throughout the lungs. The capillaries are very tiny blood vessels that connect the alveoli to larger blood vessels. When a person breathes in air, oxygen travels to the lungs and into the alveoli. It passes through the walls of the alveoli into the capillaries and into the bloodstream to be carried throughout the body. In addition, carbon dioxide passes from the bloodstream into the alveoli to be sent out of the body when a person breathes out. Because the alveoli capillaries do not develop properly in infants with ACDMPV, sufficient levels of oxygen cannot be delivered to the tissues of the body and not all of the carbon dioxide can be expelled from the body. The pulmonary veins are described as being misaligned or mispositioned.A specific process that may be associated with ACDMPV is the parental chromosome on which genetic defect arises. In contrast to point mutations within FOXF1, the ACDMPV-causative CNV deletions arise de novo almost exclusively on the maternal chromosome 16q24.1. Thus far, 50 de novo CNV deletions have been reported that arose on maternal chromosome 16 and only five de novo CNV deletions arose on paternal chromosome 16q24.1. Recently, a bimodal structure and parental functional dimorphism of the FOXF1 enhancer has been proposed as responsible for this phenomenon.Very rare cases of late onset or mild ACDMPV have been associated with non-coding single nucleotide variants (SNVs) in the lung specific FOXF1 enhancer on the other chromosome 16. They may function as so-called modifiers that up-regulate the other unaffected copy of the FOXF1 gene. | Causes of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. In most affected children, ACDMPV is caused by a point mutation in the FOXF1 gene, or by a loss of genetic material on chromosome 16q24.1 that includes the FOXF1 gene or non-coding elements (promoter and lung-specific enhancer) that regulate the expression of FOXF1. 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 or inefficient. Depending upon the functions of the protein, this can affect many organ systems of the body. For a minority of infants (~10-20%) with ACDMPV, the molecular cause remains unknown. In most instances, the disorder is sporadic, which means that the genetic changes occur at the time of fertilization and are not inherited from the parents. However, there are very rare instances where ACDMPV has been reported to run in families and can be inherited.The FOXF1 gene creates a protein that is a type of transcription factor. Transcription factors are proteins that help to control which genes are turned on and which genes are turned off. They do this by binding with DNA, other protein factors and RNA polymerase. When the FOXF1 gene is altered it does not produce enough of the transcription factor that it is supposed to (or it creates a damaged or inefficient version of it). The lack of this protein causes many problems, particularly affecting the small blood vessels within the lungs.In infants with ACDMPV, the alveolar capillaries fail to develop properly. Alveolar refers to the alveoli, the millions of tiny air sacs that are scattered throughout the lungs. The capillaries are very tiny blood vessels that connect the alveoli to larger blood vessels. When a person breathes in air, oxygen travels to the lungs and into the alveoli. It passes through the walls of the alveoli into the capillaries and into the bloodstream to be carried throughout the body. In addition, carbon dioxide passes from the bloodstream into the alveoli to be sent out of the body when a person breathes out. Because the alveoli capillaries do not develop properly in infants with ACDMPV, sufficient levels of oxygen cannot be delivered to the tissues of the body and not all of the carbon dioxide can be expelled from the body. The pulmonary veins are described as being misaligned or mispositioned.A specific process that may be associated with ACDMPV is the parental chromosome on which genetic defect arises. In contrast to point mutations within FOXF1, the ACDMPV-causative CNV deletions arise de novo almost exclusively on the maternal chromosome 16q24.1. Thus far, 50 de novo CNV deletions have been reported that arose on maternal chromosome 16 and only five de novo CNV deletions arose on paternal chromosome 16q24.1. Recently, a bimodal structure and parental functional dimorphism of the FOXF1 enhancer has been proposed as responsible for this phenomenon.Very rare cases of late onset or mild ACDMPV have been associated with non-coding single nucleotide variants (SNVs) in the lung specific FOXF1 enhancer on the other chromosome 16. They may function as so-called modifiers that up-regulate the other unaffected copy of the FOXF1 gene. | 66 | Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins |
nord_66_3 | Affects of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins | ACDMPV is a very rare disorder. The incidence and prevalence are unknown. More than 200 people with this disorder have been reported in the medical literature. However, many infants may go misdiagnosed or undiagnosed, so determining the true frequency of ACDMPV in the general population is difficult. | Affects of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. ACDMPV is a very rare disorder. The incidence and prevalence are unknown. More than 200 people with this disorder have been reported in the medical literature. However, many infants may go misdiagnosed or undiagnosed, so determining the true frequency of ACDMPV in the general population is difficult. | 66 | Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins |
nord_66_4 | Related disorders of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins | Symptoms of the following disorders can be similar to those of ACDMPV. Comparisons may be useful for a differential diagnosis.Idiopathic persistent pulmonary hypertension of the newborn (PPHN) is characterized by markedly high blood pressure in the pulmonary artery (pulmonary hypertension) of infants that, in turn, causes blood to bypass its normal route and results in less oxygen than required being delivered to the lungs (hypoxemia). PPHN may occur without known cause (idiopathic), or it may arise in connection with many different neonatal cardiorespiratory disorders, including asphyxia, meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS) and congenital diaphragmatic hernia. During fetal life, pulmonary blood flow is low, with less than 10% of the combined cardiac output directed to the lungs. Following birth, pulmonary vascular resistance falls dramatically as the lungs assume the function of gas exchange. In some newborns, the normal decrease in pulmonary vascular tone does not occur, resulting in persistent pulmonary hypertension of the newborn (PPHN). This syndrome results in substantial morbidity and mortality in otherwise healthy term infants. Most infants with PPHN respond to therapies such as inhaled nitric oxide and extracorporeal membrane oxygenation. Most (~90%) recover by the second week of life and survive.Surfactant protein B deficiency is a congenital (present at birth and associated with a gene abnormality) disorder of the lungs that occurs primarily in infants born prematurely and is a result of immaturity of the lungs. The mature lung contains a foamy fluid known as surfactant, a substance essential to expansion of the alveoli or air sacs of the lungs. Because of their immaturity, premature babies tend to lack surfactant. Without surfactant, the lungs cannot inflate, resulting in RDS. Pulmonary surfactant is a complex compound composed primarily of fatty substances and lesser amounts of cholesterol and surfactant-associated protein. When the protein component is missing, the surfactant cannot function properly. The surfactant, when functioning properly, lowers surface tension at the air-liquid interface in the alveoli of the lung, permitting the exchange of oxygen. | Related disorders of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. Symptoms of the following disorders can be similar to those of ACDMPV. Comparisons may be useful for a differential diagnosis.Idiopathic persistent pulmonary hypertension of the newborn (PPHN) is characterized by markedly high blood pressure in the pulmonary artery (pulmonary hypertension) of infants that, in turn, causes blood to bypass its normal route and results in less oxygen than required being delivered to the lungs (hypoxemia). PPHN may occur without known cause (idiopathic), or it may arise in connection with many different neonatal cardiorespiratory disorders, including asphyxia, meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS) and congenital diaphragmatic hernia. During fetal life, pulmonary blood flow is low, with less than 10% of the combined cardiac output directed to the lungs. Following birth, pulmonary vascular resistance falls dramatically as the lungs assume the function of gas exchange. In some newborns, the normal decrease in pulmonary vascular tone does not occur, resulting in persistent pulmonary hypertension of the newborn (PPHN). This syndrome results in substantial morbidity and mortality in otherwise healthy term infants. Most infants with PPHN respond to therapies such as inhaled nitric oxide and extracorporeal membrane oxygenation. Most (~90%) recover by the second week of life and survive.Surfactant protein B deficiency is a congenital (present at birth and associated with a gene abnormality) disorder of the lungs that occurs primarily in infants born prematurely and is a result of immaturity of the lungs. The mature lung contains a foamy fluid known as surfactant, a substance essential to expansion of the alveoli or air sacs of the lungs. Because of their immaturity, premature babies tend to lack surfactant. Without surfactant, the lungs cannot inflate, resulting in RDS. Pulmonary surfactant is a complex compound composed primarily of fatty substances and lesser amounts of cholesterol and surfactant-associated protein. When the protein component is missing, the surfactant cannot function properly. The surfactant, when functioning properly, lowers surface tension at the air-liquid interface in the alveoli of the lung, permitting the exchange of oxygen. | 66 | Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins |
nord_66_5 | Diagnosis of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins | ACDMPV may be suspected in any infant who presents with severe cyanosis (hypoxemia) and high pulmonary blood pressure (pulmonary hypertension) that is unresponsive to treatment in the neonatal intensive care unit (NICU). The diagnosis is confirmed through a histopathological examination of lung tissue at biopsy or autopsy by an experienced pathologist for characteristic tissue changes. The characteristics that a pathologist will look for can include a relative lack of capillaries near the alveoli, thickening of the walls (septa) of alveoli, misalignment of pulmonary veins and increased “muscularization” of the small arteries of the lungs (arterioles).Molecular genetic testing can confirm a diagnosis of ACDMPV in approximately 80-90% of children. Molecular genetic testing can detect changes in the FOXF1 gene or changes affecting the function of the FOXF1 gene that are known to cause this disorder. This testing should also be done on parents to determine whether the parents carry the genetic abnormality. | Diagnosis of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. ACDMPV may be suspected in any infant who presents with severe cyanosis (hypoxemia) and high pulmonary blood pressure (pulmonary hypertension) that is unresponsive to treatment in the neonatal intensive care unit (NICU). The diagnosis is confirmed through a histopathological examination of lung tissue at biopsy or autopsy by an experienced pathologist for characteristic tissue changes. The characteristics that a pathologist will look for can include a relative lack of capillaries near the alveoli, thickening of the walls (septa) of alveoli, misalignment of pulmonary veins and increased “muscularization” of the small arteries of the lungs (arterioles).Molecular genetic testing can confirm a diagnosis of ACDMPV in approximately 80-90% of children. Molecular genetic testing can detect changes in the FOXF1 gene or changes affecting the function of the FOXF1 gene that are known to cause this disorder. This testing should also be done on parents to determine whether the parents carry the genetic abnormality. | 66 | Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins |
nord_66_6 | Therapies of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins | Treatment
Various treatments have been tried in infants with ACDMPV, including mechanical ventilation, nitric oxide and extra corporeal membrane oxygenation (ECMO). These are standard treatments for infants with other disorders that cause respiratory distress, but they have been ineffective in treating infants with ACDMPV. In a few older infants with milder or late onset ACDMPV, lung transplantations have been successful.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. | Therapies of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. Treatment
Various treatments have been tried in infants with ACDMPV, including mechanical ventilation, nitric oxide and extra corporeal membrane oxygenation (ECMO). These are standard treatments for infants with other disorders that cause respiratory distress, but they have been ineffective in treating infants with ACDMPV. In a few older infants with milder or late onset ACDMPV, lung transplantations have been successful.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. | 66 | Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins |
nord_67_0 | Overview of Alveolar Soft Part Sarcoma | Alveolar soft part sarcoma (ASPS) is a rare, slow growing soft tissue tumor of an unclear cause. It is among the least common sarcomas, representing 0.2-1 percent of large studies of soft tissue sarcomas. ASPS is characterized by a painless mass that most commonly arises in the leg or buttock, with a particular affinity to travel to the lungs as multiple nodules, presumably while the sarcoma itself is still small. This disorder is very rare because it involves a specific breaking and joining event between two chromosomes, called an “unbalanced translocation”. This finding is observed in essentially all people with ASPS examined so far. This finding cannot be passed on to children, however, as the finding occurs only in the tumor cells, not in the body cells. In addition, there are no families in which multiple family members have the disorder. ASPS tends to occur more often in younger individuals, specifically adolescents and young adults.Treatment is with surgery for the primary place where the sarcoma arises. Radiation therapy is sometimes considered as an adjunct to surgery depending on the tumor characteristics (size, location, microscopic appearance). For disease that travels to the lungs, sometimes surgery is possible to remove nodules, but often systemic therapy is the only option for treatment. This tumor tends to be resistant to traditional chemotherapy; however newer approaches utilizing so called “targeted” chemotherapy drugs as well as “immunotherapy” are recently emerging as treatment strategies for patients that have advanced disease/higher stage.ASPS is classified as a soft tissue sarcoma. Sarcomas are malignant tumors that arise from the connective tissue, which connects, supports, and surrounds various structures and organs in the body. Soft tissue includes fat, muscle, nerves, tendons and blood and lymph vessels. | Overview of Alveolar Soft Part Sarcoma. Alveolar soft part sarcoma (ASPS) is a rare, slow growing soft tissue tumor of an unclear cause. It is among the least common sarcomas, representing 0.2-1 percent of large studies of soft tissue sarcomas. ASPS is characterized by a painless mass that most commonly arises in the leg or buttock, with a particular affinity to travel to the lungs as multiple nodules, presumably while the sarcoma itself is still small. This disorder is very rare because it involves a specific breaking and joining event between two chromosomes, called an “unbalanced translocation”. This finding is observed in essentially all people with ASPS examined so far. This finding cannot be passed on to children, however, as the finding occurs only in the tumor cells, not in the body cells. In addition, there are no families in which multiple family members have the disorder. ASPS tends to occur more often in younger individuals, specifically adolescents and young adults.Treatment is with surgery for the primary place where the sarcoma arises. Radiation therapy is sometimes considered as an adjunct to surgery depending on the tumor characteristics (size, location, microscopic appearance). For disease that travels to the lungs, sometimes surgery is possible to remove nodules, but often systemic therapy is the only option for treatment. This tumor tends to be resistant to traditional chemotherapy; however newer approaches utilizing so called “targeted” chemotherapy drugs as well as “immunotherapy” are recently emerging as treatment strategies for patients that have advanced disease/higher stage.ASPS is classified as a soft tissue sarcoma. Sarcomas are malignant tumors that arise from the connective tissue, which connects, supports, and surrounds various structures and organs in the body. Soft tissue includes fat, muscle, nerves, tendons and blood and lymph vessels. | 67 | Alveolar Soft Part Sarcoma |
nord_67_1 | Symptoms of Alveolar Soft Part Sarcoma | The typical clinical findings are of a painless thigh or buttock mass, although ASPS can occur in the trunk, arm or elsewhere. Sometimes these masses cause pain by stretching of the surrounding tissues, and cause limping or other difficulty with movement. These masses are usually soft and slow growing. In children, these masses most often occur in the head and neck, most commonly the tongue and the eye socket (orbit). In adults, the thighs and buttocks are most often affected.Although ASPS is a slow growing tumor, it can spread (metastasize) to other areas of the body. Sometimes there is a significant delay of years after resection of the original tumor before sites of spread (metastases) are detectable. The lungs, brain and bone are most frequently affected when the cancer spreads. In the advanced stages, when nodules are found in the lung, the tumor nodules can cause cough, sharp chest pain, or fluid collections around the lungs (pleural effusions). Some people will develop headaches associated with metastases to the brain, or a fracture from metastases to the bones. The involvement of the lungs or brain in ASPS are potentially life-threatening complications, but people can live for several years despite lung nodules, since the nodules grow only very slowly for most people. In people with brain metastases, surgery and radiation are the major ways to control the tumor and the side effects they cause in the brain. | Symptoms of Alveolar Soft Part Sarcoma. The typical clinical findings are of a painless thigh or buttock mass, although ASPS can occur in the trunk, arm or elsewhere. Sometimes these masses cause pain by stretching of the surrounding tissues, and cause limping or other difficulty with movement. These masses are usually soft and slow growing. In children, these masses most often occur in the head and neck, most commonly the tongue and the eye socket (orbit). In adults, the thighs and buttocks are most often affected.Although ASPS is a slow growing tumor, it can spread (metastasize) to other areas of the body. Sometimes there is a significant delay of years after resection of the original tumor before sites of spread (metastases) are detectable. The lungs, brain and bone are most frequently affected when the cancer spreads. In the advanced stages, when nodules are found in the lung, the tumor nodules can cause cough, sharp chest pain, or fluid collections around the lungs (pleural effusions). Some people will develop headaches associated with metastases to the brain, or a fracture from metastases to the bones. The involvement of the lungs or brain in ASPS are potentially life-threatening complications, but people can live for several years despite lung nodules, since the nodules grow only very slowly for most people. In people with brain metastases, surgery and radiation are the major ways to control the tumor and the side effects they cause in the brain. | 67 | Alveolar Soft Part Sarcoma |
nord_67_2 | Causes of Alveolar Soft Part Sarcoma | There is no exposure or infection that is known to predispose to ASPS. It is known that two chromosomes break and rejoin is a certain way (unbalanced translocation) and bring together two genes, normally separated on chromosomes X (the sex chromosome) and 17.Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The two genes involved in ASPS are the alveolar soft part sarcoma critical region 1 (ASPSCR1) gene on chromosome 17 and TFE3 gene on chromosome X. In an unbalanced translocation, one chromosome ends up with extra material while the other chromosome is missing material. In ASPS, the TFE3 gene breaks off from the X chromosome and attaches onto the ASPSCR1 gene on chromosome 17. This unbalanced translocation creates a new so-called “fusion” gene known as ASPSCR1-TFE3. This fusion gene creates an abnormal protein. Researchers believe that this abnormal protein plays a significant role in the development of ASPS. However, more research is necessary to determine the exact manner in how this abnormal protein functions. | Causes of Alveolar Soft Part Sarcoma. There is no exposure or infection that is known to predispose to ASPS. It is known that two chromosomes break and rejoin is a certain way (unbalanced translocation) and bring together two genes, normally separated on chromosomes X (the sex chromosome) and 17.Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The two genes involved in ASPS are the alveolar soft part sarcoma critical region 1 (ASPSCR1) gene on chromosome 17 and TFE3 gene on chromosome X. In an unbalanced translocation, one chromosome ends up with extra material while the other chromosome is missing material. In ASPS, the TFE3 gene breaks off from the X chromosome and attaches onto the ASPSCR1 gene on chromosome 17. This unbalanced translocation creates a new so-called “fusion” gene known as ASPSCR1-TFE3. This fusion gene creates an abnormal protein. Researchers believe that this abnormal protein plays a significant role in the development of ASPS. However, more research is necessary to determine the exact manner in how this abnormal protein functions. | 67 | Alveolar Soft Part Sarcoma |
nord_67_3 | Affects of Alveolar Soft Part Sarcoma | ASPS tends to affect younger people, especially those between 15 and 35 years of age. It is rare in children under 5 or in adults over 50. Women outnumber men, especially under age 25. There appears to be no link of this tumor to a particular ethnicity. ASPS accounts for about 0.2-1% of all soft tissue sarcomas. In turn, soft tissue sarcomas account for approximately 1% of all cancers. | Affects of Alveolar Soft Part Sarcoma. ASPS tends to affect younger people, especially those between 15 and 35 years of age. It is rare in children under 5 or in adults over 50. Women outnumber men, especially under age 25. There appears to be no link of this tumor to a particular ethnicity. ASPS accounts for about 0.2-1% of all soft tissue sarcomas. In turn, soft tissue sarcomas account for approximately 1% of all cancers. | 67 | Alveolar Soft Part Sarcoma |
nord_67_4 | Related disorders of Alveolar Soft Part Sarcoma | The exact same chromosomal changes are found in a rare form of kidney cancer, ASPSCR1-TFE3 translocation renal cell carcinoma in which the chromosomal translocation is “balanced” as opposed to the “unbalanced” translocation seen in ASPS. This is a cancer of an entirely different nature. Researchers are unsure why the ASPSCR1-TFE3 gene fusion causes ASPS in some people and a form of renal cell carcinoma in others.Other tumors can resemble ASPS by the way they look under the microscope. These tumors include paraganglioma, granular cell tumors, adrenal cortical carcinoma, hepatocellular carcinoma, rhabdomyosarcoma, clear cell sarcoma of the soft tissue, hibernoma, and perivascular epithelioid cell neoplasm or PEComa. However, some of these tumors have signs and symptoms that differ from those of ASPS. | Related disorders of Alveolar Soft Part Sarcoma. The exact same chromosomal changes are found in a rare form of kidney cancer, ASPSCR1-TFE3 translocation renal cell carcinoma in which the chromosomal translocation is “balanced” as opposed to the “unbalanced” translocation seen in ASPS. This is a cancer of an entirely different nature. Researchers are unsure why the ASPSCR1-TFE3 gene fusion causes ASPS in some people and a form of renal cell carcinoma in others.Other tumors can resemble ASPS by the way they look under the microscope. These tumors include paraganglioma, granular cell tumors, adrenal cortical carcinoma, hepatocellular carcinoma, rhabdomyosarcoma, clear cell sarcoma of the soft tissue, hibernoma, and perivascular epithelioid cell neoplasm or PEComa. However, some of these tumors have signs and symptoms that differ from those of ASPS. | 67 | Alveolar Soft Part Sarcoma |
nord_67_5 | Diagnosis of Alveolar Soft Part Sarcoma | Biopsy is the fastest way to come to a diagnosis of soft-tissue sarcomas. A biopsy involves taking a small sample of affected tissue and examining it under a microscope. There are more than 50 different types of sarcomas, of which ASPS is only one rare subtype. Often times, a core needle biopsy of the leg mass is enough to make the diagnosis. If a core needle biopsy is not diagnostic, then an incisional biopsy that obtains more tissue will make the diagnosis.Doctors can use a biopsy sample to check the cells to see if the characteristic chromosome change (an unbalanced translocation involving chromosomes 17 and X, resulting in the formation of the fusion gene, ASPSCR1-TFE3 is present. Detection of this fusion gene confirms a diagnosis of ASPS.Because the tumor grows slowly and usually does not cause any pronounced symptoms, affected individuals often have ASPS for years before a diagnosis is made.Typically, people will also undergo specialized imaging techniques such as computed tomography (CT) scans or magnetic resonance imaging (MRI) scans of the primary tumor site to determine if the mass is removable. A CT scan of the chest is typically performed to determine if there is disease in the lungs. Additional scans may also be considered to assess for the spread of cancer to other areas of the body. ASPS generally does not move to lymph nodes, and usually travels via the blood to get to the lungs or other parts of the body. | Diagnosis of Alveolar Soft Part Sarcoma. Biopsy is the fastest way to come to a diagnosis of soft-tissue sarcomas. A biopsy involves taking a small sample of affected tissue and examining it under a microscope. There are more than 50 different types of sarcomas, of which ASPS is only one rare subtype. Often times, a core needle biopsy of the leg mass is enough to make the diagnosis. If a core needle biopsy is not diagnostic, then an incisional biopsy that obtains more tissue will make the diagnosis.Doctors can use a biopsy sample to check the cells to see if the characteristic chromosome change (an unbalanced translocation involving chromosomes 17 and X, resulting in the formation of the fusion gene, ASPSCR1-TFE3 is present. Detection of this fusion gene confirms a diagnosis of ASPS.Because the tumor grows slowly and usually does not cause any pronounced symptoms, affected individuals often have ASPS for years before a diagnosis is made.Typically, people will also undergo specialized imaging techniques such as computed tomography (CT) scans or magnetic resonance imaging (MRI) scans of the primary tumor site to determine if the mass is removable. A CT scan of the chest is typically performed to determine if there is disease in the lungs. Additional scans may also be considered to assess for the spread of cancer to other areas of the body. ASPS generally does not move to lymph nodes, and usually travels via the blood to get to the lungs or other parts of the body. | 67 | Alveolar Soft Part Sarcoma |
nord_67_6 | Therapies of Alveolar Soft Part Sarcoma | The therapeutic management of individuals with ASPS may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis (pathologists)and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists (depending upon the area(s) of tumor involvement). Given the rarity of this disease, it is recommended that patients be treated at a high-volume referral center for sarcomas.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade), whether the tumor has spread to distant sites, individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference, and other appropriate factors.Surgery is a standard treatment option for ASPS. However, identification of the fusion gene ASPSCR1-TFE3, has opened new avenues for treatment. Researchers are studying targeted therapies designed to block the effects of this abnormal gene as well as approaches to elicit an immune response against the tumor. Please see the Investigational Therapies section below for more information.The prognosis is best if the tumor is small and localized (i.e. has not moved elsewhere in the body, such as the lungs), and can be completely removed by surgery. It is rare for amputation to be used as a surgical technique to attempt to cure sarcomas (it occurs less than 5% of the time at most major US sarcoma centers). Typical surgery is called “limb-sparing”, trying to get around the tumor completely, without having to remove so much tissue that the limb (or another site) does not work well anymore.Often, radiation is used before or after surgery to minimize the chance of the tumor coming back in the place where it started. This can be achieved by directing a radiation beam at the tumor (external beam radiation, or some variant of that) or can be achieved by placing temporary catheters (tubes) in the area where the tumor was resected. These tubes stick out of the skin and can have radiation seeds placed in them to deliver a high dose of radiation to the area of the tumor in a very specific manner. This technique is called brachytherapy. Either external beam radiation or brachytherapy are typically considered when the tumor is 5cm (approximately 2 inches) in size or greater. For smaller tumors, it is not clear that radiation helps decrease the risk of the tumor coming back.Without evidence of disease in the lungs, or other spread of ASPS beyond where it started, chemotherapy is not recommended. There is no evidence that chemotherapy for ASPS after surgery (and radiation for some people) will decrease the risk of the tumor from coming back, like it can for breast cancer or colon cancer.If the tumor is advanced and has traveled elsewhere (metastasized) or recurred, surgery is still sometimes considered depending on the extent of disease, in particular the number of sites affected. For patients in whom surgery is not an appropriate option, systemic therapy (i.e. something delivered to the whole body via pill or IV infusion) is the main consideration for therapy. However, traditional chemotherapies for metastatic disease have generally been ineffective. Standard drugs for sarcoma include doxorubicin and ifosfamide, but do not work particularly well for ASPS. Few people have shrinking of tumor, and chemotherapy will not be curative if the tumor has spread beyond the tumor’s starting place. Given these limitations with traditional chemotherapy, most specialists in the field are quick to consider newer or investigational treatments. | Therapies of Alveolar Soft Part Sarcoma. The therapeutic management of individuals with ASPS may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis (pathologists)and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists (depending upon the area(s) of tumor involvement). Given the rarity of this disease, it is recommended that patients be treated at a high-volume referral center for sarcomas.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade), whether the tumor has spread to distant sites, individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference, and other appropriate factors.Surgery is a standard treatment option for ASPS. However, identification of the fusion gene ASPSCR1-TFE3, has opened new avenues for treatment. Researchers are studying targeted therapies designed to block the effects of this abnormal gene as well as approaches to elicit an immune response against the tumor. Please see the Investigational Therapies section below for more information.The prognosis is best if the tumor is small and localized (i.e. has not moved elsewhere in the body, such as the lungs), and can be completely removed by surgery. It is rare for amputation to be used as a surgical technique to attempt to cure sarcomas (it occurs less than 5% of the time at most major US sarcoma centers). Typical surgery is called “limb-sparing”, trying to get around the tumor completely, without having to remove so much tissue that the limb (or another site) does not work well anymore.Often, radiation is used before or after surgery to minimize the chance of the tumor coming back in the place where it started. This can be achieved by directing a radiation beam at the tumor (external beam radiation, or some variant of that) or can be achieved by placing temporary catheters (tubes) in the area where the tumor was resected. These tubes stick out of the skin and can have radiation seeds placed in them to deliver a high dose of radiation to the area of the tumor in a very specific manner. This technique is called brachytherapy. Either external beam radiation or brachytherapy are typically considered when the tumor is 5cm (approximately 2 inches) in size or greater. For smaller tumors, it is not clear that radiation helps decrease the risk of the tumor coming back.Without evidence of disease in the lungs, or other spread of ASPS beyond where it started, chemotherapy is not recommended. There is no evidence that chemotherapy for ASPS after surgery (and radiation for some people) will decrease the risk of the tumor from coming back, like it can for breast cancer or colon cancer.If the tumor is advanced and has traveled elsewhere (metastasized) or recurred, surgery is still sometimes considered depending on the extent of disease, in particular the number of sites affected. For patients in whom surgery is not an appropriate option, systemic therapy (i.e. something delivered to the whole body via pill or IV infusion) is the main consideration for therapy. However, traditional chemotherapies for metastatic disease have generally been ineffective. Standard drugs for sarcoma include doxorubicin and ifosfamide, but do not work particularly well for ASPS. Few people have shrinking of tumor, and chemotherapy will not be curative if the tumor has spread beyond the tumor’s starting place. Given these limitations with traditional chemotherapy, most specialists in the field are quick to consider newer or investigational treatments. | 67 | Alveolar Soft Part Sarcoma |
nord_68_0 | Overview of Ameloblastic Carcinoma | Ameloblastic carcinoma is a rare malignant (cancerous) tumor that normally begins in the bones of the jaw. It is classified as an odontogenic tumor, meaning that it arises from the epithelium that forms the enamel of the teeth. The pattern of epithelial growth is similar to the developing tooth germ and distinctive enough to separate it from other epithelial malignances. Symptoms may include progressive pain and swelling of the jaw. Ameloblastic carcinoma may spread (metastasize) to affect other organs of the body.Carcinoma refers to a malignancy that arises from epithelium. For instance carcinoma of the skin is termed ‘squamous cell carcinoma' and carcinoma from glandular epithelium is termed ‘adenocarcinoma'. The term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including odontogenic tumors, are classified based upon the cell type involved, the specific nature of the malignancy, and the disease's clinical course. | Overview of Ameloblastic Carcinoma. Ameloblastic carcinoma is a rare malignant (cancerous) tumor that normally begins in the bones of the jaw. It is classified as an odontogenic tumor, meaning that it arises from the epithelium that forms the enamel of the teeth. The pattern of epithelial growth is similar to the developing tooth germ and distinctive enough to separate it from other epithelial malignances. Symptoms may include progressive pain and swelling of the jaw. Ameloblastic carcinoma may spread (metastasize) to affect other organs of the body.Carcinoma refers to a malignancy that arises from epithelium. For instance carcinoma of the skin is termed ‘squamous cell carcinoma' and carcinoma from glandular epithelium is termed ‘adenocarcinoma'. The term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including odontogenic tumors, are classified based upon the cell type involved, the specific nature of the malignancy, and the disease's clinical course. | 68 | Ameloblastic Carcinoma |
nord_68_1 | Symptoms of Ameloblastic Carcinoma | Some individuals with ameloblastic carcinoma may not experience any symptoms (asymptomatic). Symptoms that may occur include progressive pain and swelling of the jaw. Bleeding and headaches may also occur. Rare findings include the inability to open the mouth (trismus) or dysphonia, a voice disorder characterized by hoarseness, weakness, tingling or numbness (paresthesia), and, in rare cases, voice loss (my note: disruption of the voice because of laryngeal involvement (vocal cords) would be quite unusual but dysphagia, trouble eating, can be a problem if the tumor is large enough to cause obstruction or malocclusion). Nasal discharge and blockage of the nasal passages may occur if the tumor involves the sinuses of the maxilla. The size of the tumor may result in dental abnormalities such as causing the upper and lower teeth to fail to meet properly (malocclusion).The lower jaw (mandible) is the most common site for the development of ameloblastic carcinoma. Less frequently, the upper jaw (maxilla) is the primary tumor site. In one reported case, the primary site was the anterior skull base.Ameloblastic carcinomas are often aggressive and may spread (metastasize) to other areas of the body especially the lungs, potentially causing life-threatening complications. The bone, liver and brain are also common sites for metastasis. The most common course of the disease is persistent recurrence with local spread. | Symptoms of Ameloblastic Carcinoma. Some individuals with ameloblastic carcinoma may not experience any symptoms (asymptomatic). Symptoms that may occur include progressive pain and swelling of the jaw. Bleeding and headaches may also occur. Rare findings include the inability to open the mouth (trismus) or dysphonia, a voice disorder characterized by hoarseness, weakness, tingling or numbness (paresthesia), and, in rare cases, voice loss (my note: disruption of the voice because of laryngeal involvement (vocal cords) would be quite unusual but dysphagia, trouble eating, can be a problem if the tumor is large enough to cause obstruction or malocclusion). Nasal discharge and blockage of the nasal passages may occur if the tumor involves the sinuses of the maxilla. The size of the tumor may result in dental abnormalities such as causing the upper and lower teeth to fail to meet properly (malocclusion).The lower jaw (mandible) is the most common site for the development of ameloblastic carcinoma. Less frequently, the upper jaw (maxilla) is the primary tumor site. In one reported case, the primary site was the anterior skull base.Ameloblastic carcinomas are often aggressive and may spread (metastasize) to other areas of the body especially the lungs, potentially causing life-threatening complications. The bone, liver and brain are also common sites for metastasis. The most common course of the disease is persistent recurrence with local spread. | 68 | Ameloblastic Carcinoma |
nord_68_2 | Causes of Ameloblastic Carcinoma | The exact cause of ameloblastic carcinoma is unknown. Most cases arise spontaneously without a previous history of cancer (de novo). Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.In individuals with cancer, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. The specific cause of changes to these genes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body's genetic code, are the underlying basis of cellular malignant transformation. These abnormal genetic changes may occur spontaneously for unknown reasons or, more rarely, may be inherited. In ameloblastic carcinoma, no genetic predisposition has been identified.Ameloblastic carcinoma may develop from the epithelial tissue that remains after the development of the teeth and associated structures. In some cases, it results from malignant transformation of an existing ameloblastoma or a benign odontogenic cyst. | Causes of Ameloblastic Carcinoma. The exact cause of ameloblastic carcinoma is unknown. Most cases arise spontaneously without a previous history of cancer (de novo). Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.In individuals with cancer, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. The specific cause of changes to these genes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body's genetic code, are the underlying basis of cellular malignant transformation. These abnormal genetic changes may occur spontaneously for unknown reasons or, more rarely, may be inherited. In ameloblastic carcinoma, no genetic predisposition has been identified.Ameloblastic carcinoma may develop from the epithelial tissue that remains after the development of the teeth and associated structures. In some cases, it results from malignant transformation of an existing ameloblastoma or a benign odontogenic cyst. | 68 | Ameloblastic Carcinoma |
nord_68_3 | Affects of Ameloblastic Carcinoma | Ameloblastic carcinoma affects males and females in equal numbers. They may affect individuals of any age including children, but the mean age of affected individuals is approximately 30 years old. | Affects of Ameloblastic Carcinoma. Ameloblastic carcinoma affects males and females in equal numbers. They may affect individuals of any age including children, but the mean age of affected individuals is approximately 30 years old. | 68 | Ameloblastic Carcinoma |
nord_68_4 | Related disorders of Ameloblastic Carcinoma | Symptoms of the following disorders can be similar to those of ameloblastic carcinoma. Comparisons may be useful for a differential diagnosis.Other odontogenic tumors and cysts must be differentiated from ameloblastic carcinoma especially ameloblastomas. Odontogenic tumors typically arise in the jaws, are slow growing and often have no apparent symptoms (asymptomatic). Pain is rarely associated with benign tumors or cysts, but common among malignant odontogenic tumors. Ameloblastic carcinoma must also be differentiated from carcinoma affecting the jaw that originates from a different primary site (such as metastases from lung cancer, breast cancer etc).Ameloblastoma is a rare disorder of the jaw involving abnormal tissue growth. The resulting tumors or cysts are not malignant (benign), but the tissue growth may be aggressive in the involved area. On occasion, tissue near the jaws such as around the sinuses and the eye sockets may become involved as well. The tissues involved are most often those that give rise to the teeth so that ameloblastoma may cause facial distortion. Malignancy is uncommon as are metastases, but they do occur. (For more information on this disorder, choose “ameloblastoma” as your search term in the Rare Disease Database.)Much confusion exists in the medical literature regarding the classification of malignant odontogenic tumors. An ameloblastoma is a slow-growing benign lesion that may spread to nearby tissues, but is not malignant. The term malignant ameloblastoma is used to denote an ameloblastoma that acts malignant (i.e., metastasizes) even though its cellular makeup does not indicate malignancy. Malignant ameloblastomas may metastasize to other organs, especially the lungs. Ameloblastic carcinomas are odontogenic tumors that display cellular characteristics of both an ameloblastoma and carcinoma. Ameloblastic carcinoma occurs more often than malignant ameloblastomas by a ration of 2:1.Malignant ameloblastomas and ameloblastic carcinoma are classified as subtypes of primary intraosseous carcinoma type II, which refers to primary carcinomas of the jaw. PIOC type I refers to carcinoma arising from odontogenic cysts; PIOC type II refers to carcinoma arising from ameloblastomas or containing cellular elements of an ameloblastoma; and PIOC type III refers to carcinoma of the jaws without identifiable cause (de novo). | Related disorders of Ameloblastic Carcinoma. Symptoms of the following disorders can be similar to those of ameloblastic carcinoma. Comparisons may be useful for a differential diagnosis.Other odontogenic tumors and cysts must be differentiated from ameloblastic carcinoma especially ameloblastomas. Odontogenic tumors typically arise in the jaws, are slow growing and often have no apparent symptoms (asymptomatic). Pain is rarely associated with benign tumors or cysts, but common among malignant odontogenic tumors. Ameloblastic carcinoma must also be differentiated from carcinoma affecting the jaw that originates from a different primary site (such as metastases from lung cancer, breast cancer etc).Ameloblastoma is a rare disorder of the jaw involving abnormal tissue growth. The resulting tumors or cysts are not malignant (benign), but the tissue growth may be aggressive in the involved area. On occasion, tissue near the jaws such as around the sinuses and the eye sockets may become involved as well. The tissues involved are most often those that give rise to the teeth so that ameloblastoma may cause facial distortion. Malignancy is uncommon as are metastases, but they do occur. (For more information on this disorder, choose “ameloblastoma” as your search term in the Rare Disease Database.)Much confusion exists in the medical literature regarding the classification of malignant odontogenic tumors. An ameloblastoma is a slow-growing benign lesion that may spread to nearby tissues, but is not malignant. The term malignant ameloblastoma is used to denote an ameloblastoma that acts malignant (i.e., metastasizes) even though its cellular makeup does not indicate malignancy. Malignant ameloblastomas may metastasize to other organs, especially the lungs. Ameloblastic carcinomas are odontogenic tumors that display cellular characteristics of both an ameloblastoma and carcinoma. Ameloblastic carcinoma occurs more often than malignant ameloblastomas by a ration of 2:1.Malignant ameloblastomas and ameloblastic carcinoma are classified as subtypes of primary intraosseous carcinoma type II, which refers to primary carcinomas of the jaw. PIOC type I refers to carcinoma arising from odontogenic cysts; PIOC type II refers to carcinoma arising from ameloblastomas or containing cellular elements of an ameloblastoma; and PIOC type III refers to carcinoma of the jaws without identifiable cause (de novo). | 68 | Ameloblastic Carcinoma |
nord_68_5 | Diagnosis of Ameloblastic Carcinoma | A diagnosis of ameloblastic carcinoma is made based upon a thorough clinical evaluation, a detailed patient history, and microscopic examination of the tumor. Most cases are found incidentally. One procedure is known as fine needle aspiration, in which a thin, hollow needle is passed though the skin and inserted into the nodule or mass to withdraw small samples of tissue for study.In addition to biopsies, various x-ray techniques may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases. | Diagnosis of Ameloblastic Carcinoma. A diagnosis of ameloblastic carcinoma is made based upon a thorough clinical evaluation, a detailed patient history, and microscopic examination of the tumor. Most cases are found incidentally. One procedure is known as fine needle aspiration, in which a thin, hollow needle is passed though the skin and inserted into the nodule or mass to withdraw small samples of tissue for study.In addition to biopsies, various x-ray techniques may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases. | 68 | Ameloblastic Carcinoma |
nord_68_6 | Therapies of Ameloblastic Carcinoma | Treatment
The therapeutic management of individuals with ameloblastic carcinomas may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), dental specialists, surgeons, oncology nurses, and other specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Wide surgical excision provides the best chance of controlling the tumor. Adjunctive radiation may be used however radiation treatment has not been effective as a primary form of therapy. Radiation therapy may also be performed before surgery to decrease tumor size. Recurrence of ameloblastic carcinoma after surgical removal may occur and may involve various organs in the body with or without recurrence in the jaw. Most commonly recurrences are seen in the same area as the original tumor. Recurrence may occur within a year of surgery or several years later. Because of the risk of recurrence, life-long periodic physical examinations are necessary.Chemotherapy has not proven effective in treating individuals with ameloblastic carcinoma and is most often used to try and control wide spread metastases. Developing the optimal treatment for individuals with ameloblastic carcinoma has been hindered because of the relatively few identified cases. | Therapies of Ameloblastic Carcinoma. Treatment
The therapeutic management of individuals with ameloblastic carcinomas may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), dental specialists, surgeons, oncology nurses, and other specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Wide surgical excision provides the best chance of controlling the tumor. Adjunctive radiation may be used however radiation treatment has not been effective as a primary form of therapy. Radiation therapy may also be performed before surgery to decrease tumor size. Recurrence of ameloblastic carcinoma after surgical removal may occur and may involve various organs in the body with or without recurrence in the jaw. Most commonly recurrences are seen in the same area as the original tumor. Recurrence may occur within a year of surgery or several years later. Because of the risk of recurrence, life-long periodic physical examinations are necessary.Chemotherapy has not proven effective in treating individuals with ameloblastic carcinoma and is most often used to try and control wide spread metastases. Developing the optimal treatment for individuals with ameloblastic carcinoma has been hindered because of the relatively few identified cases. | 68 | Ameloblastic Carcinoma |
nord_69_0 | Overview of Ameloblastoma | Ameloblastoma is a rare disorder of the jaw involving abnormal tissue growth. The resulting tumors or cysts are usually not malignant (benign) but the tissue growth may be aggressive in the involved area. On occasion, tissue near the jaws, such as around the sinuses and eye sockets, may become involved as well. The tissues involved are most often those that give rise to the teeth so that ameloblastoma may cause facial distortion. Malignancy is uncommon as are metastases, but they do occur. | Overview of Ameloblastoma. Ameloblastoma is a rare disorder of the jaw involving abnormal tissue growth. The resulting tumors or cysts are usually not malignant (benign) but the tissue growth may be aggressive in the involved area. On occasion, tissue near the jaws, such as around the sinuses and eye sockets, may become involved as well. The tissues involved are most often those that give rise to the teeth so that ameloblastoma may cause facial distortion. Malignancy is uncommon as are metastases, but they do occur. | 69 | Ameloblastoma |
nord_69_1 | Symptoms of Ameloblastoma | Ameloblastoma is characterized by an abnormal growth in the sinus area or jaw, often at the site of the third molar. The tumors or cysts may be aggressive and may spread to the nose, eye socket and skull. It is important for ameloblastoma to be diagnosed and treated early in order to stop growth of the tumors and possible progression to cancer. Although it is uncommon, ameloblastomas have been known to become malignant and spread to other parts of the body, especially to the lungs. The initial surgical treatment must be carefully and scrupulously done to avoid recurrence. Ameloblastomas do not usually become malignant. There is evidence that tissue is more likely to become malignant if the condition reoccurs after surgery. | Symptoms of Ameloblastoma. Ameloblastoma is characterized by an abnormal growth in the sinus area or jaw, often at the site of the third molar. The tumors or cysts may be aggressive and may spread to the nose, eye socket and skull. It is important for ameloblastoma to be diagnosed and treated early in order to stop growth of the tumors and possible progression to cancer. Although it is uncommon, ameloblastomas have been known to become malignant and spread to other parts of the body, especially to the lungs. The initial surgical treatment must be carefully and scrupulously done to avoid recurrence. Ameloblastomas do not usually become malignant. There is evidence that tissue is more likely to become malignant if the condition reoccurs after surgery. | 69 | Ameloblastoma |
nord_69_2 | Causes of Ameloblastoma | The cause of ameloblastoma is not understood. Causes may include injury to the mouth or jaw, infections of the teeth or gums, or inflammation of these same areas. Infections by viruses or lack of protein or minerals in the persons diet are also suspected of causing the growth or development of these tumors. In general, however, scientists do not understand the cause of cysts and tumors, nor the reasons why they can become malignant. | Causes of Ameloblastoma. The cause of ameloblastoma is not understood. Causes may include injury to the mouth or jaw, infections of the teeth or gums, or inflammation of these same areas. Infections by viruses or lack of protein or minerals in the persons diet are also suspected of causing the growth or development of these tumors. In general, however, scientists do not understand the cause of cysts and tumors, nor the reasons why they can become malignant. | 69 | Ameloblastoma |
nord_69_3 | Affects of Ameloblastoma | Ameloblastoma is a rare disorder that affects males and females in equal numbers. It affects persons of all ethnic backgrounds and of all age groups. | Affects of Ameloblastoma. Ameloblastoma is a rare disorder that affects males and females in equal numbers. It affects persons of all ethnic backgrounds and of all age groups. | 69 | Ameloblastoma |
nord_69_4 | Related disorders of Ameloblastoma | Symptoms of the following disorders can be similar to those of ameloblastoma. Comparisons may be useful for a differential diagnosis:Hard Odontoma is a tumor of dental origin. It is composed of several characteristics of teeth such as enamel, dentin and cement. The Hard Odontoma grows by spreading directly; the ameloblastoma grows by infiltrating other spaces.Osteosarcoma may often be confused with ameloblastoma. This cancer of the bone differs from the dental tumor by arising from the bone forming cells of the long bones.Globulomaxillary Cysts are located between the teeth and may cause the teeth to spread apart. The cysts are either oval or heart shaped and may be removed or drained. Sometimes the treatment of the cysts can cause loss of teeth. | Related disorders of Ameloblastoma. Symptoms of the following disorders can be similar to those of ameloblastoma. Comparisons may be useful for a differential diagnosis:Hard Odontoma is a tumor of dental origin. It is composed of several characteristics of teeth such as enamel, dentin and cement. The Hard Odontoma grows by spreading directly; the ameloblastoma grows by infiltrating other spaces.Osteosarcoma may often be confused with ameloblastoma. This cancer of the bone differs from the dental tumor by arising from the bone forming cells of the long bones.Globulomaxillary Cysts are located between the teeth and may cause the teeth to spread apart. The cysts are either oval or heart shaped and may be removed or drained. Sometimes the treatment of the cysts can cause loss of teeth. | 69 | Ameloblastoma |
nord_69_5 | Diagnosis of Ameloblastoma | Ameloblastoma can show up either in a regular x-ray or in an MRI imaging study. | Diagnosis of Ameloblastoma. Ameloblastoma can show up either in a regular x-ray or in an MRI imaging study. | 69 | Ameloblastoma |
nord_69_6 | Therapies of Ameloblastoma | TreatmentSurgical removal of the affected tissue is the preferred treatment. A wide margin of healthy tissue should be removed from the treated area to keep the chance of tumor regrowth to a minimum. If the tumor does reoccur, surgery is performed again.If there is malignant spread of the tumor, radiation is the treatment choice. Chemotherapy is usually not as effective in these cases. | Therapies of Ameloblastoma. TreatmentSurgical removal of the affected tissue is the preferred treatment. A wide margin of healthy tissue should be removed from the treated area to keep the chance of tumor regrowth to a minimum. If the tumor does reoccur, surgery is performed again.If there is malignant spread of the tumor, radiation is the treatment choice. Chemotherapy is usually not as effective in these cases. | 69 | Ameloblastoma |
nord_70_0 | Overview of Amelogenesis Imperfecta | Amelogenesis imperfecta (AI) refers to a group of rare, inherited disorders characterized by abnormal enamel formation. The term is typically restricted to those disorders of enamel development not associated with other abnormalities of the body.Clinical researchers usually classify AI into four main types of which 20 subtypes are recognized. The main types are based on clinical appearance, radiographic appearance and enamel thickness, and the subtypes are based on mode of inheritance and the causal gene. The main types are: hypoplastic (type I); hypomaturation (type II); hypocalcified (type III); and hypomaturation/hypoplasia/taurodontism (type IV). AI may be inherited as an X-linked, autosomal dominant, or autosomal recessive genetic trait, depending on the subtype. | Overview of Amelogenesis Imperfecta. Amelogenesis imperfecta (AI) refers to a group of rare, inherited disorders characterized by abnormal enamel formation. The term is typically restricted to those disorders of enamel development not associated with other abnormalities of the body.Clinical researchers usually classify AI into four main types of which 20 subtypes are recognized. The main types are based on clinical appearance, radiographic appearance and enamel thickness, and the subtypes are based on mode of inheritance and the causal gene. The main types are: hypoplastic (type I); hypomaturation (type II); hypocalcified (type III); and hypomaturation/hypoplasia/taurodontism (type IV). AI may be inherited as an X-linked, autosomal dominant, or autosomal recessive genetic trait, depending on the subtype. | 70 | Amelogenesis Imperfecta |
nord_70_1 | Symptoms of Amelogenesis Imperfecta | AI is characterized by defective or missing tooth enamel.Secondary effects of this disorder may be cracked tooth, early tooth decay and/or loss, in addition to susceptibility to multiple diseases of the tissues surrounding teeth (periodontal tissues) such as gums, cementum, ligaments, and alveolar bones in which the tooth root rests. Teeth are also sensitive to both hot or cold exposures, and sometimes both. This sensitivity can be due to the exposed sensitive dentin layer which is usually entirely protected by the enamel layer on top. The dental pulp in the root canal is where all of the tooth nerves are located, and the exposed sensitive dentin typically leads to continuous severe pain.The psychological trauma of patients with AI cannot be overlooked. Patients with AI have unsightly teeth that are discolored or spaced. Moreover, some patients also suffer from what’s called an open bite (the upper and lower jaws do not align properly), which results in an unpleasant appearance of the teeth. With continuous restorative, orthodontic and periodontal restoration, however, the teeth can end up looking normal and remain functional throughout the life of the individual. These dental treatments are expensive and require huge dedication. Patients who cannot afford these treatments sometimes have their teeth pulled, which adds more to their psychological trauma.Type I hypoplastic AI is characterized by small to normal tops (crowns) of the teeth, upper and lower teeth that do not meet showing a poor bite, and teeth that vary in color from off-white to yellow-brown. The enamel thickness varies from thin and smooth to normal, with grooves, lines and/or pits.Type II hypomaturation AI is commonly associated with an open bite and creamy white to yellow-brown roughly surfaced teeth that may be tender and sore. The enamel is generally normal in thickness but tends to be chipped away or scraped.Type III hypocalcified AI is seen in patients with an open bite and creamy white to yellow-brown rough enamel-surfaced teeth that may be tender and sore. These teeth usually carry substantial precipitates of stony material from the fluids of the mouth (calculi). The enamel is generally normal in thickness but tends to be chipped away or scraped.Type IV hypomaturation/hypoplasia/taurodontism AI usually is characterized by smaller than normal teeth, the color of which may range from white to yellow-brown, and teeth that appear to be mottled or spotted. The enamel is thinner than normal with areas that are clearly less dense (hypomineralized) and pitted. | Symptoms of Amelogenesis Imperfecta. AI is characterized by defective or missing tooth enamel.Secondary effects of this disorder may be cracked tooth, early tooth decay and/or loss, in addition to susceptibility to multiple diseases of the tissues surrounding teeth (periodontal tissues) such as gums, cementum, ligaments, and alveolar bones in which the tooth root rests. Teeth are also sensitive to both hot or cold exposures, and sometimes both. This sensitivity can be due to the exposed sensitive dentin layer which is usually entirely protected by the enamel layer on top. The dental pulp in the root canal is where all of the tooth nerves are located, and the exposed sensitive dentin typically leads to continuous severe pain.The psychological trauma of patients with AI cannot be overlooked. Patients with AI have unsightly teeth that are discolored or spaced. Moreover, some patients also suffer from what’s called an open bite (the upper and lower jaws do not align properly), which results in an unpleasant appearance of the teeth. With continuous restorative, orthodontic and periodontal restoration, however, the teeth can end up looking normal and remain functional throughout the life of the individual. These dental treatments are expensive and require huge dedication. Patients who cannot afford these treatments sometimes have their teeth pulled, which adds more to their psychological trauma.Type I hypoplastic AI is characterized by small to normal tops (crowns) of the teeth, upper and lower teeth that do not meet showing a poor bite, and teeth that vary in color from off-white to yellow-brown. The enamel thickness varies from thin and smooth to normal, with grooves, lines and/or pits.Type II hypomaturation AI is commonly associated with an open bite and creamy white to yellow-brown roughly surfaced teeth that may be tender and sore. The enamel is generally normal in thickness but tends to be chipped away or scraped.Type III hypocalcified AI is seen in patients with an open bite and creamy white to yellow-brown rough enamel-surfaced teeth that may be tender and sore. These teeth usually carry substantial precipitates of stony material from the fluids of the mouth (calculi). The enamel is generally normal in thickness but tends to be chipped away or scraped.Type IV hypomaturation/hypoplasia/taurodontism AI usually is characterized by smaller than normal teeth, the color of which may range from white to yellow-brown, and teeth that appear to be mottled or spotted. The enamel is thinner than normal with areas that are clearly less dense (hypomineralized) and pitted. | 70 | Amelogenesis Imperfecta |
nord_70_2 | Causes of Amelogenesis Imperfecta | Just as the classification of AI is complex, so too is the contribution of genetics to these disorders. Changes (variants or mutations) in specific genes have been identified as the cause of 19 subtypes of AI. The causal gene and mode of inheritance for these subtypes based on the OMIM (Online Mendelian Inheritance in Man) is listed below:Type I hypoplastic AI
Type IA: autosomal dominant inheritance, LAMB3 gene variant
Type IB: autosomal dominant inheritance, ENAM gene variant
Type IC: autosomal recessive inheritance, ENAM gene variant
Type IE: X-linked dominant inheritance, AMELX gene variant
Type IE, X-linked 2: X-linked inheritance, gene unknown
Type IF: autosomal recessive inheritance, AMBN gene variant
Type IG: autosomal recessive inheritance, FAM20A gene variant
Type IH: autosomal recessive inheritance, ITGB6 gene variant
Type IJ: autosomal recessive inheritance, ACPT gene variant
Type IK: Autosomal dominant inheritance, SP6 gene variantType II hypomaturation AI
Type IIA1: autosomal recessive inheritance, KLK4 gene variant
Type IIA2: autosomal recessive inheritance, MMP20 gene variant
Type IIA3: autosomal recessive inheritance, WDR72 gene variant
Type IIA4: autosomal recessive inheritance, OPAPH gene variant
Type IIA5: autosomal recessive inheritance, SLC24A4 gene variant
Type IIA6: autosomal recessive inheritance, GPR68 gene variantType III hypocalcified AI
Type IIIA: autosomal dominant inheritance, FAM83H gene variant
Type IIIB: autosomal dominant inheritance, AMTN gene variant
Type IIIC: autosomal recessive inheritance, RELT gene variantType IV hypomaturation/hypoplasia/taurodontism AI
Type IV: autosomal dominant inheritance, DLX3 gene variantMost genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk 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.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.X-linked dominant disorders are caused by an abnormal gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the gene for a particular disease. Males with an abnormal gene for an X-linked dominant disorder are more severely affected than females and often do not survive. | Causes of Amelogenesis Imperfecta. Just as the classification of AI is complex, so too is the contribution of genetics to these disorders. Changes (variants or mutations) in specific genes have been identified as the cause of 19 subtypes of AI. The causal gene and mode of inheritance for these subtypes based on the OMIM (Online Mendelian Inheritance in Man) is listed below:Type I hypoplastic AI
Type IA: autosomal dominant inheritance, LAMB3 gene variant
Type IB: autosomal dominant inheritance, ENAM gene variant
Type IC: autosomal recessive inheritance, ENAM gene variant
Type IE: X-linked dominant inheritance, AMELX gene variant
Type IE, X-linked 2: X-linked inheritance, gene unknown
Type IF: autosomal recessive inheritance, AMBN gene variant
Type IG: autosomal recessive inheritance, FAM20A gene variant
Type IH: autosomal recessive inheritance, ITGB6 gene variant
Type IJ: autosomal recessive inheritance, ACPT gene variant
Type IK: Autosomal dominant inheritance, SP6 gene variantType II hypomaturation AI
Type IIA1: autosomal recessive inheritance, KLK4 gene variant
Type IIA2: autosomal recessive inheritance, MMP20 gene variant
Type IIA3: autosomal recessive inheritance, WDR72 gene variant
Type IIA4: autosomal recessive inheritance, OPAPH gene variant
Type IIA5: autosomal recessive inheritance, SLC24A4 gene variant
Type IIA6: autosomal recessive inheritance, GPR68 gene variantType III hypocalcified AI
Type IIIA: autosomal dominant inheritance, FAM83H gene variant
Type IIIB: autosomal dominant inheritance, AMTN gene variant
Type IIIC: autosomal recessive inheritance, RELT gene variantType IV hypomaturation/hypoplasia/taurodontism AI
Type IV: autosomal dominant inheritance, DLX3 gene variantMost genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk 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.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.X-linked dominant disorders are caused by an abnormal gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the gene for a particular disease. Males with an abnormal gene for an X-linked dominant disorder are more severely affected than females and often do not survive. | 70 | Amelogenesis Imperfecta |
nord_70_3 | Affects of Amelogenesis Imperfecta | AI affects 1 of 14,000 to 16,000 children in the United States. Of this number, about 40% have the hypocalcified dominant type. The autosomal dominant and recessive forms of the disorder affect males and females in equal numbers. The X-linked dominant type of the disorder affects twice as many males as females. The X-linked recessive type affects only males. | Affects of Amelogenesis Imperfecta. AI affects 1 of 14,000 to 16,000 children in the United States. Of this number, about 40% have the hypocalcified dominant type. The autosomal dominant and recessive forms of the disorder affect males and females in equal numbers. The X-linked dominant type of the disorder affects twice as many males as females. The X-linked recessive type affects only males. | 70 | Amelogenesis Imperfecta |
nord_70_4 | Related disorders of Amelogenesis Imperfecta | Symptoms of the following disorders can be similar to those of AI. Comparisons may be useful for a differential diagnosis:There are many syndromic conditions that affect enamel formation (or whole tooth formation). One example is tricho-dento-osseous (TDO) syndrome. TDO syndrome is one of a group of congenital disorders known as ectodermal dysplasias. The condition primarily affects hair which is strikingly curly, and the teeth. X-ray examination of persons with TDO syndrome usually shows a mild increase in bone density, particularly in the skull. Thin and brittle fingernails also occur. Children with this disorder may have to wear dentures. A person with TDO syndrome may have AI as well. Intelligence and life span are usually normal for individuals with this disorder. (For more information on this disorder, choose “TDO” as your search term in the Rare Disease Database.) | Related disorders of Amelogenesis Imperfecta. Symptoms of the following disorders can be similar to those of AI. Comparisons may be useful for a differential diagnosis:There are many syndromic conditions that affect enamel formation (or whole tooth formation). One example is tricho-dento-osseous (TDO) syndrome. TDO syndrome is one of a group of congenital disorders known as ectodermal dysplasias. The condition primarily affects hair which is strikingly curly, and the teeth. X-ray examination of persons with TDO syndrome usually shows a mild increase in bone density, particularly in the skull. Thin and brittle fingernails also occur. Children with this disorder may have to wear dentures. A person with TDO syndrome may have AI as well. Intelligence and life span are usually normal for individuals with this disorder. (For more information on this disorder, choose “TDO” as your search term in the Rare Disease Database.) | 70 | Amelogenesis Imperfecta |
nord_70_5 | Diagnosis of Amelogenesis Imperfecta | Diagnosis of AI is usually made by visual examination, family history and X-ray examination at the time teeth erupt. The dentist may use a simple hand instrument to distinguish the different types of AI. By one to two years of age, the diagnosis can be made. | Diagnosis of Amelogenesis Imperfecta. Diagnosis of AI is usually made by visual examination, family history and X-ray examination at the time teeth erupt. The dentist may use a simple hand instrument to distinguish the different types of AI. By one to two years of age, the diagnosis can be made. | 70 | Amelogenesis Imperfecta |
nord_70_6 | Therapies of Amelogenesis Imperfecta | Treatment
Full crown restorations and a type of denture that caps defective teeth and corrects open bite are excellent treatments for this disorder. Desensitizing toothpaste can prevent painful sensitivity to heat and cold. Good oral hygiene is important. Genetic counseling is recommending for families of children with AI. | Therapies of Amelogenesis Imperfecta. Treatment
Full crown restorations and a type of denture that caps defective teeth and corrects open bite are excellent treatments for this disorder. Desensitizing toothpaste can prevent painful sensitivity to heat and cold. Good oral hygiene is important. Genetic counseling is recommending for families of children with AI. | 70 | Amelogenesis Imperfecta |
nord_71_0 | Overview of Amniotic Band Syndrome | Amniotic band syndrome is a well-known condition potentially associated with a variety of different birth defects. The abnormalities occur after the affected parts of the body have formed normally in early development. The severity of amniotic band syndrome can range from a single, isolated finding to multiple, disfiguring complications. The arms and legs are most often affected. The head and face and, in some patients, various internal organs can also be affected. The exact cause of amniotic band syndrome is unknown and controversial. Two main theories have been proposed to explain the development of the disorder. One theory attributes the disorder to causes that arise internally within the fetus (intrinsic theory); the other theory attributes the disorder to causes acting upon the fetus externally (extrinsic theory). It is likely that both internal and external factors can cause the amniotic band syndrome, and that the cause of the disorder in one infant may be different from the cause in another infant. | Overview of Amniotic Band Syndrome. Amniotic band syndrome is a well-known condition potentially associated with a variety of different birth defects. The abnormalities occur after the affected parts of the body have formed normally in early development. The severity of amniotic band syndrome can range from a single, isolated finding to multiple, disfiguring complications. The arms and legs are most often affected. The head and face and, in some patients, various internal organs can also be affected. The exact cause of amniotic band syndrome is unknown and controversial. Two main theories have been proposed to explain the development of the disorder. One theory attributes the disorder to causes that arise internally within the fetus (intrinsic theory); the other theory attributes the disorder to causes acting upon the fetus externally (extrinsic theory). It is likely that both internal and external factors can cause the amniotic band syndrome, and that the cause of the disorder in one infant may be different from the cause in another infant. | 71 | Amniotic Band Syndrome |
nord_71_1 | Symptoms of Amniotic Band Syndrome | The symptoms associated with amniotic band syndrome vary greatly from one infant to another. Some infants develop only mild deformities; others develop severe and even life-threatening malformations. It seems likely that the features of amniotic band syndrome develop primarily in the first 12 weeks (first trimester) of pregnancy.Several different patterns have been identified with amniotic band syndrome. The three most common patterns are amniotic band syndrome characterized by one or more limbs being affected; the limb-body-wall complex; and amniotic band syndrome characterized by abnormalities of the head and face (craniofacial abnormalities), defects of the brain and serious malformation of the arms and legs.Most infants with amniotic band syndrome have some form of deformity of the arms and legs or fingers and toes. One or more limbs may be affected. Upper limbs are affected more often than lower limbs. In some patients, one limb or one hand or foot may be the only symptom of the disorder. The specific physical features can include abnormally short fingers or toes with absence of the end (distal) portion, webbing (fusion) of fingers or toes (syndactyly), constriction rings and extra strands of tissue adhering to the fingers. The constriction rings that encircle a limb or digit can alter blood flow.Another pattern associated with amniotic band syndrome is referred to as the limb-body wall complex, a lethal condition. Affected infants usually have protrusion of a portion of the brain and its surrounding membranes (meninges) through the skull defect (encephalocele), facial clefts, protrusion of the viscera (the soft internal organs of the body including those found in the abdominal or chest cavities) through a fissure in the abdominal wall (abdominoschisis) or the chest wall (thoracoschisis), and a variety of defects affecting the arms and legs.A third pattern associated with amniotic band syndrome involves craniofacial abnormalities such as incomplete closure of the roof of the mouth (cleft palate), facial clefts, small, underdeveloped eyes (microphthalmia), narrowing of the nasal passages (choanal atresia), and malformations affecting the size and shape of the skull. In some infants, the head is adherent to the placenta. | Symptoms of Amniotic Band Syndrome. The symptoms associated with amniotic band syndrome vary greatly from one infant to another. Some infants develop only mild deformities; others develop severe and even life-threatening malformations. It seems likely that the features of amniotic band syndrome develop primarily in the first 12 weeks (first trimester) of pregnancy.Several different patterns have been identified with amniotic band syndrome. The three most common patterns are amniotic band syndrome characterized by one or more limbs being affected; the limb-body-wall complex; and amniotic band syndrome characterized by abnormalities of the head and face (craniofacial abnormalities), defects of the brain and serious malformation of the arms and legs.Most infants with amniotic band syndrome have some form of deformity of the arms and legs or fingers and toes. One or more limbs may be affected. Upper limbs are affected more often than lower limbs. In some patients, one limb or one hand or foot may be the only symptom of the disorder. The specific physical features can include abnormally short fingers or toes with absence of the end (distal) portion, webbing (fusion) of fingers or toes (syndactyly), constriction rings and extra strands of tissue adhering to the fingers. The constriction rings that encircle a limb or digit can alter blood flow.Another pattern associated with amniotic band syndrome is referred to as the limb-body wall complex, a lethal condition. Affected infants usually have protrusion of a portion of the brain and its surrounding membranes (meninges) through the skull defect (encephalocele), facial clefts, protrusion of the viscera (the soft internal organs of the body including those found in the abdominal or chest cavities) through a fissure in the abdominal wall (abdominoschisis) or the chest wall (thoracoschisis), and a variety of defects affecting the arms and legs.A third pattern associated with amniotic band syndrome involves craniofacial abnormalities such as incomplete closure of the roof of the mouth (cleft palate), facial clefts, small, underdeveloped eyes (microphthalmia), narrowing of the nasal passages (choanal atresia), and malformations affecting the size and shape of the skull. In some infants, the head is adherent to the placenta. | 71 | Amniotic Band Syndrome |
nord_71_2 | Causes of Amniotic Band Syndrome | The causes and underlying mechanisms that cause amniotic band syndrome are complex and controversial. Several different theories have been proposed to explain the complex mechanisms that underlie amniotic band syndrome. The two main theories are known as the extrinsic theory and the intrinsic theory. The extrinsic theory states that amniotic band syndrome occurs due to factors found outside of the fetus (externally); the intrinsic theory states that amniotic band syndrome occurs due to factors found within the fetus (internally).MECHANISMS
Extrinsic Theory
The extrinsic theory for the development of amniotic band syndrome is that strands of tissue separate from the inner layer (amnion) of the amniotic sac. The amniotic sac is the thin membrane that completely surrounds an embryo or developing fetus (amniotic sac). The sac contains a liquid (amniotic fluid), which supports, cushions and protects a developing fetus. The amniotic sac is composed of two main layers – the outer layer is called the chorion and the inner layer is called the amnion.According to this theory, amniotic band syndrome occurs when the inner layer (amnion) of the amniotic sac ruptures or tears, exposing the fetus to strands of fibrous tissue that may float freely in the amniotic fluid or remain partially attached to the amniotic sac. These bands of tissue can disrupt the normal development of a fetus. The bands of tissue can wrap around or entangle (constrict) the fingers, toes, arms, legs and other parts of the developing fetus as when a rubber band had been tightly wrapped around an arm or leg or another body part. The symptoms that occur due to amniotic bands depend on the specific part of the body affected by these strands of tissue and how tightly they have wrapped around a body part. If the amniotic bands are still partially attached to the amniotic sac, they may wrap around a fetal body part and tether (anchor) that body part to the amniotic sac. This can restrict movement and proper development of the affected fetus.Intrinsic Theory
The intrinsic theory was proposed because some researchers noted that, while the above theory explains some cases of amniotic band syndrome, it is insufficient to explain all cases. The external theory fails to explain why there is an intact amniotic sac in some infants with amniotic band syndrome; why there are a high number of malformations affecting internal organs in some patients; and why some infants have defects of parts of the body not affected by amniotic (constriction) bands.The intrinsic theory attributes the development of amniotic band syndrome to impaired blood flow (circulation) to specific parts of the developing fetus (vascular disruption or compromise). The exact, underlying cause(s) of impaired blood flow is unknown. In areas where the blood flow is poor, injury occurs to the blood vessel walls of the fetus. This leads to bleeding (hemorrhaging) and tissue loss in the affected areas, which in turn results in the varied symptoms associated with the disorder. The intrinsic theory attributes the presence of constriction bands as a secondary effect of the impaired blood flow and subsequent damage to the fetus. In a 1987 article in the journal, Teratology, Webster, et al. demonstrated this theory of vascular disruption with an intact amnion in animal models.CAUSES
Damage to the amniotic sac has been implicated as a cause of amniotic band syndrome under the extrinsic theory. The exact reason that the amniotic sac tears or ruptures is not always known and researchers believe that in some cases it may happen as a random occurrence.In some cases, specific environmental factors have been identified. In some infants, trauma to the abdominal area during pregnancy or blunt trauma to the placenta seemed to have caused the amniotic band syndrome.A few infants have been affected after the performance of a diagnostic technique chorionic villus sampling (CVS), when performed early during pregnancy. The prenatal test was performed to detect certain problems in a fetus such as chromosomal abnormalities or certain genetic disorders. During the procedure, tissue is removed from the placenta and certain cells called chorionic villi are studied. One estimate of the risk for this occasional risk was 1 in 2,000 CVS procedures.It has also been reported that intense uterine contractions caused by a drug known as misoprostol (a prostaglandin E1 analogue) has resulted in amniotic band syndrome. Misoprostol is approved by the Food and Drug Administration for the treatment of gastric ulcers. However, the drug has been used to induce abortion. If the pregnancy continues after the use of misoprostol at 6 to 8 weeks of pregnancy, the infant may have the amniotic band syndrome.The exact cause of impaired fetal blood flow as suggested by the intrinsic theory is unknown. It has been noted, also, that the amniotic band syndrome occurs with greater frequency in first pregnancies, problem pregnancies or premature births. Young women and women of African descent also have higher rates of infants with amniotic band syndrome. Research is ongoing to determine why certain populations have a greater risk of developing the disorder than other populations.Some recent genetic studies have begun to identify intrinsic, genetic factors that may predispose infants to the development of amniotic band syndrome (genetic predisposition). A genetic predisposition to developing a disorder means that a person carries a gene, or more likely gene(s), for the disorder, but that the disorder is not expressed unless it is triggered or activated under certain circumstances such as particular environmental factors (multifactorial inheritance).For example, a genetic predisposition to vascular disruption may contribute to the development of amniotic band syndrome in some cases. Two medical journal articles (Hunter, et al. and Carmichael, et al.) have discussed the possibility that genetic factors influence the development of amniotic band syndrome in certain pregnancies.Although genetic factors are believed to play a role in the development of infants with some cases of amniotic band syndrome, the risk of recurrence in a subsequent child is extremely low. Most cases of amniotic band syndrome occur sporadically. Current, ongoing research into the potential intrinsic factors associated with amniotic band syndrome should reveal more about the complex causes and development of the disorder. | Causes of Amniotic Band Syndrome. The causes and underlying mechanisms that cause amniotic band syndrome are complex and controversial. Several different theories have been proposed to explain the complex mechanisms that underlie amniotic band syndrome. The two main theories are known as the extrinsic theory and the intrinsic theory. The extrinsic theory states that amniotic band syndrome occurs due to factors found outside of the fetus (externally); the intrinsic theory states that amniotic band syndrome occurs due to factors found within the fetus (internally).MECHANISMS
Extrinsic Theory
The extrinsic theory for the development of amniotic band syndrome is that strands of tissue separate from the inner layer (amnion) of the amniotic sac. The amniotic sac is the thin membrane that completely surrounds an embryo or developing fetus (amniotic sac). The sac contains a liquid (amniotic fluid), which supports, cushions and protects a developing fetus. The amniotic sac is composed of two main layers – the outer layer is called the chorion and the inner layer is called the amnion.According to this theory, amniotic band syndrome occurs when the inner layer (amnion) of the amniotic sac ruptures or tears, exposing the fetus to strands of fibrous tissue that may float freely in the amniotic fluid or remain partially attached to the amniotic sac. These bands of tissue can disrupt the normal development of a fetus. The bands of tissue can wrap around or entangle (constrict) the fingers, toes, arms, legs and other parts of the developing fetus as when a rubber band had been tightly wrapped around an arm or leg or another body part. The symptoms that occur due to amniotic bands depend on the specific part of the body affected by these strands of tissue and how tightly they have wrapped around a body part. If the amniotic bands are still partially attached to the amniotic sac, they may wrap around a fetal body part and tether (anchor) that body part to the amniotic sac. This can restrict movement and proper development of the affected fetus.Intrinsic Theory
The intrinsic theory was proposed because some researchers noted that, while the above theory explains some cases of amniotic band syndrome, it is insufficient to explain all cases. The external theory fails to explain why there is an intact amniotic sac in some infants with amniotic band syndrome; why there are a high number of malformations affecting internal organs in some patients; and why some infants have defects of parts of the body not affected by amniotic (constriction) bands.The intrinsic theory attributes the development of amniotic band syndrome to impaired blood flow (circulation) to specific parts of the developing fetus (vascular disruption or compromise). The exact, underlying cause(s) of impaired blood flow is unknown. In areas where the blood flow is poor, injury occurs to the blood vessel walls of the fetus. This leads to bleeding (hemorrhaging) and tissue loss in the affected areas, which in turn results in the varied symptoms associated with the disorder. The intrinsic theory attributes the presence of constriction bands as a secondary effect of the impaired blood flow and subsequent damage to the fetus. In a 1987 article in the journal, Teratology, Webster, et al. demonstrated this theory of vascular disruption with an intact amnion in animal models.CAUSES
Damage to the amniotic sac has been implicated as a cause of amniotic band syndrome under the extrinsic theory. The exact reason that the amniotic sac tears or ruptures is not always known and researchers believe that in some cases it may happen as a random occurrence.In some cases, specific environmental factors have been identified. In some infants, trauma to the abdominal area during pregnancy or blunt trauma to the placenta seemed to have caused the amniotic band syndrome.A few infants have been affected after the performance of a diagnostic technique chorionic villus sampling (CVS), when performed early during pregnancy. The prenatal test was performed to detect certain problems in a fetus such as chromosomal abnormalities or certain genetic disorders. During the procedure, tissue is removed from the placenta and certain cells called chorionic villi are studied. One estimate of the risk for this occasional risk was 1 in 2,000 CVS procedures.It has also been reported that intense uterine contractions caused by a drug known as misoprostol (a prostaglandin E1 analogue) has resulted in amniotic band syndrome. Misoprostol is approved by the Food and Drug Administration for the treatment of gastric ulcers. However, the drug has been used to induce abortion. If the pregnancy continues after the use of misoprostol at 6 to 8 weeks of pregnancy, the infant may have the amniotic band syndrome.The exact cause of impaired fetal blood flow as suggested by the intrinsic theory is unknown. It has been noted, also, that the amniotic band syndrome occurs with greater frequency in first pregnancies, problem pregnancies or premature births. Young women and women of African descent also have higher rates of infants with amniotic band syndrome. Research is ongoing to determine why certain populations have a greater risk of developing the disorder than other populations.Some recent genetic studies have begun to identify intrinsic, genetic factors that may predispose infants to the development of amniotic band syndrome (genetic predisposition). A genetic predisposition to developing a disorder means that a person carries a gene, or more likely gene(s), for the disorder, but that the disorder is not expressed unless it is triggered or activated under certain circumstances such as particular environmental factors (multifactorial inheritance).For example, a genetic predisposition to vascular disruption may contribute to the development of amniotic band syndrome in some cases. Two medical journal articles (Hunter, et al. and Carmichael, et al.) have discussed the possibility that genetic factors influence the development of amniotic band syndrome in certain pregnancies.Although genetic factors are believed to play a role in the development of infants with some cases of amniotic band syndrome, the risk of recurrence in a subsequent child is extremely low. Most cases of amniotic band syndrome occur sporadically. Current, ongoing research into the potential intrinsic factors associated with amniotic band syndrome should reveal more about the complex causes and development of the disorder. | 71 | Amniotic Band Syndrome |
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