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nord_485_5 | Diagnosis of Froelich Syndrome | After a physician conducts a physical examination to identify characteristic signs of Froelich syndrome, laboratory analysis typically reveals low levels of pituitary hormones. This may suggest the presence of a lesion on either the pituitary gland or hypothalamus. Blood tests including TSH tests, FSH tests, LH tests, GH tests, prolactin level and ADH level tests are used to determine the level of hypothalamus and pituitary function.If infection is suspected, blood cultures may be taken. In the event of a suspected lesion or abnormal growth, imaging studies of the brain are conducted. These may include CT scan of head region or MRI scan of the brain. Additional tests are needed to rule out Prader-Willi syndrome before a definite diagnosis of Froehlich syndrome can be made. | Diagnosis of Froelich Syndrome. After a physician conducts a physical examination to identify characteristic signs of Froelich syndrome, laboratory analysis typically reveals low levels of pituitary hormones. This may suggest the presence of a lesion on either the pituitary gland or hypothalamus. Blood tests including TSH tests, FSH tests, LH tests, GH tests, prolactin level and ADH level tests are used to determine the level of hypothalamus and pituitary function.If infection is suspected, blood cultures may be taken. In the event of a suspected lesion or abnormal growth, imaging studies of the brain are conducted. These may include CT scan of head region or MRI scan of the brain. Additional tests are needed to rule out Prader-Willi syndrome before a definite diagnosis of Froehlich syndrome can be made. | 485 | Froelich Syndrome |
nord_485_6 | Therapies of Froelich Syndrome | Treatment
If possible, tumors of the hypothalamus should be surgically removed.Pituitary extracts may be given through hormone replacement therapy (HRT) to replace the missing hormones in patients with Froehlich syndrome. For males, this usually includes human chorionic gonadotropin to reach puberty followed up by testosterone. For females, HRT with estrogen is given during teenage years followed by complex estrogen-progestin therapy. Though appetite may be very difficult to manage, weight control depends on successful management. Some modern treatments can help to control obesity (GLP1 analogues). | Therapies of Froelich Syndrome. Treatment
If possible, tumors of the hypothalamus should be surgically removed.Pituitary extracts may be given through hormone replacement therapy (HRT) to replace the missing hormones in patients with Froehlich syndrome. For males, this usually includes human chorionic gonadotropin to reach puberty followed up by testosterone. For females, HRT with estrogen is given during teenage years followed by complex estrogen-progestin therapy. Though appetite may be very difficult to manage, weight control depends on successful management. Some modern treatments can help to control obesity (GLP1 analogues). | 485 | Froelich Syndrome |
nord_486_0 | Overview of Frontofacionasal Dysplasia | Frontofacionasal dysplasia is a rare genetic disorder that is apparent at birth (congenital). The disorder is primarily characterized by malformations of the head and facial (craniofacial) area and eye (ocular) defects. Craniofacial malformations may include an unusually short, broad head (brachycephaly); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and underdevelopment (hypoplasia) of the nose with malformation of the nostrils. Affected infants may also have abnormal narrowing of the folds (palpebral fissures) between the upper and lower eyelids (blepharophimosis) and an unusually increased distance between the eyes (ocular hypertelorism). Additional eye abnormalities may include partial absence of tissue (coloboma) from the upper eyelids or the colored regions of the eyes (irides) and an inability to completely close the eyes (lagophthalmos). The signs and symptoms of frontofacionasal dysplasia are highly variable. Frontofacionasal dysplasia appears to be inherited in an autosomal recessive pattern. | Overview of Frontofacionasal Dysplasia. Frontofacionasal dysplasia is a rare genetic disorder that is apparent at birth (congenital). The disorder is primarily characterized by malformations of the head and facial (craniofacial) area and eye (ocular) defects. Craniofacial malformations may include an unusually short, broad head (brachycephaly); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and underdevelopment (hypoplasia) of the nose with malformation of the nostrils. Affected infants may also have abnormal narrowing of the folds (palpebral fissures) between the upper and lower eyelids (blepharophimosis) and an unusually increased distance between the eyes (ocular hypertelorism). Additional eye abnormalities may include partial absence of tissue (coloboma) from the upper eyelids or the colored regions of the eyes (irides) and an inability to completely close the eyes (lagophthalmos). The signs and symptoms of frontofacionasal dysplasia are highly variable. Frontofacionasal dysplasia appears to be inherited in an autosomal recessive pattern. | 486 | Frontofacionasal Dysplasia |
nord_486_1 | Symptoms of Frontofacionasal Dysplasia | Infants with frontofacionasal dysplasia typically have distinctive malformations of certain bones forming the skull as well as additional facial, nasal, and eye (ocular) defects. For example, the disorder may be associated with premature closure of the fibrous joints (sutures) between particular bones of the skull (craniosynostosis), causing the head to appear unusually short and broad (brachycephaly). In addition, there may be early conversion of fibrous tissue into bone (early ossification) within the base of the skull (sphenoid bone), and some of the air-filled cavities (i.e., paranasal ethmoidal sinuses) within certain bones around the nose may be abnormally large. Underdevelopment of the middle portion of the face (midface hypoplasia) also occurs.Affected infants may also have additional, associated skull defects, such as underdevelopment (hypoplasia) of part of the bone forming the front of the skull (frontal bone) and an abnormal opening (congenital cleft) within the frontal bone (cranium bifidum). In some infants with a congenital cleft of the skull, there may be protrusion of a portion of the brain and its surrounding membranes (meninges) through the skull defect (encephalocele). However, in others, there may be no associated abnormality of the brain or meninges (cranium bifidum occultum).
Frontofacionasal dysplasia is also typically characterized by distinctive nasal abnormalities, such as underdevelopment of the nose and malformation of the nostrils such as underdevelopment of the nasal wings (nasal alae). In addition, affected infants may have incomplete closure of the roof of the mouth (cleft palate) and an abnormal groove in the upper lip (cleft lip). Infants with cleft lip and cleft palate often experience feeding difficulties due to poor suckling ability and increased air swallowing. They also tend to develop dental abnormalities, including improper positioning, malformation, or absence of certain teeth. Some children with these malformations may also experience associated speech difficulties and have an increased susceptibility to middle ear infections. The fleshy mass (uvula) that hangs in the back of the throat may be split (bifid uvula).Infants with frontofacionasal dysplasia also have various abnormalities involving the eyes. These may include widely spaced eyes (ocular hypertelorism); an abnormally increased horizontal distance between the inner angles of the eyelids (telecanthus); and unusually narrow, “S-shaped” eyelid folds (palpebral fissures). In addition, affected individuals may have partial absence of tissue (coloboma) from the colored regions of the eyes (irides) or the upper eyelids; an inability to completely close the eyes (lagophthalmos); drooping of the upper eyelids (ptosis); and absence of eyelashes. In some cases, additional ocular defects may also be present, including adhesion of the edges of the upper and lower eyelids (ankyloblepharon), abnormal smallness of the eyes (microphthalmia), or the formation of cysts in certain regions of the eyes (e.g., limbic dermoids).In some instances, individuals with frontofacionasal dysplasia have additional physical abnormalities. For example, some may have benign (noncancerous), fatty tumors in the forehead area (frontal lipomas) or a widow’s peak, which is a “V-shaped” extension of the scalp hair onto the middle of the forehead. | Symptoms of Frontofacionasal Dysplasia. Infants with frontofacionasal dysplasia typically have distinctive malformations of certain bones forming the skull as well as additional facial, nasal, and eye (ocular) defects. For example, the disorder may be associated with premature closure of the fibrous joints (sutures) between particular bones of the skull (craniosynostosis), causing the head to appear unusually short and broad (brachycephaly). In addition, there may be early conversion of fibrous tissue into bone (early ossification) within the base of the skull (sphenoid bone), and some of the air-filled cavities (i.e., paranasal ethmoidal sinuses) within certain bones around the nose may be abnormally large. Underdevelopment of the middle portion of the face (midface hypoplasia) also occurs.Affected infants may also have additional, associated skull defects, such as underdevelopment (hypoplasia) of part of the bone forming the front of the skull (frontal bone) and an abnormal opening (congenital cleft) within the frontal bone (cranium bifidum). In some infants with a congenital cleft of the skull, there may be protrusion of a portion of the brain and its surrounding membranes (meninges) through the skull defect (encephalocele). However, in others, there may be no associated abnormality of the brain or meninges (cranium bifidum occultum).
Frontofacionasal dysplasia is also typically characterized by distinctive nasal abnormalities, such as underdevelopment of the nose and malformation of the nostrils such as underdevelopment of the nasal wings (nasal alae). In addition, affected infants may have incomplete closure of the roof of the mouth (cleft palate) and an abnormal groove in the upper lip (cleft lip). Infants with cleft lip and cleft palate often experience feeding difficulties due to poor suckling ability and increased air swallowing. They also tend to develop dental abnormalities, including improper positioning, malformation, or absence of certain teeth. Some children with these malformations may also experience associated speech difficulties and have an increased susceptibility to middle ear infections. The fleshy mass (uvula) that hangs in the back of the throat may be split (bifid uvula).Infants with frontofacionasal dysplasia also have various abnormalities involving the eyes. These may include widely spaced eyes (ocular hypertelorism); an abnormally increased horizontal distance between the inner angles of the eyelids (telecanthus); and unusually narrow, “S-shaped” eyelid folds (palpebral fissures). In addition, affected individuals may have partial absence of tissue (coloboma) from the colored regions of the eyes (irides) or the upper eyelids; an inability to completely close the eyes (lagophthalmos); drooping of the upper eyelids (ptosis); and absence of eyelashes. In some cases, additional ocular defects may also be present, including adhesion of the edges of the upper and lower eyelids (ankyloblepharon), abnormal smallness of the eyes (microphthalmia), or the formation of cysts in certain regions of the eyes (e.g., limbic dermoids).In some instances, individuals with frontofacionasal dysplasia have additional physical abnormalities. For example, some may have benign (noncancerous), fatty tumors in the forehead area (frontal lipomas) or a widow’s peak, which is a “V-shaped” extension of the scalp hair onto the middle of the forehead. | 486 | Frontofacionasal Dysplasia |
nord_486_2 | Causes of Frontofacionasal Dysplasia | Frontofacionasal dysplasia appears to be inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.The parents of some individuals with frontofacionasal dysplasia have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for development of the disease. | Causes of Frontofacionasal Dysplasia. Frontofacionasal dysplasia appears to be inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.The parents of some individuals with frontofacionasal dysplasia have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for development of the disease. | 486 | Frontofacionasal Dysplasia |
nord_486_3 | Affects of Frontofacionasal Dysplasia | Since the disorder was originally described in 1981 (T.R. Gollop) in a brother and sister, fewer than 10 cases of frontofacionasal dysplasia have been reported in the medical literature. The two siblings as well as the third individual reported with the disorder are of Brazilian descent. | Affects of Frontofacionasal Dysplasia. Since the disorder was originally described in 1981 (T.R. Gollop) in a brother and sister, fewer than 10 cases of frontofacionasal dysplasia have been reported in the medical literature. The two siblings as well as the third individual reported with the disorder are of Brazilian descent. | 486 | Frontofacionasal Dysplasia |
nord_486_4 | Related disorders of Frontofacionasal Dysplasia | Symptoms of the following disorders may be similar to those of frontofacionasal dysplasia. Comparisons may be useful for a differential diagnosis:Craniofrontonasal dysplasia is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings may vary greatly in range and severity from person to person. However, in many affected individuals, such abnormalities may include an unusually broad, prominent forehead; widely spaced eyes (ocular hypertelorism); a broad nose with a grooved nasal tip; and a wide mouth. Additional malformations may sometimes be present, such as incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); split nails; unusually broad great toes; webbing of certain fingers or toes (syndactyly); and/or additional skeletal abnormalities. (For further information on this disorder, please choose “craniofrontonasal” as your search term in the Rare Disease Database.)Frontonasal dysplasia, also known as median cleft face syndrome, is a rare disorder that typically appears to occur randomly for unknown reasons (sporadically). Associated symptoms and findings may be extremely variable. However, affected individuals typically have widely spaced eyes, a broad nasal root with lack of a nasal tip, a widow’s peak, and, in some cases, an abnormal opening in the front region of the skull (anterior cranium bifidum occultum). Due to abnormal development of certain midfacial regions, clefting of the nose may range from absence of the nasal tip to separation of the nose into two parts. Associated features may include an abnormal groove in the upper lip (cleft lip) and/or incomplete closure of the roof of the mouth (cleft palate). Some affected individuals also have additional abnormalities, such as unusually small eyes (microphthalmia), partial absence of tissue (coloboma) from the upper eyelids, or the formation of cysts on the eyeballs (epibulbar dermoids). In addition, in some cases, there may be abnormal protrusion of a portion of the brain and its surrounding membranes through the congenital skull defect (encephalocele). (For further information on this disorder, please choose “frontonasal dysplasia” as your search term in the Rare Disease Database.)There are additional disorders that may be characterized by craniofacial abnormalities, ocular defects, and other symptoms and findings similar to those associated with frontofacionasal dysplasia including Goldenhar syndrome, acrofrontofacionasal dysplasia and oculocerebrocutaneous syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Frontofacionasal Dysplasia. Symptoms of the following disorders may be similar to those of frontofacionasal dysplasia. Comparisons may be useful for a differential diagnosis:Craniofrontonasal dysplasia is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings may vary greatly in range and severity from person to person. However, in many affected individuals, such abnormalities may include an unusually broad, prominent forehead; widely spaced eyes (ocular hypertelorism); a broad nose with a grooved nasal tip; and a wide mouth. Additional malformations may sometimes be present, such as incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); split nails; unusually broad great toes; webbing of certain fingers or toes (syndactyly); and/or additional skeletal abnormalities. (For further information on this disorder, please choose “craniofrontonasal” as your search term in the Rare Disease Database.)Frontonasal dysplasia, also known as median cleft face syndrome, is a rare disorder that typically appears to occur randomly for unknown reasons (sporadically). Associated symptoms and findings may be extremely variable. However, affected individuals typically have widely spaced eyes, a broad nasal root with lack of a nasal tip, a widow’s peak, and, in some cases, an abnormal opening in the front region of the skull (anterior cranium bifidum occultum). Due to abnormal development of certain midfacial regions, clefting of the nose may range from absence of the nasal tip to separation of the nose into two parts. Associated features may include an abnormal groove in the upper lip (cleft lip) and/or incomplete closure of the roof of the mouth (cleft palate). Some affected individuals also have additional abnormalities, such as unusually small eyes (microphthalmia), partial absence of tissue (coloboma) from the upper eyelids, or the formation of cysts on the eyeballs (epibulbar dermoids). In addition, in some cases, there may be abnormal protrusion of a portion of the brain and its surrounding membranes through the congenital skull defect (encephalocele). (For further information on this disorder, please choose “frontonasal dysplasia” as your search term in the Rare Disease Database.)There are additional disorders that may be characterized by craniofacial abnormalities, ocular defects, and other symptoms and findings similar to those associated with frontofacionasal dysplasia including Goldenhar syndrome, acrofrontofacionasal dysplasia and oculocerebrocutaneous syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | 486 | Frontofacionasal Dysplasia |
nord_486_5 | Diagnosis of Frontofacionasal Dysplasia | In some instances, a diagnosis of frontofacionasal dysplasia may be suggested before birth (prenatally) based upon detection of certain physical findings during fetal ultrasound (e.g., facial clefts, cranium bifidum occultum or encephalocele). During fetal ultrasonography, sound waves are used to create an image of the developing fetus.Most patients with frontofacionasal dysplasia are diagnosed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and specialized tests, such as imaging techniques. For example, computerized tomography (CT) scanning or magnetic resonance imaging (MRI) may play an important role in confirming or characterizing the presence of certain malformations of the skull (e.g., craniosynostosis, cranium bifidum). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the skull or other internal structures. During MRI, a magnetic field and radio waves form detailed cross-sectional images of certain organs and tissues. | Diagnosis of Frontofacionasal Dysplasia. In some instances, a diagnosis of frontofacionasal dysplasia may be suggested before birth (prenatally) based upon detection of certain physical findings during fetal ultrasound (e.g., facial clefts, cranium bifidum occultum or encephalocele). During fetal ultrasonography, sound waves are used to create an image of the developing fetus.Most patients with frontofacionasal dysplasia are diagnosed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and specialized tests, such as imaging techniques. For example, computerized tomography (CT) scanning or magnetic resonance imaging (MRI) may play an important role in confirming or characterizing the presence of certain malformations of the skull (e.g., craniosynostosis, cranium bifidum). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the skull or other internal structures. During MRI, a magnetic field and radio waves form detailed cross-sectional images of certain organs and tissues. | 486 | Frontofacionasal Dysplasia |
nord_486_6 | Therapies of Frontofacionasal Dysplasia | Treatment
The treatment of frontofacionasal dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; specialists who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in neurological disorders (neurologists); eye specialists (ophthalmologists); and/or other health care professionals.Treatment may include surgical repair of certain malformations, including cleft lip and cleft palate; congenital defects of the skull (e.g., cranium bifidum); protrusion of a portion of the brain and its surrounding membranes through an abnormal opening in the skull (encephalocele); eyelid defects; and/or other malformations potentially associated with the disorder. The specific surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors.In children with cleft lip and cleft palate, supportive measures may be necessary during infancy to ensure improved feeding and appropriate intake of nutrients. In addition, affected children may require certain dental procedures to help correct improperly aligned teeth or other dental abnormalities potentially associated with cleft lip or palate. Certain drug therapies or other measures may also be required for the early, appropriate treatment of middle ear infections.Early intervention may be important to help ensure that children with frontofacionasal dysplasia reach their potential. Special services that may be beneficial include special social support, speech therapy, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. | Therapies of Frontofacionasal Dysplasia. Treatment
The treatment of frontofacionasal dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; specialists who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in neurological disorders (neurologists); eye specialists (ophthalmologists); and/or other health care professionals.Treatment may include surgical repair of certain malformations, including cleft lip and cleft palate; congenital defects of the skull (e.g., cranium bifidum); protrusion of a portion of the brain and its surrounding membranes through an abnormal opening in the skull (encephalocele); eyelid defects; and/or other malformations potentially associated with the disorder. The specific surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors.In children with cleft lip and cleft palate, supportive measures may be necessary during infancy to ensure improved feeding and appropriate intake of nutrients. In addition, affected children may require certain dental procedures to help correct improperly aligned teeth or other dental abnormalities potentially associated with cleft lip or palate. Certain drug therapies or other measures may also be required for the early, appropriate treatment of middle ear infections.Early intervention may be important to help ensure that children with frontofacionasal dysplasia reach their potential. Special services that may be beneficial include special social support, speech therapy, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. | 486 | Frontofacionasal Dysplasia |
nord_487_0 | Overview of Frontonasal Dysplasia | Frontonasal dysplasia is a rare disorder characterized by abnormal development of the head and face before birth. Major physical characteristics may include widely spaced eyes (ocular hypertelorism); a flat broad nose; and/or a vertical groove down the middle of the face. The depth and width of the vertical groove may vary greatly. In some cases, the tip of the nose may be missing; in more severe cases, the nose may separate vertically into two parts. In addition, an abnormal skin-covered gap in the front of the head (anterior cranium occultum) may also be present in some cases. There are at least three types of frontonasal dysplasia that can be distinguished by genetic causes and symptoms. | Overview of Frontonasal Dysplasia. Frontonasal dysplasia is a rare disorder characterized by abnormal development of the head and face before birth. Major physical characteristics may include widely spaced eyes (ocular hypertelorism); a flat broad nose; and/or a vertical groove down the middle of the face. The depth and width of the vertical groove may vary greatly. In some cases, the tip of the nose may be missing; in more severe cases, the nose may separate vertically into two parts. In addition, an abnormal skin-covered gap in the front of the head (anterior cranium occultum) may also be present in some cases. There are at least three types of frontonasal dysplasia that can be distinguished by genetic causes and symptoms. | 487 | Frontonasal Dysplasia |
nord_487_1 | Symptoms of Frontonasal Dysplasia | Frontonasal dysplasia-1(FND-1)
The physical characteristics associated with frontonasal dysplasia may vary greatly in severity from person to person. Features of this disorder include widely spaced eyes (ocular hypertelorism) and/or a vertical groove down the middle of the face. The depth and width of the groove may vary greatly among affected infants. The nose may be unusually flat and broad, have a “notched” or missing tip, or, in severe cases, may be completely divided in two.Other physical characteristics associated with frontonasal dysplasia may include a V-shaped hairline that extends down onto the forehead (widow’s peak), unusually small (slit-like) nostrils, an abnormal skin-covered gap in the front of the head (cranium bifidum occultum), and/or, in rare cases, a head that may appear abnormally short and wide (brachycephaly). Some infants with frontonasal dysplasia may also have incomplete closure of the roof of the mouth (cleft palate) and a vertical groove in the upper lip (cleft lip). The most severe clefts involve the lips, gums, and the bony front portion and/or soft back portions of the roof of the mouth (hard and soft palates). Less severe clefts may involve only one of these areas.Frontonasal dysplasia-2 (FND-2)
This form of fronotonasal dysplasia is characterized by a large skull defect and a premature fusion of the coronal suture (coronal craniosynostosis). Features of this disorder include widely spaced eyes (ocular hypertelorism) and severely depressed nasal bridge and ridge. Affected individuals may experience broad variations in hair development ranging from rapid hair loss and the absence of hair, eyebrows, eyelashes and body hair (total alopecia) to either normal hair or unusual hair growth on the face (facial hipertrichosis). Males with this form often have genital abnormalities, such as absence of one or both testes from the scrotum (cryptorchidism). There is a partial or complete absence of the corpus callosum, which connects the two hemispheres of the brain (agenesis of the corpus callosum). Patients will have varying degrees of intellectual disability. Frontonasal dysplasia-3 (FND-3)
Features of frontonasal dysplasia-3 include missing eyes (anophthalmia) or very small eyes (microphthalmia), as well as low set ears that are rotated backwards. FND3 is often associated with the most severe abnormalities; however the characteristics and severity vary from person to person. Rarely, infants with frontonasal dysplasia may also exhibit a form of cyanotic congenital heart disease (tetralogy of Fallot). The symptoms of tetralogy of Fallot include easy fatigability; rapid, shallow breathing; abnormal bluish coloration, especially of the lips and fingers; irregular heartbeats; and/or mild growth delays. (For more information on tetralogy of Fallot, see the Related Disorders section of this report.)A subtype of frontonasal dysplasia called acromelic frontonasal dysplasia has been described in which central nervous system (CNS) and skeletal anomalies are combined with the craniofacial anomalies. The CNS anomalies include Dandy-Walker malformation. Dandy-Walker Malformation is characterized by absence (agenesis) of part of the brain (cerebellar vermis) and an abnormally large space at the back of the brain (cystic dilatation of the 4th ventricle). Other associated CNS anomalies are absence (agenesis) of the part of the brain that connects the two cerebral hemispheres (corpus callosum); protrusion of part of the brain and membranes that cover the brain (meninges) through an abnormal gap in the skull (encephalocele); abnormally wide ventricles in the brain that inhibit the flow of cerebral spinal fluid (hydrocephalus); protrusion of only the meninges through a defect in the skull (meningocele) and intellectual disability. The associated skeletal anomalies include an underdeveloped or absent tibia bone, extra toes (preaxial polydactyly of the feet), and clubfoot (talipes). Males affected with acromelic frontonasal dysplasia sometimes have undescended testes. | Symptoms of Frontonasal Dysplasia. Frontonasal dysplasia-1(FND-1)
The physical characteristics associated with frontonasal dysplasia may vary greatly in severity from person to person. Features of this disorder include widely spaced eyes (ocular hypertelorism) and/or a vertical groove down the middle of the face. The depth and width of the groove may vary greatly among affected infants. The nose may be unusually flat and broad, have a “notched” or missing tip, or, in severe cases, may be completely divided in two.Other physical characteristics associated with frontonasal dysplasia may include a V-shaped hairline that extends down onto the forehead (widow’s peak), unusually small (slit-like) nostrils, an abnormal skin-covered gap in the front of the head (cranium bifidum occultum), and/or, in rare cases, a head that may appear abnormally short and wide (brachycephaly). Some infants with frontonasal dysplasia may also have incomplete closure of the roof of the mouth (cleft palate) and a vertical groove in the upper lip (cleft lip). The most severe clefts involve the lips, gums, and the bony front portion and/or soft back portions of the roof of the mouth (hard and soft palates). Less severe clefts may involve only one of these areas.Frontonasal dysplasia-2 (FND-2)
This form of fronotonasal dysplasia is characterized by a large skull defect and a premature fusion of the coronal suture (coronal craniosynostosis). Features of this disorder include widely spaced eyes (ocular hypertelorism) and severely depressed nasal bridge and ridge. Affected individuals may experience broad variations in hair development ranging from rapid hair loss and the absence of hair, eyebrows, eyelashes and body hair (total alopecia) to either normal hair or unusual hair growth on the face (facial hipertrichosis). Males with this form often have genital abnormalities, such as absence of one or both testes from the scrotum (cryptorchidism). There is a partial or complete absence of the corpus callosum, which connects the two hemispheres of the brain (agenesis of the corpus callosum). Patients will have varying degrees of intellectual disability. Frontonasal dysplasia-3 (FND-3)
Features of frontonasal dysplasia-3 include missing eyes (anophthalmia) or very small eyes (microphthalmia), as well as low set ears that are rotated backwards. FND3 is often associated with the most severe abnormalities; however the characteristics and severity vary from person to person. Rarely, infants with frontonasal dysplasia may also exhibit a form of cyanotic congenital heart disease (tetralogy of Fallot). The symptoms of tetralogy of Fallot include easy fatigability; rapid, shallow breathing; abnormal bluish coloration, especially of the lips and fingers; irregular heartbeats; and/or mild growth delays. (For more information on tetralogy of Fallot, see the Related Disorders section of this report.)A subtype of frontonasal dysplasia called acromelic frontonasal dysplasia has been described in which central nervous system (CNS) and skeletal anomalies are combined with the craniofacial anomalies. The CNS anomalies include Dandy-Walker malformation. Dandy-Walker Malformation is characterized by absence (agenesis) of part of the brain (cerebellar vermis) and an abnormally large space at the back of the brain (cystic dilatation of the 4th ventricle). Other associated CNS anomalies are absence (agenesis) of the part of the brain that connects the two cerebral hemispheres (corpus callosum); protrusion of part of the brain and membranes that cover the brain (meninges) through an abnormal gap in the skull (encephalocele); abnormally wide ventricles in the brain that inhibit the flow of cerebral spinal fluid (hydrocephalus); protrusion of only the meninges through a defect in the skull (meningocele) and intellectual disability. The associated skeletal anomalies include an underdeveloped or absent tibia bone, extra toes (preaxial polydactyly of the feet), and clubfoot (talipes). Males affected with acromelic frontonasal dysplasia sometimes have undescended testes. | 487 | Frontonasal Dysplasia |
nord_487_2 | Causes of Frontonasal Dysplasia | FND-1 is caused by mutations in the ALX3 gene; FND-2 is caused my mutations in the ALX4 gene; and FND-3 is caused by mutations in the ALX1 gene.The proteins produced from the ALX3, ALX4, and ALX1 genes are transcription factors, which means they bind to DNA and control the activity of certain genes. The proteins control the gene’s activities; regulate the growth and movement of cells. The ALX3 and ALX4 proteins are involved in the development of the nose, while ALX1 is involved in the development of the eyes, nose and mouth. The abnormal development can also interfere with the formation of the skull and other facial structures (e.g. distance between the eyes).FND-1 and FND-3 are autosomal recessive genetic conditions.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene from 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.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have higher change than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. FND-2 is inherited in an autosomal dominant pattern. 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 of can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.A person who carries a single copy of the ALX4 gene usually has enlarged openings (foramina) in the parietal bones only. Severe cranial defects, facial abnormalities associated with hair and genital malformations summarized above for FND-2 occur when an individual inherits two copies of the abnormal ALX4 gene, one from each parent. | Causes of Frontonasal Dysplasia. FND-1 is caused by mutations in the ALX3 gene; FND-2 is caused my mutations in the ALX4 gene; and FND-3 is caused by mutations in the ALX1 gene.The proteins produced from the ALX3, ALX4, and ALX1 genes are transcription factors, which means they bind to DNA and control the activity of certain genes. The proteins control the gene’s activities; regulate the growth and movement of cells. The ALX3 and ALX4 proteins are involved in the development of the nose, while ALX1 is involved in the development of the eyes, nose and mouth. The abnormal development can also interfere with the formation of the skull and other facial structures (e.g. distance between the eyes).FND-1 and FND-3 are autosomal recessive genetic conditions.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene from 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.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have higher change than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. FND-2 is inherited in an autosomal dominant pattern. 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 of can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.A person who carries a single copy of the ALX4 gene usually has enlarged openings (foramina) in the parietal bones only. Severe cranial defects, facial abnormalities associated with hair and genital malformations summarized above for FND-2 occur when an individual inherits two copies of the abnormal ALX4 gene, one from each parent. | 487 | Frontonasal Dysplasia |
nord_487_3 | Affects of Frontonasal Dysplasia | Frontonasal dysplasia is a very rare disorder that affects males and females in equal numbers. The number of people affected by this disorder is not known. There are at least 100 cases reported in the scientific literature. | Affects of Frontonasal Dysplasia. Frontonasal dysplasia is a very rare disorder that affects males and females in equal numbers. The number of people affected by this disorder is not known. There are at least 100 cases reported in the scientific literature. | 487 | Frontonasal Dysplasia |
nord_487_4 | Related disorders of Frontonasal Dysplasia | Symptoms of the following disorders can be similar to those of frontonasal dysplasia. Comparisons may be useful for a differential diagnosis:Craniofrontonasal dysplasia is a rare disorder characterized by widely spaced eyes (ocular hypertelorism), a missing or grooved tip of the nose, a broad nasal bridge, and/or malformation of the bone forming the center of the chest (sternum). Other abnormalities associated with this disorder may include an unusually wide mouth, webbed fingers and/or toes (syndactyly), a broad index finger, split nails, malformed ears, and/or a broad, high forehead. Craniofrontonasal dysplasia is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “craniofrontonasal dysplasia” as your search term in the Rare Disease Database.)Frontofacionasal dysplasia is a rare genetic disorder that is apparent at birth (congenital). The disorder is primarily characterized by malformations of the head and facial (craniofacial) area and eye (ocular) defects. Craniofacial malformations may include an unusually short, broad head (brachycephaly); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and underdevelopment (hypoplasia) of the nose with malformation of the nostrils. Affected infants may also have abnormal narrowing of the folds (palpebral fissures) between the upper and lower eyelids (blepharophimosis) and an unusually increased distance between the eyes (ocular hypertelorism). Additional eye abnormalities may include partial absence of tissue (coloboma) from the upper eyelids or the colored regions of the eyes (irides) and an inability to completely close the eyes (lagophthalmos). The signs and symptoms of frontofacionasal dysplasia are highly variable. Frontofacionasal dysplasia appears to be inherited as an autosomal recessive trait.(For more information on this disorder, choose “frontofacionasal dysplasia” as your search term in the Rare Disease Database.)There are many other rare craniofacial disorders that are characterized by facial and cranial abnormalities similar to those of frontonasal dysplasia. (For more information on these disorders, choose “craniofacial” as your search term in the Rare Disease Database.)The following disorders may occur in association with frontonasal dysplasia as secondary characteristics. They are not necessary for a differential diagnosis:Tetralogy of Fallot is a rare form of cyanotic congenital heart disease. Cyanosis is the abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of a combination of four different heart defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles; and the abnormal enlargement of the wall of the right ventricle. If infants with tetralogy of Fallot are not treated, the symptoms usually become more severe. Blood flow to the lungs may further decrease and severe cyanosis may result in life-threatening complications. The exact cause of Tetralogy of Fallot is not known. (For more information on this disorder, choose “tetralogy of Fallot” as your search term in the Rare Disease Database.)Cleft lip and palate are malformations of the lip and/or mouth that are noticeable at birth (congenital). A cleft is an incomplete closure or a groove of the roof of the mouth (palate) and/or upper lip. These abnormalities result when the pair of long bones that form the upper jaw (maxillae) do not fuse properly during the development of the embryo. More than 200 syndromes have cleft lip and/or palate as a feature. Dandy-Walker malformation is a rare malformation of the brain characterized by absence (agenesis) of part of the brain (cerebellar vermis), an abnormally large space at the back of the brain (cystic dilatation of the 4th ventricle. Children with this disorder may develop swelling of the head caused by the accumulation of cerebrospinal fluid in the skull (hydrocephalus). Other symptoms may include vomiting, headaches, weakness, convulsions, irritability, abnormally slow pulse, and/or unusually slow breathing. Some children with this disorder may experience delays in reaching motor (e.g., sitting and walking) and cognitive (e.g., speech and counting) milestones. The exact cause of Dandy-Walker malformation is not known. (For more information on this disorder, choose “Dandy-Walker” as your search term in the Rare Disease Database.)Agenesis of corpus callosum (ACC) is a rare disorder that is present at birth (congenital). It is characterized by a partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. This part of the brain is normally composed of transverse fibers. The cause of agenesis of corpus callosum is usually not known, but it can be inherited as either an autosomal recessive trait or an X-linked dominant trait. It can also be caused by an infection or injury during the twelfth to the twenty-second week of pregnancy (intrauterine) leading to developmental disturbance of the fetal brain. Intrauterine exposure to alcohol (Fetal alcohol syndrome) can also result in ACC. In some cases, intellectual disability may result, but intelligence may be only mildly impaired and subtle psychosocial symptoms may be present.ACC is frequently diagnosed during the first two years of life. An epileptic seizure can be the first symptom indicating that a child should be tested for a brain dysfunction. The disorder can also be without apparent symptoms in the mildest cases for many years.(For more information on this disorder, choose “agenesis of corpus callosum” as your search term in the Rare Disease Database.) | Related disorders of Frontonasal Dysplasia. Symptoms of the following disorders can be similar to those of frontonasal dysplasia. Comparisons may be useful for a differential diagnosis:Craniofrontonasal dysplasia is a rare disorder characterized by widely spaced eyes (ocular hypertelorism), a missing or grooved tip of the nose, a broad nasal bridge, and/or malformation of the bone forming the center of the chest (sternum). Other abnormalities associated with this disorder may include an unusually wide mouth, webbed fingers and/or toes (syndactyly), a broad index finger, split nails, malformed ears, and/or a broad, high forehead. Craniofrontonasal dysplasia is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “craniofrontonasal dysplasia” as your search term in the Rare Disease Database.)Frontofacionasal dysplasia is a rare genetic disorder that is apparent at birth (congenital). The disorder is primarily characterized by malformations of the head and facial (craniofacial) area and eye (ocular) defects. Craniofacial malformations may include an unusually short, broad head (brachycephaly); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and underdevelopment (hypoplasia) of the nose with malformation of the nostrils. Affected infants may also have abnormal narrowing of the folds (palpebral fissures) between the upper and lower eyelids (blepharophimosis) and an unusually increased distance between the eyes (ocular hypertelorism). Additional eye abnormalities may include partial absence of tissue (coloboma) from the upper eyelids or the colored regions of the eyes (irides) and an inability to completely close the eyes (lagophthalmos). The signs and symptoms of frontofacionasal dysplasia are highly variable. Frontofacionasal dysplasia appears to be inherited as an autosomal recessive trait.(For more information on this disorder, choose “frontofacionasal dysplasia” as your search term in the Rare Disease Database.)There are many other rare craniofacial disorders that are characterized by facial and cranial abnormalities similar to those of frontonasal dysplasia. (For more information on these disorders, choose “craniofacial” as your search term in the Rare Disease Database.)The following disorders may occur in association with frontonasal dysplasia as secondary characteristics. They are not necessary for a differential diagnosis:Tetralogy of Fallot is a rare form of cyanotic congenital heart disease. Cyanosis is the abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of a combination of four different heart defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles; and the abnormal enlargement of the wall of the right ventricle. If infants with tetralogy of Fallot are not treated, the symptoms usually become more severe. Blood flow to the lungs may further decrease and severe cyanosis may result in life-threatening complications. The exact cause of Tetralogy of Fallot is not known. (For more information on this disorder, choose “tetralogy of Fallot” as your search term in the Rare Disease Database.)Cleft lip and palate are malformations of the lip and/or mouth that are noticeable at birth (congenital). A cleft is an incomplete closure or a groove of the roof of the mouth (palate) and/or upper lip. These abnormalities result when the pair of long bones that form the upper jaw (maxillae) do not fuse properly during the development of the embryo. More than 200 syndromes have cleft lip and/or palate as a feature. Dandy-Walker malformation is a rare malformation of the brain characterized by absence (agenesis) of part of the brain (cerebellar vermis), an abnormally large space at the back of the brain (cystic dilatation of the 4th ventricle. Children with this disorder may develop swelling of the head caused by the accumulation of cerebrospinal fluid in the skull (hydrocephalus). Other symptoms may include vomiting, headaches, weakness, convulsions, irritability, abnormally slow pulse, and/or unusually slow breathing. Some children with this disorder may experience delays in reaching motor (e.g., sitting and walking) and cognitive (e.g., speech and counting) milestones. The exact cause of Dandy-Walker malformation is not known. (For more information on this disorder, choose “Dandy-Walker” as your search term in the Rare Disease Database.)Agenesis of corpus callosum (ACC) is a rare disorder that is present at birth (congenital). It is characterized by a partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. This part of the brain is normally composed of transverse fibers. The cause of agenesis of corpus callosum is usually not known, but it can be inherited as either an autosomal recessive trait or an X-linked dominant trait. It can also be caused by an infection or injury during the twelfth to the twenty-second week of pregnancy (intrauterine) leading to developmental disturbance of the fetal brain. Intrauterine exposure to alcohol (Fetal alcohol syndrome) can also result in ACC. In some cases, intellectual disability may result, but intelligence may be only mildly impaired and subtle psychosocial symptoms may be present.ACC is frequently diagnosed during the first two years of life. An epileptic seizure can be the first symptom indicating that a child should be tested for a brain dysfunction. The disorder can also be without apparent symptoms in the mildest cases for many years.(For more information on this disorder, choose “agenesis of corpus callosum” as your search term in the Rare Disease Database.) | 487 | Frontonasal Dysplasia |
nord_487_5 | Diagnosis of Frontonasal Dysplasia | Frontonasal dysplasia is usually diagnosed shortly after birth (neonatal period). Confirmation of the diagnosis typically includes a thorough clinical evaluation, specialized tests including x-ray studies, and the identification of characteristic physical features. Genetic testing for frontonasal dysplasia is available on a research basis only. | Diagnosis of Frontonasal Dysplasia. Frontonasal dysplasia is usually diagnosed shortly after birth (neonatal period). Confirmation of the diagnosis typically includes a thorough clinical evaluation, specialized tests including x-ray studies, and the identification of characteristic physical features. Genetic testing for frontonasal dysplasia is available on a research basis only. | 487 | Frontonasal Dysplasia |
nord_487_6 | Therapies of Frontonasal Dysplasia | Treatment of this disorder depends upon the severity of the physical characteristics in each individual case. Surgery may be performed to correct the craniofacial abnormalities (e.g., divided nose, cleft lip, etc.) associated with this disorder. In some cases, additional surgeries may be necessary when an affected child grows older.Genetic counseling may be of benefit for affected individuals and their families. A team approach for infants and children with this disorder may be of benefit and may include special social, educational, and medical services. Other treatment is symptomatic and supportive. | Therapies of Frontonasal Dysplasia. Treatment of this disorder depends upon the severity of the physical characteristics in each individual case. Surgery may be performed to correct the craniofacial abnormalities (e.g., divided nose, cleft lip, etc.) associated with this disorder. In some cases, additional surgeries may be necessary when an affected child grows older.Genetic counseling may be of benefit for affected individuals and their families. A team approach for infants and children with this disorder may be of benefit and may include special social, educational, and medical services. Other treatment is symptomatic and supportive. | 487 | Frontonasal Dysplasia |
nord_488_0 | Overview of Frontotemporal Degeneration | SummaryFrontotemporal degeneration is a group of varied disorders that are characterized by neurodegenerative changes that affect the brain. The clinical presentation of frontotemporal degeneration is diverse. Affected individuals can experience gradual changes in their behavior and personality, and may have difficulties in thinking and communicating effectively. The progression and the specific symptoms that develop can vary from one person to another. Generally, the clinical symptoms of these disorders can be broadly grouped into three categories which display changes in behavior, language and/or motor function. Frontotemporal degeneration is caused by progressive damage and loss of nerve cells in the frontal and temporal lobes of the brain. In most people, this is accompanied by a buildup of one or the other of two proteins, tau or TDP-43. In FTD these proteins are misfolded (misshapen) which leads to their inappropriate buildup within brain cells and so interfering with or disrupting the normal function of these cells. The FTD clinical subtypes can also be classified as ‘tauopathies’ or TDP43-opathies, depending on which misfolded protein accumulates in the brain. In about 10% of cases, a third protein, FUS, accumulates instead of tau or TDP43. The accumulation of tau protein or TDP-43 protein can also be observed in other neurological disorders.Although once used more broadly, the term Pick’s disease (after Dr. Arnold Pick, who first described it in 1892) is now reserved for a specific subtype of frontotemporal degeneration associated with a kind of abnormal tau protein known as 3R tau. In Pick’s disease, the clumps of 3R tau are found in distinctive round, silver-staining inclusions known as Pick bodies.IntroductionThere are many different terms and names that have been used to describe frontotemporal degeneration (FTD), also referred to as frontotemporal dementia. These names can be very confusing. Frontotemporal lobar degeneration is a general term that describes a group of disorders based on their neuropathology that cause damage and dysfunction of the frontal and temporal lobes of the brain. This is reflected in the spectrum of clinical subtypes listed above, which encompass behavioral, language and/or motor predominant decline in the ability to function normally. A clinical subtype refers to the symptoms that occur earliest and most prominently in a person. | Overview of Frontotemporal Degeneration. SummaryFrontotemporal degeneration is a group of varied disorders that are characterized by neurodegenerative changes that affect the brain. The clinical presentation of frontotemporal degeneration is diverse. Affected individuals can experience gradual changes in their behavior and personality, and may have difficulties in thinking and communicating effectively. The progression and the specific symptoms that develop can vary from one person to another. Generally, the clinical symptoms of these disorders can be broadly grouped into three categories which display changes in behavior, language and/or motor function. Frontotemporal degeneration is caused by progressive damage and loss of nerve cells in the frontal and temporal lobes of the brain. In most people, this is accompanied by a buildup of one or the other of two proteins, tau or TDP-43. In FTD these proteins are misfolded (misshapen) which leads to their inappropriate buildup within brain cells and so interfering with or disrupting the normal function of these cells. The FTD clinical subtypes can also be classified as ‘tauopathies’ or TDP43-opathies, depending on which misfolded protein accumulates in the brain. In about 10% of cases, a third protein, FUS, accumulates instead of tau or TDP43. The accumulation of tau protein or TDP-43 protein can also be observed in other neurological disorders.Although once used more broadly, the term Pick’s disease (after Dr. Arnold Pick, who first described it in 1892) is now reserved for a specific subtype of frontotemporal degeneration associated with a kind of abnormal tau protein known as 3R tau. In Pick’s disease, the clumps of 3R tau are found in distinctive round, silver-staining inclusions known as Pick bodies.IntroductionThere are many different terms and names that have been used to describe frontotemporal degeneration (FTD), also referred to as frontotemporal dementia. These names can be very confusing. Frontotemporal lobar degeneration is a general term that describes a group of disorders based on their neuropathology that cause damage and dysfunction of the frontal and temporal lobes of the brain. This is reflected in the spectrum of clinical subtypes listed above, which encompass behavioral, language and/or motor predominant decline in the ability to function normally. A clinical subtype refers to the symptoms that occur earliest and most prominently in a person. | 488 | Frontotemporal Degeneration |
nord_488_1 | Symptoms of Frontotemporal Degeneration | Frontotemporal degeneration clinical subtypes are organized according to:
1.progressive behavior/personality decline – behavioral variant FTD (bvFTD), Pick’s disease
2.progressive language decline – primary progressive aphasia (PPA), which comes in semantic, nonfluent-agrammatic, or logopenic variants (svPPA, naPPA, lvPPA)
3.progressive motor function decline – progressive supranuclear palsy (PSP), corticobasal syndrome, FTD with amyotrophic lateral sclerosis (FTD-ALS), FTD with motor neuron disease (FTD-MND)
A person is classified into one of these three categories based on the signs and symptoms that first appear and appear most prominently. As the disorder progresses, individuals may begin to show signs and symptoms of other classifications, and their classifications may change. It is difficult to predict the course of frontotemporal degeneration and the rate of disease progression can vary from one person to another. Ultimately, people with frontotemporal degeneration require fulltime caregiving and supervision. Behavioral variant frontotemporal degeneration (bvFTD)
The behavioral variant is the most common subtype and accounts for about 50% of people with frontotemporal degeneration. This subtype is characterized by changes in personality and behavior. Specific, early changes in behavior include disinhibition, loss of insight, apathy, loss of empathy, hyperorality, and dietary changes, and compulsive behaviors. Some individuals have a decreased sensitivity to pain. Memory is usually intact, but some individuals can display some memory loss. More commonly, people exhibit deficits in executive function such as decision making, good judgment, organizational skills, and attention.Disinhibition is defined as a loss or lack of restraint toward socially accepted norms in behavior. For example, people displaying disinhibition may engage in inappropriate or impulsive behaviors like ignoring peoples’ personal space, touching or kissing strangers, making derogatory or offensive comments to people, reckless spending of money, theft, or public urination.Apathy is defined as a general indifference or lack of interest in life, including to things or activities that were once considered exciting or emotionally moving. Apathy may lead people to show no concern for personal relationships or social interaction, work, hobbies, or personal hygiene. They may stare out a window for hours. Apathy is often mistaken for depression. Affected individuals also show little concern or sympathy for family members or friends and little responsiveness toward the social needs of family or friends as well. Affected individuals may show dramatic changes in their diet and eating habits including binge eating, eating or drinking more sweets and alcohol than normal, and putting excessive amounts of food into their mouths. Some individuals crave and eat lots of carbohydrates. Sometimes, they may attempt to eat spoiled foods or inedible objects. The term hyperorality may be used to describe placing inappropriate objects into the mouth. Some people may increase tobacco use or begin to use tobacco for the first time in their lives. Compulsive behaviors are best described as actions that a person consistently performs and repeats for no obvious reason (there is no reward and the person gets no pleasure from the act). Simple repetitive movements, continually repeating certain phrases or words, and complex ritualistic behaviors such as hoarding are examples of compulsive behaviors that can occur in individuals with behavioral variant frontotemporal degeneration.Primary progressive aphasia (PPA)
Primary progressive aphasia is characterized by changes in the ability to speak, write, read and understand language. Primary progressive aphasia is broken down into two main forms – the semantic variant and the nonfluent agrammatic variant. There is also a third form called the logopenic variant. Affected individuals have a slow, progressive loss of language skills. Aphasia, which is described as difficulties in understanding or expressing language, is the most common initial language deficit. Problems with language and loss of the ability to communicate impact a person’s day-to-day activities and living. Semantic Variant
The semantic variant of PPA is characterized by problems remembering the correct word or failing to understand individual words, this is particularly true for words that are not used often by the person. Affected individuals may be unable to remember the names of familiar people, places or everyday objects (anomia).Some individuals experience surface dyslexia or dysgraphia. Individuals with surface dyslexia have difficulty understanding written words. Individuals with dysgraphia may have difficulty writing words as well as problems with handwriting. They may have difficulty with words with irregular spellings such as yacht or colonel. These words may be mispronounced or misspelled. Non-fluent Agrammatic Variant
People with the non-fluent variant will have problems speaking with proper grammar (agrammatism). They may misuse words or leave out words such as words that connect nouns and words (e.g. to, from, the). They have difficulty finding the right word when speaking. Their speech may be stilted, which is described as slow, labored and hesitating. They often speak less than they used to. Affected individuals also have difficulty understanding complex sentences. Sometimes individuals with this variant can have difficulty writing certain words. Logopenic Variant
People with the logopenic variant have difficulties finding the right words when speaking. They will pause or hesitate frequently during speech because they must think to come up with the right word. Consequently, they have a slow rate of speech. They may have difficulties repeating short phrases or short sequences of numbers. They can understand words and sentences, even complex ones, early on but as the disease progresses may struggle to understand such information. Eventually, short term memory is affected and individuals may repeat themselves in conversation. Reading and writing ability is spared initially, but eventually problems develop with these forms of communication as well. Difficulty swallowing develops late in the course of the disease.Frontotemporal degeneration and amyotrophic lateral sclerosis (ALS)
Frontotemporal degeneration and the motor neuron disease ALS can occur in the same individual. ALS also known as Lou Gehrig’s disease in the US, is sometimes used interchangeably with the term motor neuron disease. Motor neuron disease is also used as a general term for a group of progressive neurological disorders in which there is a loss of nerve cells called motor neurons. These cells control voluntary muscle activity such as speaking, walking, and talking. Individuals may exhibit weakness, muscle loss (atrophy), tiny involuntary muscle twitches (fasciculation), difficulty speaking (dysarthria) and difficult swallowing (dysphagia). Involuntary control of muscle activity such as breathing and increased tightness and stiffness of muscles (spasticity) is also affected. When people have symptoms of frontotemporal degeneration and motor neuron disease, they may be described as having FTD associated with motor neuron disease (FTD-MND), or FTD associated with amyotrophic lateral sclerosis (FTD-ALS). Progressive supranuclear palsy, corticobasal syndrome
Corticobasal syndrome and progressive supranuclear palsy are rare movement disorders that are associated with the broad group of FTLD disorders. While a decline in motor function may be the earliest and most prominent clinical feature, these disorders can also demonstrate loss of language and behavioral or cognitive skills. Progressive supranuclear palsy causes difficulties with balance and walking resulting in frequent falls. Problems with eye movements are also seen particularly an inability to look down. Changes in behavior can also occur with time. Persons with corticobasal syndrome may have an inability to control movement, particularly with their hands and arms. Movement deficits may often appear only on one side, but eventually both sides are affected and difficulties with language can also occur. NORD has individual reports on progressive supranuclear palsy and corticobasal degeneration. For more information, choose the specific disorder name as your search term in the Rare Disease Database.Some affected individuals exhibit early-onset parkinsonism, which is the development of symptoms associated with Parkinson disease including abnormal slowness of movement (bradykinesia), resting tremor, and an inability to remain in a stable or balanced position (postural instability). Parkinsonism most often occurs in behavioral variant frontotemporal degeneration. | Symptoms of Frontotemporal Degeneration. Frontotemporal degeneration clinical subtypes are organized according to:
1.progressive behavior/personality decline – behavioral variant FTD (bvFTD), Pick’s disease
2.progressive language decline – primary progressive aphasia (PPA), which comes in semantic, nonfluent-agrammatic, or logopenic variants (svPPA, naPPA, lvPPA)
3.progressive motor function decline – progressive supranuclear palsy (PSP), corticobasal syndrome, FTD with amyotrophic lateral sclerosis (FTD-ALS), FTD with motor neuron disease (FTD-MND)
A person is classified into one of these three categories based on the signs and symptoms that first appear and appear most prominently. As the disorder progresses, individuals may begin to show signs and symptoms of other classifications, and their classifications may change. It is difficult to predict the course of frontotemporal degeneration and the rate of disease progression can vary from one person to another. Ultimately, people with frontotemporal degeneration require fulltime caregiving and supervision. Behavioral variant frontotemporal degeneration (bvFTD)
The behavioral variant is the most common subtype and accounts for about 50% of people with frontotemporal degeneration. This subtype is characterized by changes in personality and behavior. Specific, early changes in behavior include disinhibition, loss of insight, apathy, loss of empathy, hyperorality, and dietary changes, and compulsive behaviors. Some individuals have a decreased sensitivity to pain. Memory is usually intact, but some individuals can display some memory loss. More commonly, people exhibit deficits in executive function such as decision making, good judgment, organizational skills, and attention.Disinhibition is defined as a loss or lack of restraint toward socially accepted norms in behavior. For example, people displaying disinhibition may engage in inappropriate or impulsive behaviors like ignoring peoples’ personal space, touching or kissing strangers, making derogatory or offensive comments to people, reckless spending of money, theft, or public urination.Apathy is defined as a general indifference or lack of interest in life, including to things or activities that were once considered exciting or emotionally moving. Apathy may lead people to show no concern for personal relationships or social interaction, work, hobbies, or personal hygiene. They may stare out a window for hours. Apathy is often mistaken for depression. Affected individuals also show little concern or sympathy for family members or friends and little responsiveness toward the social needs of family or friends as well. Affected individuals may show dramatic changes in their diet and eating habits including binge eating, eating or drinking more sweets and alcohol than normal, and putting excessive amounts of food into their mouths. Some individuals crave and eat lots of carbohydrates. Sometimes, they may attempt to eat spoiled foods or inedible objects. The term hyperorality may be used to describe placing inappropriate objects into the mouth. Some people may increase tobacco use or begin to use tobacco for the first time in their lives. Compulsive behaviors are best described as actions that a person consistently performs and repeats for no obvious reason (there is no reward and the person gets no pleasure from the act). Simple repetitive movements, continually repeating certain phrases or words, and complex ritualistic behaviors such as hoarding are examples of compulsive behaviors that can occur in individuals with behavioral variant frontotemporal degeneration.Primary progressive aphasia (PPA)
Primary progressive aphasia is characterized by changes in the ability to speak, write, read and understand language. Primary progressive aphasia is broken down into two main forms – the semantic variant and the nonfluent agrammatic variant. There is also a third form called the logopenic variant. Affected individuals have a slow, progressive loss of language skills. Aphasia, which is described as difficulties in understanding or expressing language, is the most common initial language deficit. Problems with language and loss of the ability to communicate impact a person’s day-to-day activities and living. Semantic Variant
The semantic variant of PPA is characterized by problems remembering the correct word or failing to understand individual words, this is particularly true for words that are not used often by the person. Affected individuals may be unable to remember the names of familiar people, places or everyday objects (anomia).Some individuals experience surface dyslexia or dysgraphia. Individuals with surface dyslexia have difficulty understanding written words. Individuals with dysgraphia may have difficulty writing words as well as problems with handwriting. They may have difficulty with words with irregular spellings such as yacht or colonel. These words may be mispronounced or misspelled. Non-fluent Agrammatic Variant
People with the non-fluent variant will have problems speaking with proper grammar (agrammatism). They may misuse words or leave out words such as words that connect nouns and words (e.g. to, from, the). They have difficulty finding the right word when speaking. Their speech may be stilted, which is described as slow, labored and hesitating. They often speak less than they used to. Affected individuals also have difficulty understanding complex sentences. Sometimes individuals with this variant can have difficulty writing certain words. Logopenic Variant
People with the logopenic variant have difficulties finding the right words when speaking. They will pause or hesitate frequently during speech because they must think to come up with the right word. Consequently, they have a slow rate of speech. They may have difficulties repeating short phrases or short sequences of numbers. They can understand words and sentences, even complex ones, early on but as the disease progresses may struggle to understand such information. Eventually, short term memory is affected and individuals may repeat themselves in conversation. Reading and writing ability is spared initially, but eventually problems develop with these forms of communication as well. Difficulty swallowing develops late in the course of the disease.Frontotemporal degeneration and amyotrophic lateral sclerosis (ALS)
Frontotemporal degeneration and the motor neuron disease ALS can occur in the same individual. ALS also known as Lou Gehrig’s disease in the US, is sometimes used interchangeably with the term motor neuron disease. Motor neuron disease is also used as a general term for a group of progressive neurological disorders in which there is a loss of nerve cells called motor neurons. These cells control voluntary muscle activity such as speaking, walking, and talking. Individuals may exhibit weakness, muscle loss (atrophy), tiny involuntary muscle twitches (fasciculation), difficulty speaking (dysarthria) and difficult swallowing (dysphagia). Involuntary control of muscle activity such as breathing and increased tightness and stiffness of muscles (spasticity) is also affected. When people have symptoms of frontotemporal degeneration and motor neuron disease, they may be described as having FTD associated with motor neuron disease (FTD-MND), or FTD associated with amyotrophic lateral sclerosis (FTD-ALS). Progressive supranuclear palsy, corticobasal syndrome
Corticobasal syndrome and progressive supranuclear palsy are rare movement disorders that are associated with the broad group of FTLD disorders. While a decline in motor function may be the earliest and most prominent clinical feature, these disorders can also demonstrate loss of language and behavioral or cognitive skills. Progressive supranuclear palsy causes difficulties with balance and walking resulting in frequent falls. Problems with eye movements are also seen particularly an inability to look down. Changes in behavior can also occur with time. Persons with corticobasal syndrome may have an inability to control movement, particularly with their hands and arms. Movement deficits may often appear only on one side, but eventually both sides are affected and difficulties with language can also occur. NORD has individual reports on progressive supranuclear palsy and corticobasal degeneration. For more information, choose the specific disorder name as your search term in the Rare Disease Database.Some affected individuals exhibit early-onset parkinsonism, which is the development of symptoms associated with Parkinson disease including abnormal slowness of movement (bradykinesia), resting tremor, and an inability to remain in a stable or balanced position (postural instability). Parkinsonism most often occurs in behavioral variant frontotemporal degeneration. | 488 | Frontotemporal Degeneration |
nord_488_2 | Causes of Frontotemporal Degeneration | Frontotemporal degeneration is caused by damage to the frontal and temporal lobes of the brain. The frontal lobe is the largest lobe in the brain and is located right behind the forehead. The frontal lobe is critical for thinking, planning, decision making and other higher mental processes. The frontal lobe helps people to manage and control emotional responses. The temporal lobes are located below and to both sides of the frontal lobe. The temporal lobes are believed to be involved in semantic memory, or our knowledge of objects, people, words and faces. They also play a role in language and emotion. In individuals with frontotemporal degeneration there is an abnormal buildup of altered brain proteins in the frontal and temporal lobes of the brain. The two most common proteins involved are the tau protein and the transactive response DNA binding protein-43 (TDP-43). These proteins are normally found in the brain. Their specific functions are complex and not fully understood. However, these proteins are critical to the proper health and function of nerve cells (neurons). In individuals with frontotemporal degeneration these proteins are misfolded (misshapen); as a result, they clump together. As these protein clumps, or aggregates, build up in the brain, they interfere with or disrupt the normal functioning of nerve cells, which ultimately die. Nerve cell death within the frontal and temporal lobes causes these areas of the brain shrink (atrophy). These clumps of misfolded proteins may be referred to as “bodies” or “inclusions”. So the terms, tau bodies or tau inclusions, refer to nerve cells that contain these clumps of misfolded proteins. These inclusions may have distinctive features even when the same protein is involved. For examples, Pick’s disease refers to distinctive, round, silver-staining inclusions called Pick’s bodies. Most inclusions associated with frontotemporal degeneration contain either variations of tau protein or TDP-43. In about 60% of people, they are often the first person is their family to be affected by frontotemporal degeneration. These people are classified as having a sporadic or nonfamilial form of the disorder. Researchers do not know why these people have developed frontotemporal degeneration. Their family members do not appear to be at an increased risk of developing the disorder. However, there is a strong genetic component to frontotemporal degeneration. In about 40% percent of people there is a history of neurodegeneration or psychiatric illness in the family. In some of these people, the cause of the disorder is unknown. Researchers do not know whether there is an altered gene in these families, but the disorder occurs with more frequency than it otherwise would by chance. One theory is that, in these families, frontotemporal degeneration occurs because of the interaction of multiple factors (multifactorial cause). This might mean that there is a gene or genes that cause people to be more likely (predisposed) to develop a disorder, but the disorder will not develop unless these gene(s) are triggered or “activated” under certain circumstances such as particular environmental factors. However, despite research, no evidence has been found linking any potential environmental factor to the development of frontotemporal degeneration. There is no known risk factor for the disorder other than a family history of frontotemporal degeneration or a similar disorder. In about 10-25% of people diagnosed with FTD, an altered gene has been identified. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When an alteration 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. The major genes that have been linked to frontotemporal degeneration include the MAPT, GRN, and C9ORF72 genes. The MAPT gene produces the brain protein known as tau. The GRN gene produces the brain protein known as progranulin, which is important for optimal functioning of the protein TDP-43. The C9ORF72 gene also produces a protein that is found in nerve cells although its role in not well understood. These three genes account for the majority of people with inherited frontotemporal degeneration. In rare instances, additional genes have been identified as causing frontotemporal degeneration including the VCP, TARDBP, FUS, CHMP2B and TBK1 genes. The altered genes that cause frontotemporal degeneration are usually inherited in an autosomal dominant manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The altered gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. | Causes of Frontotemporal Degeneration. Frontotemporal degeneration is caused by damage to the frontal and temporal lobes of the brain. The frontal lobe is the largest lobe in the brain and is located right behind the forehead. The frontal lobe is critical for thinking, planning, decision making and other higher mental processes. The frontal lobe helps people to manage and control emotional responses. The temporal lobes are located below and to both sides of the frontal lobe. The temporal lobes are believed to be involved in semantic memory, or our knowledge of objects, people, words and faces. They also play a role in language and emotion. In individuals with frontotemporal degeneration there is an abnormal buildup of altered brain proteins in the frontal and temporal lobes of the brain. The two most common proteins involved are the tau protein and the transactive response DNA binding protein-43 (TDP-43). These proteins are normally found in the brain. Their specific functions are complex and not fully understood. However, these proteins are critical to the proper health and function of nerve cells (neurons). In individuals with frontotemporal degeneration these proteins are misfolded (misshapen); as a result, they clump together. As these protein clumps, or aggregates, build up in the brain, they interfere with or disrupt the normal functioning of nerve cells, which ultimately die. Nerve cell death within the frontal and temporal lobes causes these areas of the brain shrink (atrophy). These clumps of misfolded proteins may be referred to as “bodies” or “inclusions”. So the terms, tau bodies or tau inclusions, refer to nerve cells that contain these clumps of misfolded proteins. These inclusions may have distinctive features even when the same protein is involved. For examples, Pick’s disease refers to distinctive, round, silver-staining inclusions called Pick’s bodies. Most inclusions associated with frontotemporal degeneration contain either variations of tau protein or TDP-43. In about 60% of people, they are often the first person is their family to be affected by frontotemporal degeneration. These people are classified as having a sporadic or nonfamilial form of the disorder. Researchers do not know why these people have developed frontotemporal degeneration. Their family members do not appear to be at an increased risk of developing the disorder. However, there is a strong genetic component to frontotemporal degeneration. In about 40% percent of people there is a history of neurodegeneration or psychiatric illness in the family. In some of these people, the cause of the disorder is unknown. Researchers do not know whether there is an altered gene in these families, but the disorder occurs with more frequency than it otherwise would by chance. One theory is that, in these families, frontotemporal degeneration occurs because of the interaction of multiple factors (multifactorial cause). This might mean that there is a gene or genes that cause people to be more likely (predisposed) to develop a disorder, but the disorder will not develop unless these gene(s) are triggered or “activated” under certain circumstances such as particular environmental factors. However, despite research, no evidence has been found linking any potential environmental factor to the development of frontotemporal degeneration. There is no known risk factor for the disorder other than a family history of frontotemporal degeneration or a similar disorder. In about 10-25% of people diagnosed with FTD, an altered gene has been identified. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When an alteration 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. The major genes that have been linked to frontotemporal degeneration include the MAPT, GRN, and C9ORF72 genes. The MAPT gene produces the brain protein known as tau. The GRN gene produces the brain protein known as progranulin, which is important for optimal functioning of the protein TDP-43. The C9ORF72 gene also produces a protein that is found in nerve cells although its role in not well understood. These three genes account for the majority of people with inherited frontotemporal degeneration. In rare instances, additional genes have been identified as causing frontotemporal degeneration including the VCP, TARDBP, FUS, CHMP2B and TBK1 genes. The altered genes that cause frontotemporal degeneration are usually inherited in an autosomal dominant manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The altered 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. | 488 | Frontotemporal Degeneration |
nord_488_3 | Affects of Frontotemporal Degeneration | Frontotemporal degeneration is the second most common form of dementia in people under the age of 65 after Alzheimer’s disease. The mean age of onset is usually given as the late 50s, with an age range of 20-80. However, onset before 40 or after 75 is less common. Frontotemporal degeneration is estimated to affect about 50,000-60,000 people in the United States. Researchers believe that many people go undiagnosed or misdiagnosed with another condition. This makes it difficult to determine the true frequency of frontotemporal degeneration in the general population. | Affects of Frontotemporal Degeneration. Frontotemporal degeneration is the second most common form of dementia in people under the age of 65 after Alzheimer’s disease. The mean age of onset is usually given as the late 50s, with an age range of 20-80. However, onset before 40 or after 75 is less common. Frontotemporal degeneration is estimated to affect about 50,000-60,000 people in the United States. Researchers believe that many people go undiagnosed or misdiagnosed with another condition. This makes it difficult to determine the true frequency of frontotemporal degeneration in the general population. | 488 | Frontotemporal Degeneration |
nord_488_4 | Related disorders of Frontotemporal Degeneration | Symptoms of the following disorders can be similar to those of frontotemporal degeneration. Comparisons may be useful for a differential diagnosis.Because of the psychiatric symptoms associated with frontotemporal degeneration, individuals can be misdiagnosed with various different psychiatric disorders including obsessive-compulsive disorder, depression, schizophrenia, and bipolar disorder. This would depend on how frontotemporal degeneration develops in an individual. For example, someone who exhibits the repetitive and compulsive behaviors in the behavioral variant of frontotemporal degeneration can be mistaken for having obsessive-compulsive disorder. Someone experiencing apathy could be misdiagnosed with depression. Alzheimer’s disease is a progressive condition of the brain that affects memory, thought, and language. The degenerative changes of Alzheimer’s disease lead to patches or plaques in the brain and the entanglement of nerve fibers (neurofibrillary tangles). Memory loss and behavioral changes occur as a result of these changes in brain tissue. Alzheimer’s disease is usually a slow progressive illness that occurs in midlife but becomes increasingly more common over the age of 65 years, in contrast to the frontotemporal degenerations. Difficulty with short-term memory is usually the first symptom and early behavioral changes may not be noticed. As the disease progresses, memory loss increases and there are changes in personality, mood and behavior. Disturbances of judgment and concentration occur, along with confusion and restlessness. The type, severity, sequence, and progression of mental changes vary widely. Long periods with little change are common, although occasionally the disease can be rapidly progressive. Many of the ‘ FTD syndromes' such as agrammatic PPA, logopenic PPA, corticobasal syndrome and the bvFTD syndrome can also be caused by atypical forms of AD. (For more information on this disorder, choose “Alzheimer” as your search term in the Rare Disease Database.)Dementia with Lewy bodies (DLB), which is also called Lewy body dementia (LBD), is a neurodegenerative disorder characterized by Parkinsonism and degeneration that begin more or less simultaneously. People with DLB have difficulty with attention, concentration and multitasking (executive function). They are also prone to depression, visual hallucinations, sleep disturbances and day-to-day fluctuations in cognitive function. Memory is often less affected than in Alzheimer disease. The Parkinsonism in DLB is gradually progressive and consists of slowness (bradykinesia), muscle stiffness (rigidity), stooped posture, and slow shuffling gait that is often poorly responsive to levodopa. Tremor is frequently mild or absent, compared to classic Parkinson disease. | Related disorders of Frontotemporal Degeneration. Symptoms of the following disorders can be similar to those of frontotemporal degeneration. Comparisons may be useful for a differential diagnosis.Because of the psychiatric symptoms associated with frontotemporal degeneration, individuals can be misdiagnosed with various different psychiatric disorders including obsessive-compulsive disorder, depression, schizophrenia, and bipolar disorder. This would depend on how frontotemporal degeneration develops in an individual. For example, someone who exhibits the repetitive and compulsive behaviors in the behavioral variant of frontotemporal degeneration can be mistaken for having obsessive-compulsive disorder. Someone experiencing apathy could be misdiagnosed with depression. Alzheimer’s disease is a progressive condition of the brain that affects memory, thought, and language. The degenerative changes of Alzheimer’s disease lead to patches or plaques in the brain and the entanglement of nerve fibers (neurofibrillary tangles). Memory loss and behavioral changes occur as a result of these changes in brain tissue. Alzheimer’s disease is usually a slow progressive illness that occurs in midlife but becomes increasingly more common over the age of 65 years, in contrast to the frontotemporal degenerations. Difficulty with short-term memory is usually the first symptom and early behavioral changes may not be noticed. As the disease progresses, memory loss increases and there are changes in personality, mood and behavior. Disturbances of judgment and concentration occur, along with confusion and restlessness. The type, severity, sequence, and progression of mental changes vary widely. Long periods with little change are common, although occasionally the disease can be rapidly progressive. Many of the ‘ FTD syndromes' such as agrammatic PPA, logopenic PPA, corticobasal syndrome and the bvFTD syndrome can also be caused by atypical forms of AD. (For more information on this disorder, choose “Alzheimer” as your search term in the Rare Disease Database.)Dementia with Lewy bodies (DLB), which is also called Lewy body dementia (LBD), is a neurodegenerative disorder characterized by Parkinsonism and degeneration that begin more or less simultaneously. People with DLB have difficulty with attention, concentration and multitasking (executive function). They are also prone to depression, visual hallucinations, sleep disturbances and day-to-day fluctuations in cognitive function. Memory is often less affected than in Alzheimer disease. The Parkinsonism in DLB is gradually progressive and consists of slowness (bradykinesia), muscle stiffness (rigidity), stooped posture, and slow shuffling gait that is often poorly responsive to levodopa. Tremor is frequently mild or absent, compared to classic Parkinson disease. | 488 | Frontotemporal Degeneration |
nord_488_5 | Diagnosis of Frontotemporal Degeneration | A diagnosis of frontotemporal degeneration is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A neuropsychological evaluation involves an interview and certain tests, often pencil and paper type tests. This evaluation will allow a physician to assess behavior, language, memory, visual-spatial and other cognitive functions. Early in the course of the disorder, people with the behavioral variant of frontotemporal degeneration tend to score very well on neuropsychological testing. Clinical Testing and Workup
Specialized imaging techniques may include magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET) scans. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain. In SPECT, physicians use a radioactive substance and a special camera to create 3-D images of internal areas of the body, including the brain. SPECT can reveal characteristic changes such as reduced blood flow in certain areas of the brain. In PET scans of the brain, a radioactive atom is attached to glucose (blood sugar). This allows physicians to see the chemical activity (metabolism) in the brain. Individuals with frontotemporal degeneration exhibit reduced chemical activity (hypometabolism) in the frontal and temporal areas of the brain, a finding that can distinguish the disorder from Alzheimer disease. More recently, an amyloid PET tracer has been developed that can bind to misfolded amyloid proteins accumulated in the brain. This can support or rule out a diagnosis of Alzheimer’s disease which can then be ruled out during the diagnostic process for FTD. A spinal tap (lumbar puncture) can be performed to measure amyloid and tau proteins. This test can also support or decrease the likelihood of an Alzheimer’s diagnosisMolecular genetic testing can confirm a diagnosis of frontotemporal degeneration in certain people. Molecular genetic testing can detect mutations in the MAPT, GRN or C9ORF72 genes known to cause FTD, but testing is currently available only as a diagnostic service at specialized laboratories or as part of a clinical research study. Genetic testing should only be performed after genetic counseling. | Diagnosis of Frontotemporal Degeneration. A diagnosis of frontotemporal degeneration is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A neuropsychological evaluation involves an interview and certain tests, often pencil and paper type tests. This evaluation will allow a physician to assess behavior, language, memory, visual-spatial and other cognitive functions. Early in the course of the disorder, people with the behavioral variant of frontotemporal degeneration tend to score very well on neuropsychological testing. Clinical Testing and Workup
Specialized imaging techniques may include magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET) scans. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain. In SPECT, physicians use a radioactive substance and a special camera to create 3-D images of internal areas of the body, including the brain. SPECT can reveal characteristic changes such as reduced blood flow in certain areas of the brain. In PET scans of the brain, a radioactive atom is attached to glucose (blood sugar). This allows physicians to see the chemical activity (metabolism) in the brain. Individuals with frontotemporal degeneration exhibit reduced chemical activity (hypometabolism) in the frontal and temporal areas of the brain, a finding that can distinguish the disorder from Alzheimer disease. More recently, an amyloid PET tracer has been developed that can bind to misfolded amyloid proteins accumulated in the brain. This can support or rule out a diagnosis of Alzheimer’s disease which can then be ruled out during the diagnostic process for FTD. A spinal tap (lumbar puncture) can be performed to measure amyloid and tau proteins. This test can also support or decrease the likelihood of an Alzheimer’s diagnosisMolecular genetic testing can confirm a diagnosis of frontotemporal degeneration in certain people. Molecular genetic testing can detect mutations in the MAPT, GRN or C9ORF72 genes known to cause FTD, but testing is currently available only as a diagnostic service at specialized laboratories or as part of a clinical research study. Genetic testing should only be performed after genetic counseling. | 488 | Frontotemporal Degeneration |
nord_488_6 | Therapies of Frontotemporal Degeneration | Treatment
There are no approved treatments for frontotemporal degeneration. Treatment is directed toward the specific clinical symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychologists, psychiatrists, neuropsychologists, speech pathologists, occupational and physical therapists, and other healthcare professionals may need to systematically and comprehensively plan an affected person’s treatment as the disease progresses. Genetic counseling is of benefit when frontotemporal degeneration is believed to run in families or an underlying genetic cause is known. Psychosocial support for the entire family is essential as well. Frontotemporal degeneration slowly worsens over time. However, the rate of this decline and the specific symptoms that develop vary among affected individuals. Treatments are aimed at managing the symptoms. Treatments can include medications for behavioral changes, medications for memory loss, speech therapy, physical therapy, lifestyle and environmental changes, and other therapies. Some of the behavioral symptoms associated with frontotemporal degeneration can be treated with antidepressants such as selective serotonin reuptake inhibitors (SSRIs), although these are not successful in all cases. Sometimes doctors recommend low doses of atypical antipsychotics to treat the associated behavioral problems. Antipsychotic drugs must be used with caution, particularly in elderly individuals, because of the risk of serious complications including stroke, heart issues and increased mortality. Individuals with speech problems or language deficits may benefit from speech therapy. There are alternative communication techniques that can be taught to individuals who experience difficulties with expressing language. Physical and occupational therapy and an exercise program may be of benefit to some people. Behavioral modification techniques are sometimes recommended. Individuals with frontotemporal degeneration eventually require managed and supportive care. Planning must be made for many issues including handling financial matters, driving, and managing behavioral problems. Various lifestyle changes and changes in a person’s living environment can be beneficial. The scope of these interventions are not covered in this report, but the organizations listed in the Resources section can provide detailed information on supportive and coordinated management of individuals with frontotemporal degeneration. | Therapies of Frontotemporal Degeneration. Treatment
There are no approved treatments for frontotemporal degeneration. Treatment is directed toward the specific clinical symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychologists, psychiatrists, neuropsychologists, speech pathologists, occupational and physical therapists, and other healthcare professionals may need to systematically and comprehensively plan an affected person’s treatment as the disease progresses. Genetic counseling is of benefit when frontotemporal degeneration is believed to run in families or an underlying genetic cause is known. Psychosocial support for the entire family is essential as well. Frontotemporal degeneration slowly worsens over time. However, the rate of this decline and the specific symptoms that develop vary among affected individuals. Treatments are aimed at managing the symptoms. Treatments can include medications for behavioral changes, medications for memory loss, speech therapy, physical therapy, lifestyle and environmental changes, and other therapies. Some of the behavioral symptoms associated with frontotemporal degeneration can be treated with antidepressants such as selective serotonin reuptake inhibitors (SSRIs), although these are not successful in all cases. Sometimes doctors recommend low doses of atypical antipsychotics to treat the associated behavioral problems. Antipsychotic drugs must be used with caution, particularly in elderly individuals, because of the risk of serious complications including stroke, heart issues and increased mortality. Individuals with speech problems or language deficits may benefit from speech therapy. There are alternative communication techniques that can be taught to individuals who experience difficulties with expressing language. Physical and occupational therapy and an exercise program may be of benefit to some people. Behavioral modification techniques are sometimes recommended. Individuals with frontotemporal degeneration eventually require managed and supportive care. Planning must be made for many issues including handling financial matters, driving, and managing behavioral problems. Various lifestyle changes and changes in a person’s living environment can be beneficial. The scope of these interventions are not covered in this report, but the organizations listed in the Resources section can provide detailed information on supportive and coordinated management of individuals with frontotemporal degeneration. | 488 | Frontotemporal Degeneration |
nord_489_0 | Overview of Fructose Intolerance, Hereditary | There are three inherited disorders of fructose metabolism that are recognized and characterized. Essential fructosuria, is a mild disorder not requiring treatment, while Hereditary fructose intolerance (HFI) and Hereditary fructose-1,6-biphosphatase deficiency (HFBP) are treatable and controllable but must be taken seriously.Hereditary Fructose Intolerance (HFI) is an inherited inability to digest fructose (fruit sugar) or its precursors (sugar, sorbitol and brown sugar). This is due to a deficiency of activity of the enzyme fructose-1-phosphate aldolase, resulting in an accumulation of fructose-1-phosphate in the liver, kidney, and small intestine. Fructose is a naturally occurring sugar that is used as a sweetener in many foods, including many baby foods. This disorder can be life threatening in infants and ranges from mild to severe in older children and adults.People who have HFI usually develop a strong dislike for sweets and fruit. After eating foods containing fructose, they may experience such symptoms as severe abdominal pain, vomiting, and low blood sugar (hypoglycemia).Early diagnosis is important because, while most people who have HFI can lead normal lives if they adopt a fructose-free diet. If left untreated however, the condition can lead to permanent physical harm, including especially, serious liver and kidney damage. | Overview of Fructose Intolerance, Hereditary. There are three inherited disorders of fructose metabolism that are recognized and characterized. Essential fructosuria, is a mild disorder not requiring treatment, while Hereditary fructose intolerance (HFI) and Hereditary fructose-1,6-biphosphatase deficiency (HFBP) are treatable and controllable but must be taken seriously.Hereditary Fructose Intolerance (HFI) is an inherited inability to digest fructose (fruit sugar) or its precursors (sugar, sorbitol and brown sugar). This is due to a deficiency of activity of the enzyme fructose-1-phosphate aldolase, resulting in an accumulation of fructose-1-phosphate in the liver, kidney, and small intestine. Fructose is a naturally occurring sugar that is used as a sweetener in many foods, including many baby foods. This disorder can be life threatening in infants and ranges from mild to severe in older children and adults.People who have HFI usually develop a strong dislike for sweets and fruit. After eating foods containing fructose, they may experience such symptoms as severe abdominal pain, vomiting, and low blood sugar (hypoglycemia).Early diagnosis is important because, while most people who have HFI can lead normal lives if they adopt a fructose-free diet. If left untreated however, the condition can lead to permanent physical harm, including especially, serious liver and kidney damage. | 489 | Fructose Intolerance, Hereditary |
nord_489_1 | Symptoms of Fructose Intolerance, Hereditary | Soon after fructose is added to the diet of an infant with HFI, symptoms become apparent. These may include prolonged vomiting, failure to thrive, jaundice and growth retardation. There may be occasional episodes of unconsciousness. Other symptoms include enlargement of the liver and frequently cirrhosis, and a tendency towards gastrointestinal bleeding because of deficiency of clotting factors. There are decreased levels of glucose and phosphate in the blood and increased levels of fructose in the blood and urine.Patients with Hereditary Fructose Intolerance usually develop a strong dislike for sweets and fruit. Although infants may exhibit growth delays and even experience malnutrition, there is no intellectual impairment.It is very important to recognize the intolerance early to avoid damage to the liver, kidney, and small intestine. | Symptoms of Fructose Intolerance, Hereditary. Soon after fructose is added to the diet of an infant with HFI, symptoms become apparent. These may include prolonged vomiting, failure to thrive, jaundice and growth retardation. There may be occasional episodes of unconsciousness. Other symptoms include enlargement of the liver and frequently cirrhosis, and a tendency towards gastrointestinal bleeding because of deficiency of clotting factors. There are decreased levels of glucose and phosphate in the blood and increased levels of fructose in the blood and urine.Patients with Hereditary Fructose Intolerance usually develop a strong dislike for sweets and fruit. Although infants may exhibit growth delays and even experience malnutrition, there is no intellectual impairment.It is very important to recognize the intolerance early to avoid damage to the liver, kidney, and small intestine. | 489 | Fructose Intolerance, Hereditary |
nord_489_2 | Causes of Fructose Intolerance, Hereditary | Studies of families in which HFI occurs leads geneticists to believe that the disorder is inherited as an autosomal recessive trait, The responsible gene has been mapped to the long arm (q) of chromosome 9 at gene map locus 9q22.3. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 9q22.3” refers to band 22.3 on the long (q) arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Fructose Intolerance, Hereditary. Studies of families in which HFI occurs leads geneticists to believe that the disorder is inherited as an autosomal recessive trait, The responsible gene has been mapped to the long arm (q) of chromosome 9 at gene map locus 9q22.3. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 9q22.3” refers to band 22.3 on the long (q) arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 489 | Fructose Intolerance, Hereditary |
nord_489_3 | Affects of Fructose Intolerance, Hereditary | Hereditary Fructose Intolerance may be diagnosed at birth or shortly thereafter when the infant is weaned. Like other autosomal disorders it is equally distributed among males and females. Estimates of the incidence of the disorder range widely from 1:10,000 to 1:100,000 births. | Affects of Fructose Intolerance, Hereditary. Hereditary Fructose Intolerance may be diagnosed at birth or shortly thereafter when the infant is weaned. Like other autosomal disorders it is equally distributed among males and females. Estimates of the incidence of the disorder range widely from 1:10,000 to 1:100,000 births. | 489 | Fructose Intolerance, Hereditary |
nord_489_4 | Related disorders of Fructose Intolerance, Hereditary | Essential Fructosuria is characterized by the presence of fructose in the urine after ingesting fructose. It arises as a result of a deficiency of the hepatic enzyme fructokinase and is an autosomal recessive genetic disorder. The disorder is mild and it probably remains undiagnosed in many, many people.Hereditary fructose-1,6-biphosphatase deficiency interferes with and even interrupts the ability of the liver and other organs to metabolize glycogen, which is a chemical that stores the body's energy reserves. As a consequence, the patient shows signs of hypoglycemia (low blood sugar), breathing difficulties (apnea), hyperventilation, ketosis (a sign of incomplete sugar metabolism) and lactic acidosis. These problems can be life threatening in newborns if left untreated. | Related disorders of Fructose Intolerance, Hereditary. Essential Fructosuria is characterized by the presence of fructose in the urine after ingesting fructose. It arises as a result of a deficiency of the hepatic enzyme fructokinase and is an autosomal recessive genetic disorder. The disorder is mild and it probably remains undiagnosed in many, many people.Hereditary fructose-1,6-biphosphatase deficiency interferes with and even interrupts the ability of the liver and other organs to metabolize glycogen, which is a chemical that stores the body's energy reserves. As a consequence, the patient shows signs of hypoglycemia (low blood sugar), breathing difficulties (apnea), hyperventilation, ketosis (a sign of incomplete sugar metabolism) and lactic acidosis. These problems can be life threatening in newborns if left untreated. | 489 | Fructose Intolerance, Hereditary |
nord_489_5 | Diagnosis of Fructose Intolerance, Hereditary | A diagnosis of HFI can be definitively confirmed by either of two tests: an enzyme assay, requiring a liver biopsy, to determine the level of aldolase activity or a fructose tolerance test in which the patient's response to intravenous fructose feeding is carefully monitored. It should be carefully noted, however, that each of these tests carries with it a substantial risk, especially to a newborn child. A non-invasive DNA test is increasingly being recommended instead. | Diagnosis of Fructose Intolerance, Hereditary. A diagnosis of HFI can be definitively confirmed by either of two tests: an enzyme assay, requiring a liver biopsy, to determine the level of aldolase activity or a fructose tolerance test in which the patient's response to intravenous fructose feeding is carefully monitored. It should be carefully noted, however, that each of these tests carries with it a substantial risk, especially to a newborn child. A non-invasive DNA test is increasingly being recommended instead. | 489 | Fructose Intolerance, Hereditary |
nord_489_6 | Therapies of Fructose Intolerance, Hereditary | TreatmentThe standard therapy is a fructose-free diet. As long as patients with Hereditary Fructose Intolerance do not ingest fructose, they can lead normal lives. However, it is important that this disorder be diagnosed early, and the special diet adopted, to prevent permanent physical damage. | Therapies of Fructose Intolerance, Hereditary. TreatmentThe standard therapy is a fructose-free diet. As long as patients with Hereditary Fructose Intolerance do not ingest fructose, they can lead normal lives. However, it is important that this disorder be diagnosed early, and the special diet adopted, to prevent permanent physical damage. | 489 | Fructose Intolerance, Hereditary |
nord_490_0 | Overview of Fryns Syndrome | SummaryFryns syndrome is a rare genetic condition in which multiple abnormalities are present at birth. Characteristics of the syndrome are broadly categorized into diaphragmatic defects (diaphragmatic hernia) with incomplete development of the lungs, distinctive facial features, underdevelopment of the ends of the fingers and toes (distal digital hypoplasia), and other associated abnormalities of the brain, eyes, heart, gastrointestinal and genitourinary system. Fryns syndrome is thought to be inherited as an autosomal recessive condition, but the specific causal gene or genes have not yet been identified.IntroductionFryns syndrome was described for the first time in 1979, and about 50 patients have been reported in the medical literature since then. While originally thought to be a lethal disorder, there are few documented individuals that have survived into childhood, although survival beyond the neonatal period is extremely are. Since there is a wide variety of signs and symptoms, treatment and prognosis for the condition vary greatly from person to person. | Overview of Fryns Syndrome. SummaryFryns syndrome is a rare genetic condition in which multiple abnormalities are present at birth. Characteristics of the syndrome are broadly categorized into diaphragmatic defects (diaphragmatic hernia) with incomplete development of the lungs, distinctive facial features, underdevelopment of the ends of the fingers and toes (distal digital hypoplasia), and other associated abnormalities of the brain, eyes, heart, gastrointestinal and genitourinary system. Fryns syndrome is thought to be inherited as an autosomal recessive condition, but the specific causal gene or genes have not yet been identified.IntroductionFryns syndrome was described for the first time in 1979, and about 50 patients have been reported in the medical literature since then. While originally thought to be a lethal disorder, there are few documented individuals that have survived into childhood, although survival beyond the neonatal period is extremely are. Since there is a wide variety of signs and symptoms, treatment and prognosis for the condition vary greatly from person to person. | 490 | Fryns Syndrome |
nord_490_1 | Symptoms of Fryns Syndrome | Fryns syndrome is characterized by multiple congenital anomalies that vary in severity from person to person. Although not all patients present with the following characteristics, the most common clinical features in this condition are: 1.Diaphragmatic defects and pulmonary hypoplasia
2.Distinctive facial appearance
3.Distal digital hypoplasia
4.Characteristic associated anomalies: excess amniotic fluid (polyhydramnios), cloudy corneas and/or abnormally small eyes (microphthalmia), orofacial clefting, brain malformation, cardiovascular malformation, gastrointestinal malformation, renal dysplasia/renal cortical cysts, genital malformation1. More than 90% of individuals with Fryns syndrome have congenital diaphragmatic hernia (CDH): this means that the diaphragm is not completely formed, resulting in contents like the small intestine, liver, and stomach moving into the chest cavity. The most common hernia is a unilateral, left-sided hernia. Underdevelopment of the lung (lung hypoplasia) and other respiratory concerns are commonly associated.2. Individuals with Fryns syndrome commonly have characteristic facial features such as coarse face, widely spaced eyes (hypertelorism), and a cloudy outer layer of the eye (cloudy cornea), broad and flat nasal bridge with nostrils that face the top of the head (anteverted nares), malformed (dysplastic) and low-set ears, wide mouth (macrostomia), and small jaw (microretrognathia). Cleft palate, or incomplete closure of the two sides of the roof of the mouth, has been reported in 50% of individuals. Cleft lip was reported in 25% of patients.3. Individuals with Fryns syndrome can have underdevelopment (hypoplasia) of nails and finger bones, reported in 60% of those affected. 10% of the patients have broad first digits, and bent fingers (camptodactyly). Side-to-side curvature of the spine (scoliosis), extra ribs, abnormalities of development of bone and cartilage (osteochondrodysplasia) have also been described.4. Other associated anomalies have been reported in some individuals with Fryns syndrome.Neurological abnormalities due to structural brain malformations were found in the majority of affected children, with seizures presenting in at least one child. Examples of abnormalities are ventriculomegaly, failure of development (agenesis) of the corpus callosum, and Dandy-Walker malformation. Ventriculomegaly is the enlargement of the lateral ventricles of the brain, the cavities where cerebrospinal fluid flows. The corpus callosum connects the two halves of the brain with nerve fibers. In Dandy-Walker malformation, the fourth ventricle of the brain and the base of the skull (posterior fossa) are enlarged, and the cerebellar vermis, an area of the brain responsible for coordination of body arrangement, is underdeveloped. More information on these syndromes and how they can be diagnosed and treated may be found in the Rare Disease Database. Cardiac defects are frequently observed, with 40% presenting with ventricular septal defect, 10% with atrial septal defects, and 10% with abnormalities of the aorta. Ventricular septal defects have an opening in the heart’s lower two chambers, while atrial septal defects are in the upper two chambers.Due to the abnormality in the diaphragm in CDH patients, other abdominal defects sometimes occur. These can include omphalocele, where intestines, liver, and other organs develop outside of the abdominal wall, anal malformations, and intestinal malrotation, when intestines are twisted preventing passage of food.About 10% of individuals with Fryns syndrome also present with genital and urinary abnormalities. Cysts in the kidneys (renal cysts) can be present, and the connected structure, the ureter, may be big or dilated (mega- or hydro-ureter) or have cysts. The kidney may not develop properly (renal dysplasia). Males can have one or both testes that have not descended in the scrotum (cryptorchidism) or have a small penis; sometimes the urethral opening is in an unusual position (hypospadias). Females may have an abnormal heart-shaped uterus that is split into two instead of one large cavity, called a bicornuate uterus. Survival beyond the neonatal period is rare, and those who survive past this stage have documented developmental delays. The degree of developmental delay and intellectual disability varies from individual to individual. While previously it was thought that all individuals had severe developmental delay, a few children have been reported with milder learning disabilities. Growth has been reported to be normal in two children, but growth data for most individuals who survived past the neonatal period is not available. | Symptoms of Fryns Syndrome. Fryns syndrome is characterized by multiple congenital anomalies that vary in severity from person to person. Although not all patients present with the following characteristics, the most common clinical features in this condition are: 1.Diaphragmatic defects and pulmonary hypoplasia
2.Distinctive facial appearance
3.Distal digital hypoplasia
4.Characteristic associated anomalies: excess amniotic fluid (polyhydramnios), cloudy corneas and/or abnormally small eyes (microphthalmia), orofacial clefting, brain malformation, cardiovascular malformation, gastrointestinal malformation, renal dysplasia/renal cortical cysts, genital malformation1. More than 90% of individuals with Fryns syndrome have congenital diaphragmatic hernia (CDH): this means that the diaphragm is not completely formed, resulting in contents like the small intestine, liver, and stomach moving into the chest cavity. The most common hernia is a unilateral, left-sided hernia. Underdevelopment of the lung (lung hypoplasia) and other respiratory concerns are commonly associated.2. Individuals with Fryns syndrome commonly have characteristic facial features such as coarse face, widely spaced eyes (hypertelorism), and a cloudy outer layer of the eye (cloudy cornea), broad and flat nasal bridge with nostrils that face the top of the head (anteverted nares), malformed (dysplastic) and low-set ears, wide mouth (macrostomia), and small jaw (microretrognathia). Cleft palate, or incomplete closure of the two sides of the roof of the mouth, has been reported in 50% of individuals. Cleft lip was reported in 25% of patients.3. Individuals with Fryns syndrome can have underdevelopment (hypoplasia) of nails and finger bones, reported in 60% of those affected. 10% of the patients have broad first digits, and bent fingers (camptodactyly). Side-to-side curvature of the spine (scoliosis), extra ribs, abnormalities of development of bone and cartilage (osteochondrodysplasia) have also been described.4. Other associated anomalies have been reported in some individuals with Fryns syndrome.Neurological abnormalities due to structural brain malformations were found in the majority of affected children, with seizures presenting in at least one child. Examples of abnormalities are ventriculomegaly, failure of development (agenesis) of the corpus callosum, and Dandy-Walker malformation. Ventriculomegaly is the enlargement of the lateral ventricles of the brain, the cavities where cerebrospinal fluid flows. The corpus callosum connects the two halves of the brain with nerve fibers. In Dandy-Walker malformation, the fourth ventricle of the brain and the base of the skull (posterior fossa) are enlarged, and the cerebellar vermis, an area of the brain responsible for coordination of body arrangement, is underdeveloped. More information on these syndromes and how they can be diagnosed and treated may be found in the Rare Disease Database. Cardiac defects are frequently observed, with 40% presenting with ventricular septal defect, 10% with atrial septal defects, and 10% with abnormalities of the aorta. Ventricular septal defects have an opening in the heart’s lower two chambers, while atrial septal defects are in the upper two chambers.Due to the abnormality in the diaphragm in CDH patients, other abdominal defects sometimes occur. These can include omphalocele, where intestines, liver, and other organs develop outside of the abdominal wall, anal malformations, and intestinal malrotation, when intestines are twisted preventing passage of food.About 10% of individuals with Fryns syndrome also present with genital and urinary abnormalities. Cysts in the kidneys (renal cysts) can be present, and the connected structure, the ureter, may be big or dilated (mega- or hydro-ureter) or have cysts. The kidney may not develop properly (renal dysplasia). Males can have one or both testes that have not descended in the scrotum (cryptorchidism) or have a small penis; sometimes the urethral opening is in an unusual position (hypospadias). Females may have an abnormal heart-shaped uterus that is split into two instead of one large cavity, called a bicornuate uterus. Survival beyond the neonatal period is rare, and those who survive past this stage have documented developmental delays. The degree of developmental delay and intellectual disability varies from individual to individual. While previously it was thought that all individuals had severe developmental delay, a few children have been reported with milder learning disabilities. Growth has been reported to be normal in two children, but growth data for most individuals who survived past the neonatal period is not available. | 490 | Fryns Syndrome |
nord_490_2 | Causes of Fryns Syndrome | The specific gene/s that cause Fryns syndrome are not known, but due to patterns detected within families, it is thought that Fryns syndrome is an autosomal recessive condition.Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same condition, 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. The risk is also the same for each pregnancy.All individuals in the general population carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder. | Causes of Fryns Syndrome. The specific gene/s that cause Fryns syndrome are not known, but due to patterns detected within families, it is thought that Fryns syndrome is an autosomal recessive condition.Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same condition, 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. The risk is also the same for each pregnancy.All individuals in the general population carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder. | 490 | Fryns Syndrome |
nord_490_3 | Affects of Fryns Syndrome | Fryns syndrome is a rare disease that affects both males and females equally. A 1989 French study reported 7 cases per 100,000 live births, but no other recent estimates of prevalence have been published. | Affects of Fryns Syndrome. Fryns syndrome is a rare disease that affects both males and females equally. A 1989 French study reported 7 cases per 100,000 live births, but no other recent estimates of prevalence have been published. | 490 | Fryns Syndrome |
nord_490_4 | Related disorders of Fryns Syndrome | Symptoms of the following disorders may be similar to those of Fryns syndrome. Comparisons may be useful for a differential diagnosis:In studies, 1.3% to 4%-10% of persons with congenital diaphragmatic hernia have Fryns syndrome, making it the most common autosomal recessive condition associated with CDH. However, not all individuals with CDH have Fryns syndrome.Pallister-Killian syndrome is a rare chromosomal disorder characterized by characteristic facial features, intellectual disability, and seizures. Characteristic facial features give infants with this disorder a coarse facial appearance. Infants with Pallister-Killian syndrome may have diaphragmatic hernia, Dandy-Walker malformation, congenital heart defects, and skin abnormalities. It is caused by tetrasomy (or four copies, instead of the normal two) for the short arm of chromosome 12. This syndrome can be differentiated from Fryns syndrome through chromosome analysis and inheritance patterns. (For more information on this disorder, choose “Pallister-Killian” as your search term in the Rare Disease Database.)Cornelia de Lange syndrome (CdLS) is a rare genetic disease. Associated signs and symptoms are growth delay before and after birth, distinctive facial features, abnormal growth of hair, malformations of the hands and arms (upper limbs), and mild to severe intellectual disability. CdLS can be inherited as an autosomal dominant or X-linked condition, and five genes have been found to be associated with CdLS. (For more information on this disorder, choose “Cornelia de Lange Syndrome” as your search term in the Rare Disease Database.)Donnai-Barrow syndrome is a rare genetic disorder characterized by distinctive facial features, eye findings, hearing loss, agenesis of the corpus callosum, intellectual disability, and congenital diaphragmatic hernia. It is caused by mutations in the LRP2 gene and is inherited as an autosomal recessive condition.Matthew-Wood syndrome is another autosomal recessive condition characterized by congenital diaphragmatic hernia, pulmonary hypoplasia and severe ocular malformations (underdevelopment or complete absence of the globe). It is caused by mutations in the STRA6 gene. Patients with this syndrome usually lack the digital findings of Fryns syndrome. Trisomy 18 is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice. Many affected infants have growth deficiency, feeding and breathing difficulties, developmental delays, intellectual disability, and, in affected males, undescended testes (cryptorchidism). Individuals with Trisomy 18 may also have distinctive craniofacial features and structural heart defects (For more information on this disorder, choose “Trisomy 18 Syndrome” as your search term in the Rare Disease Database.) | Related disorders of Fryns Syndrome. Symptoms of the following disorders may be similar to those of Fryns syndrome. Comparisons may be useful for a differential diagnosis:In studies, 1.3% to 4%-10% of persons with congenital diaphragmatic hernia have Fryns syndrome, making it the most common autosomal recessive condition associated with CDH. However, not all individuals with CDH have Fryns syndrome.Pallister-Killian syndrome is a rare chromosomal disorder characterized by characteristic facial features, intellectual disability, and seizures. Characteristic facial features give infants with this disorder a coarse facial appearance. Infants with Pallister-Killian syndrome may have diaphragmatic hernia, Dandy-Walker malformation, congenital heart defects, and skin abnormalities. It is caused by tetrasomy (or four copies, instead of the normal two) for the short arm of chromosome 12. This syndrome can be differentiated from Fryns syndrome through chromosome analysis and inheritance patterns. (For more information on this disorder, choose “Pallister-Killian” as your search term in the Rare Disease Database.)Cornelia de Lange syndrome (CdLS) is a rare genetic disease. Associated signs and symptoms are growth delay before and after birth, distinctive facial features, abnormal growth of hair, malformations of the hands and arms (upper limbs), and mild to severe intellectual disability. CdLS can be inherited as an autosomal dominant or X-linked condition, and five genes have been found to be associated with CdLS. (For more information on this disorder, choose “Cornelia de Lange Syndrome” as your search term in the Rare Disease Database.)Donnai-Barrow syndrome is a rare genetic disorder characterized by distinctive facial features, eye findings, hearing loss, agenesis of the corpus callosum, intellectual disability, and congenital diaphragmatic hernia. It is caused by mutations in the LRP2 gene and is inherited as an autosomal recessive condition.Matthew-Wood syndrome is another autosomal recessive condition characterized by congenital diaphragmatic hernia, pulmonary hypoplasia and severe ocular malformations (underdevelopment or complete absence of the globe). It is caused by mutations in the STRA6 gene. Patients with this syndrome usually lack the digital findings of Fryns syndrome. Trisomy 18 is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice. Many affected infants have growth deficiency, feeding and breathing difficulties, developmental delays, intellectual disability, and, in affected males, undescended testes (cryptorchidism). Individuals with Trisomy 18 may also have distinctive craniofacial features and structural heart defects (For more information on this disorder, choose “Trisomy 18 Syndrome” as your search term in the Rare Disease Database.) | 490 | Fryns Syndrome |
nord_490_5 | Diagnosis of Fryns Syndrome | Diagnosis of Fryns syndrome is clinical, and based on the following six clinical features:1.Diaphragmatic defect
2.Distinctive facial appearance
3.Distal digital hypoplasia
4.Pulmonary hypoplasia
5.At least one characteristic associated anomaly: polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, brain malformation, cardiovascular malformation, gastrointestinal malformation, renal dysplasia/renal cortical cysts, genital malformation
6.Affected sibs or parental consanguinity Due to the variability of physical findings associated with the condition, several definitions have been suggested. A narrow definition of Fryns syndrome is if four out of six clinical features are present. A broad definition is the presence of three of the six clinical features (without distinctive facial characteristics of another syndrome). An atypical definition includes unusual features of Fryns syndrome, such as absence of the radius bone in the arm (radial aplasia) or excessive tissue membrane occurring in various parts of the body (pterygia).It is important to rule out chromosomal disorders, usually by chromosomal microarray analysis, before making a diagnosis of Fryns syndrome.Recently, three fetuses with Fryns syndrome were found to have two (biallelic) mutations in the PIGN gene, but further studies are needed to confirm whether or not mutations in this gene cause Fryns syndrome in a subset of patients.The extent of the disease may be evaluated through imaging scans of the chest, brain, abdomen, and more as needed. The diagnosis is usually made after birth. Only rarely, a diagnosis of Fryns syndrome may be suspected before birth based on the results of an ultrasound, where pictures are taken of the fetus using sound waves. | Diagnosis of Fryns Syndrome. Diagnosis of Fryns syndrome is clinical, and based on the following six clinical features:1.Diaphragmatic defect
2.Distinctive facial appearance
3.Distal digital hypoplasia
4.Pulmonary hypoplasia
5.At least one characteristic associated anomaly: polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, brain malformation, cardiovascular malformation, gastrointestinal malformation, renal dysplasia/renal cortical cysts, genital malformation
6.Affected sibs or parental consanguinity Due to the variability of physical findings associated with the condition, several definitions have been suggested. A narrow definition of Fryns syndrome is if four out of six clinical features are present. A broad definition is the presence of three of the six clinical features (without distinctive facial characteristics of another syndrome). An atypical definition includes unusual features of Fryns syndrome, such as absence of the radius bone in the arm (radial aplasia) or excessive tissue membrane occurring in various parts of the body (pterygia).It is important to rule out chromosomal disorders, usually by chromosomal microarray analysis, before making a diagnosis of Fryns syndrome.Recently, three fetuses with Fryns syndrome were found to have two (biallelic) mutations in the PIGN gene, but further studies are needed to confirm whether or not mutations in this gene cause Fryns syndrome in a subset of patients.The extent of the disease may be evaluated through imaging scans of the chest, brain, abdomen, and more as needed. The diagnosis is usually made after birth. Only rarely, a diagnosis of Fryns syndrome may be suspected before birth based on the results of an ultrasound, where pictures are taken of the fetus using sound waves. | 490 | Fryns Syndrome |
nord_490_6 | Therapies of Fryns Syndrome | TreatmentThere is currently no cure for Fryns syndrome. Treatment is geared toward addressing the individual’s needs. Surgery for diaphragmatic hernia and/or supportive measures are often suggested.Due to the life-threatening nature of certain complications such as diaphragmatic hernia, underdevelopment of the lungs, and cardiac defects, procedures shortly after birth may be needed for the newborn. For example, children with diaphragmatic hernia are intubated to prevent inflation of the herniated bowel. Consultation by pediatric neurologists, cardiologists, gastroenterologists, nephrologists, and craniofacial specialists may be appropriate.Genetic counseling is recommended for parents of a child with Fryns syndrome. | Therapies of Fryns Syndrome. TreatmentThere is currently no cure for Fryns syndrome. Treatment is geared toward addressing the individual’s needs. Surgery for diaphragmatic hernia and/or supportive measures are often suggested.Due to the life-threatening nature of certain complications such as diaphragmatic hernia, underdevelopment of the lungs, and cardiac defects, procedures shortly after birth may be needed for the newborn. For example, children with diaphragmatic hernia are intubated to prevent inflation of the herniated bowel. Consultation by pediatric neurologists, cardiologists, gastroenterologists, nephrologists, and craniofacial specialists may be appropriate.Genetic counseling is recommended for parents of a child with Fryns syndrome. | 490 | Fryns Syndrome |
nord_491_0 | Overview of Fucosidosis | SummaryFucosidosis is a rare genetic disorder characterized by deficiency of the enzyme alpha-L-fucosidase, which is required to break down (metabolize) certain complex compounds (e.g., fucose-containing glycolipids or fucose-containing glycoproteins). Fucose is a type of the sugar required by the body to perform certain functions (essential sugar). The inability to breakdown fucose-containing compounds results in their accumulation in various tissues in the body. Fucosidosis results in progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease and coarsening of facial features. The symptoms and severity of fucosidosis are highly variable and the disorder represents a disease spectrum in which individuals with mild cases have been known to live into the third or fourth decades. Individuals with severe cases of fucosidosis can develop life-threatening complications early in childhood.IntroductionThe disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. Low levels or inactivity of the alpha-L-fucosidase enzyme leads to the abnormal accumulation of fucose-containing compounds in the tissues of individuals with fucosidosis. | Overview of Fucosidosis. SummaryFucosidosis is a rare genetic disorder characterized by deficiency of the enzyme alpha-L-fucosidase, which is required to break down (metabolize) certain complex compounds (e.g., fucose-containing glycolipids or fucose-containing glycoproteins). Fucose is a type of the sugar required by the body to perform certain functions (essential sugar). The inability to breakdown fucose-containing compounds results in their accumulation in various tissues in the body. Fucosidosis results in progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease and coarsening of facial features. The symptoms and severity of fucosidosis are highly variable and the disorder represents a disease spectrum in which individuals with mild cases have been known to live into the third or fourth decades. Individuals with severe cases of fucosidosis can develop life-threatening complications early in childhood.IntroductionThe disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. Low levels or inactivity of the alpha-L-fucosidase enzyme leads to the abnormal accumulation of fucose-containing compounds in the tissues of individuals with fucosidosis. | 491 | Fucosidosis |
nord_491_1 | Symptoms of Fucosidosis | The symptoms of fucosidosis vary greatly even among individuals within the same family. Fucosidosis can be rapidly progressive causing severe, life-threatening complications in children or develop during adolescence and progress more slowly eventually causing serious complications in adulthood. In the past, fucosidosis was sometimes separated in type I and type II. However, researchers now believe that fucosidosis represents a disease spectrum with a wide variety of expression. Cases labeled fucosidosis type I (early onset, rapid progression) represent the severe end of the spectrum and those labeled fucosidosis type II represent the mild end.Infants with severe forms of fucosidosis may not exhibit any symptoms until 6 months to one year of life. Initial symptoms may be associated with mental and motor deterioration such as delayed acquisition of skills required to coordinate mental and muscular activities (psychomotor retardation). Physicals findings may also develop including coarse facial features, thickened lips and tongue, multiple deformities of the bone (mild dysostosis multiplex), loss of muscle tone (hypotonia) resulting in “floppiness” and growth retardation. Progressive neurological deterioration may result in a variety of symptoms including intellectual disability, various movement disorders and/or uncontrolled rigid extensions and rotations of the arms, legs, fingers, and toes (decerebrate rigidity). Severe fucosidosis often progresses to cause life-threatening neurodegenerative complications and/or severe, progressive loss of weight and muscle mass (cachexia), usually within the first few years of life.Less common findings associated with severe forms of fucosidosis include abnormally enlarged internal organs (visceromegaly), such as the liver and spleen (hepatosplenomegaly) or heart (cardiomegaly), seizures, hearing loss, abnormal curvature of the spine (kyphoscoliosis), and repeated respiratory infections. Some affeced individuals may sweat excessively and their sweat may contain abnormally high levels of salt.In some less severe cases, the symptoms associated progressive deterioration of the central nervous system may not become obvious until the age of 18 months to three years. The symptoms of less severe forms of fucosidosis are similar to the more severe forms, but tend to be milder with slower progression. Affected individuals may develop wart-like growths (angiokeratomas) on the skin around the age of two years. These lesions occur mainly on the abdomen, buttocks, thighs, and/or external genitalia. Some individuals may experience fixation of certain joints in a permanently flexed position (contractures), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs and inadequate ability to sweat (anhidrosis). Individuals with less severe forms of fucosidosis may live well into their second, third or fourth decades before the disorder progresses to cause life-threatening complications. | Symptoms of Fucosidosis. The symptoms of fucosidosis vary greatly even among individuals within the same family. Fucosidosis can be rapidly progressive causing severe, life-threatening complications in children or develop during adolescence and progress more slowly eventually causing serious complications in adulthood. In the past, fucosidosis was sometimes separated in type I and type II. However, researchers now believe that fucosidosis represents a disease spectrum with a wide variety of expression. Cases labeled fucosidosis type I (early onset, rapid progression) represent the severe end of the spectrum and those labeled fucosidosis type II represent the mild end.Infants with severe forms of fucosidosis may not exhibit any symptoms until 6 months to one year of life. Initial symptoms may be associated with mental and motor deterioration such as delayed acquisition of skills required to coordinate mental and muscular activities (psychomotor retardation). Physicals findings may also develop including coarse facial features, thickened lips and tongue, multiple deformities of the bone (mild dysostosis multiplex), loss of muscle tone (hypotonia) resulting in “floppiness” and growth retardation. Progressive neurological deterioration may result in a variety of symptoms including intellectual disability, various movement disorders and/or uncontrolled rigid extensions and rotations of the arms, legs, fingers, and toes (decerebrate rigidity). Severe fucosidosis often progresses to cause life-threatening neurodegenerative complications and/or severe, progressive loss of weight and muscle mass (cachexia), usually within the first few years of life.Less common findings associated with severe forms of fucosidosis include abnormally enlarged internal organs (visceromegaly), such as the liver and spleen (hepatosplenomegaly) or heart (cardiomegaly), seizures, hearing loss, abnormal curvature of the spine (kyphoscoliosis), and repeated respiratory infections. Some affeced individuals may sweat excessively and their sweat may contain abnormally high levels of salt.In some less severe cases, the symptoms associated progressive deterioration of the central nervous system may not become obvious until the age of 18 months to three years. The symptoms of less severe forms of fucosidosis are similar to the more severe forms, but tend to be milder with slower progression. Affected individuals may develop wart-like growths (angiokeratomas) on the skin around the age of two years. These lesions occur mainly on the abdomen, buttocks, thighs, and/or external genitalia. Some individuals may experience fixation of certain joints in a permanently flexed position (contractures), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs and inadequate ability to sweat (anhidrosis). Individuals with less severe forms of fucosidosis may live well into their second, third or fourth decades before the disorder progresses to cause life-threatening complications. | 491 | Fucosidosis |
nord_491_2 | Causes of Fucosidosis | Fucosidosis is caused by disruptions or changes (mutations) of the alpha-L-fucosidase (FUCA1) gene resulting in deficiency of the alpha-L-fucosidase enzyme. The symptoms of fucosidosis occur as a result of excessive accumulation of fucose-containing compounds (e.g., certain glycosphingolipids or certain glycoproteins) in the body due to abnormally low levels of this enzyme. Researchers do not know why the symptoms and severity vary so greatly in individuals with fucosidosis. Some researchers believe that mutation of the FUCA1 gene in combination with certain genetic and environmental factors all play a role in the severity of the disease in individuals. More research is necessary to determine what these factors may be.Individuals with fucosidosis also have a pseudogene- a gene that can no longer creates proteins or is no longer expressed in the body. The pseudogene associated with fucosidosis is called FUCA1P. Fucosidosis is inherited as an autosomal recessive trait. 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. | Causes of Fucosidosis. Fucosidosis is caused by disruptions or changes (mutations) of the alpha-L-fucosidase (FUCA1) gene resulting in deficiency of the alpha-L-fucosidase enzyme. The symptoms of fucosidosis occur as a result of excessive accumulation of fucose-containing compounds (e.g., certain glycosphingolipids or certain glycoproteins) in the body due to abnormally low levels of this enzyme. Researchers do not know why the symptoms and severity vary so greatly in individuals with fucosidosis. Some researchers believe that mutation of the FUCA1 gene in combination with certain genetic and environmental factors all play a role in the severity of the disease in individuals. More research is necessary to determine what these factors may be.Individuals with fucosidosis also have a pseudogene- a gene that can no longer creates proteins or is no longer expressed in the body. The pseudogene associated with fucosidosis is called FUCA1P. Fucosidosis is inherited as an autosomal recessive trait. 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. | 491 | Fucosidosis |
nord_491_3 | Affects of Fucosidosis | Fucosidosis affects males and females in equal numbers. Fewer than 100 cases have been reported in the medical literature. One estimate place the incidence rates at below 1 in 200,000 live births. Some researchers believe fucosidosis is underdiagnosed making it difficult to determine its true frequency in the general population.Although rare, fucosidosis has been identified in more than 20 countries across North and South America, Europe, Asia and Africa, with many patients found in the southwestern United States and southern Italy. As a group, the lysosomal storage diseases are believed to have an estimated frequency of about one in every 5,000 live births. | Affects of Fucosidosis. Fucosidosis affects males and females in equal numbers. Fewer than 100 cases have been reported in the medical literature. One estimate place the incidence rates at below 1 in 200,000 live births. Some researchers believe fucosidosis is underdiagnosed making it difficult to determine its true frequency in the general population.Although rare, fucosidosis has been identified in more than 20 countries across North and South America, Europe, Asia and Africa, with many patients found in the southwestern United States and southern Italy. As a group, the lysosomal storage diseases are believed to have an estimated frequency of about one in every 5,000 live births. | 491 | Fucosidosis |
nord_491_4 | Related disorders of Fucosidosis | Symptoms of the following disorders can be similar to those of fucosidosis. 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 on this disorder, choose “lysosomal storage disease” as your search term in the Rare Disease Database.)Fabry disease is a rare genetic disorder of lipid metabolism characterized by a deficiency of the enzyme alpha-galactosidase A, also known as ceramidetrihexosidase. The disorder belongs to a group of diseases known as lysosomal storage disorders. Low levels or inactivity of the alpha-galactosidase A enzyme leads to the abnormal accumulation of a substance consisting of fatty material and carbohydrates (i.e., glycolipids such as glycosphingolipid) in various organs of the body, particularly blood vessels and the eyes. Symptoms of Fabry disease may include the appearance of clusters of wart-like discolorations on the skin (angiokeratomas), abdominal pain, and/or visual impairment. Later in the course of the disease, kidney failure, heart irregularities, and/or progressive neurological abnormalities may cause serious complications. Fabry disease, which is inherited as an X-linked recessive trait, primarily affects males. A milder form of the disease has been identified in females. (For more information on this disorder, choose “Fabry” as your search term in the Rare Disease Database.)
Alpha-mannosidosis is a rare genetic disorder that belongs to group of disorders known as the lysosomal storage diseases. The enzyme that is lacking is known as alpha-D-mannosidase. Alpha-mannosidosis is generally separated into three types: type 1, the most mild form, generally appears after the age of 10 years; type 2, the moderate form, may be accompanied by skeletal and muscular defects, and is usually slow to progress; type 3, the most severe form, usually becomes apparent shortly after birth and involves the central nervous system. Alpha-mannosidosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “alpha mannosidosis” as your search term in the Rare Disease Database.)Aspartylglycosaminuria is a rare genetic disorder characterized by deficient levels or activity of an enzyme aspartylglucosaminidase. This enzyme is required to metabolize certain glycoproteins in the body. Deficiency or inactivity of this enzyme causes these compounds to accumulate in the tissues of the body, resulting in a variety of symptoms. Affected infants often develop normally for 2-4 years. Eventually they begin to experience repeated respiratory infections and diarrhea. Additional symptoms develop including coarsening of facial features, skeletal abnormalities, seizures, developmental delays and intellectual disability. Aspartylglycosaminuria is inherited as an autosomal recessive trait. (For more information on this disorder, choose “aspartylglycosaminuria” as your search term in the Rare Disease Database.) | Related disorders of Fucosidosis. Symptoms of the following disorders can be similar to those of fucosidosis. 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 on this disorder, choose “lysosomal storage disease” as your search term in the Rare Disease Database.)Fabry disease is a rare genetic disorder of lipid metabolism characterized by a deficiency of the enzyme alpha-galactosidase A, also known as ceramidetrihexosidase. The disorder belongs to a group of diseases known as lysosomal storage disorders. Low levels or inactivity of the alpha-galactosidase A enzyme leads to the abnormal accumulation of a substance consisting of fatty material and carbohydrates (i.e., glycolipids such as glycosphingolipid) in various organs of the body, particularly blood vessels and the eyes. Symptoms of Fabry disease may include the appearance of clusters of wart-like discolorations on the skin (angiokeratomas), abdominal pain, and/or visual impairment. Later in the course of the disease, kidney failure, heart irregularities, and/or progressive neurological abnormalities may cause serious complications. Fabry disease, which is inherited as an X-linked recessive trait, primarily affects males. A milder form of the disease has been identified in females. (For more information on this disorder, choose “Fabry” as your search term in the Rare Disease Database.)
Alpha-mannosidosis is a rare genetic disorder that belongs to group of disorders known as the lysosomal storage diseases. The enzyme that is lacking is known as alpha-D-mannosidase. Alpha-mannosidosis is generally separated into three types: type 1, the most mild form, generally appears after the age of 10 years; type 2, the moderate form, may be accompanied by skeletal and muscular defects, and is usually slow to progress; type 3, the most severe form, usually becomes apparent shortly after birth and involves the central nervous system. Alpha-mannosidosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “alpha mannosidosis” as your search term in the Rare Disease Database.)Aspartylglycosaminuria is a rare genetic disorder characterized by deficient levels or activity of an enzyme aspartylglucosaminidase. This enzyme is required to metabolize certain glycoproteins in the body. Deficiency or inactivity of this enzyme causes these compounds to accumulate in the tissues of the body, resulting in a variety of symptoms. Affected infants often develop normally for 2-4 years. Eventually they begin to experience repeated respiratory infections and diarrhea. Additional symptoms develop including coarsening of facial features, skeletal abnormalities, seizures, developmental delays and intellectual disability. Aspartylglycosaminuria is inherited as an autosomal recessive trait. (For more information on this disorder, choose “aspartylglycosaminuria” as your search term in the Rare Disease Database.) | 491 | Fucosidosis |
nord_491_5 | Diagnosis of Fucosidosis | A diagnosis of fucosidosis may be suspected in infants with skeletal disease during the first year of life that is accompanied by neurological deterioration and intellectual disability. The diagnosis may be confirmed thorough clinical evaluation, detailed patient history, and a variety of specialized tests. For example, electron microscopic examination of tissue samples from the skin, liver, spleen, heart, lung, kidney, sweat glands, and/or other cells may reveal abnormal “cavities” (vacuoles) inside these cells. These vacuoles may be clear or filled with sand-like granules or thin, disc-like (lamellar) bodies. Advanced imaging techniques, such as magnetic resonance imaging (MRI) and computer-assisted tomography (CT scan) of the brain may confirm degeneration of the white matter of the brain. Laboratory analysis of urinary samples may reveal increased levels of certain fucose-containing complex compounds in the urine (e.g., oligosacchariduria and glycopeptiduria). In addition, reduced activity of the alpha-L-fucosidase enzyme may be confirmed by enzyme tests (assays) on cultured fibroblasts and leukocytes. (As some unaffected individuals may normally show reduced levels of alpha-L-fucosidase in the serum and plasma, assays conducted on the serum and plasma alone may not be conclusive; therefore, fibroblast and leukocyte assay testing is necessary.)Fucosidosis has been successfully diagnosed before birth (prenatally) through the use of specialized tests such as chorionic villus sampling (CVS) and/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 fluid that surrounds the developing fetus is removed and studied. | Diagnosis of Fucosidosis. A diagnosis of fucosidosis may be suspected in infants with skeletal disease during the first year of life that is accompanied by neurological deterioration and intellectual disability. The diagnosis may be confirmed thorough clinical evaluation, detailed patient history, and a variety of specialized tests. For example, electron microscopic examination of tissue samples from the skin, liver, spleen, heart, lung, kidney, sweat glands, and/or other cells may reveal abnormal “cavities” (vacuoles) inside these cells. These vacuoles may be clear or filled with sand-like granules or thin, disc-like (lamellar) bodies. Advanced imaging techniques, such as magnetic resonance imaging (MRI) and computer-assisted tomography (CT scan) of the brain may confirm degeneration of the white matter of the brain. Laboratory analysis of urinary samples may reveal increased levels of certain fucose-containing complex compounds in the urine (e.g., oligosacchariduria and glycopeptiduria). In addition, reduced activity of the alpha-L-fucosidase enzyme may be confirmed by enzyme tests (assays) on cultured fibroblasts and leukocytes. (As some unaffected individuals may normally show reduced levels of alpha-L-fucosidase in the serum and plasma, assays conducted on the serum and plasma alone may not be conclusive; therefore, fibroblast and leukocyte assay testing is necessary.)Fucosidosis has been successfully diagnosed before birth (prenatally) through the use of specialized tests such as chorionic villus sampling (CVS) and/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 fluid that surrounds the developing fetus is removed and studied. | 491 | Fucosidosis |
nord_491_6 | Therapies of Fucosidosis | TreatmentThe treatment of fucosidosis is directed toward the specific symptoms that are apparent in each individual. For example, antibiotic therapy may be administered to treat recurrent respiratory infections or fluid replacement may be considered to counter the effects of dehydration that may occur due to excessive sweating. A team approach for individuals with fucosidosis may be necessary and may include special social support and other medical services. Genetic counseling is recommended for affected individuals and their families. | Therapies of Fucosidosis. TreatmentThe treatment of fucosidosis is directed toward the specific symptoms that are apparent in each individual. For example, antibiotic therapy may be administered to treat recurrent respiratory infections or fluid replacement may be considered to counter the effects of dehydration that may occur due to excessive sweating. A team approach for individuals with fucosidosis may be necessary and may include special social support and other medical services. Genetic counseling is recommended for affected individuals and their families. | 491 | Fucosidosis |
nord_492_0 | Overview of Fukuyama Type Congenital Muscular Dystrophy | Fukuyama type congenital muscular dystrophy (FCMD) is one of several forms of a rare type of muscular dystrophy known as congenital muscular dystrophy. It is inherited in an autosomal recessive pattern. Symptoms of this disorder are apparent at birth and progress slowly. In addition to general muscle weakness and deformities of the joints (contractures), FCMD is often accompanied by seizures, intellectual disability and speech problems. This disorder is predominantly found in Japan. | Overview of Fukuyama Type Congenital Muscular Dystrophy. Fukuyama type congenital muscular dystrophy (FCMD) is one of several forms of a rare type of muscular dystrophy known as congenital muscular dystrophy. It is inherited in an autosomal recessive pattern. Symptoms of this disorder are apparent at birth and progress slowly. In addition to general muscle weakness and deformities of the joints (contractures), FCMD is often accompanied by seizures, intellectual disability and speech problems. This disorder is predominantly found in Japan. | 492 | Fukuyama Type Congenital Muscular Dystrophy |
nord_492_1 | Symptoms of Fukuyama Type Congenital Muscular Dystrophy | Infants with FCMD are “floppy” at birth and usually have problems sucking and swallowing. They have a weak cry and there is a loss of muscle tone as well as weakness of the muscles. The joints in the knees and elbows may be in a fixed position (contractures) and reflexes of the tendons are poor.Intellectual disability is characteristic of this form of muscular dystrophy. Also, some affected infants and children have seizures. A sunken chest and a severe form of grand mal seizures called status epilepticus has been found in a few individuals with FCMD. | Symptoms of Fukuyama Type Congenital Muscular Dystrophy. Infants with FCMD are “floppy” at birth and usually have problems sucking and swallowing. They have a weak cry and there is a loss of muscle tone as well as weakness of the muscles. The joints in the knees and elbows may be in a fixed position (contractures) and reflexes of the tendons are poor.Intellectual disability is characteristic of this form of muscular dystrophy. Also, some affected infants and children have seizures. A sunken chest and a severe form of grand mal seizures called status epilepticus has been found in a few individuals with FCMD. | 492 | Fukuyama Type Congenital Muscular Dystrophy |
nord_492_2 | Causes of Fukuyama Type Congenital Muscular Dystrophy | FCMD occurs because of a change (mutation or variant) in the gene that gives instructions for the production of (codes for) a protein known as fukutin. The normal role of this protein isn’t yet well understood.Fukuyama congenital muscular dystrophy is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.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.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. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | Causes of Fukuyama Type Congenital Muscular Dystrophy. FCMD occurs because of a change (mutation or variant) in the gene that gives instructions for the production of (codes for) a protein known as fukutin. The normal role of this protein isn’t yet well understood.Fukuyama congenital muscular dystrophy is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.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.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. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | 492 | Fukuyama Type Congenital Muscular Dystrophy |
nord_492_3 | Affects of Fukuyama Type Congenital Muscular Dystrophy | FCMD is almost nonexistent in the United States, but in Japan is second only to Duchenne muscular dystrophy in frequency. The incidence in Japan is reported as about 0.7-1.2 cases per 100,000 children. | Affects of Fukuyama Type Congenital Muscular Dystrophy. FCMD is almost nonexistent in the United States, but in Japan is second only to Duchenne muscular dystrophy in frequency. The incidence in Japan is reported as about 0.7-1.2 cases per 100,000 children. | 492 | Fukuyama Type Congenital Muscular Dystrophy |
nord_492_4 | Related disorders of Fukuyama Type Congenital Muscular Dystrophy | Symptoms of the following disorders can be similar to those of Fukuyama type congenital muscular dystrophy. Comparisons may be useful for a differential diagnosis:Becker muscular dystrophy (BMD) is much like Duchenne muscular dystrophy and is characterized by weakness of the muscles of the legs that usually first is noticed in a boy’s pre-teen and teen years. The muscle weakness is progressive but milder in severity than in Duchenne muscular dystrophy. (For more information on this disorder, choose “Becker” as your search term in the Rare Disease Database.)Distal muscular dystrophy (DD) generates weakness in the legs but, in addition, affects the strength of the muscles of the hands and feet. This form of MD progresses more slowly than others and generally less severe.Duchenne muscular dystrophy (DMD) is the most rapidly progressive form of muscular dystrophy and one of the most common. This muscle-wasting disorder, which affects boys almost exclusively, typically has onset between the ages of two and five and progresses rapidly. For a brief period, between ages three and seven, the child’s natural growth and development may produce a deceptive improvement in this condition. However, muscle degeneration continues, resulting in weakness that advances rapidly after the age of eight or nine. (For more information on this disorder, choose “Duchenne” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy (EDMD) usually presents during childhood or the teen years. It affects the muscles of the calves, shoulders and upper arms. EDMD progresses slowly. Contractions of the calf and elbow flexors muscles are prominent. Among other significant symptoms are the abnormal heartbeats and EKGs caused by peculiarities in the way electrical impulses pass through the heart. (For more information on this disorder, choose “Emery-Dreifuss” as your search term in the Rare Disease Database.)Fascioscapulohumeral muscular dystrophy (FSH) affects both males and females and has onset during the teen years or the decade afterward. It usually generates weakness in the muscles of the face, shoulders and upper arms. Less frequently, it may also affect the muscles of the legs and hips. (For more information on this disorder, choose “Fascioscapulohumeral Muscular Dystrophy” as your search term in the Rare Disease Database.)Limb-girdle muscular dystrophy (LGMD) usually begins in the teen years or early adulthood. The first muscles affected are usually those of the shoulders and hips. Slowly, the disorder progresses to include the arms and legs. (For more information on this disorder, choose “Limb-Girdle” as your search term in the Rare Disease Database.)Myotonic dystrophy presents as muscle weakness. It may specifically involve distal legs, hands and facial muscle weakness, slack jaw and drooping eyelids. The disorder is progressive, usually leading to severe disability over a period of years. (For more information on this disorder, choose “Myotonic Dystrophy” as your search term in the Rare Disease Database.)Oculopharyngeal muscular dystrophy (OPMD) is a disorder of adulthood that affects both males and females. Initially, it weakens the muscles of the eyes and throat causing symptoms such as drooping eyelids and difficulty in swallowing or eating (dysphagia). The disorder may progress to affect the muscles of the face and neck and rarely, the muscles of the thighs. | Related disorders of Fukuyama Type Congenital Muscular Dystrophy. Symptoms of the following disorders can be similar to those of Fukuyama type congenital muscular dystrophy. Comparisons may be useful for a differential diagnosis:Becker muscular dystrophy (BMD) is much like Duchenne muscular dystrophy and is characterized by weakness of the muscles of the legs that usually first is noticed in a boy’s pre-teen and teen years. The muscle weakness is progressive but milder in severity than in Duchenne muscular dystrophy. (For more information on this disorder, choose “Becker” as your search term in the Rare Disease Database.)Distal muscular dystrophy (DD) generates weakness in the legs but, in addition, affects the strength of the muscles of the hands and feet. This form of MD progresses more slowly than others and generally less severe.Duchenne muscular dystrophy (DMD) is the most rapidly progressive form of muscular dystrophy and one of the most common. This muscle-wasting disorder, which affects boys almost exclusively, typically has onset between the ages of two and five and progresses rapidly. For a brief period, between ages three and seven, the child’s natural growth and development may produce a deceptive improvement in this condition. However, muscle degeneration continues, resulting in weakness that advances rapidly after the age of eight or nine. (For more information on this disorder, choose “Duchenne” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy (EDMD) usually presents during childhood or the teen years. It affects the muscles of the calves, shoulders and upper arms. EDMD progresses slowly. Contractions of the calf and elbow flexors muscles are prominent. Among other significant symptoms are the abnormal heartbeats and EKGs caused by peculiarities in the way electrical impulses pass through the heart. (For more information on this disorder, choose “Emery-Dreifuss” as your search term in the Rare Disease Database.)Fascioscapulohumeral muscular dystrophy (FSH) affects both males and females and has onset during the teen years or the decade afterward. It usually generates weakness in the muscles of the face, shoulders and upper arms. Less frequently, it may also affect the muscles of the legs and hips. (For more information on this disorder, choose “Fascioscapulohumeral Muscular Dystrophy” as your search term in the Rare Disease Database.)Limb-girdle muscular dystrophy (LGMD) usually begins in the teen years or early adulthood. The first muscles affected are usually those of the shoulders and hips. Slowly, the disorder progresses to include the arms and legs. (For more information on this disorder, choose “Limb-Girdle” as your search term in the Rare Disease Database.)Myotonic dystrophy presents as muscle weakness. It may specifically involve distal legs, hands and facial muscle weakness, slack jaw and drooping eyelids. The disorder is progressive, usually leading to severe disability over a period of years. (For more information on this disorder, choose “Myotonic Dystrophy” as your search term in the Rare Disease Database.)Oculopharyngeal muscular dystrophy (OPMD) is a disorder of adulthood that affects both males and females. Initially, it weakens the muscles of the eyes and throat causing symptoms such as drooping eyelids and difficulty in swallowing or eating (dysphagia). The disorder may progress to affect the muscles of the face and neck and rarely, the muscles of the thighs. | 492 | Fukuyama Type Congenital Muscular Dystrophy |
nord_492_5 | Diagnosis of Fukuyama Type Congenital Muscular Dystrophy | The diagnosis depends on a thorough physical examination and medical history. In addition, the physician will look for information to assist in the diagnosis from several tests such as blood tests to detect abnormally high levels of a particular enzyme (creatine kinase) released form the cells of damaged muscles, genetic testing for fukutin gene variants, electromyographic studies to determine the area of muscle that is damaged and muscle biopsy to distinguish muscular dystrophy from other neuromuscular disorders. | Diagnosis of Fukuyama Type Congenital Muscular Dystrophy. The diagnosis depends on a thorough physical examination and medical history. In addition, the physician will look for information to assist in the diagnosis from several tests such as blood tests to detect abnormally high levels of a particular enzyme (creatine kinase) released form the cells of damaged muscles, genetic testing for fukutin gene variants, electromyographic studies to determine the area of muscle that is damaged and muscle biopsy to distinguish muscular dystrophy from other neuromuscular disorders. | 492 | Fukuyama Type Congenital Muscular Dystrophy |
nord_492_6 | Therapies of Fukuyama Type Congenital Muscular Dystrophy | TreatmentPatients with Fukuyama congenital muscular dystrophy may benefit from physical therapy to help prevent joints from becoming fixed.For patients who have seizures, anti-seizure medications such as phenytoin, valproic acid, phenobarbitol, clonazepam, ethusuximide, primidone, corticotropin and corticosteroid drugs may help prevent and control seizures.Genetic counseling is recommended for patients and their families. | Therapies of Fukuyama Type Congenital Muscular Dystrophy. TreatmentPatients with Fukuyama congenital muscular dystrophy may benefit from physical therapy to help prevent joints from becoming fixed.For patients who have seizures, anti-seizure medications such as phenytoin, valproic acid, phenobarbitol, clonazepam, ethusuximide, primidone, corticotropin and corticosteroid drugs may help prevent and control seizures.Genetic counseling is recommended for patients and their families. | 492 | Fukuyama Type Congenital Muscular Dystrophy |
nord_493_0 | Overview of Functional Neurological Disorder | Functional neurological disorder (FND) is a medical condition in which there is a problem with the functioning of the nervous system and how the brain and body sends and/or receives signals, rather than a structural disease process such as multiple sclerosis or stroke. FND can encompass a wide variety of neurological symptoms, such as limb weakness or seizures.FND is a condition at the interface between the specialties of neurology and psychiatry. Conventional tests such as MRI brain scans and EEGs are usually normal in patients with FND. This had led, historically, to the condition being relatively neglected by both clinicians and researchers. However, it is now established that FND is a common cause of disability and distress, which may overlap with other problems such as chronic pain and fatigue. Encouraging studies support the potential reversibility of FND with specifically tailored treatments. New scientific findings are influencing how patients are diagnosed and treated, which is creating an overall change in attitude towards people with FND.Older ideas that FND is “all psychological” and therefore always associated with stress or past trauma, and that the diagnosis is made only when someone has normal tests, have changed since the mid-2000s. The new understanding, including modern neuroscientific studies, has shown that FND is not a diagnosis of exclusion. It has specific clinical features of its own and is a disorder of the nervous system functioning in which many perspectives are necessary. These vary a lot from person to person. In some people, psychological factors are important; in others, they are not. | Overview of Functional Neurological Disorder. Functional neurological disorder (FND) is a medical condition in which there is a problem with the functioning of the nervous system and how the brain and body sends and/or receives signals, rather than a structural disease process such as multiple sclerosis or stroke. FND can encompass a wide variety of neurological symptoms, such as limb weakness or seizures.FND is a condition at the interface between the specialties of neurology and psychiatry. Conventional tests such as MRI brain scans and EEGs are usually normal in patients with FND. This had led, historically, to the condition being relatively neglected by both clinicians and researchers. However, it is now established that FND is a common cause of disability and distress, which may overlap with other problems such as chronic pain and fatigue. Encouraging studies support the potential reversibility of FND with specifically tailored treatments. New scientific findings are influencing how patients are diagnosed and treated, which is creating an overall change in attitude towards people with FND.Older ideas that FND is “all psychological” and therefore always associated with stress or past trauma, and that the diagnosis is made only when someone has normal tests, have changed since the mid-2000s. The new understanding, including modern neuroscientific studies, has shown that FND is not a diagnosis of exclusion. It has specific clinical features of its own and is a disorder of the nervous system functioning in which many perspectives are necessary. These vary a lot from person to person. In some people, psychological factors are important; in others, they are not. | 493 | Functional Neurological Disorder |
nord_493_1 | Symptoms of Functional Neurological Disorder | FND patients can experience a wide range and combination of symptoms that are physical, sensory and/or cognitive. The most common include:Motor dysfunction
• Functional limb weakness/paralysis
• Functional movement disorders including tremor, spasms (dystonia), jerky movements (myoclonus) and problems walking (gait disorder)
• Functional speech symptoms including whispering speech (dysphonia), slurred or stuttering speechSensory dysfunction
• Functional sensory disturbance includes altered sensation; e.g., numbness, tingling or pain in the face, torso or limbs; this often occurs on one side of the body
• Functional visual symptoms including loss of vision or double visionEpisodes of altered awareness
• Functional seizures (also called dissociative or non-epileptic) seizures, blackouts and faints: these symptoms can overlap and can look like epileptic seizures or faints (syncope)Dizziness
Functional dizziness is often called persistent perceptual postural dizziness and has its own set of diagnostic criteriaCognitive Symptoms
Functional cognitive symptoms include difficulties with memory, concentration or word finding difficulty where there are typical features consistent with an FND diagnosisSymptoms often fluctuate and may vary from day to day or be present all the time. Some patients with FND may experience substantial or even complete remission followed by sudden relapses of symptoms.Other physical and psychological symptoms are commonly experienced by patients with FND although they are not defined as part of the disorder. These include chronic pain, fatigue, sleep problems, bowel and bladder symptoms, anxiety, panic attacks and depression. | Symptoms of Functional Neurological Disorder. FND patients can experience a wide range and combination of symptoms that are physical, sensory and/or cognitive. The most common include:Motor dysfunction
• Functional limb weakness/paralysis
• Functional movement disorders including tremor, spasms (dystonia), jerky movements (myoclonus) and problems walking (gait disorder)
• Functional speech symptoms including whispering speech (dysphonia), slurred or stuttering speechSensory dysfunction
• Functional sensory disturbance includes altered sensation; e.g., numbness, tingling or pain in the face, torso or limbs; this often occurs on one side of the body
• Functional visual symptoms including loss of vision or double visionEpisodes of altered awareness
• Functional seizures (also called dissociative or non-epileptic) seizures, blackouts and faints: these symptoms can overlap and can look like epileptic seizures or faints (syncope)Dizziness
Functional dizziness is often called persistent perceptual postural dizziness and has its own set of diagnostic criteriaCognitive Symptoms
Functional cognitive symptoms include difficulties with memory, concentration or word finding difficulty where there are typical features consistent with an FND diagnosisSymptoms often fluctuate and may vary from day to day or be present all the time. Some patients with FND may experience substantial or even complete remission followed by sudden relapses of symptoms.Other physical and psychological symptoms are commonly experienced by patients with FND although they are not defined as part of the disorder. These include chronic pain, fatigue, sleep problems, bowel and bladder symptoms, anxiety, panic attacks and depression. | 493 | Functional Neurological Disorder |
nord_493_2 | Causes of Functional Neurological Disorder | The exact cause of FND is unknown, although ongoing research is starting to provide suggestions as to how and why it develops. Many different predisposing factors can make patients more susceptible to FND such as having another neurological condition, experiencing chronic pain, fatigue or stress. Childhood abuse, maltreatment or neglect and life stress, particularly around the time of symptom onset, is also more common in people with FND than in the general population. However, many people with FND have none of these risk factors which are also unfortunately common in all, including healthy, populations. As with most complex disorders affecting the brain, it’s likely that genetic factors play a role in the condition, but it is not a problem that someone should expect to pass on genetically.At the time FND begins, studies have shown that there may be triggering factors like a physical injury, infectious illness, vaccination, panic attack or migraine which can give someone the first experience of neurological symptoms. These symptoms normally settle down on their own. However, in FND the symptoms become ‘stuck’ in a ‘pattern’ in the nervous system. That ‘pattern’ is reflected in altered brain functioning. The result is a genuine and disabling problem, which the patient cannot control. The aim of treatment is to ‘retrain the brain’, for example by unlearning abnormal and dysfunctional movement patterns that have developed and relearning normal movement. For seizures, the aim is to unlearn the seizure program that has become stuck in the brain, and which activates typically with very little trigger or perhaps just in response to being relaxed.One way of thinking about FND is looking at it as a bit like a ‘software’ problem on a computer. The ‘hardware’ is not damaged but there is a problem with the ‘software’ and so the computer doesn’t work properly. A different analogy is a piano that is not broken but is out of tune. Conventional structural MRI brain scans are usually normal in FND unless the person has another neurological condition. Special functional brain scans (fMRI) used in research, which show patterns of brain activity, are starting to provide early evidence for how the brain goes wrong in FND. fMRI scans show changes in patients with FND which look different from healthy patients without these symptoms as well as being different from healthy people pretending to have these symptoms. Functional imaging is still just a research tool and is not developed enough to be used in diagnosing individual cases of FND. Scans support what patients and researchers already know – these are genuine disorders in which there is a change in brain functioning, which is out of the control of the person with FND.Historically, FND has traditionally been viewed as an entirely psychological disorder in which repressed psychological stress or trauma gets converted into a physical symptom. This is where the term conversion disorder comes from. Psychological disorders and stressful life events, both recent and in childhood, are risk factors for developing the condition and can be relevant for some patients, but they rarely provide a full explanation for the cause of the condition and are absent in many patients. Patients do not have to be depressed, anxious or the survivor of adverse childhood experience to develop FND.Modern theories propose that FND has many causes, which vary from patient to patient. One comparison is to think about heart disease. There are lots of causes of heart disease – smoking, genetic factors, diet and even stress-related/psychological factors such as depression. Smoking may be a factor in heart disease in many people, but it is not in everyone. The same analogy can be made for FND. In some, psychological factors such as past trauma or stress at the time of symptom onset in FND are important in understanding how the brain has gone wrong. In others, the presence of a problem like migraine or a physical injury may be the most important thing. | Causes of Functional Neurological Disorder. The exact cause of FND is unknown, although ongoing research is starting to provide suggestions as to how and why it develops. Many different predisposing factors can make patients more susceptible to FND such as having another neurological condition, experiencing chronic pain, fatigue or stress. Childhood abuse, maltreatment or neglect and life stress, particularly around the time of symptom onset, is also more common in people with FND than in the general population. However, many people with FND have none of these risk factors which are also unfortunately common in all, including healthy, populations. As with most complex disorders affecting the brain, it’s likely that genetic factors play a role in the condition, but it is not a problem that someone should expect to pass on genetically.At the time FND begins, studies have shown that there may be triggering factors like a physical injury, infectious illness, vaccination, panic attack or migraine which can give someone the first experience of neurological symptoms. These symptoms normally settle down on their own. However, in FND the symptoms become ‘stuck’ in a ‘pattern’ in the nervous system. That ‘pattern’ is reflected in altered brain functioning. The result is a genuine and disabling problem, which the patient cannot control. The aim of treatment is to ‘retrain the brain’, for example by unlearning abnormal and dysfunctional movement patterns that have developed and relearning normal movement. For seizures, the aim is to unlearn the seizure program that has become stuck in the brain, and which activates typically with very little trigger or perhaps just in response to being relaxed.One way of thinking about FND is looking at it as a bit like a ‘software’ problem on a computer. The ‘hardware’ is not damaged but there is a problem with the ‘software’ and so the computer doesn’t work properly. A different analogy is a piano that is not broken but is out of tune. Conventional structural MRI brain scans are usually normal in FND unless the person has another neurological condition. Special functional brain scans (fMRI) used in research, which show patterns of brain activity, are starting to provide early evidence for how the brain goes wrong in FND. fMRI scans show changes in patients with FND which look different from healthy patients without these symptoms as well as being different from healthy people pretending to have these symptoms. Functional imaging is still just a research tool and is not developed enough to be used in diagnosing individual cases of FND. Scans support what patients and researchers already know – these are genuine disorders in which there is a change in brain functioning, which is out of the control of the person with FND.Historically, FND has traditionally been viewed as an entirely psychological disorder in which repressed psychological stress or trauma gets converted into a physical symptom. This is where the term conversion disorder comes from. Psychological disorders and stressful life events, both recent and in childhood, are risk factors for developing the condition and can be relevant for some patients, but they rarely provide a full explanation for the cause of the condition and are absent in many patients. Patients do not have to be depressed, anxious or the survivor of adverse childhood experience to develop FND.Modern theories propose that FND has many causes, which vary from patient to patient. One comparison is to think about heart disease. There are lots of causes of heart disease – smoking, genetic factors, diet and even stress-related/psychological factors such as depression. Smoking may be a factor in heart disease in many people, but it is not in everyone. The same analogy can be made for FND. In some, psychological factors such as past trauma or stress at the time of symptom onset in FND are important in understanding how the brain has gone wrong. In others, the presence of a problem like migraine or a physical injury may be the most important thing. | 493 | Functional Neurological Disorder |
nord_493_3 | Affects of Functional Neurological Disorder | The exact prevalence of FND is unknown. However, research suggests FND is the second most common reason for a neurological outpatient visit after headache/migraine, accounting for one sixth of diagnoses. This means FND could be as common as multiple sclerosis or Parkinson’s disease.FND can affect anyone, at any time, although it is uncommon in children under 10. FND is 2-3 times more likely to affect females than males for most symptoms, although when patients present over the age of 50, it occurs equally in both groups. | Affects of Functional Neurological Disorder. The exact prevalence of FND is unknown. However, research suggests FND is the second most common reason for a neurological outpatient visit after headache/migraine, accounting for one sixth of diagnoses. This means FND could be as common as multiple sclerosis or Parkinson’s disease.FND can affect anyone, at any time, although it is uncommon in children under 10. FND is 2-3 times more likely to affect females than males for most symptoms, although when patients present over the age of 50, it occurs equally in both groups. | 493 | Functional Neurological Disorder |
nord_493_4 | Related disorders of Functional Neurological Disorder | It is common for FND to co-exist with other illnesses. FND can have similar symptoms to most other types of conditions seen in neurological practice such as multiple sclerosis, stroke and epilepsy. Some patients have another neurological disease diagnosis such as stroke and FND. A neurologist is normally required to assess which symptoms relate to FND and to monitor where required for any new symptoms.Anxiety disorders and depression can sometimes cause physical symptoms which overlap with FND symptoms. For example, panic attacks can present with symptoms such as pins and needles in the fingers or mouth and depression often causes poor concentration or fatigue. Anxiety, panic attacks and depression are common in patients with FND, but many patients do not have such problems.Other psychiatric conditions are more common in people with FND including post-traumatic stress disorder (PTSD), and emotionally unstable personality traits (often related to past trauma). There is also some emerging evidence that obsessive compulsive disorder (OCD) and autistic spectrum disorder (ASD) are more common in FND populations and might predispose individuals to developing FND symptoms.Chronic pain is also common in patients with FND including fibromyalgia, which is also related to disturbed nervous system functioning. Pain disorders are also usually associated with fatigue, sleep disturbance, and poor concentration. Migraine and chronic headaches are also common.Other functional disorders including irritable bowel syndrome or overactive bladder syndrome are more common in patients with FND.There is some newer research suggesting that joint hypermobility spectrum disorder (which includes Ehlers Danlos type 3) may be more common in people with FND as well as other functional disorders. It should be remembered, though, that in these studies around 10-30% of healthy controls also had hypermobility.It is important that new symptoms not automatically be considered related to FND and other causes are considered and investigated as appropriate. | Related disorders of Functional Neurological Disorder. It is common for FND to co-exist with other illnesses. FND can have similar symptoms to most other types of conditions seen in neurological practice such as multiple sclerosis, stroke and epilepsy. Some patients have another neurological disease diagnosis such as stroke and FND. A neurologist is normally required to assess which symptoms relate to FND and to monitor where required for any new symptoms.Anxiety disorders and depression can sometimes cause physical symptoms which overlap with FND symptoms. For example, panic attacks can present with symptoms such as pins and needles in the fingers or mouth and depression often causes poor concentration or fatigue. Anxiety, panic attacks and depression are common in patients with FND, but many patients do not have such problems.Other psychiatric conditions are more common in people with FND including post-traumatic stress disorder (PTSD), and emotionally unstable personality traits (often related to past trauma). There is also some emerging evidence that obsessive compulsive disorder (OCD) and autistic spectrum disorder (ASD) are more common in FND populations and might predispose individuals to developing FND symptoms.Chronic pain is also common in patients with FND including fibromyalgia, which is also related to disturbed nervous system functioning. Pain disorders are also usually associated with fatigue, sleep disturbance, and poor concentration. Migraine and chronic headaches are also common.Other functional disorders including irritable bowel syndrome or overactive bladder syndrome are more common in patients with FND.There is some newer research suggesting that joint hypermobility spectrum disorder (which includes Ehlers Danlos type 3) may be more common in people with FND as well as other functional disorders. It should be remembered, though, that in these studies around 10-30% of healthy controls also had hypermobility.It is important that new symptoms not automatically be considered related to FND and other causes are considered and investigated as appropriate. | 493 | Functional Neurological Disorder |
nord_493_5 | Diagnosis of Functional Neurological Disorder | FND is not a diagnosis of exclusion. It should be diagnosed on the basis of positive physical signs and clinical features, and usually requires a neurologist or a doctor familiar with neurological diagnosis. There are dozens of these clinical features but some examples are:Hoover’s test of functional leg weakness – the patient may have difficulty pushing their affected leg down (hip extension), but when they are asked to lift their unaffected leg, movement in the affected leg returns transiently to normal.The tremor entrainment test for functional tremor – this is when the shaking of an arm or leg becomes momentarily better or alters frequency when the person concentrates on copying a movement that the examiner makes.Functional seizures can often be recognized by a trained health professional using a combination of typical features such as: an episode of violent limb thrashing in which the eyes remain closed, side-to-side head movements, or an event lasting longer than 5 minutes where the eyes are closed, hyperventilation during a shaking attack or tearfulness on recovery.Persistent postural perceptual dizziness (PPPD) which is recognized as a subtype of FND has its own diagnostic criteria set by the Barany society and adopted by the World Health Organization.Functional cognitive disorder is characterized by the presence of variability in cognitive function, often called internal inconsistency. For example, someone with functional cognitive disorder may be able to recall in great detail an occasion when they forgot something, whereas someone with dementia often doesn’t think there is a problem.These diagnostic positive signs should not be used in isolation. Instead, clinicians with expertise in neurological diagnosis need to assess features in combination, while being mindful of the possibility of comorbid other neurological or psychiatric disorders influencing the presentation. | Diagnosis of Functional Neurological Disorder. FND is not a diagnosis of exclusion. It should be diagnosed on the basis of positive physical signs and clinical features, and usually requires a neurologist or a doctor familiar with neurological diagnosis. There are dozens of these clinical features but some examples are:Hoover’s test of functional leg weakness – the patient may have difficulty pushing their affected leg down (hip extension), but when they are asked to lift their unaffected leg, movement in the affected leg returns transiently to normal.The tremor entrainment test for functional tremor – this is when the shaking of an arm or leg becomes momentarily better or alters frequency when the person concentrates on copying a movement that the examiner makes.Functional seizures can often be recognized by a trained health professional using a combination of typical features such as: an episode of violent limb thrashing in which the eyes remain closed, side-to-side head movements, or an event lasting longer than 5 minutes where the eyes are closed, hyperventilation during a shaking attack or tearfulness on recovery.Persistent postural perceptual dizziness (PPPD) which is recognized as a subtype of FND has its own diagnostic criteria set by the Barany society and adopted by the World Health Organization.Functional cognitive disorder is characterized by the presence of variability in cognitive function, often called internal inconsistency. For example, someone with functional cognitive disorder may be able to recall in great detail an occasion when they forgot something, whereas someone with dementia often doesn’t think there is a problem.These diagnostic positive signs should not be used in isolation. Instead, clinicians with expertise in neurological diagnosis need to assess features in combination, while being mindful of the possibility of comorbid other neurological or psychiatric disorders influencing the presentation. | 493 | Functional Neurological Disorder |
nord_493_6 | Therapies of Functional Neurological Disorder | Overview
FND can be hard to understand, and most people haven’t heard of it. Treatment should start with a clear and supportive explanation of the positive clinical features that have allowed the diagnosis to be made, even though scans and other laboratory tests may be normal.When it goes well, understanding the diagnosis enables patients to see that they have a genuine and relatively common condition which has the potential for improvement over time. This creates a foundation for treatment to build upon. Written information, like that available at www.neurosymptoms.org or www.fndhope.org may help individuals comprehend this complex and difficult-to-understand disorder.Evidence is now emerging for the efficacy of certain specific treatment developed for FND, especially physiotherapy for motor symptoms and psychological therapies for functional seizures. Other therapies such as speech therapy and occupational therapy may also have a role depending on the symptoms.Physical Therapy
For patients with motor symptoms such as limb weakness, gait problems or movement disorder, physical therapy from a therapist who understands FND can be helpful. Physiotherapy approaches are active treatments that focus on retraining movement patterns that have gone wrong. There is some evidence from clinical trials that physiotherapy designed specifically for FND can be helpful for some patients. In recent years, we have learned that physical therapy for FND is different from that used for stroke or MS in many ways. For example, patients with stroke benefit from being asked to focus on the affected body part, whereas in FND that tends to make things worse. Physical therapy for FND promotes automatic movements and reduces the abnormal brain patterns that have been interfering with movement.Psychological Therapies
Psychological therapy such as cognitive behavioral therapy (CBT) is generally the first line of treatment for patients with dissociative (non-epileptic) seizures or attacks as part of their FND and is supported by clinical trials. It is also often used for other FND symptoms. CBT includes time to learn more about their attacks and recognizing brief warning symptoms and learning techniques to regain control. For some patients, it is helpful to look more widely at thoughts, emotions, and experiences that could have played a role in the development of symptoms. For those patients without anxiety and depression, psychological therapy may still be useful in regaining confidence. FND itself is often experienced as a stressful condition to manage and live with. Other types of psychological therapies can also be used depending on the individual patient, such as mindfulness, psychodynamic interpersonal therapy (PIT) or more trauma-focused approaches.Occupational Therapy
Occupational therapy assists patients in finding adaptations and regaining confidence in their ability to carry out daily activities in the home or workplace. Occupational therapy can help build on other therapies to contribute to a better overall quality of life.Speech Therapy
For patients with speech symptoms as part of FND, speech therapy is an important part of treatment. As with physical therapy, the approach is different from that used, for example, after a stroke.Other Therapies
There is no research evidence that any specific medication is beneficial for FND itself, but medications may be useful for other symptoms commonly occurring with FND such as pain, migraine, other headaches, insomnia, PTSD, anxiety, panic attacks or depression. Other therapies such as eye movement desensitization reprocessing therapy (EMDR – effective for PTSD), virtual reality (VR) treatments, transcranial magnetic stimulation (TMS) and other new treatments are being investigated in research studies.
Not everyone with FND can benefit from treatment even if they do understand their condition and are well motivated. | Therapies of Functional Neurological Disorder. Overview
FND can be hard to understand, and most people haven’t heard of it. Treatment should start with a clear and supportive explanation of the positive clinical features that have allowed the diagnosis to be made, even though scans and other laboratory tests may be normal.When it goes well, understanding the diagnosis enables patients to see that they have a genuine and relatively common condition which has the potential for improvement over time. This creates a foundation for treatment to build upon. Written information, like that available at www.neurosymptoms.org or www.fndhope.org may help individuals comprehend this complex and difficult-to-understand disorder.Evidence is now emerging for the efficacy of certain specific treatment developed for FND, especially physiotherapy for motor symptoms and psychological therapies for functional seizures. Other therapies such as speech therapy and occupational therapy may also have a role depending on the symptoms.Physical Therapy
For patients with motor symptoms such as limb weakness, gait problems or movement disorder, physical therapy from a therapist who understands FND can be helpful. Physiotherapy approaches are active treatments that focus on retraining movement patterns that have gone wrong. There is some evidence from clinical trials that physiotherapy designed specifically for FND can be helpful for some patients. In recent years, we have learned that physical therapy for FND is different from that used for stroke or MS in many ways. For example, patients with stroke benefit from being asked to focus on the affected body part, whereas in FND that tends to make things worse. Physical therapy for FND promotes automatic movements and reduces the abnormal brain patterns that have been interfering with movement.Psychological Therapies
Psychological therapy such as cognitive behavioral therapy (CBT) is generally the first line of treatment for patients with dissociative (non-epileptic) seizures or attacks as part of their FND and is supported by clinical trials. It is also often used for other FND symptoms. CBT includes time to learn more about their attacks and recognizing brief warning symptoms and learning techniques to regain control. For some patients, it is helpful to look more widely at thoughts, emotions, and experiences that could have played a role in the development of symptoms. For those patients without anxiety and depression, psychological therapy may still be useful in regaining confidence. FND itself is often experienced as a stressful condition to manage and live with. Other types of psychological therapies can also be used depending on the individual patient, such as mindfulness, psychodynamic interpersonal therapy (PIT) or more trauma-focused approaches.Occupational Therapy
Occupational therapy assists patients in finding adaptations and regaining confidence in their ability to carry out daily activities in the home or workplace. Occupational therapy can help build on other therapies to contribute to a better overall quality of life.Speech Therapy
For patients with speech symptoms as part of FND, speech therapy is an important part of treatment. As with physical therapy, the approach is different from that used, for example, after a stroke.Other Therapies
There is no research evidence that any specific medication is beneficial for FND itself, but medications may be useful for other symptoms commonly occurring with FND such as pain, migraine, other headaches, insomnia, PTSD, anxiety, panic attacks or depression. Other therapies such as eye movement desensitization reprocessing therapy (EMDR – effective for PTSD), virtual reality (VR) treatments, transcranial magnetic stimulation (TMS) and other new treatments are being investigated in research studies.
Not everyone with FND can benefit from treatment even if they do understand their condition and are well motivated. | 493 | Functional Neurological Disorder |
nord_494_0 | Overview of Galactosemia | Galactosemia is a rare, hereditary disorder of carbohydrate metabolism that affects the body’s ability to convert galactose to glucose. Galactose is a sugar contained in milk, including human mother’s milk as well as other dairy products. It is also produced by the human body, and this is called endogenous galactose. Glucose is a different type of sugar. The disorder is caused by a deficiency of an enzyme galactose-1-phosphate uridylyl transferase (GALT) which is vital to this process. Early diagnosis and treatment with a lactose-restricted (dairy-free) diet is absolutely essential to avoid profound intellectual disability, liver failure and death in the newborn period. Galactosemia is inherited as an autosomal recessive genetic condition. Classic galactosemia and clinical variant galactosemia can both result in life-threatening health problems unless lactose is removed from the diet shortly after birth. A biochemical variant form of galactosemia termed Duarte is not thought to cause clinical disease due to lactose consumption. | Overview of Galactosemia. Galactosemia is a rare, hereditary disorder of carbohydrate metabolism that affects the body’s ability to convert galactose to glucose. Galactose is a sugar contained in milk, including human mother’s milk as well as other dairy products. It is also produced by the human body, and this is called endogenous galactose. Glucose is a different type of sugar. The disorder is caused by a deficiency of an enzyme galactose-1-phosphate uridylyl transferase (GALT) which is vital to this process. Early diagnosis and treatment with a lactose-restricted (dairy-free) diet is absolutely essential to avoid profound intellectual disability, liver failure and death in the newborn period. Galactosemia is inherited as an autosomal recessive genetic condition. Classic galactosemia and clinical variant galactosemia can both result in life-threatening health problems unless lactose is removed from the diet shortly after birth. A biochemical variant form of galactosemia termed Duarte is not thought to cause clinical disease due to lactose consumption. | 494 | Galactosemia |
nord_494_1 | Symptoms of Galactosemia | An infant with galactosemia appears normal at birth, but within a few days or weeks loses their appetite and starts vomiting excessively. Yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), enlargement of the liver (hepatomegaly), appearance of amino acids and protein in the urine, growth failure, and, ultimately, accumulation of fluid in the abdominal cavity (ascites) with abdominal swelling (edema) may also occur. Diarrhea, irritability, lethargy and a bacterial infection may also be early signs of galactosemia. In time, wasting of body tissues, marked weakness, and extreme weight loss occur unless lactose is removed from the diet.Children with galactosemia who have not received early treatment may show arrested physical and mental development and are particularly susceptible to cataracts in infancy or childhood. In severely affected children, overwhelming infection in the newborn period can cause life-threatening complications, but children with Duarte variant galactosemia may have few signs and no serious impairment(s).In order to avoid the consequences of galactosemia, which may include liver failure and kidney dysfunction, brain damage and/or cataracts, infants must be treated promptly by removing lactose from the diet. Children treated with this special diet may still experience complications. Speech and learning difficulties and some behavioral problems are still likely to occur. Ovarian impairment is almost always seen in girls with classic galactosemia and is associated with an increase in the blood level of the gonadotropin hormone, follicle-stimulating hormone (FSH); males with galactosemia do not usually exhibit abnormalities in gonadal function.The above-mentioned complications associated with classic galactosemia and clinical variant galactosemia have not occurred in individuals with Duarte variant galactosemia, a type of biochemical variant galactosemia. However, in a minority of these children, developmental delay and/or a speech abnormality has occurred, but it is unclear whether this is related to accumulation of galactose and its metabolites. Individuals with Duarte variant galactosemia do not need to maintain a special diet. | Symptoms of Galactosemia. An infant with galactosemia appears normal at birth, but within a few days or weeks loses their appetite and starts vomiting excessively. Yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), enlargement of the liver (hepatomegaly), appearance of amino acids and protein in the urine, growth failure, and, ultimately, accumulation of fluid in the abdominal cavity (ascites) with abdominal swelling (edema) may also occur. Diarrhea, irritability, lethargy and a bacterial infection may also be early signs of galactosemia. In time, wasting of body tissues, marked weakness, and extreme weight loss occur unless lactose is removed from the diet.Children with galactosemia who have not received early treatment may show arrested physical and mental development and are particularly susceptible to cataracts in infancy or childhood. In severely affected children, overwhelming infection in the newborn period can cause life-threatening complications, but children with Duarte variant galactosemia may have few signs and no serious impairment(s).In order to avoid the consequences of galactosemia, which may include liver failure and kidney dysfunction, brain damage and/or cataracts, infants must be treated promptly by removing lactose from the diet. Children treated with this special diet may still experience complications. Speech and learning difficulties and some behavioral problems are still likely to occur. Ovarian impairment is almost always seen in girls with classic galactosemia and is associated with an increase in the blood level of the gonadotropin hormone, follicle-stimulating hormone (FSH); males with galactosemia do not usually exhibit abnormalities in gonadal function.The above-mentioned complications associated with classic galactosemia and clinical variant galactosemia have not occurred in individuals with Duarte variant galactosemia, a type of biochemical variant galactosemia. However, in a minority of these children, developmental delay and/or a speech abnormality has occurred, but it is unclear whether this is related to accumulation of galactose and its metabolites. Individuals with Duarte variant galactosemia do not need to maintain a special diet. | 494 | Galactosemia |
nord_494_2 | Causes of Galactosemia | Galactosemia occurs due to disruptions or changes (mutations) in the GALT gene resulting in deficiency of the GALT enzyme. This leads to abnormal accumulation of galactose-related chemicals in various organs of the body causes the signs and symptoms and physical findings of galactosemia.The GALT enzyme is needed for the breakdown of the milk sugar, galactose. Deficiency of this enzyme results in the accumulation of toxic products: galactose-1-phosphate (a derivative of galactose) and galactitol (an alcohol derivative of galactose). Galactitol accumulates in the lens of the eye where it causes lens swelling and protein precipitation and subsequently, cataracts. Accumulation of galactose-1-phosphate is thought to cause the other signs and symptoms of disease.Galactosemia is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Galactosemia. Galactosemia occurs due to disruptions or changes (mutations) in the GALT gene resulting in deficiency of the GALT enzyme. This leads to abnormal accumulation of galactose-related chemicals in various organs of the body causes the signs and symptoms and physical findings of galactosemia.The GALT enzyme is needed for the breakdown of the milk sugar, galactose. Deficiency of this enzyme results in the accumulation of toxic products: galactose-1-phosphate (a derivative of galactose) and galactitol (an alcohol derivative of galactose). Galactitol accumulates in the lens of the eye where it causes lens swelling and protein precipitation and subsequently, cataracts. Accumulation of galactose-1-phosphate is thought to cause the other signs and symptoms of disease.Galactosemia is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 494 | Galactosemia |
nord_494_3 | Affects of Galactosemia | Classic galactosemia is diagnosed in the range of 1/16,000 to 1/48,000 births through newborn screening programs around the world, depending on the diagnostic criteria used by the program. The disorder has been reported in all ethnic groups. An increased frequency of galactosemia occurs in individuals of Irish ancestry. Clinical variant galactosemia occurs most often in African Americans and native Africans in South Africa who have a specific gene mutation. | Affects of Galactosemia. Classic galactosemia is diagnosed in the range of 1/16,000 to 1/48,000 births through newborn screening programs around the world, depending on the diagnostic criteria used by the program. The disorder has been reported in all ethnic groups. An increased frequency of galactosemia occurs in individuals of Irish ancestry. Clinical variant galactosemia occurs most often in African Americans and native Africans in South Africa who have a specific gene mutation. | 494 | Galactosemia |
nord_494_4 | Related disorders of Galactosemia | Symptoms of the following disorders can be similar to those of galactosemia. Comparisons may be useful for a differential diagnosis:Galactokinase (GALK) deficiency is associated with cataracts, increased blood concentration of galactose and increased concentration of galactitol in the urine. Galactitol accumulates in the lens of the eye where it causes lens swelling and protein precipitation and subsequently, cataracts. GALK deficiency is an autosomal recessive genetic disorder caused by mutations in the GALK1 gene and diagnosed by reduced GALK enzyme activity.Uridine diphosphate galactose 4-epimerase (GALE) deficiency is similar to GALT deficiency when it presents in the newborn period. The severe form has been reported in only 8 patients. GALE deficiency is an autosomal recessive genetic disorder caused by mutations in the GALE gene and diagnosed by reduced GALE enzyme activity.Lactose intolerance (LI) is a metabolic disorder characterized by the inability to break down lactose, the predominant sugar found in milk and milk products. People with LI cannot properly digest lactose because they lack or are deficient in the intestinal enzyme, lactase, which is key to the digestion of lactose. Lactose is a complex sugar made up of two different sugar molecules (disaccharide), galactose and glucose, each of which is a simple (monosaccharide) sugar and more readily absorbed in the body’s intestines and processed in other organs. Individuals with a deficiency of lactase experience cramps, nausea, bloating, stomach rumbling (Borborygmi), gas (flatus) and/or diarrhea after eating or drinking lactose-rich foods, not all of which are dairy products. Signs are more severe when they occur in a newborn infant. The signs of congenital lactose intolerance are apparent soon after birth and usually include severe diarrhea, vomiting, abnormally low levels of body fluids (dehydration) and failure to thrive.Neonatal hepatitis is a general term used to denote injury to the liver that occurs shortly before and/or after birth. Neonatal hepatitis may be caused by viruses, metabolic disease or genetic disorders, as well as other rare diseases that affect or impair the function of the liver. In some children, the cause of liver injury is unknown – these cases are referred to as idiopathic neonatal hepatitis (INH). The signs of idiopathic neonatal hepatitis may vary greatly from one individual to another. Findings common to liver disease often occur including yellowing of the whites of the eyes and the skin (jaundice), enlargement of the liver (hepatomegaly) and unusually dark urine. Most individuals with idiopathic neonatal hepatitis fully recover from the condition; however, some will progress to chronic liver disease. (For more information on this disorder, choose “neonatal hepatitis” as your search term in the Rare Disease Database.) | Related disorders of Galactosemia. Symptoms of the following disorders can be similar to those of galactosemia. Comparisons may be useful for a differential diagnosis:Galactokinase (GALK) deficiency is associated with cataracts, increased blood concentration of galactose and increased concentration of galactitol in the urine. Galactitol accumulates in the lens of the eye where it causes lens swelling and protein precipitation and subsequently, cataracts. GALK deficiency is an autosomal recessive genetic disorder caused by mutations in the GALK1 gene and diagnosed by reduced GALK enzyme activity.Uridine diphosphate galactose 4-epimerase (GALE) deficiency is similar to GALT deficiency when it presents in the newborn period. The severe form has been reported in only 8 patients. GALE deficiency is an autosomal recessive genetic disorder caused by mutations in the GALE gene and diagnosed by reduced GALE enzyme activity.Lactose intolerance (LI) is a metabolic disorder characterized by the inability to break down lactose, the predominant sugar found in milk and milk products. People with LI cannot properly digest lactose because they lack or are deficient in the intestinal enzyme, lactase, which is key to the digestion of lactose. Lactose is a complex sugar made up of two different sugar molecules (disaccharide), galactose and glucose, each of which is a simple (monosaccharide) sugar and more readily absorbed in the body’s intestines and processed in other organs. Individuals with a deficiency of lactase experience cramps, nausea, bloating, stomach rumbling (Borborygmi), gas (flatus) and/or diarrhea after eating or drinking lactose-rich foods, not all of which are dairy products. Signs are more severe when they occur in a newborn infant. The signs of congenital lactose intolerance are apparent soon after birth and usually include severe diarrhea, vomiting, abnormally low levels of body fluids (dehydration) and failure to thrive.Neonatal hepatitis is a general term used to denote injury to the liver that occurs shortly before and/or after birth. Neonatal hepatitis may be caused by viruses, metabolic disease or genetic disorders, as well as other rare diseases that affect or impair the function of the liver. In some children, the cause of liver injury is unknown – these cases are referred to as idiopathic neonatal hepatitis (INH). The signs of idiopathic neonatal hepatitis may vary greatly from one individual to another. Findings common to liver disease often occur including yellowing of the whites of the eyes and the skin (jaundice), enlargement of the liver (hepatomegaly) and unusually dark urine. Most individuals with idiopathic neonatal hepatitis fully recover from the condition; however, some will progress to chronic liver disease. (For more information on this disorder, choose “neonatal hepatitis” as your search term in the Rare Disease Database.) | 494 | Galactosemia |
nord_494_5 | Diagnosis of Galactosemia | Classic galactosemia and clinical variant galactosemia are diagnosed when galactose-1-phosphate is elevated in red blood cells and GALT enzyme activity is reduced. Molecular genetic testing is also available to identify mutations in the GALT gene.Nearly 100% of infants with galactosemia can be diagnosed in newborn screening programs using a blood sample from the heel stick. Infants with clinical variant galactosemia can be missed at newborn screening if GALT enzyme activity is not measured. | Diagnosis of Galactosemia. Classic galactosemia and clinical variant galactosemia are diagnosed when galactose-1-phosphate is elevated in red blood cells and GALT enzyme activity is reduced. Molecular genetic testing is also available to identify mutations in the GALT gene.Nearly 100% of infants with galactosemia can be diagnosed in newborn screening programs using a blood sample from the heel stick. Infants with clinical variant galactosemia can be missed at newborn screening if GALT enzyme activity is not measured. | 494 | Galactosemia |
nord_494_6 | Therapies of Galactosemia | Treatment
Infants and children with galactosemia should have a lactose-restricted (dairy-free) diet that contains lactose-free milk substitutes and other foods such as soybean products.A lactose tolerance test should NOT be administered to children with galactosemia. Fortunately, infants with galactosemia can synthesize galactolipids and other essential galactose-containing compounds without the presence of galactose in food. Therefore, satisfactory physical development is largely possible if a strict diet is followed.Speech therapy may be necessary for children with childhood apraxia of speech or dysarthria. For school age children, individual education plans and/or professional help with learning skills may be necessary for some individuals, depending on psychological developmental assessments. Hormone replacement therapies may also be used in cases of delayed puberty and later in adolescence for the secondary loss of menstrual periods, termed premature ovarian insufficiency (POI).Appropriate treatment (i.e., antibiotic drugs) may be used to control infection in the newborn period. The emotional effects of the strict diet may require attention and supportive measures throughout childhood.Genetic counseling is recommended for families with children who have galactosemia.Following several conferences, a consensus on the treatment and follow-up of patients with galactosemia was published in 2017. | Therapies of Galactosemia. Treatment
Infants and children with galactosemia should have a lactose-restricted (dairy-free) diet that contains lactose-free milk substitutes and other foods such as soybean products.A lactose tolerance test should NOT be administered to children with galactosemia. Fortunately, infants with galactosemia can synthesize galactolipids and other essential galactose-containing compounds without the presence of galactose in food. Therefore, satisfactory physical development is largely possible if a strict diet is followed.Speech therapy may be necessary for children with childhood apraxia of speech or dysarthria. For school age children, individual education plans and/or professional help with learning skills may be necessary for some individuals, depending on psychological developmental assessments. Hormone replacement therapies may also be used in cases of delayed puberty and later in adolescence for the secondary loss of menstrual periods, termed premature ovarian insufficiency (POI).Appropriate treatment (i.e., antibiotic drugs) may be used to control infection in the newborn period. The emotional effects of the strict diet may require attention and supportive measures throughout childhood.Genetic counseling is recommended for families with children who have galactosemia.Following several conferences, a consensus on the treatment and follow-up of patients with galactosemia was published in 2017. | 494 | Galactosemia |
nord_495_0 | Overview of Galloway-Mowat Syndrome | Galloway-Mowat syndrome is an extremely rare genetic disorder that is characterized by a variety of physical and developmental abnormalities, particularly neurological abnormalities and early onset progressive kidney disease. Physical features may include microcephaly, (a condition that indicates that the head circumference is significantly smaller than would be expected based upon an infant’s age and gender) and, in some cases, protrusion of part of the stomach through an abnormal opening in the diaphragm (hiatal hernia). Neurological abnormalities can include: various malformations of the brain, seizures, muscle spasms and abnormal movements (dystonia), diminished muscle tone throughout the body (generalized hypotonia), and visual impairment and abnormal eye movements (nystagmus). Infants and children exhibit a delay in obtaining developmental milestones. The majority of affected children do not obtain independent sitting or ambulation or the acquisition of any purposeful hand use or verbal communication. Severe/profound intellectual disability is typically present. Kidney disease is characterized by damage to the clusters of capillaries in the kidneys (focal glomerulosclerosis and/or diffuse mesangial sclerosis) resulting in loss of protein in the urine and abnormal kidney function with associated swelling of the face and peripheries resistant to current medical treatment (steroid resistant nephrotic syndrome). Most affected individuals do not survive beyond teenage years, with the commonest causes of death being nephrotic syndrome or seizures. Galloway-Mowat syndrome appears to be genetically heterogeneous and is believed to be inherited in an autosomal recessive manner, a significant proportion of cases identified to date have been shown to be caused by biallelic alterations (mutations) in the WDR73 gene.IntroductionGalloway-Mowat syndrome was first described in the medical literature in 1968 in two siblings who had microcephaly, hiatal hernia and kidney disease. Consequently, the disorder was also known as microcephaly-hiatal hernia-nephrotic syndrome. However, additional reports of this disorder have shown that affected individuals have neurological manifestations and kidney disease (nephrotic syndrome) as the main characteristics. Hiatal hernia is no longer considered a “key” feature of the disorder since it does not occur in many affected children.In 2014, autosomal recessive loss of function mutations in the WDR73 gene were found to account for a significant proportion of Galloway-Mowat syndrome cases. | Overview of Galloway-Mowat Syndrome. Galloway-Mowat syndrome is an extremely rare genetic disorder that is characterized by a variety of physical and developmental abnormalities, particularly neurological abnormalities and early onset progressive kidney disease. Physical features may include microcephaly, (a condition that indicates that the head circumference is significantly smaller than would be expected based upon an infant’s age and gender) and, in some cases, protrusion of part of the stomach through an abnormal opening in the diaphragm (hiatal hernia). Neurological abnormalities can include: various malformations of the brain, seizures, muscle spasms and abnormal movements (dystonia), diminished muscle tone throughout the body (generalized hypotonia), and visual impairment and abnormal eye movements (nystagmus). Infants and children exhibit a delay in obtaining developmental milestones. The majority of affected children do not obtain independent sitting or ambulation or the acquisition of any purposeful hand use or verbal communication. Severe/profound intellectual disability is typically present. Kidney disease is characterized by damage to the clusters of capillaries in the kidneys (focal glomerulosclerosis and/or diffuse mesangial sclerosis) resulting in loss of protein in the urine and abnormal kidney function with associated swelling of the face and peripheries resistant to current medical treatment (steroid resistant nephrotic syndrome). Most affected individuals do not survive beyond teenage years, with the commonest causes of death being nephrotic syndrome or seizures. Galloway-Mowat syndrome appears to be genetically heterogeneous and is believed to be inherited in an autosomal recessive manner, a significant proportion of cases identified to date have been shown to be caused by biallelic alterations (mutations) in the WDR73 gene.IntroductionGalloway-Mowat syndrome was first described in the medical literature in 1968 in two siblings who had microcephaly, hiatal hernia and kidney disease. Consequently, the disorder was also known as microcephaly-hiatal hernia-nephrotic syndrome. However, additional reports of this disorder have shown that affected individuals have neurological manifestations and kidney disease (nephrotic syndrome) as the main characteristics. Hiatal hernia is no longer considered a “key” feature of the disorder since it does not occur in many affected children.In 2014, autosomal recessive loss of function mutations in the WDR73 gene were found to account for a significant proportion of Galloway-Mowat syndrome cases. | 495 | Galloway-Mowat Syndrome |
nord_495_1 | Symptoms of Galloway-Mowat Syndrome | Although researchers have been able to establish a syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genetic causes aside from WDR73 and other yet undiscovered genetic factors influencing the disorder, have prevented physicians from developing a complete picture of associated symptoms and prognosis. Some researchers believe that Galloway-Mowat syndrome represents a clinically and genetically heterogeneous group of disorders, which means disorders that have different underlying causes (e.g. different aberrant genes), but that result in the same symptoms or spectrum of symptoms. Consequently, the specific symptoms present and overall severity can vary greatly from one person to another. It is important to note that affected individuals will not have all of the symptoms discussed below and every affected individual is unique. Galloway-Mowat syndrome can, in some instances, be associated with life-threatening complications very early in life. Parents should talk to the physician and medical team about their child’s specific case, associated symptoms and overall prognosis. Physical features may include malformations of the head and facial (craniofacial) area including microcephaly, which can be present at birth or develop shortly after birth, an abnormally high, narrow forehead and unusually small jaw bones (micrognathia). The head may appear flat at the top (vertex) and back (occiput). Abnormalities affecting the eyes may also occur including optic atrophy, a condition characterized by degeneration of the optic nerve, which transmit information from the retina of the eye to the brain. In some infants, part of the stomach may protrude through an abnormal opening where the esophagus passes through the diaphragm (hiatal hernia). As a result, the muscle that joins the esophagus and the stomach (esophagogastric junction) may not function appropriately, and there may be low pressure or inappropriate relaxation of the band of muscle fibers that closes the opening of the esophagus (lower esophageal sphincter). This allows the stomach's acidic contents to flow back into the esophagus (gastroesophageal reflux). Such gastroesophageal reflux may cause affected infants to spit up and/or vomit repeatedly; in some cases, vomiting may be particularly forceful (projectile vomiting). Affected infants may fail to thrive due to the resulting loss of necessary calories and nutrients. Gastroesophageal reflux may also cause inflammation of the esophagus (esophagitis); choking; closure of the larynx due to sudden, violent laryngeal contractions (laryngospasm); an inflammatory condition of the lungs caused by the entrance of food particles into the respiratory passages (aspiration pneumonia); and/or additional respiratory complications. Affected infants may also have kidney (renal) abnormalities that may be present at birth (congenital) or not develop until later in childhood. The kidney function becomes progressively impaired, and the kidneys excrete high levels of protein in to the urine (nephrotic syndrome), specifically, the protein albumin (albuminuria). This means that affected children have unusually low levels of albumin remaining in the blood (hypoalbuminemia); and exhibit anemia, weakness, an accumulation of fluid in the abdominal cavity (ascites), and/or an abnormal accumulation of fluid between layers of tissue under the skin (edema), particularly around the eye sockets (periorbital edema) and in the lowermost parts of the body, such as the ankles (dependent edema). The kidneys eventually lose their ability to excrete waste products through the urine, to regulate the balance of salt and water in the body, and to perform their other vital functions (renal failure). Affected individuals do not respond to the standard treatments for nephrotic syndrome and symptoms and disease progression worsen with intercurrent infections such as viral cold and flu.Infants with Galloway-Mowat syndrome may also exhibit various malformations of the central nervous system. Neurological symptoms can precede the development of kidney abnormalities. Affected infants may have an abnormally small brain (microcephaly) at birth, or this can develop/progress as they get older. The cerebellum, which controls the coordination of movement, may be smaller than normal. The outer layer of the brain (cerebral cortex), which is responsible for conscious movement and thought, normally consists of several deep folds (gyri) and grooves (sulci). However, in some affected infants, the outer layer of the brain may have folds that are abnormally small (microgyria), or there may be a reduced number of folds that are larger than normal (pachygyria). In other cases, the folds may be absent (agyria) or incompletely formed (lissencephaly); as a result, the brain may have a smooth surface. Neurological features may include a lack of response to stimuli in the environment and/or episodes of uncontrolled electrical disturbances in the brain that may cause convulsions, spasms, and/or other symptoms (seizures). Neuromuscular abnormalities may include diminished muscle tone throughout the body (generalized hypotonia); poor ability to control movements of the head; and/or an inability to control hand, feet, and/or eye movements, muscle spasms and abnormal movements of the limbs (dystonic and choreiform movements). Developmental abnormalities in affected infants and children may include an inability to perform certain movement (motor) skills normal for their age (e.g., sitting up, crawling, walking, and other developmental milestones) and a profound delay in the attainment of skills requiring the coordination of muscular and mental activity (psychomotor retardation). Severe intellectual disability is often present.Additional symptoms and physical features have been described in specific cases including skeletal malformations such as underdeveloped nails, clubfeet, fingers that stuck or fixed in a bent position (camptodactyly), shortening of muscle tissue and tendons in a joint, forcing the joint into a flexed or bent position (flexion contractures), malformation of the central canal of the spinal cord, underdevelopment of the thyroid and/or adrenal glands, replacement of diaphragmatic muscle tissue with fibroelastic tissue that can cause displacement of the diaphragm (eventration of the diaphragm). A brain malformation known as Dandy-Walker malformation (DWM) has been reported in a few specific cases. Individuals with Galloway-Mowat syndrome as a result of mutations in the WDR73 gene appear to have a core set of features which include: progressive microcephaly, cerebellar atrophy (progressive shrinking of the cerebellum), generalized hypotonia, severe/profound psychomotor impairment and intellectual disability and progressive nephrotic syndrome. Seizures of different types that are difficult to control and dystonia and choreiform movements have been frequently observed. | Symptoms of Galloway-Mowat Syndrome. Although researchers have been able to establish a syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genetic causes aside from WDR73 and other yet undiscovered genetic factors influencing the disorder, have prevented physicians from developing a complete picture of associated symptoms and prognosis. Some researchers believe that Galloway-Mowat syndrome represents a clinically and genetically heterogeneous group of disorders, which means disorders that have different underlying causes (e.g. different aberrant genes), but that result in the same symptoms or spectrum of symptoms. Consequently, the specific symptoms present and overall severity can vary greatly from one person to another. It is important to note that affected individuals will not have all of the symptoms discussed below and every affected individual is unique. Galloway-Mowat syndrome can, in some instances, be associated with life-threatening complications very early in life. Parents should talk to the physician and medical team about their child’s specific case, associated symptoms and overall prognosis. Physical features may include malformations of the head and facial (craniofacial) area including microcephaly, which can be present at birth or develop shortly after birth, an abnormally high, narrow forehead and unusually small jaw bones (micrognathia). The head may appear flat at the top (vertex) and back (occiput). Abnormalities affecting the eyes may also occur including optic atrophy, a condition characterized by degeneration of the optic nerve, which transmit information from the retina of the eye to the brain. In some infants, part of the stomach may protrude through an abnormal opening where the esophagus passes through the diaphragm (hiatal hernia). As a result, the muscle that joins the esophagus and the stomach (esophagogastric junction) may not function appropriately, and there may be low pressure or inappropriate relaxation of the band of muscle fibers that closes the opening of the esophagus (lower esophageal sphincter). This allows the stomach's acidic contents to flow back into the esophagus (gastroesophageal reflux). Such gastroesophageal reflux may cause affected infants to spit up and/or vomit repeatedly; in some cases, vomiting may be particularly forceful (projectile vomiting). Affected infants may fail to thrive due to the resulting loss of necessary calories and nutrients. Gastroesophageal reflux may also cause inflammation of the esophagus (esophagitis); choking; closure of the larynx due to sudden, violent laryngeal contractions (laryngospasm); an inflammatory condition of the lungs caused by the entrance of food particles into the respiratory passages (aspiration pneumonia); and/or additional respiratory complications. Affected infants may also have kidney (renal) abnormalities that may be present at birth (congenital) or not develop until later in childhood. The kidney function becomes progressively impaired, and the kidneys excrete high levels of protein in to the urine (nephrotic syndrome), specifically, the protein albumin (albuminuria). This means that affected children have unusually low levels of albumin remaining in the blood (hypoalbuminemia); and exhibit anemia, weakness, an accumulation of fluid in the abdominal cavity (ascites), and/or an abnormal accumulation of fluid between layers of tissue under the skin (edema), particularly around the eye sockets (periorbital edema) and in the lowermost parts of the body, such as the ankles (dependent edema). The kidneys eventually lose their ability to excrete waste products through the urine, to regulate the balance of salt and water in the body, and to perform their other vital functions (renal failure). Affected individuals do not respond to the standard treatments for nephrotic syndrome and symptoms and disease progression worsen with intercurrent infections such as viral cold and flu.Infants with Galloway-Mowat syndrome may also exhibit various malformations of the central nervous system. Neurological symptoms can precede the development of kidney abnormalities. Affected infants may have an abnormally small brain (microcephaly) at birth, or this can develop/progress as they get older. The cerebellum, which controls the coordination of movement, may be smaller than normal. The outer layer of the brain (cerebral cortex), which is responsible for conscious movement and thought, normally consists of several deep folds (gyri) and grooves (sulci). However, in some affected infants, the outer layer of the brain may have folds that are abnormally small (microgyria), or there may be a reduced number of folds that are larger than normal (pachygyria). In other cases, the folds may be absent (agyria) or incompletely formed (lissencephaly); as a result, the brain may have a smooth surface. Neurological features may include a lack of response to stimuli in the environment and/or episodes of uncontrolled electrical disturbances in the brain that may cause convulsions, spasms, and/or other symptoms (seizures). Neuromuscular abnormalities may include diminished muscle tone throughout the body (generalized hypotonia); poor ability to control movements of the head; and/or an inability to control hand, feet, and/or eye movements, muscle spasms and abnormal movements of the limbs (dystonic and choreiform movements). Developmental abnormalities in affected infants and children may include an inability to perform certain movement (motor) skills normal for their age (e.g., sitting up, crawling, walking, and other developmental milestones) and a profound delay in the attainment of skills requiring the coordination of muscular and mental activity (psychomotor retardation). Severe intellectual disability is often present.Additional symptoms and physical features have been described in specific cases including skeletal malformations such as underdeveloped nails, clubfeet, fingers that stuck or fixed in a bent position (camptodactyly), shortening of muscle tissue and tendons in a joint, forcing the joint into a flexed or bent position (flexion contractures), malformation of the central canal of the spinal cord, underdevelopment of the thyroid and/or adrenal glands, replacement of diaphragmatic muscle tissue with fibroelastic tissue that can cause displacement of the diaphragm (eventration of the diaphragm). A brain malformation known as Dandy-Walker malformation (DWM) has been reported in a few specific cases. Individuals with Galloway-Mowat syndrome as a result of mutations in the WDR73 gene appear to have a core set of features which include: progressive microcephaly, cerebellar atrophy (progressive shrinking of the cerebellum), generalized hypotonia, severe/profound psychomotor impairment and intellectual disability and progressive nephrotic syndrome. Seizures of different types that are difficult to control and dystonia and choreiform movements have been frequently observed. | 495 | Galloway-Mowat Syndrome |
nord_495_2 | Causes of Galloway-Mowat Syndrome | In 2014, Galloway-Mowat syndrome was shown to be caused by alterations (mutations) in the WDR73 gene in a subset of cases. 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.Galloway-Mowat syndrome is consistent with autosomal recessive inheritance. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same altered gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Although the WDR73 gene has been shown to cause Galloway-Mowat syndrome is certain cases, researchers believe that additional, as-yet-unidentified genes may cause the disorder in other cases (genetic heterogeneity). | Causes of Galloway-Mowat Syndrome. In 2014, Galloway-Mowat syndrome was shown to be caused by alterations (mutations) in the WDR73 gene in a subset of cases. 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.Galloway-Mowat syndrome is consistent with autosomal recessive inheritance. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same altered gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Although the WDR73 gene has been shown to cause Galloway-Mowat syndrome is certain cases, researchers believe that additional, as-yet-unidentified genes may cause the disorder in other cases (genetic heterogeneity). | 495 | Galloway-Mowat Syndrome |
nord_495_3 | Affects of Galloway-Mowat Syndrome | Galloway-Mowat syndrome affects males and females in equal numbers. More than 70 cases have been reported in the medical literature. Because cases may go misdiagnosed or undiagnosed, determining the true frequency of Galloway-Mowat syndrome in the general population is difficult. There is a WDR73 founder mutation present at high frequency in the Old Order Amish population, leading to an increased frequency of Galloway-Mowat syndrome within this population. | Affects of Galloway-Mowat Syndrome. Galloway-Mowat syndrome affects males and females in equal numbers. More than 70 cases have been reported in the medical literature. Because cases may go misdiagnosed or undiagnosed, determining the true frequency of Galloway-Mowat syndrome in the general population is difficult. There is a WDR73 founder mutation present at high frequency in the Old Order Amish population, leading to an increased frequency of Galloway-Mowat syndrome within this population. | 495 | Galloway-Mowat Syndrome |
nord_495_4 | Related disorders of Galloway-Mowat Syndrome | Because of the varied symptoms and presentation of Galloway-Mowat syndrome, there are many disorders that can have overlapping symptoms or similar disease expression. | Related disorders of Galloway-Mowat Syndrome. Because of the varied symptoms and presentation of Galloway-Mowat syndrome, there are many disorders that can have overlapping symptoms or similar disease expression. | 495 | Galloway-Mowat Syndrome |
nord_495_5 | Diagnosis of Galloway-Mowat Syndrome | Galloway-Mowat syndrome can be diagnosed after birth (postnatally) by a thorough clinical evaluation, characteristic physical findings, specialized laboratory tests, imaging techniques, and genetic testing. Several main symptoms associated with the disorder such as nephrotic syndrome, and a small brain (microcephaly) may be obvious at birth.Clinical Testing and Workup
In affected infants, symptoms associated with nephrotic syndrome may become apparent within days, weeks, months, or in some cases, years after birth. Urinary analysis may reveal small traces of blood (hematuria) and abnormally high levels of protein (proteinuria), specifically albumin (albuminuria), in the urine. Additional laboratory studies may reveal unusually low levels of albumin in an affected individual's blood (hypoalbuminemia). These findings, occurring in association with anemia and an abnormal accumulation of fluid that causes swelling (edema), may indicate a diagnosis of nephrotic syndrome. Detailed imaging of the brain such as magnetic resonance imaging (MRI) may reveal specific brain abnormalities seen in Galloway-Mowat syndrome such as a small cerebellum. | Diagnosis of Galloway-Mowat Syndrome. Galloway-Mowat syndrome can be diagnosed after birth (postnatally) by a thorough clinical evaluation, characteristic physical findings, specialized laboratory tests, imaging techniques, and genetic testing. Several main symptoms associated with the disorder such as nephrotic syndrome, and a small brain (microcephaly) may be obvious at birth.Clinical Testing and Workup
In affected infants, symptoms associated with nephrotic syndrome may become apparent within days, weeks, months, or in some cases, years after birth. Urinary analysis may reveal small traces of blood (hematuria) and abnormally high levels of protein (proteinuria), specifically albumin (albuminuria), in the urine. Additional laboratory studies may reveal unusually low levels of albumin in an affected individual's blood (hypoalbuminemia). These findings, occurring in association with anemia and an abnormal accumulation of fluid that causes swelling (edema), may indicate a diagnosis of nephrotic syndrome. Detailed imaging of the brain such as magnetic resonance imaging (MRI) may reveal specific brain abnormalities seen in Galloway-Mowat syndrome such as a small cerebellum. | 495 | Galloway-Mowat Syndrome |
nord_495_6 | Therapies of Galloway-Mowat Syndrome | Treatment is directed toward the specific symptoms that are apparent in each individual and may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), gastroenterologists, neurologists, surgeons, physical therapists, and/or other healthcare professionals may need to work together to ensure a systematic, comprehensive approach to treatment. Genetic counseling may be of benefit for affected individuals and their families.Treatment for nephrotic syndrome may include a low-sodium diet with low levels of protein, albumin infusion, and vitamins, thyroid and mineral supplementation. The edema associated with nephrotic syndrome may be treated with medications that promote the excretion of urine (diuretics). Drug therapy may also include antibiotics to help fight infection. Treatment with corticosteroids and/or immunosuppressive drugs has not been effective for nephrotic syndrome associated with Galloway-Mowat syndrome. In cases that progress to renal failure, hemodialysis may be required to remove excess waste products from the blood. 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. Early intervention services are important in ensuring that affected children reach their potential. Special services that may be beneficial include special remedial education, physical therapy, speech therapy, and/or other medical, social, and/or vocational services.
Additional treatment for this disorder is symptom specific and supportive. Specific symptoms associated with Galloway-Mowat syndrome are treated by routine, accepted guidelines. Surgery may be necessary for certain symptoms such as hiatal hernia. Therapy with anti-seizure (anticonvulsant) drugs may be prescribed for affected individuals who experience seizures to help prevent, reduce, or control seizures. Because affected individuals may be receiving other drugs that may prohibit the use of certain anticonvulsant medications, each patient's case must be thoroughly coordinated by the physician team to determine the most appropriate therapies for each group of symptoms. | Therapies of Galloway-Mowat Syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual and may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), gastroenterologists, neurologists, surgeons, physical therapists, and/or other healthcare professionals may need to work together to ensure a systematic, comprehensive approach to treatment. Genetic counseling may be of benefit for affected individuals and their families.Treatment for nephrotic syndrome may include a low-sodium diet with low levels of protein, albumin infusion, and vitamins, thyroid and mineral supplementation. The edema associated with nephrotic syndrome may be treated with medications that promote the excretion of urine (diuretics). Drug therapy may also include antibiotics to help fight infection. Treatment with corticosteroids and/or immunosuppressive drugs has not been effective for nephrotic syndrome associated with Galloway-Mowat syndrome. In cases that progress to renal failure, hemodialysis may be required to remove excess waste products from the blood. 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. Early intervention services are important in ensuring that affected children reach their potential. Special services that may be beneficial include special remedial education, physical therapy, speech therapy, and/or other medical, social, and/or vocational services.
Additional treatment for this disorder is symptom specific and supportive. Specific symptoms associated with Galloway-Mowat syndrome are treated by routine, accepted guidelines. Surgery may be necessary for certain symptoms such as hiatal hernia. Therapy with anti-seizure (anticonvulsant) drugs may be prescribed for affected individuals who experience seizures to help prevent, reduce, or control seizures. Because affected individuals may be receiving other drugs that may prohibit the use of certain anticonvulsant medications, each patient's case must be thoroughly coordinated by the physician team to determine the most appropriate therapies for each group of symptoms. | 495 | Galloway-Mowat Syndrome |
nord_496_0 | Overview of Gastritis, Chronic, Erosive | Chronic, Erosive Gastritis is characterized by many inflamed lesions in the mucous lining of the stomach. It may be a transitory or a chronic condition lasting for years. | Overview of Gastritis, Chronic, Erosive. Chronic, Erosive Gastritis is characterized by many inflamed lesions in the mucous lining of the stomach. It may be a transitory or a chronic condition lasting for years. | 496 | Gastritis, Chronic, Erosive |
nord_496_1 | Symptoms of Gastritis, Chronic, Erosive | Chronic, Erosive Gastritis is an inflammation of the stomach characterized by multiple lesions in the mucous lining causing ulcer-like symptoms. These symptoms may include a burning and heavy feeling in the pit of the stomach, mild nausea, vomiting, loss of appetite and weakness. In severe cases there can be bleeding of the stomach which may result in anemia. Some people with this disorder, especially chronic aspirin users, may show no apparent symptoms until the disease has advanced. An accurate diagnosis can be made by physician's visual inspection of the stomach using a gastroscope. | Symptoms of Gastritis, Chronic, Erosive. Chronic, Erosive Gastritis is an inflammation of the stomach characterized by multiple lesions in the mucous lining causing ulcer-like symptoms. These symptoms may include a burning and heavy feeling in the pit of the stomach, mild nausea, vomiting, loss of appetite and weakness. In severe cases there can be bleeding of the stomach which may result in anemia. Some people with this disorder, especially chronic aspirin users, may show no apparent symptoms until the disease has advanced. An accurate diagnosis can be made by physician's visual inspection of the stomach using a gastroscope. | 496 | Gastritis, Chronic, Erosive |
nord_496_2 | Causes of Gastritis, Chronic, Erosive | The exact cause of Chronic, Erosive Gastritis is unknown. It may be the result of an infection, over indulgence of alcohol, or persistent use of aspirin or non-steroidal anti-inflammatory medications such as ibuprofen. Stress tends to make symptoms worse. Crohn's disease and Sarcoidosis have been known to be factors in some cases of Chronic, Erosive Gastritis, while some cases have no apparent cause at all. | Causes of Gastritis, Chronic, Erosive. The exact cause of Chronic, Erosive Gastritis is unknown. It may be the result of an infection, over indulgence of alcohol, or persistent use of aspirin or non-steroidal anti-inflammatory medications such as ibuprofen. Stress tends to make symptoms worse. Crohn's disease and Sarcoidosis have been known to be factors in some cases of Chronic, Erosive Gastritis, while some cases have no apparent cause at all. | 496 | Gastritis, Chronic, Erosive |
nord_496_3 | Affects of Gastritis, Chronic, Erosive | Chronic, Erosive Gastritis usually occurs during middle age and is more common in males than females. Alcoholics and chronic aspirin or ibuprofen users (e.g. people with arthritis) are more susceptible to this disorder. | Affects of Gastritis, Chronic, Erosive. Chronic, Erosive Gastritis usually occurs during middle age and is more common in males than females. Alcoholics and chronic aspirin or ibuprofen users (e.g. people with arthritis) are more susceptible to this disorder. | 496 | Gastritis, Chronic, Erosive |
nord_496_4 | Related disorders of Gastritis, Chronic, Erosive | The following disorders may have symptoms similar to Chronic, Erosive Gastritis. Comparisons may be useful for a differential diagnosis:Crohn's Disease, also known as ileitis, regional enteritis, or granulomatous colitis is a form of inflammatory bowel disease characterized by severe, often granulomatous, chronic inflammation of the wall of the gastrointestinal tract. In most cases, a segment of the intestines called the ileum. Crohn's disease can be difficult to manage. Mortality due to the disease itself, or to complications from the disease, is low. (For more information on this disorder, choose “Crohn's” as your search term in the Rare Disease Database.)Acute Erosive Gastritis is an inflammation of the stomach characterized by lesions in the mucous membranes of the stomach and ulcer-like symptoms. This type of Gastritis is caused by a variety of stresses such as major trauma, multiple injuries or serious burns.Peptic Ulcer is a common disorder usually characterized by a single lesion of the mucous membranes of the esophagus, stomach or duodenum. These lesions may be caused by an over secretion of acid or pepsin and are characterized by pain, heartburn, nausea and vomiting.Zollinger-Ellison Syndrome is a rare condition characterized by stomach ulcers and small tumors (usually of the pancreas) which secrete a hormone that produces excessive amounts of gastric juices in the stomach. These tumors can also appear in the lower stomach wall, spleen or lymph nodes close to the stomach. Large amounts of gastric acid can be found in lower stomach areas where ulcers can form. Ulcers can appear suddenly even in areas where they are rarely found, may persist following treatment, and can be accompanied by diarrhea. Prompt medical treatment of these ulcers is necessary to prevent complications such as bleeding and perforation. (For more information on this disorder, choose “Zollinger-Ellison” as your search term in the Rare Disease Database.) | Related disorders of Gastritis, Chronic, Erosive. The following disorders may have symptoms similar to Chronic, Erosive Gastritis. Comparisons may be useful for a differential diagnosis:Crohn's Disease, also known as ileitis, regional enteritis, or granulomatous colitis is a form of inflammatory bowel disease characterized by severe, often granulomatous, chronic inflammation of the wall of the gastrointestinal tract. In most cases, a segment of the intestines called the ileum. Crohn's disease can be difficult to manage. Mortality due to the disease itself, or to complications from the disease, is low. (For more information on this disorder, choose “Crohn's” as your search term in the Rare Disease Database.)Acute Erosive Gastritis is an inflammation of the stomach characterized by lesions in the mucous membranes of the stomach and ulcer-like symptoms. This type of Gastritis is caused by a variety of stresses such as major trauma, multiple injuries or serious burns.Peptic Ulcer is a common disorder usually characterized by a single lesion of the mucous membranes of the esophagus, stomach or duodenum. These lesions may be caused by an over secretion of acid or pepsin and are characterized by pain, heartburn, nausea and vomiting.Zollinger-Ellison Syndrome is a rare condition characterized by stomach ulcers and small tumors (usually of the pancreas) which secrete a hormone that produces excessive amounts of gastric juices in the stomach. These tumors can also appear in the lower stomach wall, spleen or lymph nodes close to the stomach. Large amounts of gastric acid can be found in lower stomach areas where ulcers can form. Ulcers can appear suddenly even in areas where they are rarely found, may persist following treatment, and can be accompanied by diarrhea. Prompt medical treatment of these ulcers is necessary to prevent complications such as bleeding and perforation. (For more information on this disorder, choose “Zollinger-Ellison” as your search term in the Rare Disease Database.) | 496 | Gastritis, Chronic, Erosive |
nord_496_5 | Diagnosis of Gastritis, Chronic, Erosive | Diagnosis of Gastritis, Chronic, Erosive. | 496 | Gastritis, Chronic, Erosive |
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nord_496_6 | Therapies of Gastritis, Chronic, Erosive | Because Chronic, Erosive Gastritis may cause symptoms similar to other gastrointestinal disorders, a full medical history must be known before an effective treatment can be determined. Most cases are usually treated with acid neutralizing medications (antacids) and H2 blocker drugs such as Zantac (ranitidine) or Tagamet (cimetidine). Dietary changes and avoiding the irritating causes such as stomach irritating drugs or stressful situations are also helpful in eliminating the symptoms of Chronic, Erosive Gastritis.The prostaglandin E1 analog drug, Cytotec (misoprostol) has proven to be an effective preventative medication for gastric lesions associated with high-dose aspirin or ibuprofen therapy. This drug is effective in healing the gastric mucosal lesions without altering the therapeutic benefits of the non-steroidal anti-inflammatory drugs given to arthritis patients. Misoprostol can have severe effects on a developing fetus and must be administered with extreme caution. Other treatment is symptomatic and supportive. | Therapies of Gastritis, Chronic, Erosive. Because Chronic, Erosive Gastritis may cause symptoms similar to other gastrointestinal disorders, a full medical history must be known before an effective treatment can be determined. Most cases are usually treated with acid neutralizing medications (antacids) and H2 blocker drugs such as Zantac (ranitidine) or Tagamet (cimetidine). Dietary changes and avoiding the irritating causes such as stomach irritating drugs or stressful situations are also helpful in eliminating the symptoms of Chronic, Erosive Gastritis.The prostaglandin E1 analog drug, Cytotec (misoprostol) has proven to be an effective preventative medication for gastric lesions associated with high-dose aspirin or ibuprofen therapy. This drug is effective in healing the gastric mucosal lesions without altering the therapeutic benefits of the non-steroidal anti-inflammatory drugs given to arthritis patients. Misoprostol can have severe effects on a developing fetus and must be administered with extreme caution. Other treatment is symptomatic and supportive. | 496 | Gastritis, Chronic, Erosive |
nord_497_0 | Overview of Gastrointestinal Stromal Tumors | SummaryGastrointestinal stromal tumors (GISTs) are among a group of cancers known as sarcomas. The number of new cases in the United States each year has been estimated at 5,000–6,000. These tumors arise from nerve cells in the wall of the gastrointestinal (GI) tract and can occur anywhere from the esophagus to the rectum. However, most arise in the stomach (55%) and the small intestine (29%), while the colon/rectum (3%) and esophagus (0.5%) are less common sites of the disease. There have also been rare reports of tumors arising in the appendix, pancreas, gallbladder, and lining of the abdominal cavity.These tumors most commonly present with non-specific symptoms, including feeling full sooner than normal after eating (early satiety) and abdominal pain, but may also present with bleeding or signs of intestinal obstruction. They spread most commonly to sites within the abdominal cavity and to the liver, although certain subtypes spread to lymph nodes and very rare cases spread to the lungs and bone. Although it was previously believed that some cases of GIST are benign (do not spread), it is now understood that all GISTs have some potential to metastasize, with risk ranging from very low to high. A better understanding of GIST biology has also revealed that its prevalence varies across racial and ethnic groups.Most GISTs result from a non-inherited change (mutation) in one of two genes, KIT or PDGFRA, which leads to inappropriate and ongoing division of tumor cells. However, approximately 10%–15% of cases of GIST in adults and 85% of cases in children are not associated with mutations in either the KIT or PDGFRA genes. These previously uncategorized cases were originally grouped under the umbrella terms “wild-type GIST” and “pediatric-like GIST.” Advances in research have since revealed that these tumors have mutations in as many as 20 other genes, and defining the specific mutations in individual patients can help guide further research and treatment.Most GIST-causing mutations arise randomly and are not inherited. However, there are rare cases in which a gene mutation is inherited, for example in succinate dehydrogenase (SDH)-deficient GIST associated with Carney–Stratakis syndrome (CSS; also known as GIST-paraganglioma syndrome). Though most GIST arise in older adults, these rarer cases of inherited GIST often present in children, adolescents, and young adults.GIST is most commonly diagnosed by pathological analysis of biopsy tissue taken during an endoscopy or through the skin. Computed tomography (CT) and magnetic resonance (MR) imaging are also used to diagnose GIST and determine the location and extent of the tumor. Molecular characterization of the tumor, through identification of specific gene mutations or the presence of markers on the tumor surface, provides further information for diagnosis and can help guide treatment.Surgical removal is the most common treatment for GIST that has not spread, and an operation provides the best chance of a cure if the tumor is completely removed. In cases where the tumor has spread, oral chemotherapy (i.e., pills) is usually indicated in conjunction with surgery. The most frequently used drugs are tyrosine kinase inhibitors (e.g., Gleevec), which target the commonly observed mutations in KIT and PDFGRA. Patients respond differently to the range of available tyrosine kinase inhibitors, so it can be useful to test for specific mutations in the tumor when selecting a course of therapy. Clinical trials are also underway to target subtypes of GIST with rare genetic abnormalities. Finally, it is noteworthy that there is no role for radiation therapy in the management of GIST.OverviewGISTs belong to the family of sarcomas, which are malignant tumors that arise from various tissues, including fat, muscle, nerves, cartilage, bone, blood vessels, and lymphatic vessels. This distinguishes sarcomas from carcinomas, which arise from the lining of organs/tissues (e.g., lung, colon, breast, prostate, and pancreas), lymphomas, which arise from immune cells in lymph nodes, and leukemias, which arise from immune cells in the bone marrow.Until the late 1990s, the diagnosis of GIST did not exist. We now know that GISTs are the most common sarcomas and that these tumors arise from the interstitial cells of Cajal (ICC), pacemaker cells in the wall of the bowel that regulate the muscular contractions that help propel food through the digestive system (peristalsis). Recently, cells called telocytes have been postulated as an additional source of some GISTs. Overall, GISTs are molecularly heterogeneous, with their genetic traits linked to tumor location, prognosis, and pattern of spread, as well as drug sensitivity and resistance. | Overview of Gastrointestinal Stromal Tumors. SummaryGastrointestinal stromal tumors (GISTs) are among a group of cancers known as sarcomas. The number of new cases in the United States each year has been estimated at 5,000–6,000. These tumors arise from nerve cells in the wall of the gastrointestinal (GI) tract and can occur anywhere from the esophagus to the rectum. However, most arise in the stomach (55%) and the small intestine (29%), while the colon/rectum (3%) and esophagus (0.5%) are less common sites of the disease. There have also been rare reports of tumors arising in the appendix, pancreas, gallbladder, and lining of the abdominal cavity.These tumors most commonly present with non-specific symptoms, including feeling full sooner than normal after eating (early satiety) and abdominal pain, but may also present with bleeding or signs of intestinal obstruction. They spread most commonly to sites within the abdominal cavity and to the liver, although certain subtypes spread to lymph nodes and very rare cases spread to the lungs and bone. Although it was previously believed that some cases of GIST are benign (do not spread), it is now understood that all GISTs have some potential to metastasize, with risk ranging from very low to high. A better understanding of GIST biology has also revealed that its prevalence varies across racial and ethnic groups.Most GISTs result from a non-inherited change (mutation) in one of two genes, KIT or PDGFRA, which leads to inappropriate and ongoing division of tumor cells. However, approximately 10%–15% of cases of GIST in adults and 85% of cases in children are not associated with mutations in either the KIT or PDGFRA genes. These previously uncategorized cases were originally grouped under the umbrella terms “wild-type GIST” and “pediatric-like GIST.” Advances in research have since revealed that these tumors have mutations in as many as 20 other genes, and defining the specific mutations in individual patients can help guide further research and treatment.Most GIST-causing mutations arise randomly and are not inherited. However, there are rare cases in which a gene mutation is inherited, for example in succinate dehydrogenase (SDH)-deficient GIST associated with Carney–Stratakis syndrome (CSS; also known as GIST-paraganglioma syndrome). Though most GIST arise in older adults, these rarer cases of inherited GIST often present in children, adolescents, and young adults.GIST is most commonly diagnosed by pathological analysis of biopsy tissue taken during an endoscopy or through the skin. Computed tomography (CT) and magnetic resonance (MR) imaging are also used to diagnose GIST and determine the location and extent of the tumor. Molecular characterization of the tumor, through identification of specific gene mutations or the presence of markers on the tumor surface, provides further information for diagnosis and can help guide treatment.Surgical removal is the most common treatment for GIST that has not spread, and an operation provides the best chance of a cure if the tumor is completely removed. In cases where the tumor has spread, oral chemotherapy (i.e., pills) is usually indicated in conjunction with surgery. The most frequently used drugs are tyrosine kinase inhibitors (e.g., Gleevec), which target the commonly observed mutations in KIT and PDFGRA. Patients respond differently to the range of available tyrosine kinase inhibitors, so it can be useful to test for specific mutations in the tumor when selecting a course of therapy. Clinical trials are also underway to target subtypes of GIST with rare genetic abnormalities. Finally, it is noteworthy that there is no role for radiation therapy in the management of GIST.OverviewGISTs belong to the family of sarcomas, which are malignant tumors that arise from various tissues, including fat, muscle, nerves, cartilage, bone, blood vessels, and lymphatic vessels. This distinguishes sarcomas from carcinomas, which arise from the lining of organs/tissues (e.g., lung, colon, breast, prostate, and pancreas), lymphomas, which arise from immune cells in lymph nodes, and leukemias, which arise from immune cells in the bone marrow.Until the late 1990s, the diagnosis of GIST did not exist. We now know that GISTs are the most common sarcomas and that these tumors arise from the interstitial cells of Cajal (ICC), pacemaker cells in the wall of the bowel that regulate the muscular contractions that help propel food through the digestive system (peristalsis). Recently, cells called telocytes have been postulated as an additional source of some GISTs. Overall, GISTs are molecularly heterogeneous, with their genetic traits linked to tumor location, prognosis, and pattern of spread, as well as drug sensitivity and resistance. | 497 | Gastrointestinal Stromal Tumors |
nord_497_1 | Symptoms of Gastrointestinal Stromal Tumors | GIST can present with a wide spectrum of subjective symptoms, such as nausea, early satiety, bloating, and weight loss. Patients can also experience objective signs of a tumor, such as anemia (low red blood cell count) or a lump in the abdomen. These signs and symptoms depend on the tumor location (e.g., stomach versus rectum), size, and pattern of growth. The most common site of origin is in the stomach (~55%), and these tumors are often associated with pain, GI bleeding, and/or a mass that can be seen or felt (palpable). Other primary sites are the small intestine (~29%), the colon and rectum (~3%), and the esophagus (~0.5%). Rarely, cases of so-called extra-intestinal GIST (E-GIST) have been reported to occur outside the bowel, along the lining of the abdomen or within the abdominal fat. Tumors present visually as discrete masses. GI bleeding can lead to anemia, which can cause paleness, lightheadedness, fatigue, and other symptoms. Patients presenting with tumors of these sites may also experience weight loss, fever, abscess, and/or urinary symptoms. There are rare cases presenting in the lowest third of the esophagus, which can cause difficulty with swallowing and resultant weight loss.The primary site of the tumor may be a prognostic factor, with small intestinal GIST having a poorer survival rate than that originating in the stomach (though this notion has been questioned in recent studies). In addition, intestinal location has been correlated with a high risk of spread (metastases). Approximately 75%–90% of GISTs are limited to one site upon diagnosis. GIST spreads most commonly to sites within the abdominal cavity and to the liver, although there are rare cases that have spread to the lungs and bone. GIST rarely spreads to the lymph nodes. Although some cases of GIST were previously thought to be benign, it is now known that all GISTs have the potential to spread. This risk is dependent on the tumor location and size, as well as the number of cells that are dividing (i.e., mitotic index), as counted by a pathologist using a microscope.GIST in children and adolescents
GIST is extremely rare in children and adolescents, and the symptoms and pathology in these age groups are different from those in most adults. These cases generally present in the stomach, are more likely to show lymph node involvement, and are more likely to spread to the liver and abdominal lining. They are usually not associated with the KIT or PDGFRA gene mutations found in most adults, and about 80% of these cases have a hereditary mutation of the gene for the succinate dehydrogenase (SDH) enzyme complex. Patients with these SDH-deficient tumors most often have an accompanying diagnosis of hormone-secreting paraganglioma in a condition known as Carney–Stratakis syndrome (CSS). Thus, patients should be screened for neck and chest paragangliomas, and also assessed for the presence of specific hormone metabolites in urine (catecholamines and metanephrines). It was previously believed that age was a determining factor in the differences between cases of GIST affecting adults versus children, and cases in children were distinguished as “pediatric-type” GIST or “wild-type” GIST. However, some adult cases of GIST share the distinct characteristics found in most pediatric cases, rendering the separation of these cases based on age unwarranted and somewhat of a misnomer. It is now best to discuss GIST subtypes based upon the specific characteristics of the tumor. | Symptoms of Gastrointestinal Stromal Tumors. GIST can present with a wide spectrum of subjective symptoms, such as nausea, early satiety, bloating, and weight loss. Patients can also experience objective signs of a tumor, such as anemia (low red blood cell count) or a lump in the abdomen. These signs and symptoms depend on the tumor location (e.g., stomach versus rectum), size, and pattern of growth. The most common site of origin is in the stomach (~55%), and these tumors are often associated with pain, GI bleeding, and/or a mass that can be seen or felt (palpable). Other primary sites are the small intestine (~29%), the colon and rectum (~3%), and the esophagus (~0.5%). Rarely, cases of so-called extra-intestinal GIST (E-GIST) have been reported to occur outside the bowel, along the lining of the abdomen or within the abdominal fat. Tumors present visually as discrete masses. GI bleeding can lead to anemia, which can cause paleness, lightheadedness, fatigue, and other symptoms. Patients presenting with tumors of these sites may also experience weight loss, fever, abscess, and/or urinary symptoms. There are rare cases presenting in the lowest third of the esophagus, which can cause difficulty with swallowing and resultant weight loss.The primary site of the tumor may be a prognostic factor, with small intestinal GIST having a poorer survival rate than that originating in the stomach (though this notion has been questioned in recent studies). In addition, intestinal location has been correlated with a high risk of spread (metastases). Approximately 75%–90% of GISTs are limited to one site upon diagnosis. GIST spreads most commonly to sites within the abdominal cavity and to the liver, although there are rare cases that have spread to the lungs and bone. GIST rarely spreads to the lymph nodes. Although some cases of GIST were previously thought to be benign, it is now known that all GISTs have the potential to spread. This risk is dependent on the tumor location and size, as well as the number of cells that are dividing (i.e., mitotic index), as counted by a pathologist using a microscope.GIST in children and adolescents
GIST is extremely rare in children and adolescents, and the symptoms and pathology in these age groups are different from those in most adults. These cases generally present in the stomach, are more likely to show lymph node involvement, and are more likely to spread to the liver and abdominal lining. They are usually not associated with the KIT or PDGFRA gene mutations found in most adults, and about 80% of these cases have a hereditary mutation of the gene for the succinate dehydrogenase (SDH) enzyme complex. Patients with these SDH-deficient tumors most often have an accompanying diagnosis of hormone-secreting paraganglioma in a condition known as Carney–Stratakis syndrome (CSS). Thus, patients should be screened for neck and chest paragangliomas, and also assessed for the presence of specific hormone metabolites in urine (catecholamines and metanephrines). It was previously believed that age was a determining factor in the differences between cases of GIST affecting adults versus children, and cases in children were distinguished as “pediatric-type” GIST or “wild-type” GIST. However, some adult cases of GIST share the distinct characteristics found in most pediatric cases, rendering the separation of these cases based on age unwarranted and somewhat of a misnomer. It is now best to discuss GIST subtypes based upon the specific characteristics of the tumor. | 497 | Gastrointestinal Stromal Tumors |
nord_497_2 | Causes of Gastrointestinal Stromal Tumors | Current research suggests that genetic abnormalities (mutations) underlie the processes by which cells become cancerous. Specifically, malignancies most often develop due to mutations in genes known as “oncogenes” or “tumor suppressor genes.” Oncogenes promote cell division, while tumor suppressor genes block cell division and ensure that cells die at the proper time; abnormalities of either type of gene can contribute to cancer development. In the case of GIST, the majority of tumors have mutations in the KIT oncogene and a minority have mutations in the PDGFRA oncogene. Both of the genes encode proteins called tyrosine kinases, a finding that has been critical for better understanding and treating the disease. Most of these cancer-causing mutations are acquired during life, rather than being inherited, and are found only in the cancerous cells. There is no environmental exposure or infection that is known to predispose individuals to GIST and the relevant mutations most often happen randomly (sporadically) rather than being inherited. There are also common sites for mutations for each. For the KIT gene, the most common mutation site is in exon 11, but can also involve exons 9, 13/14, and 17/18. Mutations in the PDGFRA gene involve exon 12 or 18. The term exon refers to the regions of a gene that contain the code for producing the gene’s protein, and are used to delineate different regions of a gene. Though very rare, a few families with inherited mutations of the KIT gene have been described. They experience early onset of GIST in adolescence or young adulthood. Some of these families have altered skin pigmentation or difficult swallowing (dysphagia). In addition, at least one family has been described with an inherited mutation of the PDGFRA gene. Inherited cases are rare and are known as familial GIST.There are also instances of GIST that do not have mutations of the KIT or PDGFRA genes. Most of these cases have been linked to mutations in the genes that encode the succinate dehydrogenase (SDH) enzyme complex (i.e., SDHA, SDHB, SDHC, or SDHD). These mutations lead to loss of the SDH complex and lack of SDHB protein staining in tumors. These SDH-deficient GISTs are clinically distinct in that they generally affect younger patients and are associated with additional tumors in two syndromes known as Carney–Stratakis syndrome (CSS) and Carney triad. CSS is a hereditary condition in which the gene sequence of an SDH gene is mutated. Carney triad, on the other hand, is a non-hereditary condition in which the DNA code is not affected, but the DNA structure of the SDHC gene is modified by a process called methylation (also known as epigenetic mutation). Because SDH-deficient GISTs are not caused by KIT or PDGFRA mutations, they are generally resistant to tyrosine kinase inhibitors.Additional gene mutations have also been linked to GIST, including in the BRAF, KRAS, and NF1 genes of the RAS/MAPK pathway. While BRAF and KRAS are not associated with inherited GIST, inherited mutations in the NF1 gene lead to a disorder called neurofibromatosis type 1, which is associated with greater risk of GIST. These cases usually present as multiple tumors in the small intestine. There is also emerging evidence that, even in the absence of inherited NF-1 mutations, specific BRAF and NF1 mutations frequently occur in GISTs of the proximal small bowel (known as the duodenal-jejunal flexure or ligament of Treitz). These findings are important because these mutations do not respond to standard drug treatments.Some cases of GIST were previously called “quadruple wild-type” GIST, as they lacked mutations in the KIT, PDGFRA, RAS pathway (KRAS, NF1, BRAF), and SDH genes. Because this designation was based on the absence of identifiable gene mutations, it was believed that additional genes were responsible for these “unclassified” cases. In recent years, studies have identified a number of new genetic aberrations associated with GIST. These include gene fusions, in which a hybrid forms from two previously independent genes. Various GIST-associated fusions have been identified that include the FGFR1 gene, the ETV6–NTRK3 fusion, and the BRAF gene. Importantly, these GIST subtypes respond differently to the available drug treatments, highlighting the importance of understanding the specific biology of individual tumors. | Causes of Gastrointestinal Stromal Tumors. Current research suggests that genetic abnormalities (mutations) underlie the processes by which cells become cancerous. Specifically, malignancies most often develop due to mutations in genes known as “oncogenes” or “tumor suppressor genes.” Oncogenes promote cell division, while tumor suppressor genes block cell division and ensure that cells die at the proper time; abnormalities of either type of gene can contribute to cancer development. In the case of GIST, the majority of tumors have mutations in the KIT oncogene and a minority have mutations in the PDGFRA oncogene. Both of the genes encode proteins called tyrosine kinases, a finding that has been critical for better understanding and treating the disease. Most of these cancer-causing mutations are acquired during life, rather than being inherited, and are found only in the cancerous cells. There is no environmental exposure or infection that is known to predispose individuals to GIST and the relevant mutations most often happen randomly (sporadically) rather than being inherited. There are also common sites for mutations for each. For the KIT gene, the most common mutation site is in exon 11, but can also involve exons 9, 13/14, and 17/18. Mutations in the PDGFRA gene involve exon 12 or 18. The term exon refers to the regions of a gene that contain the code for producing the gene’s protein, and are used to delineate different regions of a gene. Though very rare, a few families with inherited mutations of the KIT gene have been described. They experience early onset of GIST in adolescence or young adulthood. Some of these families have altered skin pigmentation or difficult swallowing (dysphagia). In addition, at least one family has been described with an inherited mutation of the PDGFRA gene. Inherited cases are rare and are known as familial GIST.There are also instances of GIST that do not have mutations of the KIT or PDGFRA genes. Most of these cases have been linked to mutations in the genes that encode the succinate dehydrogenase (SDH) enzyme complex (i.e., SDHA, SDHB, SDHC, or SDHD). These mutations lead to loss of the SDH complex and lack of SDHB protein staining in tumors. These SDH-deficient GISTs are clinically distinct in that they generally affect younger patients and are associated with additional tumors in two syndromes known as Carney–Stratakis syndrome (CSS) and Carney triad. CSS is a hereditary condition in which the gene sequence of an SDH gene is mutated. Carney triad, on the other hand, is a non-hereditary condition in which the DNA code is not affected, but the DNA structure of the SDHC gene is modified by a process called methylation (also known as epigenetic mutation). Because SDH-deficient GISTs are not caused by KIT or PDGFRA mutations, they are generally resistant to tyrosine kinase inhibitors.Additional gene mutations have also been linked to GIST, including in the BRAF, KRAS, and NF1 genes of the RAS/MAPK pathway. While BRAF and KRAS are not associated with inherited GIST, inherited mutations in the NF1 gene lead to a disorder called neurofibromatosis type 1, which is associated with greater risk of GIST. These cases usually present as multiple tumors in the small intestine. There is also emerging evidence that, even in the absence of inherited NF-1 mutations, specific BRAF and NF1 mutations frequently occur in GISTs of the proximal small bowel (known as the duodenal-jejunal flexure or ligament of Treitz). These findings are important because these mutations do not respond to standard drug treatments.Some cases of GIST were previously called “quadruple wild-type” GIST, as they lacked mutations in the KIT, PDGFRA, RAS pathway (KRAS, NF1, BRAF), and SDH genes. Because this designation was based on the absence of identifiable gene mutations, it was believed that additional genes were responsible for these “unclassified” cases. In recent years, studies have identified a number of new genetic aberrations associated with GIST. These include gene fusions, in which a hybrid forms from two previously independent genes. Various GIST-associated fusions have been identified that include the FGFR1 gene, the ETV6–NTRK3 fusion, and the BRAF gene. Importantly, these GIST subtypes respond differently to the available drug treatments, highlighting the importance of understanding the specific biology of individual tumors. | 497 | Gastrointestinal Stromal Tumors |
nord_497_3 | Affects of Gastrointestinal Stromal Tumors | The exact incidence and prevalence of GIST are unknown, but estimates range from 3.2–19 people per million in the general population. GISTs are the most common sarcomas of the GI tract, though they account for only a small fraction of all GI cancers. The typical GIST patient presents in the fifth to seventh decade of life, with some studies suggesting that males are affected more often than females. Children have also been found to present with GIST, but these cases are very rare and usually occur as SDH-deficient GIST in the setting of CSS (males or females) or Carney triad (females only). The disease in children may have a slower time course, but this is not always so; in rare cases, the disease may be more aggressive. As a better understanding of GIST biology has emerged, and potential links between the incidence of GIST and ethnic backgrounds have been revealed. In the U.S., the highest rate is within the black population, followed by Asian/Pacific Islanders, whites, and Hispanics. | Affects of Gastrointestinal Stromal Tumors. The exact incidence and prevalence of GIST are unknown, but estimates range from 3.2–19 people per million in the general population. GISTs are the most common sarcomas of the GI tract, though they account for only a small fraction of all GI cancers. The typical GIST patient presents in the fifth to seventh decade of life, with some studies suggesting that males are affected more often than females. Children have also been found to present with GIST, but these cases are very rare and usually occur as SDH-deficient GIST in the setting of CSS (males or females) or Carney triad (females only). The disease in children may have a slower time course, but this is not always so; in rare cases, the disease may be more aggressive. As a better understanding of GIST biology has emerged, and potential links between the incidence of GIST and ethnic backgrounds have been revealed. In the U.S., the highest rate is within the black population, followed by Asian/Pacific Islanders, whites, and Hispanics. | 497 | Gastrointestinal Stromal Tumors |
nord_497_4 | Related disorders of Gastrointestinal Stromal Tumors | Related disorders of Gastrointestinal Stromal Tumors. | 497 | Gastrointestinal Stromal Tumors |
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nord_497_5 | Diagnosis of Gastrointestinal Stromal Tumors | GIST diagnosis can be confirmed by biopsy during endoscopy or by percutaneous biopsy (through the skin). The use of endoscopic ultrasound for lesions in the stomach can be helpful, as these tumors can be below the surface of the stomach and therefore not seen by standard endoscopy. If tumors are larger than 2 cm, a biopsy suggesting a benign lesion should be interpreted with caution.Most patients undergo a computed tomography (CT) or magnetic resonance imaging (MRI) scan to determine the extent of the tumor involved. It is most important to image the abdomen and pelvis, as the most common sites of spread are within the abdominal cavity and the liver. PET/CT scanning may be helpful as an additional test in cases where there is diagnostic uncertainty; however, it is not routinely performed.The molecular characteristics of a tumor can also help identify it as GIST. As indicated above, genetic mutations in the KIT, PDGFRA, or SDH genes are present in most cases of GIST and their presence can be used for diagnosis. A growing number of rarer mutations have also been discovered, meaning that gene-based diagnosis of GIST is becoming increasingly sensitive. In addition, markers (antigens) on the surface of cancer cells can help classify them as GIST. For example, researchers have discovered that most GIST cells have the marker CD117 on their surface. CD117 is the protein product of the KIT gene, which is commonly mutated in GIST. A different marker, DOG1 (so-named because it was Discovered On GIST), is also present on the vast majority of GISTs, but not always overlapping with CD117. As a result, a tumor that is positive for both CD117 and DOG1 has over 97% likelihood of being GIST. | Diagnosis of Gastrointestinal Stromal Tumors. GIST diagnosis can be confirmed by biopsy during endoscopy or by percutaneous biopsy (through the skin). The use of endoscopic ultrasound for lesions in the stomach can be helpful, as these tumors can be below the surface of the stomach and therefore not seen by standard endoscopy. If tumors are larger than 2 cm, a biopsy suggesting a benign lesion should be interpreted with caution.Most patients undergo a computed tomography (CT) or magnetic resonance imaging (MRI) scan to determine the extent of the tumor involved. It is most important to image the abdomen and pelvis, as the most common sites of spread are within the abdominal cavity and the liver. PET/CT scanning may be helpful as an additional test in cases where there is diagnostic uncertainty; however, it is not routinely performed.The molecular characteristics of a tumor can also help identify it as GIST. As indicated above, genetic mutations in the KIT, PDGFRA, or SDH genes are present in most cases of GIST and their presence can be used for diagnosis. A growing number of rarer mutations have also been discovered, meaning that gene-based diagnosis of GIST is becoming increasingly sensitive. In addition, markers (antigens) on the surface of cancer cells can help classify them as GIST. For example, researchers have discovered that most GIST cells have the marker CD117 on their surface. CD117 is the protein product of the KIT gene, which is commonly mutated in GIST. A different marker, DOG1 (so-named because it was Discovered On GIST), is also present on the vast majority of GISTs, but not always overlapping with CD117. As a result, a tumor that is positive for both CD117 and DOG1 has over 97% likelihood of being GIST. | 497 | Gastrointestinal Stromal Tumors |
nord_497_6 | Therapies of Gastrointestinal Stromal Tumors | Treatment
Tumors that are confined to one site without evidence of spread (i.e., localized) are treated by surgical removal. There is no clear benefit for radiation therapy before/after surgery for this type of sarcoma. Surgery offers the best chance of cure if a localized tumor is completely removed without rupturing the tumor (i.e., breaking the tumor into pieces and spilling tumor cells). However, not all patients are diagnosed at an early stage; 10%–25% of patients present with metastatic disease. Tumors that have spread are more aggressive, or are locally advanced may benefit from chemotherapy in combination with surgery.Older generations of intravenous chemotherapies are not effective for this type of sarcoma, with less than 5% of patients responding. In 2002, however, the tyrosine kinase inhibitor Gleevec (imatinib), which inhibits the proteins encoded by the KIT and PDGRFA oncogenes, was granted accelerated approval by the FDA for the treatment of advanced or metastatic GIST. It is very effective in controlling disease that has spread and the majority of patients will have their tumors decrease in size or stabilize for many months. It is also effective in patients with recurrent tumors. Although Gleevec is effective at controlling GIST, patients who have disease that has spread from the initial site (metastatic disease) rarely experience the complete disappearance of all tumors. In addition, some individuals eventually develop resistance to Gleevec, with about half of patients experiencing this after 20 months of treatment. Surgery may be combined with Gleevec to control metastatic disease.A subsequent accelerated approval for Gleevec was received in 2008 for adjuvant (post-operative) use in patients with GIST who have potentially curative resection (surgical removal) of GISTs, but who are at increased risk for recurrence. This accelerated approval program provided earlier patient access to Gleevec while the confirmatory clinical trials were being conducted. In 2008, regular approval for the metastatic GIST indication was also granted. Gleevec was granted regular approval by the FDA in 2012 as a treatment for use in adult patients following surgical removal of CD117-positive GIST. There is an increase in overall patient survival when the drug is taken for 36 months rather than the standard 12 months of treatment. Studies are ongoing to evaluate the use of imatinib for longer periods of time. Concerns have been raised over the cost of long-term imatinib treatment, but the recent availability of generic versions has reduced these costs. In 2006, another tyrosine kinase inhibitor, Sutent (sunitinib), was approved by the FDA for the treatment of GIST in individuals in whom the disease had progressed, despite therapy with Gleevec, or in patients who cannot take Gleevec. In 2013, a third type of tyrosine kinase inhibitor known as Stivarga (regorafenib) was approved by the FDA for the treatment of GIST, specifically for individuals with advanced GIST that cannot be treated surgically and who no longer respond to other FDA-approved treatments (i.e., Gleevec and Sutent). Stivarga inhibits that activity of numerous tyrosine kinases that promote cancer growth. In 2018, the FDA approved larotrectinib, also a tyrosine kinase inhibitor, for the treatment of any tumor bearing a fusion of the NTRK3 gene (not only in GIST). This was only the second drug to be approved for treatment of cancers with a specific mutation, regardless of tissue type, underscoring the importance of categorizing GISTs by their specific biology. In January 2020, the FDA approved a drug known as Avyakit (avapritinib) for treatment of unresectable metastatic GIST harboring a mutations in the PDGFRA gene that are not sensitive to imatinib, sunitinib, or regorafenib. The clinical trial showed a remarkable response rate of 84% in these cases, indicating that targeting specific patient mutations could be key for developing new therapies. Most recently, in May 2020, Qinlock (ripretinib) was approved as the first new drug to be used specifically as a fourth-line treatment for advanced GIST. It is an inhibitor of the kinases encoded by the KIT and PDGFRA genes. Alternative approaches to surgery and chemotherapy include treatments directed at sites of liver involvement. Bland, radio-, or chemo-embolization are ways of decreasing blood supply to the tumor sites within the liver and can control disease for some time. Another approach, called microwave ablation, uses localized microwaves to burn tumors in the liver. | Therapies of Gastrointestinal Stromal Tumors. Treatment
Tumors that are confined to one site without evidence of spread (i.e., localized) are treated by surgical removal. There is no clear benefit for radiation therapy before/after surgery for this type of sarcoma. Surgery offers the best chance of cure if a localized tumor is completely removed without rupturing the tumor (i.e., breaking the tumor into pieces and spilling tumor cells). However, not all patients are diagnosed at an early stage; 10%–25% of patients present with metastatic disease. Tumors that have spread are more aggressive, or are locally advanced may benefit from chemotherapy in combination with surgery.Older generations of intravenous chemotherapies are not effective for this type of sarcoma, with less than 5% of patients responding. In 2002, however, the tyrosine kinase inhibitor Gleevec (imatinib), which inhibits the proteins encoded by the KIT and PDGRFA oncogenes, was granted accelerated approval by the FDA for the treatment of advanced or metastatic GIST. It is very effective in controlling disease that has spread and the majority of patients will have their tumors decrease in size or stabilize for many months. It is also effective in patients with recurrent tumors. Although Gleevec is effective at controlling GIST, patients who have disease that has spread from the initial site (metastatic disease) rarely experience the complete disappearance of all tumors. In addition, some individuals eventually develop resistance to Gleevec, with about half of patients experiencing this after 20 months of treatment. Surgery may be combined with Gleevec to control metastatic disease.A subsequent accelerated approval for Gleevec was received in 2008 for adjuvant (post-operative) use in patients with GIST who have potentially curative resection (surgical removal) of GISTs, but who are at increased risk for recurrence. This accelerated approval program provided earlier patient access to Gleevec while the confirmatory clinical trials were being conducted. In 2008, regular approval for the metastatic GIST indication was also granted. Gleevec was granted regular approval by the FDA in 2012 as a treatment for use in adult patients following surgical removal of CD117-positive GIST. There is an increase in overall patient survival when the drug is taken for 36 months rather than the standard 12 months of treatment. Studies are ongoing to evaluate the use of imatinib for longer periods of time. Concerns have been raised over the cost of long-term imatinib treatment, but the recent availability of generic versions has reduced these costs. In 2006, another tyrosine kinase inhibitor, Sutent (sunitinib), was approved by the FDA for the treatment of GIST in individuals in whom the disease had progressed, despite therapy with Gleevec, or in patients who cannot take Gleevec. In 2013, a third type of tyrosine kinase inhibitor known as Stivarga (regorafenib) was approved by the FDA for the treatment of GIST, specifically for individuals with advanced GIST that cannot be treated surgically and who no longer respond to other FDA-approved treatments (i.e., Gleevec and Sutent). Stivarga inhibits that activity of numerous tyrosine kinases that promote cancer growth. In 2018, the FDA approved larotrectinib, also a tyrosine kinase inhibitor, for the treatment of any tumor bearing a fusion of the NTRK3 gene (not only in GIST). This was only the second drug to be approved for treatment of cancers with a specific mutation, regardless of tissue type, underscoring the importance of categorizing GISTs by their specific biology. In January 2020, the FDA approved a drug known as Avyakit (avapritinib) for treatment of unresectable metastatic GIST harboring a mutations in the PDGFRA gene that are not sensitive to imatinib, sunitinib, or regorafenib. The clinical trial showed a remarkable response rate of 84% in these cases, indicating that targeting specific patient mutations could be key for developing new therapies. Most recently, in May 2020, Qinlock (ripretinib) was approved as the first new drug to be used specifically as a fourth-line treatment for advanced GIST. It is an inhibitor of the kinases encoded by the KIT and PDGFRA genes. Alternative approaches to surgery and chemotherapy include treatments directed at sites of liver involvement. Bland, radio-, or chemo-embolization are ways of decreasing blood supply to the tumor sites within the liver and can control disease for some time. Another approach, called microwave ablation, uses localized microwaves to burn tumors in the liver. | 497 | Gastrointestinal Stromal Tumors |
nord_498_0 | Overview of Gastroparesis | Gastroparesis (abbreviated as GP) represents a clinical syndrome characterized by sluggish emptying of solid food (and more rarely, liquid nutrients) from the stomach, which causes persistent digestive symptoms especially nausea and primarily affects young to middle-aged women, but is also known to affect younger children and males. Diagnosis is made based upon a radiographic gastric emptying test. Diabetics and those acquiring gastroparesis for unknown (or, idiopathic) causes represent the two largest groups of gastroparetic patients; however, numerous etiologies (both rare and common) can lead to a gastroparesis syndrome.Gastroparesis is also known as delayed gastric emptying and is an old term that does not adequately describe all the motor impairments that may occur within the gastroparetic stomach. Furthermore, there is no expert agreement on the use of the term, gastroparesis. Some specialists will reserve the term, gastroparesis, for grossly impaired emptying of the stomach while retaining the label of delayed gastric emptying, or functional dyspepsia (non-ulcer dyspepsia), for less pronounced evidence of impaired emptying. These terms are all very subjective. There is no scientific basis by which to separate functional dyspepsia from classical gastroparesis except by symptom intensity. In both conditions, there is significant overlap in treatment, symptomatology and underlying physiological disturbances of stomach function.For the most part, the finding of delayed emptying (gastric stasis) provides a “marker” for a gastric motility problem. Regardless, the symptoms generated by the stomach dysmotility greatly impair quality of life for the vast majority of patients and disable about 1 in 10 patients with the condition.While delayed emptying of the stomach is the clinical feature of gastroparesis, the relationship between the degree of delay in emptying and the intensity of digestive symptoms does not always match. For instance, some diabetics may exhibit pronounced gastric stasis yet suffer very little from the classical gastroparetic symptoms of: nausea, vomiting, reflux, abdominal pain, bloating, fullness, and loss of appetite. Rather, erratic blood-glucose control and life-threatening hypoglycemic episodes may be the only indication of diabetic gastroparesis. In another subset of patients (diabetic and non-diabetic) who suffer from disabling nausea that is to the degree that their ability to eat, sleep or carry out activities of daily living is disrupted gastric emptying may be normal, near normal, or intermittently delayed. In such cases, a gastric neuro-electrical dysfunction, or gastric dysrhythmia (commonly found associated with gastroparesis syndrome), may be at fault.Therefore, these disorders of functional dyspepsia, gastric dysrhythms, and gastroparesis are all descriptive labels sharing similar symptoms and perhaps representing a similar entity of disordered gastric neuromuscular function. For this reason, a more encompassing term, gastropathy, can be used interchangeably with gastroparesis. | Overview of Gastroparesis. Gastroparesis (abbreviated as GP) represents a clinical syndrome characterized by sluggish emptying of solid food (and more rarely, liquid nutrients) from the stomach, which causes persistent digestive symptoms especially nausea and primarily affects young to middle-aged women, but is also known to affect younger children and males. Diagnosis is made based upon a radiographic gastric emptying test. Diabetics and those acquiring gastroparesis for unknown (or, idiopathic) causes represent the two largest groups of gastroparetic patients; however, numerous etiologies (both rare and common) can lead to a gastroparesis syndrome.Gastroparesis is also known as delayed gastric emptying and is an old term that does not adequately describe all the motor impairments that may occur within the gastroparetic stomach. Furthermore, there is no expert agreement on the use of the term, gastroparesis. Some specialists will reserve the term, gastroparesis, for grossly impaired emptying of the stomach while retaining the label of delayed gastric emptying, or functional dyspepsia (non-ulcer dyspepsia), for less pronounced evidence of impaired emptying. These terms are all very subjective. There is no scientific basis by which to separate functional dyspepsia from classical gastroparesis except by symptom intensity. In both conditions, there is significant overlap in treatment, symptomatology and underlying physiological disturbances of stomach function.For the most part, the finding of delayed emptying (gastric stasis) provides a “marker” for a gastric motility problem. Regardless, the symptoms generated by the stomach dysmotility greatly impair quality of life for the vast majority of patients and disable about 1 in 10 patients with the condition.While delayed emptying of the stomach is the clinical feature of gastroparesis, the relationship between the degree of delay in emptying and the intensity of digestive symptoms does not always match. For instance, some diabetics may exhibit pronounced gastric stasis yet suffer very little from the classical gastroparetic symptoms of: nausea, vomiting, reflux, abdominal pain, bloating, fullness, and loss of appetite. Rather, erratic blood-glucose control and life-threatening hypoglycemic episodes may be the only indication of diabetic gastroparesis. In another subset of patients (diabetic and non-diabetic) who suffer from disabling nausea that is to the degree that their ability to eat, sleep or carry out activities of daily living is disrupted gastric emptying may be normal, near normal, or intermittently delayed. In such cases, a gastric neuro-electrical dysfunction, or gastric dysrhythmia (commonly found associated with gastroparesis syndrome), may be at fault.Therefore, these disorders of functional dyspepsia, gastric dysrhythms, and gastroparesis are all descriptive labels sharing similar symptoms and perhaps representing a similar entity of disordered gastric neuromuscular function. For this reason, a more encompassing term, gastropathy, can be used interchangeably with gastroparesis. | 498 | Gastroparesis |
nord_498_1 | Symptoms of Gastroparesis | The digestive symptom profile of nausea, vomiting, abdominal pain, reflux, bloating, a feeling of fullness after a few bites of food (early satiety), and anorexia can vary in patients both in combination and severity. A small percentage of patients who live with poorly managed symptoms despite numerous treatment interventions, and an inability to meet their nutritional needs represent the extreme end of the gastroparesis spectrum of gastric failure. For most, the prevailing symptom experience is persistent nausea that often intensifies a few hours after eating. Nausea may become so intense as to trigger vomiting even after a few sips of water. Vomiting, also commonly reported, typically starts a couple of hours after eating so that the food is still recognizable and undigested. Chronic abdominal pain, which may also occur, is felt to result from visceral neuropathy. The pain, often diffuse, is described as burning, shearing or gnawing in character. The nature of pain may also be complex with some individuals experiencing acute pain, trigged by eating, layered on top of the chronic pain. This acute, sharp pain may be related to intestinal cramping and/or to spasms in the upper portion of the stomach caused by its failure to relax and “accommodate” the just-eaten food. As well, a gall bladder that is sluggish to empty (paresis) is commonly found in association with a poorly emptying stomach. This may all add to the pain experienced soon after eating. A poorly emptying stomach additionally predisposes patients to regurgitation of solid food, as well as gastric esophageal reflux disease (GERD). The reflux may range from mild through to severe. GERD complications can create esophageal spasm (also called non-cardiac chest pain) and can add to the burden of chronic pain. In severe cases, reflux aspiration pneumonitis compounds the clinical picture.Other symptoms include belching and bloating-again, developing soon after meal ingestion and lasting for hours-along with visible abdominal distention. The distention and bloating may push up against the diaphragm making breathing uncomfortable. Loss of appetite (anorexia), a conscious avoidance of food in an attempt to moderate digestive symptoms, or food craving that are all frequently reported as well.Vomiting, which can result in the life-threatening conditions of dehydration and electrolyte imbalances, represents the most troubling of all the digestive symptoms related to gastroparesis. Repeated vomiting usually necessitates a visit to the emergency room. Concomitant spiraling malnourishment accompanies frequent, chronic vomiting and precipitates repeated and prolonged hospital admissions. Approximately 5 to 10% of insulin-dependent diabetics may progress to severe symptomatic gastroparesis.In the majority of insulin-dependent diabetics, gastroparesis is often overlooked and under-diagnosed, especially in its early stages. The characteristics of poor glucose control and acid reflux are often the only signatures of delayed gastric emptying. The typical picture seen in the diabetic gastroparetic stomach is low blood-glucose levels at bedtime with very high blood-glucose levels by the next morning. This situation is interspersed with days of good blood-sugar control. Some scientific studies have found diabetic gastroparesis to correlate with autonomic neuropathy (diabetic autonomic neuropathy, or DAN and cardiac autonomic neuropathy, or CAN), but not with the duration of diabetes, metabolic control or other chronic complications. It is to be noted that acute hyperglycemia profoundly retards gastric emptying.If DAN is present, then regaining control of blood glucose can be enormously challenging. For Type 2 diabetics (non-insulin dependent), absorption of oral hypoglycemic agents may be very unpredictable due to the delayed gastric emptying.Gastroparetic symptoms in most patients show either a pattern of cycling with flare-ups, or daily occurrences persisting for years. | Symptoms of Gastroparesis. The digestive symptom profile of nausea, vomiting, abdominal pain, reflux, bloating, a feeling of fullness after a few bites of food (early satiety), and anorexia can vary in patients both in combination and severity. A small percentage of patients who live with poorly managed symptoms despite numerous treatment interventions, and an inability to meet their nutritional needs represent the extreme end of the gastroparesis spectrum of gastric failure. For most, the prevailing symptom experience is persistent nausea that often intensifies a few hours after eating. Nausea may become so intense as to trigger vomiting even after a few sips of water. Vomiting, also commonly reported, typically starts a couple of hours after eating so that the food is still recognizable and undigested. Chronic abdominal pain, which may also occur, is felt to result from visceral neuropathy. The pain, often diffuse, is described as burning, shearing or gnawing in character. The nature of pain may also be complex with some individuals experiencing acute pain, trigged by eating, layered on top of the chronic pain. This acute, sharp pain may be related to intestinal cramping and/or to spasms in the upper portion of the stomach caused by its failure to relax and “accommodate” the just-eaten food. As well, a gall bladder that is sluggish to empty (paresis) is commonly found in association with a poorly emptying stomach. This may all add to the pain experienced soon after eating. A poorly emptying stomach additionally predisposes patients to regurgitation of solid food, as well as gastric esophageal reflux disease (GERD). The reflux may range from mild through to severe. GERD complications can create esophageal spasm (also called non-cardiac chest pain) and can add to the burden of chronic pain. In severe cases, reflux aspiration pneumonitis compounds the clinical picture.Other symptoms include belching and bloating-again, developing soon after meal ingestion and lasting for hours-along with visible abdominal distention. The distention and bloating may push up against the diaphragm making breathing uncomfortable. Loss of appetite (anorexia), a conscious avoidance of food in an attempt to moderate digestive symptoms, or food craving that are all frequently reported as well.Vomiting, which can result in the life-threatening conditions of dehydration and electrolyte imbalances, represents the most troubling of all the digestive symptoms related to gastroparesis. Repeated vomiting usually necessitates a visit to the emergency room. Concomitant spiraling malnourishment accompanies frequent, chronic vomiting and precipitates repeated and prolonged hospital admissions. Approximately 5 to 10% of insulin-dependent diabetics may progress to severe symptomatic gastroparesis.In the majority of insulin-dependent diabetics, gastroparesis is often overlooked and under-diagnosed, especially in its early stages. The characteristics of poor glucose control and acid reflux are often the only signatures of delayed gastric emptying. The typical picture seen in the diabetic gastroparetic stomach is low blood-glucose levels at bedtime with very high blood-glucose levels by the next morning. This situation is interspersed with days of good blood-sugar control. Some scientific studies have found diabetic gastroparesis to correlate with autonomic neuropathy (diabetic autonomic neuropathy, or DAN and cardiac autonomic neuropathy, or CAN), but not with the duration of diabetes, metabolic control or other chronic complications. It is to be noted that acute hyperglycemia profoundly retards gastric emptying.If DAN is present, then regaining control of blood glucose can be enormously challenging. For Type 2 diabetics (non-insulin dependent), absorption of oral hypoglycemic agents may be very unpredictable due to the delayed gastric emptying.Gastroparetic symptoms in most patients show either a pattern of cycling with flare-ups, or daily occurrences persisting for years. | 498 | Gastroparesis |
nord_498_2 | Causes of Gastroparesis | The etiologies (causes) for gastroparesis are extensive and varied. Reports from one tertiary referral center found that out of their 146 patients with gastroparesis: 36% were idiopathic (unknown causes), 29% were diabetic, 13% were post-surgical, 7.5% had Parkinson's disease and 4.8% had collagen diseases. Any disease of metabolic, neurological (psychiatric, brainstem, autonomic including sympathetic and parasympathetic or enteric), or connective tissue (autoimmune) origin has the potential to disrupt gastric neural circuitry. Regional areas of the stomach may show various degrees of dysfunction, such as: failure of fundic relaxation, weakened postprandial antral contractions, pylorospasm, and / or gastric hyperalgesia; yet, rarely is gastroparesis restricted exclusively to the stomach. If perturbation of stomach function occurs, this will indirectly impact function in many other regions along the GI tract due to the complex enteric reflexes and neuronal relays which exist throughout the gastrointestinal (GI) system. The ability of the GI track to “cross-talk” is essential for coordination of normal digestion. Gastroparesis then is a complex, multifactor, chronic, digestive disease state with possible genetic, physiological, immune, psychological, social and environmental interplays.Gastroparesis has been documented to occur as a sequel to viral gastroenteritis, slowly resolving over one to two years. However, any upper-gut infection of bacterial, parasitic or viral origin has the potential to disrupt, for prolonged periods of time, gastric motility. In gastroparesis patients, and others with unexplained chronic nausea and vomiting, one recent study reported up to 80% of 121 patients were found to have structural abnormalities of enteric nerves on full-thickness tissue biopsies of the duodenum.Examples of gastroparesis include insulin-dependent diabetes, post-vagotomy (surgical), anorexia nervosa and bulimia, chronic liver or renal failure, and chronic pancreatitis. Gastroparesis may also be induced by medications, or associated with total parenteral nutrition or related to bone marrow and other organ transplants. Additional causes include paraneoplastic syndrome, mitochondrial disorders, abnormal gastric pacemaker activity (gastric dysrhythmias), visceral neuropathies, (for example: Guillain-Barre syndrome) and visceral myopathies (for example: systemic scleroderma)[For more information on any of the listed disorders, choose the specific name as your search term in the Rare Disease Database.]A great deal of research into the enteric nervous system has begun to identify specific cellular and neuronal abnormalities associated in gastroparesis such as:+ Loss of ICC (interstitial cells of Cajal)*+ Loss of neuronal nitric oxide synthase (nNOS)+ Enteric neuronal degeneration (visceral neuropathy)+ Smooth muscle disease (myopathy), often related to collagen diseases*Interstitial cells of Cajal (ICC) are critical components for GI motility. Various types of ICCs have been identified. They are involved in the generation and propagation of electrical rhythmic activity (hence, they are known as the “pacemaker” cells) and serve as well to bridge communication, and amplify the signals from neuronal inputs to mechanical smooth muscle action (transduction).So far, there is no consensus on how to classify histopathological findings.Other significant serological abnormalities have been documented in diabetic, post-surgical and idiopathic cases of gastroparesis. In one case study a high prevalence (89%) of acquired and congenital hypercoagulable defects was documented, which would predispose patients to arterial and venous clots. Coagulation evaluation would then be prudent in patients with severe gastroparesis, especially in high-risk thrombophilic situations such as hospitalization, prolonged intravenous access, and surgery. | Causes of Gastroparesis. The etiologies (causes) for gastroparesis are extensive and varied. Reports from one tertiary referral center found that out of their 146 patients with gastroparesis: 36% were idiopathic (unknown causes), 29% were diabetic, 13% were post-surgical, 7.5% had Parkinson's disease and 4.8% had collagen diseases. Any disease of metabolic, neurological (psychiatric, brainstem, autonomic including sympathetic and parasympathetic or enteric), or connective tissue (autoimmune) origin has the potential to disrupt gastric neural circuitry. Regional areas of the stomach may show various degrees of dysfunction, such as: failure of fundic relaxation, weakened postprandial antral contractions, pylorospasm, and / or gastric hyperalgesia; yet, rarely is gastroparesis restricted exclusively to the stomach. If perturbation of stomach function occurs, this will indirectly impact function in many other regions along the GI tract due to the complex enteric reflexes and neuronal relays which exist throughout the gastrointestinal (GI) system. The ability of the GI track to “cross-talk” is essential for coordination of normal digestion. Gastroparesis then is a complex, multifactor, chronic, digestive disease state with possible genetic, physiological, immune, psychological, social and environmental interplays.Gastroparesis has been documented to occur as a sequel to viral gastroenteritis, slowly resolving over one to two years. However, any upper-gut infection of bacterial, parasitic or viral origin has the potential to disrupt, for prolonged periods of time, gastric motility. In gastroparesis patients, and others with unexplained chronic nausea and vomiting, one recent study reported up to 80% of 121 patients were found to have structural abnormalities of enteric nerves on full-thickness tissue biopsies of the duodenum.Examples of gastroparesis include insulin-dependent diabetes, post-vagotomy (surgical), anorexia nervosa and bulimia, chronic liver or renal failure, and chronic pancreatitis. Gastroparesis may also be induced by medications, or associated with total parenteral nutrition or related to bone marrow and other organ transplants. Additional causes include paraneoplastic syndrome, mitochondrial disorders, abnormal gastric pacemaker activity (gastric dysrhythmias), visceral neuropathies, (for example: Guillain-Barre syndrome) and visceral myopathies (for example: systemic scleroderma)[For more information on any of the listed disorders, choose the specific name as your search term in the Rare Disease Database.]A great deal of research into the enteric nervous system has begun to identify specific cellular and neuronal abnormalities associated in gastroparesis such as:+ Loss of ICC (interstitial cells of Cajal)*+ Loss of neuronal nitric oxide synthase (nNOS)+ Enteric neuronal degeneration (visceral neuropathy)+ Smooth muscle disease (myopathy), often related to collagen diseases*Interstitial cells of Cajal (ICC) are critical components for GI motility. Various types of ICCs have been identified. They are involved in the generation and propagation of electrical rhythmic activity (hence, they are known as the “pacemaker” cells) and serve as well to bridge communication, and amplify the signals from neuronal inputs to mechanical smooth muscle action (transduction).So far, there is no consensus on how to classify histopathological findings.Other significant serological abnormalities have been documented in diabetic, post-surgical and idiopathic cases of gastroparesis. In one case study a high prevalence (89%) of acquired and congenital hypercoagulable defects was documented, which would predispose patients to arterial and venous clots. Coagulation evaluation would then be prudent in patients with severe gastroparesis, especially in high-risk thrombophilic situations such as hospitalization, prolonged intravenous access, and surgery. | 498 | Gastroparesis |
nord_498_3 | Affects of Gastroparesis | Gastroparesis demonstrates a gender bias affecting more women than men. Approximately 80% of idiopathic cases are women. Idiopathic gastroparesis may be linked to an as yet-to-be-elucidated enteric autoimmune disease. The prevalence of delayed gastric emptying in Type 1 diabetics has been reported to be 50% and in type 2 diabetics, reports range from 30% to 50%. Post surgical gastroparesis is a recognized as inadvertent vagal nerve damage or entrapment following upper abdominal surgery, examples are: fundoplication for the treatment of GERD, bariatric surgery, peptic ulcer surgery, anterior approach for spinal surgery (scoliosis), heart, lung transplant, or pancreatic surgery. | Affects of Gastroparesis. Gastroparesis demonstrates a gender bias affecting more women than men. Approximately 80% of idiopathic cases are women. Idiopathic gastroparesis may be linked to an as yet-to-be-elucidated enteric autoimmune disease. The prevalence of delayed gastric emptying in Type 1 diabetics has been reported to be 50% and in type 2 diabetics, reports range from 30% to 50%. Post surgical gastroparesis is a recognized as inadvertent vagal nerve damage or entrapment following upper abdominal surgery, examples are: fundoplication for the treatment of GERD, bariatric surgery, peptic ulcer surgery, anterior approach for spinal surgery (scoliosis), heart, lung transplant, or pancreatic surgery. | 498 | Gastroparesis |
nord_498_4 | Related disorders of Gastroparesis | A stomach motor disturbance known as “dumping syndrome” whereby food or liquids empty too quickly from the stomach can present with similar symptoms as are found in gastroparesis. Other disorders that may clinically present as gastroparesis (gastritis, gastric ulcers, pyloric stenosis, celiac disease, and GI obstructions) need to be ruled out. | Related disorders of Gastroparesis. A stomach motor disturbance known as “dumping syndrome” whereby food or liquids empty too quickly from the stomach can present with similar symptoms as are found in gastroparesis. Other disorders that may clinically present as gastroparesis (gastritis, gastric ulcers, pyloric stenosis, celiac disease, and GI obstructions) need to be ruled out. | 498 | Gastroparesis |
nord_498_5 | Diagnosis of Gastroparesis | A diagnosis of gastroparesis is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Tests may first be performed to rule out other causes of delayed gastric emptying such as obstruction of the gastrointestinal tract. Additional tests are then performed to confirm a diagnosis of gastroparesis.Tests to rule out other causes of delayed gastric emptying include routine blood tests, an upper gastrointestinal endoscopy, a barium gastrointestinal series with small-bowel-follow-through, and an abdominal ultrasound. During an upper GI endoscopy, a thin, flexible tube (endoscope) is run down the throat to the stomach and the small intestines. The tube has a tiny camera attached to it that allows a physician to search for abnormalities and obstructions within the gastrointestinal tract. During an ultrasound, reflected sound waves create an image of the abdomen.An upper endosocpic procedure may lead to a serendipitous diagnosis of gastroparesis through the discovery of identifiable food within the stomach after the pre-procedure overnight fast.The radionuclide (scintigraphy) solid-phase gastric emptying test (GET), the gold standard for diagnosing gastroparesis, can now be measured using only four images: baseline, 1-hour, 2-hour, and 4-hour. The GET, a non-invasive test, is widely available and accessible. The test involves eating food that contains a small amount of radioactive material (radioisotope). This tiny dose of radiation can be seen on a gamma camera (much like an X-ray machine), but is not dangerous. The scans allow a physician to determine the rate at which food leaves the stomach. Many other methods are now being employed to track gastric emptying times; for instance a gastric breath test (not in common use in North America) and a new encapsulated recording device, called SmartPill has the ability to measure gastric pH, GI luminal pressures, and determine gastric and intestinal transit time.Other diagnostic tests for GP can include electrogastrography (EGG). This is often referred to as the EKG of the stomach. EGG can serve as a screening tool and is complementary to the gastric emptying test. The EGG is capable of detecting specific gastric electrical rhythm abnormalities and indirectly gives an indication of the integrity of the stomach's ICC network. This test is generally done using a non-invasive method with cutaneous (skin) leads. A less common method of administering an EGG is a direct, invasive means via mucosa (either during endoscopy or serosa recordings can be done at the time of gastric electrical stimulation placement for the treatment of nausea and vomiting).Many patients with symptoms of gastroparesis often have related nutritional deficiencies and disorders. Nutritional laboratory measurements are important. Laboratory tests to include are albumin, pre-albumin, hemoglobin A1C (on all diabetic patients), ferritin, B-12, and 25-hydroxy vitamin D. | Diagnosis of Gastroparesis. A diagnosis of gastroparesis is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Tests may first be performed to rule out other causes of delayed gastric emptying such as obstruction of the gastrointestinal tract. Additional tests are then performed to confirm a diagnosis of gastroparesis.Tests to rule out other causes of delayed gastric emptying include routine blood tests, an upper gastrointestinal endoscopy, a barium gastrointestinal series with small-bowel-follow-through, and an abdominal ultrasound. During an upper GI endoscopy, a thin, flexible tube (endoscope) is run down the throat to the stomach and the small intestines. The tube has a tiny camera attached to it that allows a physician to search for abnormalities and obstructions within the gastrointestinal tract. During an ultrasound, reflected sound waves create an image of the abdomen.An upper endosocpic procedure may lead to a serendipitous diagnosis of gastroparesis through the discovery of identifiable food within the stomach after the pre-procedure overnight fast.The radionuclide (scintigraphy) solid-phase gastric emptying test (GET), the gold standard for diagnosing gastroparesis, can now be measured using only four images: baseline, 1-hour, 2-hour, and 4-hour. The GET, a non-invasive test, is widely available and accessible. The test involves eating food that contains a small amount of radioactive material (radioisotope). This tiny dose of radiation can be seen on a gamma camera (much like an X-ray machine), but is not dangerous. The scans allow a physician to determine the rate at which food leaves the stomach. Many other methods are now being employed to track gastric emptying times; for instance a gastric breath test (not in common use in North America) and a new encapsulated recording device, called SmartPill has the ability to measure gastric pH, GI luminal pressures, and determine gastric and intestinal transit time.Other diagnostic tests for GP can include electrogastrography (EGG). This is often referred to as the EKG of the stomach. EGG can serve as a screening tool and is complementary to the gastric emptying test. The EGG is capable of detecting specific gastric electrical rhythm abnormalities and indirectly gives an indication of the integrity of the stomach's ICC network. This test is generally done using a non-invasive method with cutaneous (skin) leads. A less common method of administering an EGG is a direct, invasive means via mucosa (either during endoscopy or serosa recordings can be done at the time of gastric electrical stimulation placement for the treatment of nausea and vomiting).Many patients with symptoms of gastroparesis often have related nutritional deficiencies and disorders. Nutritional laboratory measurements are important. Laboratory tests to include are albumin, pre-albumin, hemoglobin A1C (on all diabetic patients), ferritin, B-12, and 25-hydroxy vitamin D. | 498 | Gastroparesis |
nord_498_6 | Therapies of Gastroparesis | TreatmentTreating the underlying cause of gastroparesis (such as tightening up blood glucose control in diabetes) is usually the first step in treating individuals with gastroparesis. The specific therapeutic techniques used depend upon several factors, including the severity of the disorder. Therapies that are used to treat individuals with gastroparesis include non-pharmacological steps, dietary modification, medications that stimulate gastric emptying (prokinetics), medications that reduce vomiting (antiemetics), medications for controlling pain and intestinal spasms, and surgery.Some researchers have proposed a classification system to help determine appropriate treatment options. Grade 1, or mild gastroparesis, is characterized by symptoms that come and go and can easily be controlled by dietary modification and by avoiding medications that slow gastric emptying. Grade 2, or compensated gastroparesis, is characterized by moderately severe symptoms. Individuals with Grade 2 gastroparesis are treated with medications that stimulate gastric emptying and medications that reduce vomiting; such individuals require hospitalization only infrequently. Grade 3, or gastric failure, is characterized by individuals who do not respond to medications used to treat gastroparesis. These individuals cannot maintain proper nutrition or hydration. Required therapies may include intravenous fluids and medications and nutrition, or surgery. Individuals with Grade 3 gastroparesis often require hospitalization.Non-pharmacological interventions include: liquid vitamin supplements (including optimal levels of vitamin D), discontinuation of smoking and alcohol use, learning techniques of deep relaxation, the use of acupuncture or acupoint stimulation, and reviewing all medications and supplements with a pharmacist to insure current regimen is not contributing to delayed gastric emptying. Other non-pharmacological therapies for GP include autonomic retraining; often related to autogenic feedback training developed by NASA for space motion sickness, autonomic retraining has shown promise in selected patients.Dietary changes include eating five to six small meals each day and avoiding high-insoluble fiber and high-fat foods, both of which can slow down stomach emptying. Lactose intolerance is common in gastroparesis, so avoidance of dairy is helpful, but fermented milk (yogurt) is fine. Some individuals do better with liquid or pureed foods while avoiding difficult-to-digest solid foods. Liquid nutritional supplements are also an excellent source of additional calories and proteins to make up for nutritional deficiencies resulting from a poor appetite.Medications that stimulate gastric emptying are called prokinetics. They are the primary treatment for individuals with gastroparesis. First-line medical treatment begins with the dopamine blockers. Of the two drugs, metoclopromide (Reglan) and domperidone (Motilitum), domperidone has a much better safety profile. Metoclopromide has serious neurological side effects, including irreversible tartive dyskinesia. Domperidone is now available in the United States through the FDA's Investigational New Drug protocol. Next are the motilin agonists, such as erythromycin. Unfortunately, motilin agonists have a number of potential drug interactions and lose effectiveness over time. Cholinergic agonists, either direct-acting or via 5HT receptors, such as bethanecol (Urecholine) and cisapride (Propulsid), have been limited by the side-effect profile (especially, in the case of cisapride, for possible drug interactions) or are not used widely. Tegaserod is no longer available for the treatment of gastroparesis.The most common symptom of gastroparesis is nausea and it can be enormously challenging to control. Often, medications used to reduce nausea and vomiting “antiemetics” are used in combinations and in conjunction with prokinetics. Common antiemetics used are prochlorperazine (Compazine), promethazine (Phenergan), and ondansetron (Zofran).Abdominal pain is best managed by a pain specialty clinic where a selection of analgesics with the least impact on slowing the GI tract can be made.Keeping a good bowel routine and avoiding constipation helps in the management of upper digestive symptoms of gastroparesis.Other clinical management issues to consider are metabolic bone disease (all gastroparetic patients are at risk) and routine monitoring for small bowel bacterial overgrowth (SBBO). SBBO commonly occurs in gastroparesis and may greatly contribute to upper digestive symptoms, malnutrition and vitamin deficiencies. Antibiotics and perhaps probiotics help to keep SBBO in check.Bezoars (congealed food residue left in the stomach) are a rare occurrence in gastroparesis but are found in more severe cases of gastric stasis. Whenever a patient's usual pattern of nausea and vomiting rises to a new intensity, then suspicion of a bezoar should be investigated via endoscopy.Individuals with severe gastroparesis, or those who do not respond to medications, may require enteral or parenteral feeding to compensate for nutritional deficiencies and to prevent dehydration. Enteral feeding refers to a feeding tube that transverses from the skin and comes to rest directly in either the stomach (G-tube) or small intestine (J-tube, for jejeunal) or a G-J tube (a tube that enters the stomach and transverses the pylorus to enter the small intestine). Feeding tubes are generally needed for long durations (> 3 months) and selection of a tube should be made with this in mind.Parenteral feeding refers to the implantation of a small, thin tube (catheter) into a vein so that nutrients and fluids can be delivered directly into the bloodstream.Enteral Tubes for GP PatientsEnteral tubes are often not successful for feeding (due to slow infusion rates related to stomach and small bowel dysmotilities) but may be helpful as a conduit for free water or medications. In fact, medications are more evenly absorbed when administered via enteral tubes. For diabetics, improved blood glucose can be achieved when nutrients bypass the gastroparetic stomach and are then absorbed in a more predictable way for matching insulin needs.Additionally, enteral tubes-either gastric or small intestinal may be useful as venting, particularly for patients with localized dilated segments of small bowel or stomach (watermelon stomach) commonly the result of visceral myopathies.Finally, small bowel bacterial overgrowth may be treated more successfully if antibiotics can be given by tube, especially if the patient suffers from vomiting.IV Access for GastroparesisIntravenous access may be a life-saving delivery of medication and nutrition for some severely affected patients. However, IV access may also be life-threatening due to infection and/or thrombosis. Recent work has revealed that many GP patients are hypercoagulable and in some centers, all GP patients who receive IV access also undergo a hypercoagulable evaluation. Those that are at highest risk for thrombosis are then usually started on anticoagulation. Gastroparesis, itself, may pose special problems for anticoagulation, as absorption of oral anticoagulants may be erratic. A good short-term plan is to use sub-cutaneous, low molecular-weight heparin, at least until nausea and vomiting can be controlled.Surgical Interventions for GastroparesisSurgical interventions for palliation of symptoms of severe diabetic and idiopathic gastroparesis such as: pyloroplasty, or elimination of the stomach through near total gastrectomy (Billroth I, Antrectomy, Roux-En-Y); show little improvement in symptom management. A review of the literature by Reardon et al, showed that of 12 patients, only 3 had resolution of their symptoms, with the majority having no improvement or only temporary improvements, or a worsening of symptoms to include bilious vomiting.Experts agree that the entire stomach is affected in severe gastroparesis; therefore, treatment by partial gastrectomy is unsatisfactory as a method to attempt to ameliorate symptoms. Treatment by total gastrectomy is used as a palliative measure; however, it is a major surgical procedure which carries risks. This procedure has significant morbidity, and a mortality rate of 3.5%. Also, once the stomach is removed, the option no longer exists to take advantage of any new pharmacological therapies that may come along; and dependency on enteral / parenteral nutrition is permanent. Also, nausea remains a very troubling symptom even after total gastrectomy. | Therapies of Gastroparesis. TreatmentTreating the underlying cause of gastroparesis (such as tightening up blood glucose control in diabetes) is usually the first step in treating individuals with gastroparesis. The specific therapeutic techniques used depend upon several factors, including the severity of the disorder. Therapies that are used to treat individuals with gastroparesis include non-pharmacological steps, dietary modification, medications that stimulate gastric emptying (prokinetics), medications that reduce vomiting (antiemetics), medications for controlling pain and intestinal spasms, and surgery.Some researchers have proposed a classification system to help determine appropriate treatment options. Grade 1, or mild gastroparesis, is characterized by symptoms that come and go and can easily be controlled by dietary modification and by avoiding medications that slow gastric emptying. Grade 2, or compensated gastroparesis, is characterized by moderately severe symptoms. Individuals with Grade 2 gastroparesis are treated with medications that stimulate gastric emptying and medications that reduce vomiting; such individuals require hospitalization only infrequently. Grade 3, or gastric failure, is characterized by individuals who do not respond to medications used to treat gastroparesis. These individuals cannot maintain proper nutrition or hydration. Required therapies may include intravenous fluids and medications and nutrition, or surgery. Individuals with Grade 3 gastroparesis often require hospitalization.Non-pharmacological interventions include: liquid vitamin supplements (including optimal levels of vitamin D), discontinuation of smoking and alcohol use, learning techniques of deep relaxation, the use of acupuncture or acupoint stimulation, and reviewing all medications and supplements with a pharmacist to insure current regimen is not contributing to delayed gastric emptying. Other non-pharmacological therapies for GP include autonomic retraining; often related to autogenic feedback training developed by NASA for space motion sickness, autonomic retraining has shown promise in selected patients.Dietary changes include eating five to six small meals each day and avoiding high-insoluble fiber and high-fat foods, both of which can slow down stomach emptying. Lactose intolerance is common in gastroparesis, so avoidance of dairy is helpful, but fermented milk (yogurt) is fine. Some individuals do better with liquid or pureed foods while avoiding difficult-to-digest solid foods. Liquid nutritional supplements are also an excellent source of additional calories and proteins to make up for nutritional deficiencies resulting from a poor appetite.Medications that stimulate gastric emptying are called prokinetics. They are the primary treatment for individuals with gastroparesis. First-line medical treatment begins with the dopamine blockers. Of the two drugs, metoclopromide (Reglan) and domperidone (Motilitum), domperidone has a much better safety profile. Metoclopromide has serious neurological side effects, including irreversible tartive dyskinesia. Domperidone is now available in the United States through the FDA's Investigational New Drug protocol. Next are the motilin agonists, such as erythromycin. Unfortunately, motilin agonists have a number of potential drug interactions and lose effectiveness over time. Cholinergic agonists, either direct-acting or via 5HT receptors, such as bethanecol (Urecholine) and cisapride (Propulsid), have been limited by the side-effect profile (especially, in the case of cisapride, for possible drug interactions) or are not used widely. Tegaserod is no longer available for the treatment of gastroparesis.The most common symptom of gastroparesis is nausea and it can be enormously challenging to control. Often, medications used to reduce nausea and vomiting “antiemetics” are used in combinations and in conjunction with prokinetics. Common antiemetics used are prochlorperazine (Compazine), promethazine (Phenergan), and ondansetron (Zofran).Abdominal pain is best managed by a pain specialty clinic where a selection of analgesics with the least impact on slowing the GI tract can be made.Keeping a good bowel routine and avoiding constipation helps in the management of upper digestive symptoms of gastroparesis.Other clinical management issues to consider are metabolic bone disease (all gastroparetic patients are at risk) and routine monitoring for small bowel bacterial overgrowth (SBBO). SBBO commonly occurs in gastroparesis and may greatly contribute to upper digestive symptoms, malnutrition and vitamin deficiencies. Antibiotics and perhaps probiotics help to keep SBBO in check.Bezoars (congealed food residue left in the stomach) are a rare occurrence in gastroparesis but are found in more severe cases of gastric stasis. Whenever a patient's usual pattern of nausea and vomiting rises to a new intensity, then suspicion of a bezoar should be investigated via endoscopy.Individuals with severe gastroparesis, or those who do not respond to medications, may require enteral or parenteral feeding to compensate for nutritional deficiencies and to prevent dehydration. Enteral feeding refers to a feeding tube that transverses from the skin and comes to rest directly in either the stomach (G-tube) or small intestine (J-tube, for jejeunal) or a G-J tube (a tube that enters the stomach and transverses the pylorus to enter the small intestine). Feeding tubes are generally needed for long durations (> 3 months) and selection of a tube should be made with this in mind.Parenteral feeding refers to the implantation of a small, thin tube (catheter) into a vein so that nutrients and fluids can be delivered directly into the bloodstream.Enteral Tubes for GP PatientsEnteral tubes are often not successful for feeding (due to slow infusion rates related to stomach and small bowel dysmotilities) but may be helpful as a conduit for free water or medications. In fact, medications are more evenly absorbed when administered via enteral tubes. For diabetics, improved blood glucose can be achieved when nutrients bypass the gastroparetic stomach and are then absorbed in a more predictable way for matching insulin needs.Additionally, enteral tubes-either gastric or small intestinal may be useful as venting, particularly for patients with localized dilated segments of small bowel or stomach (watermelon stomach) commonly the result of visceral myopathies.Finally, small bowel bacterial overgrowth may be treated more successfully if antibiotics can be given by tube, especially if the patient suffers from vomiting.IV Access for GastroparesisIntravenous access may be a life-saving delivery of medication and nutrition for some severely affected patients. However, IV access may also be life-threatening due to infection and/or thrombosis. Recent work has revealed that many GP patients are hypercoagulable and in some centers, all GP patients who receive IV access also undergo a hypercoagulable evaluation. Those that are at highest risk for thrombosis are then usually started on anticoagulation. Gastroparesis, itself, may pose special problems for anticoagulation, as absorption of oral anticoagulants may be erratic. A good short-term plan is to use sub-cutaneous, low molecular-weight heparin, at least until nausea and vomiting can be controlled.Surgical Interventions for GastroparesisSurgical interventions for palliation of symptoms of severe diabetic and idiopathic gastroparesis such as: pyloroplasty, or elimination of the stomach through near total gastrectomy (Billroth I, Antrectomy, Roux-En-Y); show little improvement in symptom management. A review of the literature by Reardon et al, showed that of 12 patients, only 3 had resolution of their symptoms, with the majority having no improvement or only temporary improvements, or a worsening of symptoms to include bilious vomiting.Experts agree that the entire stomach is affected in severe gastroparesis; therefore, treatment by partial gastrectomy is unsatisfactory as a method to attempt to ameliorate symptoms. Treatment by total gastrectomy is used as a palliative measure; however, it is a major surgical procedure which carries risks. This procedure has significant morbidity, and a mortality rate of 3.5%. Also, once the stomach is removed, the option no longer exists to take advantage of any new pharmacological therapies that may come along; and dependency on enteral / parenteral nutrition is permanent. Also, nausea remains a very troubling symptom even after total gastrectomy. | 498 | Gastroparesis |
nord_499_0 | Overview of Gastroschisis | Summary
Gastroschisis is a rare defect apparent at birth in which the intestines prolapse through the right side of the umbilical ring with an intact umbilical cord on the left side. Based on human evidence, gastroschisis likely occurs because of an amnio-ectodermal separation at the pars flaccida (i.e., thinner right side of the rudimentary umbilical ring) or an amniotic rupture. These findings suggest that gastroschisis is more likely a disruption rather than a structural malformation. Gastroschisis can be detected by a routine prenatal ultrasound during a mother’s pregnancy, usually around 18-20 weeks gestation. While the cause(s) is(are) unknown, gastroschisis may result from multiple maternal genes interacting with environmental factors. Treatment is a surgery that slowly returns the intestines to the abdomen (silo repair).Introduction
The name gastroschisis is derived from two words. Gastro meaning related to the stomach. Schisis, is a Greek term, meaning separation. Translating gastroschisis would suggest the separation of the stomach, but in reality, it is not the stomach that separates but likely the amnio-ectodermal connection or an amniotic rupture at the right edge of the umbilical ring. | Overview of Gastroschisis. Summary
Gastroschisis is a rare defect apparent at birth in which the intestines prolapse through the right side of the umbilical ring with an intact umbilical cord on the left side. Based on human evidence, gastroschisis likely occurs because of an amnio-ectodermal separation at the pars flaccida (i.e., thinner right side of the rudimentary umbilical ring) or an amniotic rupture. These findings suggest that gastroschisis is more likely a disruption rather than a structural malformation. Gastroschisis can be detected by a routine prenatal ultrasound during a mother’s pregnancy, usually around 18-20 weeks gestation. While the cause(s) is(are) unknown, gastroschisis may result from multiple maternal genes interacting with environmental factors. Treatment is a surgery that slowly returns the intestines to the abdomen (silo repair).Introduction
The name gastroschisis is derived from two words. Gastro meaning related to the stomach. Schisis, is a Greek term, meaning separation. Translating gastroschisis would suggest the separation of the stomach, but in reality, it is not the stomach that separates but likely the amnio-ectodermal connection or an amniotic rupture at the right edge of the umbilical ring. | 499 | Gastroschisis |
nord_499_1 | Symptoms of Gastroschisis | Gastroschisis is apparent at birth and can also be detected prenatally with ultrasound. Infants with this disorder have a 2-5 cm opening at the umbilical ring in which prolapsed abdominal organs appear on the outer surface of the abdomen. The abdominal cavity is smaller than normal, and the prolapsed intestines and other organs have no membranous sac covering it. This opening is typically found to the right, adjacent to the umbilical cord attached on the left side. The stomach, small intestine and large intestine are the most common organs that extend outside the abdomen. If the liver is also prolapsed, this should not be considered a gastroschisis. The intestines may look swollen, inflamed, thickened, short and covered with a thick fibrous peel due to exposure to the liquid that surrounds the fetus during pregnancy (amniotic fluid). Twisting (malrotation) of the bowel is always present and the exposed bowel is at risk for obstruction leading to deterioration of the intestines and interruption of the blood supply due to the small size of the defect.Bowel function is delayed in most infants due to malabsorption and deficient movement (hypomotility). Absence or closure (atresia) of intestines and other gastrointestinal tract abnormalities occur in as many as 10% of infants with gastroschisis.Other medically related issues with this disorder may be infection, dehydration and dangerously low body temperature (hypothermia).Some children with gastroschisis may have other health problems such as shorter intestines, slow growth before birth, prematurity or heart abnormalities. | Symptoms of Gastroschisis. Gastroschisis is apparent at birth and can also be detected prenatally with ultrasound. Infants with this disorder have a 2-5 cm opening at the umbilical ring in which prolapsed abdominal organs appear on the outer surface of the abdomen. The abdominal cavity is smaller than normal, and the prolapsed intestines and other organs have no membranous sac covering it. This opening is typically found to the right, adjacent to the umbilical cord attached on the left side. The stomach, small intestine and large intestine are the most common organs that extend outside the abdomen. If the liver is also prolapsed, this should not be considered a gastroschisis. The intestines may look swollen, inflamed, thickened, short and covered with a thick fibrous peel due to exposure to the liquid that surrounds the fetus during pregnancy (amniotic fluid). Twisting (malrotation) of the bowel is always present and the exposed bowel is at risk for obstruction leading to deterioration of the intestines and interruption of the blood supply due to the small size of the defect.Bowel function is delayed in most infants due to malabsorption and deficient movement (hypomotility). Absence or closure (atresia) of intestines and other gastrointestinal tract abnormalities occur in as many as 10% of infants with gastroschisis.Other medically related issues with this disorder may be infection, dehydration and dangerously low body temperature (hypothermia).Some children with gastroschisis may have other health problems such as shorter intestines, slow growth before birth, prematurity or heart abnormalities. | 499 | Gastroschisis |
nord_499_2 | Causes of Gastroschisis | The exact mechanism of gastroschisis is not known; however, several theories have been suggested.Most recently, it has been proposed that gastroschisis is a midline defect of the primordial umbilical ring based on findings in human fetuses and newborns. As early as 35 days post conception after merging of the two body stalks (body stalk and the omphalomesenteric/yolk stalk), the amnio-ectodermal junction is either not intact on the right side, or it later separates, or the amnion ruptures permitting the bowel and other organs to prolapse. This hypothesis is based on detailed clinical evaluation of human fetuses and infants in addition to our current understanding of the evolution of amniotes and developmental biology.Several families have been reported in which gastroschisis has occurred in siblings or distantly related children within multigenerational families. Different studies suggest that gastroschisis may follow an autosomal recessive or dominant inheritance pattern in a small number of families.Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Chromosomal or genetic abnormalities have not been consistently reported as a cause of gastroschisis. Approximately 85% of babies born with gastroschisis do not have any other unrelated birth defects. The two most consistent risk factors for gastroschisis are maternal age (highest risk in the youngest population of women, less than 20 years of age) and maternal exposure to cigarette smoke. In addition, ten studies have reported that maternal genitourinary tract (urinary tract infection and/or sexually transmitted infections) infections increase the risk for gastroschisis.Changes (pathogenic variants or mutations) in several genes (ICAM1, NOS3, and NPPA) have been associated with an increased risk for gastroschisis. These results are considered preliminary, and more research is needed to determine if these variants can cause gastroschisis. | Causes of Gastroschisis. The exact mechanism of gastroschisis is not known; however, several theories have been suggested.Most recently, it has been proposed that gastroschisis is a midline defect of the primordial umbilical ring based on findings in human fetuses and newborns. As early as 35 days post conception after merging of the two body stalks (body stalk and the omphalomesenteric/yolk stalk), the amnio-ectodermal junction is either not intact on the right side, or it later separates, or the amnion ruptures permitting the bowel and other organs to prolapse. This hypothesis is based on detailed clinical evaluation of human fetuses and infants in addition to our current understanding of the evolution of amniotes and developmental biology.Several families have been reported in which gastroschisis has occurred in siblings or distantly related children within multigenerational families. Different studies suggest that gastroschisis may follow an autosomal recessive or dominant inheritance pattern in a small number of families.Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Chromosomal or genetic abnormalities have not been consistently reported as a cause of gastroschisis. Approximately 85% of babies born with gastroschisis do not have any other unrelated birth defects. The two most consistent risk factors for gastroschisis are maternal age (highest risk in the youngest population of women, less than 20 years of age) and maternal exposure to cigarette smoke. In addition, ten studies have reported that maternal genitourinary tract (urinary tract infection and/or sexually transmitted infections) infections increase the risk for gastroschisis.Changes (pathogenic variants or mutations) in several genes (ICAM1, NOS3, and NPPA) have been associated with an increased risk for gastroschisis. These results are considered preliminary, and more research is needed to determine if these variants can cause gastroschisis. | 499 | Gastroschisis |
nord_499_3 | Affects of Gastroschisis | As of 2023, this condition is estimated to affect about 2 to 5 per 10,000 newborns. The Centers for Disease Control and Prevention (CDC) estimates that there are about 1,953 babies born with gastroschisis in the United States each year. | Affects of Gastroschisis. As of 2023, this condition is estimated to affect about 2 to 5 per 10,000 newborns. The Centers for Disease Control and Prevention (CDC) estimates that there are about 1,953 babies born with gastroschisis in the United States each year. | 499 | Gastroschisis |
nord_499_4 | Related disorders of Gastroschisis | Clinical findings of the following disorders can be similar to those of gastroschisis. Comparisons may be useful for a differential diagnosis:Omphalocele is a herniation of internal abdominal organs located within the umbilicus from a defect of an enlarged umbilical ring. The umbilical cord is inserted centrally in the distal membrane of the protruded organs. The umbilical ring is intact. The protrusion may be very small with just a few loops of bowel protruding or may contain all the intestines, liver and stomach. Unlike gastroschisis, the organs that are protruding are covered with a membranous sac. It has been suggested that omphalocele and gastroschisis may be the same disorder but that the omphalocele may rupture during fetal growth thus absorbing the membranous sac. This theory has not been proven to date. | Related disorders of Gastroschisis. Clinical findings of the following disorders can be similar to those of gastroschisis. Comparisons may be useful for a differential diagnosis:Omphalocele is a herniation of internal abdominal organs located within the umbilicus from a defect of an enlarged umbilical ring. The umbilical cord is inserted centrally in the distal membrane of the protruded organs. The umbilical ring is intact. The protrusion may be very small with just a few loops of bowel protruding or may contain all the intestines, liver and stomach. Unlike gastroschisis, the organs that are protruding are covered with a membranous sac. It has been suggested that omphalocele and gastroschisis may be the same disorder but that the omphalocele may rupture during fetal growth thus absorbing the membranous sac. This theory has not been proven to date. | 499 | Gastroschisis |
nord_499_5 | Diagnosis of Gastroschisis | Gastroschisis can be diagnosed by prenatal ultrasound or after birth. It is differentiated from omphalocele by the presence of freely floating abdominal organs in the amniotic cavity without a membranous covering. The organs appear on the outer surface of the abdomen, and at delivery, the diagnosis is confirmed. | Diagnosis of Gastroschisis. Gastroschisis can be diagnosed by prenatal ultrasound or after birth. It is differentiated from omphalocele by the presence of freely floating abdominal organs in the amniotic cavity without a membranous covering. The organs appear on the outer surface of the abdomen, and at delivery, the diagnosis is confirmed. | 499 | Gastroschisis |
nord_499_6 | Therapies of Gastroschisis | Treatment
Females with pregnancies in which gastroschisis has been prenatally diagnosed should be delivered at a tertiary care center where neonatal and pediatric surgical care is available.Surgery is needed to close the abdominal defect and slowly return the intestines to the abdomen (silo repair). After the organs have all been put back in the belly, the opening is closed. Prior to and after surgery, infants are fed through an IV line and are slowly introduced to normal feeding (total parenteral nutritional feedings). This allows the infant to receive adequate nutrition since it takes time for their bowel function to normalize. | Therapies of Gastroschisis. Treatment
Females with pregnancies in which gastroschisis has been prenatally diagnosed should be delivered at a tertiary care center where neonatal and pediatric surgical care is available.Surgery is needed to close the abdominal defect and slowly return the intestines to the abdomen (silo repair). After the organs have all been put back in the belly, the opening is closed. Prior to and after surgery, infants are fed through an IV line and are slowly introduced to normal feeding (total parenteral nutritional feedings). This allows the infant to receive adequate nutrition since it takes time for their bowel function to normalize. | 499 | Gastroschisis |
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